Search Results (175)

Background: Remdesivir (RDV) is a broad-spectrum antiviral prodrug, which is rapidly metabolized in vivo within cells to the pharmacologically active triphosphate metabolite, GS-443902. On the other hand, the dephosphorylated metabolite GS-441524 is the main form detected in plasma. RDV acts against RNA viruses, and it was the first antiviral drug to receive EMA and FDA approval for treating COVID-19. Nevertheless, its intracellular pharmacokinetics in real life are poorly explored, particularly due to technical challenges. Methods: The aim of this study was to validate an HPLC-MS/MS method for the direct quantification of GS-443902 in peripheral blood mononuclear cells (PBMCs) with a chromatographic separation of 15 min. Results: The method was validated following EMA and FDA guidelines in terms of sensitivity, specificity, accuracy, precision, matrix effect, recovery, carryover, and stability, and then applied to PBMC isolates from a small cohort of patients with severe COVID-19 who received RDV. Conclusions: This work represents the first method for the direct quantification of GS-443902 in PBMCs, with possible future application to intracellular pharmacokinetic studies in different scenarios, such as new oral prodrugs or drug–drug interaction studies. Full article

Background: Out-of-hospital cardiac arrest (OHCA) survivors and their relatives may face challenges following hospital discharge, relating to mood, cognition, and returning to normal day-to-day activities. Identified research gaps include a lack of knowledge around what type of intervention is needed to best navigate recovery. In this study, we investigate the feasibility and patient acceptability of a new virtual psychoeducational group intervention for OHCA survivors and their relatives and compare it to a control group receiving a digital information booklet. Methods: V-CARE is a comparative, single-blind randomized pilot trial including participants at selected sites of the STEPCARE trial, in the United Kingdom and Sweden. Inclusion criteria are a modified Rankin Scale (mRS) ≤ 3 at 30-day follow-up; no diagnosis of dementia; and not experiencing an acute psychiatric episode. One caregiver per patient is invited to participate optionally. The intervention group in V-CARE receives four semi-structured, one-hour-long, psychoeducational sessions delivered remotely via video call by a trained clinician once a week, 2–3 months after hospital discharge. The sessions cover understanding cardiac arrest; coping with fatigue and memory problems; managing low mood and anxiety; and returning to daily life. The control group receives an information booklet focused on fatigue, memory/cognitive problems, mental health, and practical coping strategies. Results: Primary: feasibility (number of patients consented) and acceptability (retention rate); secondary: satisfaction with care (Client Satisfaction Questionnaire 8 item), self-management skills (Self-Management Assessment Scale) and, where available, health-related outcomes assessed in the STEPCARE Extended Follow-up sub-study including cognition, fatigue, mood, quality of life, and return to work. Conclusions: If preliminary insights from the V-CARE trial suggest the intervention to be feasible and acceptable, the results will be used to design a larger trial aimed at informing future interventions to support OHCA recovery. Full article

The electrocardiogram (ECG) remains a cornerstone of modern cardiology, providing rapid, non-invasive, and widely accessible diagnostic insights. While ECG interpretation is an essential skill for clinicians, certain patterns can be subtle or atypical, posing diagnostic challenges. In our previous review (doi.org/10.3390/jpm12111754), we explored several uncommon ECG syndromes with significant clinical implications. However, the spectrum of electrocardiographic abnormalities extends far beyond those initially discussed. In this second installment, we expand our discussion of rare and underrecognized ECG syndromes, including Long QT, Jervell and Lange-Nielsen, Romano–Ward, Andersen–Tawil, Timothy, Short QT, and Twiddler’s syndromes, as well as Noonan, Barlow’s, Bundgaard, BRASH, Carvajal, Naxos, and Danon disease. We highlight their clinical context, characteristic findings, and implications for diagnosis and management. These conditions range from acute, life-threatening emergencies requiring immediate intervention to chronic electrical disorders necessitating long-term monitoring and risk stratification. By broadening our focus, we aim to enhance awareness and recognition of these entities, ultimately improving patient outcomes through timely and accurate diagnosis. Full article

