Nutrients. 2025 Jan 26;17(3):455. doi: 10.3390/nu17030455.

ABSTRACT

Background: Telemedicine represents a growing opportunity to improve access to personalized care for patients with rare diseases, addressing the challenges of specialized healthcare that is often limited by geographical barriers. The aim of this narrative review is to explore how telemedicine can facilitate tailored nutritional interventions for rare diseases, focusing on inherited metabolic diseases, rare neurological disorders, such as leukodystrophies, and neuromuscular disorders, including spinal muscular atrophies. Methods: This narrative review is based on a systematic search of the published literature over the past 20 years, and includes systematic reviews, meta-analysis, retrospective studies, and original articles. References were selected through searches in databases such as PubMed and Scopus, applying predefined inclusion and exclusion criteria. Among the inclusion criteria, studies focusing on pediatric patients aged 0 to 18 years, diagnosed with rare neurological diseases or inherited metabolic disorders, and using telemedicine in addition to in-person visits at their reference center were considered. Among the exclusion criteria, studies involving patients with other pathologies or comorbidities and those involving patients older than 18 years were excluded. Results: A total of 66 documents were analyzed to examine the challenges and specific needs of patients with rare diseases, highlighting the advantages and limitations of telemedicine compared to traditional care. The use of telemedicine has revolutionized the medical approach, facilitating integrated care by multidisciplinary teams. Conclusions: Telemedicine still faces several technical, organizational, and security challenges, as well as disparities in access across different geographical areas. Emerging technologies such as artificial intelligence could positively transform the monitoring and management of patients with rare diseases. Telemedicine has great potential ahead of it in the development of increasingly personalized and effective care, in fact, emerging technologies are important to provide remote care, especially for patients with rare diseases.

PMID:39940313 | DOI:10.3390/nu17030455

Cancers (Basel). 2025 Jan 27;17(3):439. doi: 10.3390/cancers17030439.

ABSTRACT

Central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children, with prognosis remaining dismal for some of these malignancies. Though the past two decades have seen advancements in surgery, radiation, and targeted therapy, major unresolved hurdles continue to undermine the therapeutic efficacy. These include challenges in suboptimal drug delivery through the blood-brain barrier (BBB), marked intra-tumoral molecular heterogeneity, and the elusive tumor microenvironment. Drug repurposing or re-tasking FDA-approved drugs with evidence of penetration into the CNS, using newer methods of intracranial drug delivery facilitating optimal drug exposure, has been an area of intense research. This could be a valuable tool, as most of these agents have already gone through the lengthy process of drug development and the evaluation of safety risks and the optimal pharmacokinetic profile. They can now be used and tested in clinics with an accelerated and different approach. Conclusions: The next-generation therapeutic strategy should prioritize repurposing oncologic and non-oncologic drugs that have been used for other indication, and have demonstrated robust preclinical activity against pediatric brain tumors. In combination with novel drug delivery techniques, these drugs could hold significant therapeutic promise in pediatric neurooncology.

PMID:39941807 | DOI:10.3390/cancers17030439

Int J Mol Sci. 2025 Feb 6;26(3):1389. doi: 10.3390/ijms26031389.

ABSTRACT

Multiple signaling pathways are dysregulated in melanoma, notably the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways, which can be targeted therapeutically. The high immunogenicity of melanoma has been exploited using checkpoint inhibitors. Whilst targeted therapies and immune checkpoint inhibitors have improved the survival of patients with advanced melanoma, treatment resistance, their side effect profiles, and the prohibitive cost remain a challenge, and the survival outcomes remain suboptimal. Treatment resistance has been attributed to the presence of cancer stem cells (CSCs), a small subpopulation of pluripotent, highly tumorigenic cells proposed to drive cancer progression, recurrence, metastasis, and treatment resistance. CSCs reside within the tumor microenvironment (TME) regulated by the immune system, and the paracrine renin-angiotensin system, which is expressed in many cancer types, including melanoma. This narrative review discusses the role of CSCs and the paracrine renin-angiotensin system in the melanoma TME, and its implications on the current treatment of advanced melanoma with targeted therapy and immune checkpoint blockers. It also highlights the regulation of the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways by the renin-angiotensin system via pro-renin receptors, and how this may relate to CSCs and treatment resistance, underscoring the potential for improving the efficacy of targeted therapy and immunotherapy by concurrently modulating the renin-angiotensin system.

PMID:39941158 | DOI:10.3390/ijms26031389

Int J Mol Sci. 2025 Jan 23;26(3):925. doi: 10.3390/ijms26030925.

ABSTRACT

Human immunodeficiency virus (HIV) and hepatitis B virus (HBV) continue to be global public health issues. Globally, about 39.9 million persons live with HIV in 2023, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS) 2024 Fact Sheet. Consequently, the World Health Organisation (WHO) reported that about 1.5 million new cases of HBV occur, with approximately 820 thousand mortalities yearly. Conversely, the lower percentage of HBV (30%) cases that receive a diagnosis is a setback in achieving the WHO 2030 target for zero HBV globally. This has necessitated a public health concern to repurpose antiretroviral (ARV) drugs for the treatment of HBV diseases. This review provides an introductory background, including the pros and cons of repurposing antiretrovirals (ARVs) for HBV treatment. We examine the similarities in replication mechanisms between HIV and HBV. We further investigate some clinical studies and trials of co-infected and mono-infected patients with HIV-HBV. The topical keywords including repurposing ARV drugs, repurposing antiretroviral therapy, Hepatitis B drugs, HBV therapy, title, and abstracts are searched in PubMed, Web of Science, and Google Scholar. The advanced search includes the search period 2014-2024, full text, clinical trials, randomized control trials, and review. The search results filtered from 361 to 51 relevant articles. The investigations revealed that HIV and HBV replicate via a common route known as 'reverse transcription'. Clinical trial results indicate that an early initiation of ARVs, particularly with tenofovir disoproxil fumarate (TDF) as part of a regimen, significantly reduced the HBV viral load in co-infected patients. In mono-infected HBV, timely and correct precise medication is essential for HBV viral load reduction. Therefore, genetic profiling is pivotal for successful ARV drug repurposing in HBV treatment. Pharmacogenetics enables the prediction of the right dosages, specific individual responses, and reactions. This study uniquely explores the intersection of pharmacogenetics and drug repurposing for optimized HBV therapy. Additional in vivo, clinical trials, and in silico research are important for validation of the potency, optimum dosage, and safety of repurposed antiretrovirals in HBV therapy. Furthermore, a prioritization of research collaborations comprising of regulators and funders to foster clinically adopting and incorporating repurposed ARVs for HBV therapy is recommended.

PMID:39940695 | DOI:10.3390/ijms26030925

Int J Mol Sci. 2025 Jan 21;26(3):888. doi: 10.3390/ijms26030888.

ABSTRACT

Classic galactosemia is a rare disease with long-term consequences that seriously affect the quality of life of patients. To date, various therapeutic approaches are being developed, but treatments that target the molecular defects in the mutant galactose-1-phosphate uridylyltransferase (GALT) gene are lacking. We conducted a computational search for putative pharmacochaperones by applying a drug repurposing strategy, and we found that one compound, already active as a pharmacochaperone in another pathology, doubled the enzymatic activity of the purified mutant enzyme in an in vitro test. Furthermore, an extensive computational search in a database of known active molecules found another compound able in its turn to improve in vitro enzymatic activity. Both compounds are predicted to interact with a cavity at the enzyme interface previously supposed to be an allosteric site for the GALT enzyme. In vitro tests confirmed also the reduced accumulation of galactose-1-phosphate (G1P) in fibroblasts of patients. Although these results must be considered preliminary, our findings pave the way for future research lines focused on the search for promising pharmacochaperones that can directly rescue the activity of the enzyme.

PMID:39940658 | DOI:10.3390/ijms26030888

Arkh Patol. 2025;87(1):28-36. doi: 10.17116/patol20258701128.

ABSTRACT

Dysferlinopathy represents an orphan disease within the spectrum of progressive muscular dystrophies, occurring at a frequency of 1 to 9 cases per 1.000.000 individuals (Orphanet, 2024). It arises from mutations in the DYSF gene (OMIM 603009, 2p13, NM_003494.4), which is responsible for coding the transmembrane protein dysferlin. Dysferlin plays a critical role in the repair of muscle fiber membranes and the cellular processes of skeletal muscle regeneration. Although the molecular mechanisms of dysferlin-mediated repair are under active investigation, reports on the ultrastructural alterations in human skeletal muscles due to dysferlin deficiency are sparse.

OBJECTIVE: To identify the ultrastructural pathomorphological features of skeletal muscles in 6 patients with dysferlinopathy.

MATERIAL AND METHODS: This study presents pathomorphological, immunohistochemical, and ultrastructural data from skeletal muscle biopsies of 6 patients with molecularly confirmed dysferlinopathy.