Coronary artery disease (CAD) and peripheral artery disease (PAD) are associated with increased blood viscosity, which contributes to vascular inflammation and impaired microcirculation. Blood viscosity plays a crucial role in disease progression, influencing endothelial function and tissue perfusion. Sarpogrelate hydrochloride, a serotonin receptor antagonist, has antiplatelet and vasodilatory properties that may improve microvascular function and blood rheology. This randomized, parallel-group, open-label, single-center, phase IV clinical trial enrolled 68 patients with both CAD and PAD. The participants were randomized in a 1:1 ratio to receive either aspirin monotherapy (100 mg) or aspirin (100 mg) plus sarpogrelate (300 mg) for 12 weeks. The primary outcome was the change in blood viscosity from baseline to week 12, assessed using the scanning capillary technique. Secondary outcomes included erythrocyte deformability, flow-mediated dilation (FMD), and tissue oxygen delivery index (tODI), which collectively provide insights into microvascular function and oxygen transport efficiency. Elevated blood viscosity is a key factor in cardiovascular disease progression, yet conventional antiplatelet therapy has shown limited effects on hemorheology. Sarpogrelate, by targeting serotonin-mediated pathways, may enhance microcirculatory function and optimize vascular health. These effects could lead to better oxygen delivery and overall vascular health, thereby optimizing cardiovascular outcomes. By integrating hemorheological and vascular markers, this study aims to provide evidence on the potential benefits of combination therapy. Findings could inform optimized antiplatelet strategies to improve vascular health and reduce cardiovascular risk in patients with CAD and PAD. Full article

Understanding the function of the blood–brain barrier (BBB) in health and disease, as well as improving drug delivery across the BBB, remains a critical priority in neuroscience research. However, current in vitro models of the BBB have become increasingly complex and challenging to implement. In this study, we present a simplified microfluidic BBB model in which human umbilical vein endothelial cells (HUVECs) are cultured as a monolayer along a fibrin gel containing human pericytes and astrocytes. Remarkably, within just three days, the 3D co-culture significantly enhanced barrier formation and upregulated the expression of tight-junction proteins in HUVECs. These findings demonstrate that HUVECs, which have been extensively used for over 50 years to study vascular endothelium due to their ease of isolation and culture, can adapt their phenotype towards that of BBB endothelial cells under appropriate conditions. This microfluidic BBB model offers a valuable tool for drug development and for advancing our understanding of BBB physiology in both health and disease contexts. Full article

BK virus (BKV) reactivation is a significant complication in renal transplant recipients, often leading to BK viremia and BK virus-associated nephropathy (BKVAN), which can compromise graft survival. While the routine monitoring of BKV DNA in blood aids in early detection, identifying pre-transplant risk factors remains a challenge. This study investigates the role of pre- and post-transplant anti-BKV IgG levels and human leukocyte antigen (HLA) alleles in predicting BKV reactivation. The hospital-based cross-sectional study was conducted on 38 renal transplant recipients, stratified into viremic, non-viremic, and BKVAN groups. Anti-BKV IgG levels were measured pre-transplant, at viremia onset, and post-viremia using ELISA. BKV DNA was detected via qPCR, and HLA typing was performed using sequence-specific oligonucleotide probe (SSOP) hybridization. Statistical analyses included Kaplan–Meier survival curves and Cox regression models. Pre-transplant anti-BKV IgG seropositivity was higher in viremic (94%) and BKVAN (100%) patients than in non-viremic recipients (66.6%). Post-transplant IgG levels increased significantly in viremic recipients (p < 0.05). HLA-B44 and HLA-DR15 were significantly associated with increased BKV viremia risk (p = 0.02 and p = 0.01, respectively). Pre-transplant anti-BKV IgG levels and specific HLA alleles influence BKV reactivation risk. These findings highlight the potential for integrating serological and genetic screening into pre-transplant assessments to improve risk stratification and post-transplant monitoring strategies. Full article

Background/Objectives: Health locus of control (LOC) refers to one’s perceptions of who or what controls one’s health. Recent evidence has found that chance LOC (CLOC) is associated with improved quality of life (QoL) in multiple sclerosis (MS). The purpose of the current study was to identify mediators and moderators of the LOC-QoL relationship in MS. Methods: For this study, 5266 participants with MS completed a questionnaire pack that included the Multidimensional Health Locus of Control Scale, the Unidimensional Self-Efficacy Scale for MS (USE-MS), and the World Health Organization Quality of Life Scale—BREF (WHOQoL-BREF). The relationship between LOC and QoL was examined within a structural equation model (SEM). Results: In the total sample, self-efficacy was found to fully mediate the relationship between LOC and QoL for both internal (ILOC) and CLOC orientations. Powerful others LOC (PLOC) had no association with QoL. The same results were found for the relationship of LOC to functioning. In the secondary progressive MS subgroup, the relationship between CLOC and QoL was only partially mediated by self-efficacy. Conclusions: LOC influences QoL through its impact on self-efficacy, one of several potentially mediating factors between LOC and QoL in MS. Disability did not moderate the associations of LOC, but moderation of the CLOC-QoL relationship by disease subtype was found. Psychological training to improve self-efficacy in MS may be particularly useful in those subgroups where LOC-QoL is largely mediated by self-efficacy. Full article