RESULTS: Examination of paraffin-embedded sections of the anterior tibialis and vastus lateralis muscles, stained with hematoxylin and eosin, identified a primarily myopathic pattern of skeletal muscle injury. Immunohistochemical staining with dysferlin antibodies revealed the absence of the protein in muscle tissue compared to the positive control. Transmission electron microscopy has revealed ultrastructural alterations characteristic of dysferlinopathy, although not specific, including thickening and fragmentation of the basal membrane, thinning and lysis of myofibrils, folding and disruptions of the sarcolemma, destruction of mitochondria, and, newly described in this disease, necrosis of myosatellite cells and telocytes in skeletal muscles.

CONCLUSION: Despite the non-specificity of the identified ultrastructural alterations, electron microscopy of skeletal muscle biopsies in dysferlinopathy can provide additional information about the mechanisms underlying the disease development. The finding of myosatellite cell and telocyte necrosis indicates the impairment of skeletal muscle regenerative capacity, which may be a novel link in the pathogenesis of dysferlinopathy.

PMID:39943726 | DOI:10.17116/patol20258701128

Front Robot AI. 2025 Jan 29;11:1363150. doi: 10.3389/frobt.2024.1363150. eCollection 2024.

ABSTRACT

This article introduces a model-based design, implementation, deployment, and execution methodology, with tools supporting the systematic composition of algorithms from generic and domain-specific computational building blocks that prevent code duplication and enable robots to adapt their software themselves. The envisaged algorithms are numerical solvers based on graph structures. In this article, we focus on kinematics and dynamics algorithms, but examples such as message passing on probabilistic networks and factor graphs or cascade control diagrams fall under the same pattern. The tools rely on mature standards from the Semantic Web. They first synthesize algorithms symbolically, from which they then generate efficient code. The use case is an overactuated mobile robot with two redundant arms.

PMID:39944358 | PMC:PMC11813742 | DOI:10.3389/frobt.2024.1363150

J Endocrinol Invest. 2025 Feb 13. doi: 10.1007/s40618-025-02550-3. Online ahead of print.

ABSTRACT

PURPOSE: To detect the expression of miR-27a-5p in differentiated thyroid cancer (DTC) and to explore its correlation with SREBP1 expression, DTC malignant progression, and TSH suppression therapy.

METHODS: The expression levels of SREBP1 and miR-27a-5p in DTC tissues (n = 75) were detected by qRT-PCR. The expression of miR-27a-5p and SREBP1 was statistically analyzed for correlation with patients' postoperative TSH inhibition therapy. Dual luciferase reporter gene assay was performed to verify the target-regulatory relationship between miR-27a-5p and SREBP1. qRT-PCR and Western blots were performed to detect the effect of miR-27a-5p on the expression level of SREBP1. MTS, plate clone formation assay was performed to detect the effect of miR-27a-5p on the proliferative capacity of cells. Flow cytometry was performed to detect the effect of miR-27a-5p on cell cycle and apoptosis. Scratch assay and Transwell assay was performed to detect the effect of miR-27a-5p on cell migration invasion ability.

RESULTS: MiR-27a-5p expression was significantly downregulated in DTC cancer tissues and significantly negatively correlated with SREBP1 expression. It correlated with the outcome of postoperative TSH suppression therapy in DTC patients. The results of dual luciferase reporter gene assay showed that the 3'-UTR region of SREBP1 mRNA was the target site of action of miR-27a-5p. Overexpression of miR-27a-5p was associated with a significant reduction in cell proliferation, cell cycle arrest, increased apoptosis, and diminished cell invasive migration.

CONCLUSION: The miR-27a-5p expression level was negatively correlated with the progression of DTC, which may be inhibited by targeting SREBP1 and correlated with the outcome of TSH inhibitory therapy.

PMID:39946050 | DOI:10.1007/s40618-025-02550-3

Curr Gene Ther. 2025 Feb 12. doi: 10.2174/0115665232342211250207064205. Online ahead of print.

ABSTRACT

This article provides a detailed look at Parkinson's disease (PD), a neurodegenerative ailment mostly known for movement difficulties such tremor, stiffness, and bradykinesia, which affects approximately 1% of persons over the age of 60. Although the precise cause of PD is still unknown, various factors such as pesticide exposure, genetics, and lifestyle choices like smoking and caffeine consumption are thought to play a role in its development. The presence of Lewy bodies characterizes the disease, the aggregation of alpha-synuclein, the loss of dopaminergic neurons in the substantia nigra, and disruptions in basal ganglia circuitry, resulting in both motor and nonmotor symptoms. This review is structured into several key sections, beginning with an exploration of the pathophysiological mechanisms behind PD, including how genetic mutations can lead to deficits in the Ubiquitin Proteasome System and mitochondrial function, which are linked to familial cases of the disease. Following this, the article explores diagnostic methods, such as the UK Brain Bank Criteria, advanced imaging techniques, olfactory testing, and innovative technologies like machine learning, all of which support early detection and accurate diagnosis of PD. Treatment strategies are also comprehensively reviewed, focusing on traditional pharmacological options like levodopa and dopamine agonists, as well as surgical interventions such as deep brain stimulation. Additionally, the review discusses promising new therapies, including immunotherapy aimed at neuroinflammation and gene therapy for disease modification. The impact of lifestyle changes such as exercise and diet on reducing PD risk and enhancing symptom management are also considered. In conclusion, this review highlights the complex nature of Parkinson's disease and underscores the need for a holistic approach that combines pharmacotherapy, advanced treatments, and lifestyle adjustments. By addressing both symptom management and disease modification, these strategies provide hope for improving quality of life.

PMID:39945257 | DOI:10.2174/0115665232342211250207064205

Front Nephrol. 2025 Jan 29;4:1465380. doi: 10.3389/fneph.2024.1465380. eCollection 2024.

ABSTRACT

BACKGROUND: Homocysteine (Hcy) is a risk factor for stroke. In this study, we investigated the relationship between gene polymorphisms, particularly SLCO1B1 and homocysteine (Hcy) concentrations in ischemic stroke patients, with a focus on identifying potential risk factors for elevated Hcy levels.

METHODS: A total of 177 ischemic stroke patients, including 99 with single nucleotide polymorphisms (SNPs), underwent pharmacogenomics (PGx) sequencing tests, from September 2022 to November 2023 at the hospital. Logistic regression analysis was used to analyze the relationship between clinical characteristics, SNPs, and Hcy concentrations. In the sub-study, 207 ischemic stroke and 244 non-stroke patients underwent SLCO1B1c.521T>C polymorphism to further demonstrate the role of SLCO1B1c.521T>C polymorphism and homocysteine.

RESULTS: Higher Hcy concentrations were observed in men compared to women. Univariate logistic analysis identified gender, GGT concentrations, B12 concentrations, folic acid concentrations, and SLCO1B1 c.521 CC+CT polymorphism as risk factors for elevated Hcy. Multivariate logistic analysis confirmed that B12 concentrations, folic acid concentrations, and SLCO1B1 CT + CC polymorphism were significant dependent risk factors. In the sub-study, SLCO1B1 CT + CC polymorphism and the male sex were identified as risk factors for Hcy, with the effect of SLCO1B1 polymorphism being more pronounced in men.

CONCLUSION: Folic acid and vitamin B12 reduce Hcy concentrations, while the SLCO1B1 CT and CC polymorphisms are associated with higher Hcy levels. The impact of SLCO1B1 gene polymorphism on Hcy is notably stronger in the male population, suggesting that genetic factors play a significant role in determining Hcy levels.

PMID:39944478 | PMC:PMC11815283 | DOI:10.3389/fneph.2024.1465380

Int J Mol Sci. 2025 Feb 6;26(3):1362. doi: 10.3390/ijms26031362.

ABSTRACT

Hypoxia, a common feature in many malignancies, is particularly prominent in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Investigating the mechanisms underlying hypoxia is essential for understanding the heterogeneity of CESC and developing personalized therapeutic regimens. Firstly, the CESC-specific hypoxia gene sets shared between single-cell RNA sequencing (scRNA-seq) and bulk data were identified through Weighted Gene Correlation Network Analysis (WGCNA)and FindMarkers analyses. A CESC-specific hypoxia-related score (CSHRS) risk model was constructed using the least absolute shrinkage and selection operator (LASSO)and Cox regression analyses based on these genes. The prognostic differences were analyzed in terms of immune infiltration, mutations, and drug resistance. Finally, a nomogram model was constructed by integrating clinicopathological features to facilitate precision treatment for CESC. This study constructed a CSHRS risk model that divides patients into two groups, and this model can comprehensively evaluate the tumor microenvironment characteristics of CESC, provide accurate prognostic predictions, and offer rational treatment options for patients.

PMID:39941131 | DOI:10.3390/ijms26031362

Int J Mol Sci. 2025 Jan 31;26(3):1269. doi: 10.3390/ijms26031269.