Microbial-induced carbonate precipitation (MICP) is gaining attention as an eco-friendly and sustainable method for concrete crack repair. However, key challenges related to its large-scale implementation, regulatory approval, and integration into existing construction standards remain underexplored. This review examines recent advances in MICP, emphasizing its role in circular economy practices and sustainable building solutions. Traditional synthetic sealants contribute to environmental pollution and have limited long-term durability, highlighting the need for greener alternatives. Global research trends reveal an increasing focus on self-healing materials, biomineralization, and durability enhancement, alongside emerging innovations such as encapsulation technologies, marine applications, and bio-based composites. Unlike previous reviews, this study integrates bibliometric analysis to systematically assess research trends, identify key collaboration networks, and evaluate regulatory challenges that impact MICP adoption. While MICP offers significant advantages, including self-healing capabilities and compatibility with industrial by-products, barriers related to cost, scalability, and policy integration persist. This review identifies critical thematic clusters which include microbial action, sustainability, and engineering applications. This helps to provide actionable insights for researchers, engineers, and policymakers. By fostering interdisciplinary collaboration, MICP has the potential to become a transformative solution for resilient and environmentally sustainable infrastructure. Full article

The interaction between antibiotics and antibiotic resistance genes (ARGs) in freshwater ecosystems has become a critical environmental concern. This study investigates seasonal variations of sulfonamide and tetracycline antibiotics and their relationship with ARGs in three urban reservoirs in Nanjing, China: Pingshan Forest Park, Shanhu Lake Wetland Park, and Zhaoqiao Reservoir. Sampling was conducted in May and September 2023 to assess water quality, antibiotic concentrations, and ARG abundance. A total of 30 water samples were analyzed in regard to their physicochemical parameters, heavy metals, and antibiotics. A quantitative PCR assay was used to measure the ARG abundance relative to the 16S rRNA gene. Sulfonamide concentrations ranged from 30 to 120 ng/L, while the concentrations of tetracyclines were 50–160 ng/L. Notably, sulfamethazine decreased significantly in two reservoirs (Shanhu and Zhaoqiao, p < 0.05), while other antibiotics showed minimal variation, indicating persistent contamination from agricultural runoff and wastewater discharge. ARG abundance was lower in May than in September, with sulfonamide resistance genes being lower cumulatively than tetracycline resistance genes. Strong correlations (r > 0.7) were observed between ARGs and parameters like dissolved oxygen and pH. High antibiotic levels were observed in areas without nearby hospitals or pharmaceutical companies, implicating agriculture as a major pollution source. By analyzing sulfonamide and tetracycline antibiotics and their resistance genes across three eutrophic reservoirs in Nanjing, China, we highlight critical environmental drivers of ARG proliferation and propose targeted mitigation strategies. Full article

Background: Lower socioeconomic status (SES) has been associated with increased mortality from coronary heart disease. This excess risk, relative to affluent patients, may be due to a combination of more adverse cardiovascular-risk factors, inequalities in access to cardiac investigations, longer waiting times for cardiac revascularisation and lower use of secondary prevention drugs. We sought to investigate whether socio-economic status influenced long-term all-cause mortality after PCI in a large metropolitan city (London), which serves a population of 11 million people with a mixed social background over a 10-year period. Methods: We conducted an observational cohort study of 123,780 consecutive PCI procedures from the Pan-London (United Kingdom) PCI registry. This data set is collected prospectively and includes all patients treated between January 2005 and December 2015. The database includes PCI performed for stable angina and ACS (ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), and unstable angina). Patient socio-economic status was defined by the English Index of Multiple Deprivation (IMD) score, according to residential postcode. Patients were analysed by quintile of IMD score (Q1, least deprived; Q5, most deprived). Median follow-up was 3.7 (IQR: 2.0–5.1) years and the primary outcome was all-cause mortality. Results: The mean age of the patients was 64.3 ± 12.1 years and 25.2% were female. A total of 22.4% of patients were diabetic and 27.3% had a history of previous myocardial infarction. The rates of long-term all-cause mortality increased progressively across quintiles of IMD score, with patients in Q5 showing significantly higher long-term mortality rates compared with patients in Q1 (p = 0.0044). This persisted following the inclusion of a propensity score in the proportional hazard model as a covariate (HR for Q5 compared to Q1: 1.15 [95% CI: 1.10–1.42]). Conclusions: This study has demonstrated that low SES is an independent predictor of adverse clinical outcomes following PCI in the large, diverse metropolitan city of London. There clearly are inequalities in cardio-vascular risk factors, time to access to medical treatment/PCI, access to complex imaging and devices during PCI, access to secondary prevention after PCI, and even race differences. Hence, attention to reducing the burden of cardiovascular risk factors and improving primary prevention, particularly in patients with lower SES, is required. Full article