ABSTRACT

This study investigated the diagnostic, prognostic, and therapeutic significance of Fc receptor-like 1 (FCRL1) and B-cell activating factor (BAFF) mRNA expression in Egyptian patients with diffuse large B-cell lymphoma (DLBCL) undergoing the standard R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) using quantitative real-time PCR (RT-qPCR). The results demonstrated that FCRL1 and BAFF mRNA expression were significantly elevated in DLBCL patients compared to healthy controls. A strong positive correlation existed between BAFF and FCRL1 expression levels. Diagnostic performance assessed through combined ROC curve analysis revealed that BAFF, FCRL1, and lactate dehydrogenase (LDH) achieved perfect diagnostic accuracy (AUC = 1.0), demonstrating 100% sensitivity, specificity, and predictive values. Further prognostic analysis using COX regression identified elevated FCRL1 expression as the most significant predictor of poor clinical outcomes. Kaplan-Meier survival analysis reinforced this finding, with high FCRL1 expression showing significant associations with reduced overall survival (OS, p = 0.031) and progression-free survival (PFS, p = 0.038). The study underscores the potential utility of BAFF and FCRL1 mRNA as diagnostic markers for DLBCL, with FCRL1 emerging as a promising prognostic marker and potential therapeutic target enabling more tailored treatment approaches for DLBCL, the most common type of B-cell non-Hodgkin lymphoma, and patients receiving R-CHOP therapy.

PMID:39941037 | DOI:10.3390/ijms26031269

Int J Mol Sci. 2025 Jan 26;26(3):1082. doi: 10.3390/ijms26031082.

ABSTRACT

The landscape of psychiatric care is poised for transformation through the integration of pharmaco-multiomics, encompassing genomics, proteomics, metabolomics, transcriptomics, epigenomics, and microbiomics. This review discusses how these approaches can revolutionize personalized treatment strategies in psychiatry by providing a nuanced understanding of the molecular bases of psychiatric disorders and individual pharmacotherapy responses. With nearly one billion affected individuals globally, the shortcomings of traditional treatments, characterized by inconsistent efficacy and frequent adverse effects, are increasingly evident. Advanced computational technologies such as artificial intelligence (AI) and machine learning (ML) play crucial roles in processing and integrating complex omics data, enhancing predictive accuracy, and creating tailored therapeutic strategies. To effectively harness the potential of pharmaco-multiomics approaches in psychiatry, it is crucial to address challenges such as high costs, technological demands, and disparate healthcare systems. Additionally, navigating stringent ethical considerations, including data security, potential discrimination, and ensuring equitable access, is essential for the full realization of this approach. This process requires ongoing validation and comprehensive integration efforts. By analyzing recent advances and elucidating how different omic dimensions contribute to therapeutic customization, this review aims to highlight the promising role of pharmaco-multiomics in enhancing patient outcomes and shifting psychiatric treatments from a one-size-fits-all approach towards a more precise and patient-centered model of care.

PMID:39940850 | DOI:10.3390/ijms26031082

Int J Mol Sci. 2025 Jan 23;26(3):925. doi: 10.3390/ijms26030925.

ABSTRACT

Human immunodeficiency virus (HIV) and hepatitis B virus (HBV) continue to be global public health issues. Globally, about 39.9 million persons live with HIV in 2023, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS) 2024 Fact Sheet. Consequently, the World Health Organisation (WHO) reported that about 1.5 million new cases of HBV occur, with approximately 820 thousand mortalities yearly. Conversely, the lower percentage of HBV (30%) cases that receive a diagnosis is a setback in achieving the WHO 2030 target for zero HBV globally. This has necessitated a public health concern to repurpose antiretroviral (ARV) drugs for the treatment of HBV diseases. This review provides an introductory background, including the pros and cons of repurposing antiretrovirals (ARVs) for HBV treatment. We examine the similarities in replication mechanisms between HIV and HBV. We further investigate some clinical studies and trials of co-infected and mono-infected patients with HIV-HBV. The topical keywords including repurposing ARV drugs, repurposing antiretroviral therapy, Hepatitis B drugs, HBV therapy, title, and abstracts are searched in PubMed, Web of Science, and Google Scholar. The advanced search includes the search period 2014-2024, full text, clinical trials, randomized control trials, and review. The search results filtered from 361 to 51 relevant articles. The investigations revealed that HIV and HBV replicate via a common route known as 'reverse transcription'. Clinical trial results indicate that an early initiation of ARVs, particularly with tenofovir disoproxil fumarate (TDF) as part of a regimen, significantly reduced the HBV viral load in co-infected patients. In mono-infected HBV, timely and correct precise medication is essential for HBV viral load reduction. Therefore, genetic profiling is pivotal for successful ARV drug repurposing in HBV treatment. Pharmacogenetics enables the prediction of the right dosages, specific individual responses, and reactions. This study uniquely explores the intersection of pharmacogenetics and drug repurposing for optimized HBV therapy. Additional in vivo, clinical trials, and in silico research are important for validation of the potency, optimum dosage, and safety of repurposed antiretrovirals in HBV therapy. Furthermore, a prioritization of research collaborations comprising of regulators and funders to foster clinically adopting and incorporating repurposed ARVs for HBV therapy is recommended.

PMID:39940695 | DOI:10.3390/ijms26030925

Drug Metab Pers Ther. 2025 Feb 14. doi: 10.1515/dmpt-2024-0061. Online ahead of print.

ABSTRACT

OBJECTIVES: The clinical outcomes of tamsulosin therapy for LUTS/BPH patients vary, with up to one-third of patients reporting unsatisfactory results. Enhancing the effectiveness and safety of tamsulosin therapy for LUTS/BPH patients remains a significant challenge in current medical practice. Limited data exists regarding the impact of CYP2D6 genetic polymorphisms on the efficacy and safety of tamsulosin therapy. Given that tamsulosin is metabolized by CYP2D6, variations in this enzyme may influence the drug's pharmacodynamic response. The objective of this study was to evaluate the impact of CYP2D6 pharmacogenetic markers on tamsulosin efficacy and safety in patients with LUTS associated with BPH.

METHODS: The study included 142 male patients with LUTS and a confirmed diagnosis of BPH (N40 ICD-10). Patients were followed for a minimum of 8 weeks and underwent four examinations (at days 0, 14, 28, and 56). Treatment efficacy was assessed using the IPSS with quality of life assessment, transrectal ultrasound of the prostate with estimation of prostate volume and residual urine volume, and maximum urinary flow rate (Qmax). Allelic variants of CYP2D6 (*2, *3, *4, *6, *9, *10, and *41) were determined by polymerase chain reaction in all patients..

RESULTS: In the subgroup with moderate symptoms, individuals classified as poor and intermediate metabolizers exhibited significantly higher ΔQmax compared to normal metabolizers (4.25 [2.5; 6.1] vs. [0.6; 4.3], p=0.001826). Moreover, carriers of the CYP2D6*10 CT heterozygous genotype demonstrated lower IPSS scores at the last two visits compared to those with the CC genotype (visit 3: -7.45 ± 3.93 vs. -5.25 ± p=0.05; visit 4: -8.91 ± 3.88 vs. -6.31 ± 5.7), as well as reduced IPSS irritative symptoms at visit 2 (-3.87 ± 2.70 vs -2.47 ± 3.1, p=0.05), and a significant increase in ΔQmax ([2.5; 5.9] vs. [0.6; 4.7], p=0.01). In the subgroup with severe symptoms, individuals with CYP2D6*41 GA + AA genotypes exhibited less residual urine volume following therapy compared to those with the GG genotype ([15.0; 32.0] vs. [3.0; 19.0], p=0.007029). The CYP2D6 polymorphic variants did not impact the tamsulosin safety. The study did not reach the estimated power for CYP2D6*3, CYP2D6*6, and CYP2D6*9 polymorphisms due to their low frequency of occurrence in the study population. The multivariate logistic regression model indicated that potential predictors of tamsulosin therapy efficacy in LUTS/BPH patients may include BMI (p<0.001), prostate volume (p<0.002), as well as the carriage of CYP2D6*4 (p<0.001) and CYP2D6*10 (p=0.012) markers. The model explained 81.9 % of the variance in the predicted outcome and accurately forecasted tamsulosin therapy efficacy in BPH with a precision of 92.1 %.

CONCLUSIONS: The present study identified potential markers that could serve as predictors of the effectiveness of tamsulosin. Specifically, genetic markers such as CYP2D6*4, CYP2D6*10, CYP2D6*41, and non-genetic factors like BMI and prostate volume were associated with the clinical efficacy of tamsulosin therapy in LUTS/BPH patients..

PMID:39940086 | DOI:10.1515/dmpt-2024-0061

Cytotherapy. 2025 Jan 20:S1465-3249(25)00034-9. doi: 10.1016/j.jcyt.2025.01.006. Online ahead of print.

ABSTRACT

The acute respiratory distress syndrome (ARDS) inflammatory environment alters mesenchymal stromal cell (MSC) gene and protein expression but effects on microRNA (miRNA) content of MSC-extracellular vesicle (EVs) remain unknown. To assess this, sequencing analysis of EV-miRNAs prepared from human bone marrow-derived MSCs (hMSCs) exposed ex vivo to bronchoalveolar lavage fluid (BALF) from ARDS patients or healthy volunteers (HV) identified a number of differentially expressed miRNAs. Discriminant, differential expression, and functional enrichment analyses identified 14 miRNAs significantly changed following ARDS versus HV BALF exposure. Network analysis showed 4 (miR-760, miR-3175, miR-885-3p, and miR-766-3p) of the 14 EV-miRNAs formed a regulatory "hub", suggesting co-targeting of specific gene pathways. In silico prediction identified a number of pathways important in lung injury. Two miRNAs involved in regulation of the cystic fibrosis transmembrane conductance regulator (CFTR), miRNA-145-5p and miRNA-138-5p, were also significantly increased in ARDS BALF-exposed hMSCs EVs. Functionally, EVs from hMSCs exposed to either ARDS or HV BALF had differential effects on CFTR Cl- secretion by cultured primary human bronchial epithelial cells, an effect predicted to reduce mucociliary clearance. The potential clinical impact of these finding highlights the need for further studies assessing the role of hMSC-EV miRNAs in regulating lung inflammation and mucociliary clearance.