Background/Objectives: The published report of the MARS2 trial suggested that the addition of extended pleurectomy/decortication to chemotherapy for pleural mesothelioma was harmful. Thus, the report goes on, all disease should be considered as unresectable and no further mesothelioma surgery for survival benefit should be considered. This statement has changed clinical practice in the UK; however, the design of the MARS2 trial has several limitations which should prevent its conclusions being over interpreted. These limitations include the following: the inclusion of too many patients who would fall outside contemporary selection criteria including age, co-morbidity and histology; the unnecessary resection of too much tissue, particularly the diaphragm, and operating on patients too late in the disease process due to less than rigorous staging. Methods: We retrospectively analysed the selection and outcome of data of 79 of the 158 (50%) patients who underwent surgery in the surgical arm of the MARS2 study who were operated by the authors in four of the five trial surgical centres. We revised the clinical staging of these patients by applying the criteria in the forthcoming 9th TNM edition including the measurement of pleural thickness. Results: Based on reported guidelines, the selection for surgery was reset as stage I or II epithelioid PM. We found that 52 (66%) of these patients (group A) would not have been considered for surgery using contemporary selection criteria for the following reasons: non-epithelioid PM in 5; cT/4 in 35; cT2N1 in 10 and 2 cT2N0 (pN1), which would have been detected on preoperative mediastinal biopsy. Of the 27 (34%) trial patients fulfilling current criteria (group B), 12 were cT1N0, 1 was cT1N1, 6 were cT1N0pN1 and 8 were cT2N0, all with epithelioid PM. The median survival of group B was 32 (1–72) months, which was significantly higher than in group A: 8.5 (1–55) months, p < 0.0005 (Mann–Whitney). Conclusions: As contemporary selection criteria were not applied in MARS2, its conclusions cannot be universally applied to all those with PM. Together with the favourable postoperative survival in this selected group, we suggest that there is still scope for a further trial of surgery in early-stage epithelioid mesothelioma. Full article

Background: Transanal endoscopic microsurgery (TEMS) is an organ-preserving approach for treatment of early rectal cancer (ERC). However, adverse histopathological features identified post-TEMS often necessitate adjuvant therapy. This study aims to compare the long-term oncological outcomes of patients who underwent TEMS and were offered adjuvant treatments with total mesorectal excision (TME), chemoradiotherapy (CRT), radiotherapy (RT), active surveillance, or dose escalation with contact X-ray brachytherapy (CXB). Methods: This study included patients treated with TEMS for ERC between September 2012 and December 2022, with follow-up until December 2023. Patients with adverse histopathological features (extra-mural venous invasion, lympho-vascular invasion, R1 margins, tumour budding) were assigned to adjuvant treatments. Inverse probability of treatment weighting (IPTW) was applied to mitigate selection bias. Results: Of the 117 patients, 24 underwent TME, 17 received CRT, 25 received RT, 14 underwent active surveillance, and 37 patients received CXB boost along with CRT. The median follow-up was 60 months (IQR 52–73). During this time, 29 patients developed recurrence, and 15 died. The 5-year overall survival (OS) was 78.6%, and disease-free survival (DFS) was 70.9%. Compared to CXB, the mortality risk for CRT (HR = 0.81; 95% CI: 0.20–3.28; p = 0.77) and TME (HR = 3.68; 95% CI: 0.46–29.79; p = 0.22) was not significantly different. However, TME was associated with a significantly higher recurrence risk compared to CXB (HR = 7.57; 95% CI: 1.23–46.84; p = 0.029). Conclusions: An organ-preserving strategy with CRT or CRT combined with a CXB boost may offer comparable long-term outcomes and reduced recurrence risks for patients undergoing TEMS for ERC with poor prognostic features. Further research with larger cohorts is needed to validate these results. Full article