PMID:39945694 | DOI:10.1016/j.jcyt.2025.01.006

Pediatr Crit Care Med. 2025 Feb 13. doi: 10.1097/PCC.0000000000003695. Online ahead of print.

ABSTRACT

OBJECTIVE: To develop consensus statements that clinicians can apply to standardize and optimize endotracheal aspirate culture (EAC) practices in hospitalized children with artificial airways who are being evaluated for a bacterial lower respiratory tract infection (LRTI).

DESIGN: A modified Delphi consensus process with expert panelists. Panelists conducted a "pre-survey" to itemize respiratory signs of bacterial LRTI. Round 1 included a literature summary and electronic survey of 50 potential statements sent to all panelists. We surveyed panelist opinions using a 5-point Likert scale. We grouped the responses "agree" and "strongly agree" as agreement. Consensus was defined as statements reaching greater than 75% agreement. Round 2 was moderated by an independent expert in consensus methodology. Panelists convened in person in November 2023, discussed any statements not reaching consensus or statements with disagreement, were resurveyed, and finalized statements in real time.

SETTING: Electronic surveys and in-person meetings in Baltimore, MD.

SUBJECTS: The BrighT STAR (Testing STewardship for Antibiotic Reduction) collaborative along with U.S.-based pediatric experts in critical care, cardiac critical care, infectious diseases, hospital medicine, otolaryngology, pulmonology, and clinical microbiology.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: Thirty-eight of 40 invited panelists completed round 1. Of 50 initial statements, 28 reached greater than 90% agreement, 16 had 75-89% agreement, and 6 had less than 75% agreement. Twenty-eight statements were finalized. Round 2 involved 37 panelists: 23 statements were discussed, of which 17 reached an agreement and 6 did not reach consensus. We concluded with 30 statements and 15 sub-statements, 37 of which had greater than 90% agreement. Final statements informed a clinical decision support algorithm.

CONCLUSIONS: The BrighT STAR collaborative group achieved consensus for 45 clinical practice statements that can standardize EAC practices, including indications to consider for testing, reasons to defer, optimal specimen collection, and result interpretation. These statements offer a starting point for clinical decision support tools and diagnostic stewardship programs for EAC practices in patients with artificial airways.

PMID:39945582 | DOI:10.1097/PCC.0000000000003695

mBio. 2025 Feb 13:e0342024. doi: 10.1128/mbio.03420-24. Online ahead of print.

ABSTRACT

The healthy human infant gut microbiome undergoes stereotypical changes in taxonomic composition between birth and maturation to an adult-like stable state. During this time, extensive communication between microbiota and the host immune system contributes to health status later in life. Although there are many reported associations between microbiota compositional alterations and disease in adults, less is known about how microbiome development is altered in pediatric diseases. One pediatric disease linked to altered gut microbiota composition is cystic fibrosis (CF), a multi-organ genetic disease involving impaired chloride secretion across epithelia and heightened inflammation both in the gut and at other body sites. Here, we use shotgun metagenomics to profile the strain-level composition and developmental dynamics of the infant fecal microbiota from several CF and non-CF longitudinal cohorts spanning from birth to greater than 36 months of life. We identify a set of keystone species that define microbiota development in early life in non-CF infants but are missing or decreased in relative abundance in infants with CF, resulting in a delayed pattern of microbiota maturation, persistent entrenchment in a transitional developmental phase, and subsequent failure to attain an adult-like stable microbiota. Delayed maturation is strongly associated with cumulative antibiotic treatments, and we also detect the increased relative abundance of oral-derived bacteria and higher levels of fungi in infants with CF, features that are associated with decreased gut bacterial density. These findings suggest the potential for future directed therapies targeted at overcoming developmental delays in microbiota maturation for infants with CF.IMPORTANCEThe human gastrointestinal tract harbors a diversity of microbes that colonize upon birth and collectively contribute to host health throughout life. Infants with the disease cystic fibrosis (CF) harbor altered gut microbiota compared to non-CF counterparts, with lower levels of beneficial bacteria. How this altered population is established in infants with CF and how it develops over the first years of life is not well understood. By leveraging multiple large non-CF infant fecal metagenomic data sets and samples from a CF cohort collected prior to highly effective modulator therapy, we define microbiome maturation in infants up to 3 years of age. Our findings identify conserved age-diagnostic species in the non-CF infant microbiome that are diminished in abundance in CF counterparts that instead exhibit an enrichment of oral-derived bacteria and fungi associated with antibiotic exposure. Together, our study builds toward microbiota-targeted therapy to restore healthy microbiota dynamics in infants with CF.

PMID:39945545 | DOI:10.1128/mbio.03420-24

mSphere. 2025 Feb 13:e0090424. doi: 10.1128/msphere.00904-24. Online ahead of print.

ABSTRACT

Lysogenic bacteriophages can integrate their genome into the bacterial chromosome in the form of a prophage and can promote genetic transfer between bacterial strains in vitro. However, the contribution of lysogenic bacteriophages to the incidence of antimicrobial resistance (AMR) in clinical settings is poorly understood. Here, in a set of 186 clinical isolates of Pseudomonas aeruginosa collected from respiratory cultures from 82 patients with cystic fibrosis, we evaluate the links between prophage counts and both genomic and phenotypic resistance to six anti-pseudomonal antibiotics: tobramycin, colistin, ciprofloxacin, meropenem, aztreonam, and piperacillin-tazobactam. We identified 239 different prophages in total. We find that P. aeruginosa isolates contain on average 3.06 ± 1.84 (SD) predicted prophages. We find no significant association between the number of prophages per isolate and the minimum inhibitory concentration for any of these antibiotics. We then investigate the relationship between particular prophages and AMR. We identify a single lysogenic phage associated with phenotypic resistance to the antibiotic tobramycin and, consistent with this association, we observe that AMR genes associated with resistance to tobramycin are more likely to be found when this prophage is present. However, we find that they are not encoded directly on prophage sequences. Additionally, we identify a single prophage statistically associated with ciprofloxacin resistance but do not identify any genes associated with ciprofloxacin phenotypic resistance. These findings suggest that prophages are only infrequently associated with the AMR genes in clinical isolates of P. aeruginosa.IMPORTANCEAntibiotic-resistant infections of Pseudomonas aeruginosa (Pa), a leading pathogen in patients with cystic fibrosis (CF), are a global health threat. While lysogenic bacteriophages are known to facilitate horizontal gene transfer, their role in promoting antibiotic resistance in clinical settings remains poorly understood. In our analysis of 186 clinical isolates of P. aeruginosa from CF patients, we find that prophage abundance does not predict phenotypic resistance to key antibiotics but that specific prophages are infrequently associated with tobramycin resistance genes. In addition, we do not find antimicrobial resistance (AMR) genes encoded directly on prophages. These results highlight that while phages can be associated with AMR, phage-mediated AMR transfer may be rare in clinical isolates and difficult to identify. This work is important for future efforts on mitigating AMR in CFCF and other vulnerable populations affected by Pa infections and advances our understanding of bacterial-phage dynamics in clinical infections.

PMID:39945525 | DOI:10.1128/msphere.00904-24

JPGN Rep. 2024 Nov 20;6(1):27-38. doi: 10.1002/jpr3.12147. eCollection 2025 Feb.

ABSTRACT

OBJECTIVES: Cow's milk allergy (CMA) is a common food allergy in infants. Guidelines and recommendations for the diagnosis and management of CMA are based on scientific review of the available evidence. However, real-world situations may oblige clinicians to adapt a different attitude.

METHODS: This paper evaluated the opinion of 42 Mexican paediatricians on the 73 statements presented in the recent position paper of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Voting on the statements and their interpretation were identical for both groups (online and anonymous). Both groups were unaware of the other's outcome at the moment of the voting.

RESULTS: While the ESPGHAN group accepted all 73 statements, the Mexican group rejected 19 statements. Two rejections were due to the mean and median being below the predefined and agreed-upon cut-off, and 17 were due to over 75% of participants disagreeing with the statements. The greatest discrepancy was observed regarding the role of vitamin D in preventing CMA.

CONCLUSION: While opinions on the prevalence, diagnosis and management of CMA were comparable between European paediatric gastroenterologists and Mexican general paediatricians for the majority of statements, significant differences were observed. It is essential to gather information from various regions and healthcare levels to enhance the impact of recommendations.

PMID:39944093 | PMC:PMC11810815 | DOI:10.1002/jpr3.12147