Background: Elevated choline kinase alpha (ChoK) levels are observed in most solid tumors, including glioblastomas (GBM), and ChoK inhibitors have demonstrated limited efficacy in GBM models. Given that hypoxia is associated with resistance to GBM therapy, we hypothesized that tumor hypoxia could be responsible for the limited response. Therefore, we evaluated the effects of hypoxia on the function of JAS239, a potent ChoK inhibitor in four GBM cell lines. Methods: Rodent (F98 and 9L) and human (U-87 MG and U-251 MG) GBM cell lines were subjected to 72 h of hypoxic conditioning and treated with JAS239 for 24 h. NMR metabolomic measurements and analyses were performed to evaluate the signaling pathways involved. In addition, cell proliferation, cell cycle progression, and cell invasion parameters were measured in 2D cell monolayers as well as in 3D cell spheroids, with or without JAS239 treatment, in normoxic or hypoxic cells to assess the effect of hypoxia on JAS239 function. Results: Hypoxia and JAS239 treatment led to significant changes in the cellular metabolic pathways, specifically the phospholipid and glycolytic pathways, associated with a reduction in cell proliferation via induced cell cycle arrest. Interestingly, JAS239 also impaired GBM invasion. However, effects from JAS239 were variable depending on the cell line, reflecting the inherent heterogeneity of GBMs. Conclusions: Our findings indicate that JAS239 and hypoxia can deregulate cellular metabolism, inhibit cell proliferation, and alter cell invasion. These results may be useful for designing new therapeutic strategies based on ChoK inhibition, which can act on multiple pro-tumorigenic features. Full article

We have previously shown that the hepatitis C virus (HCV) E1E2 envelope glycoprotein can regulate HIV-1 long-terminal repeat (LTR) activity through disruption to NF-κB activation. This response is associated with upregulation of the endoplasmic reticulum (ER) stress response pathway. Here, we demonstrate that the SARS-CoV-2 S, M, and E but not the N structural protein can perform similar downmodulation of HIV-1 LTR activation, and in a dose-dependent manner, in both HEK293 and lung BEAS-2B cell lines. This effect is highest with the SARS-CoV-2 Wuhan S strain and decreases over time for the subsequent emerging variants of concern (VOC), with Omicron providing the weakest effect. We developed pseudo-typed viral particle (PVP) viral tools that allowed for the generation of cell lines constitutively expressing the four SARS-CoV-2 structural proteins and utilising the VSV-g envelope protein to deliver the integrated gene construct. Differential gene expression analysis (DGEA) was performed on cells expressing S, E, M, or N to determine cell activation status. Gene expression differences were found in a number of interferon-stimulated genes (ISGs), including IF16, IFIT1, IFIT2, and ISG15, as well as for a number of heat shock protein (HSP) genes, including HSPH1, HSPA6, and HSPBP1, with all four SARS-CoV-2 structural proteins. There were also differences observed in expression patterns of transcription factors, with both SP1 and MAVS upregulated in the presence of S, M, and E but not the N protein. Collectively, the results indicate that gene expression patterns associated with ER stress pathways can be activated by SARS-CoV-2 envelope glycoprotein expression. The results suggest the SARS-CoV-2 infection can modulate an array of cell pathways, resulting in disruption to NF-κB signalling, hence providing alterations to multiple physiological responses of SARS-CoV-2-infected cells. Full article

Background: Urinary tract infections (UTIs) are among the most prevalent bacterial infections. With many patients turning to the Internet as a health resource, this study seeks to understand public engagement with online resources concerning recurrent UTIs (rUTIs), assess their reliability, and identify common questions/concerns about rUTIs. Methods: Social media analysis tool BuzzSumo was used to calculate online engagement (likes, shares, comments, views) with information on rUTIs. The reliability of highly engaged articles was evaluated using the DISCERN questionnaire. Highly engaged categories were entered as keywords in Google Trends to quantify search interest. To categorize patient-specific concerns, a database containing anonymously collected patient questions about rUTIs was created. Results: BuzzSumo revealed four search categories: general information, treatment, causes, and herbal remedies. DISCERN scores indicated moderate reliability overall; however, the “herbal remedies” category demonstrated poor reliability despite high engagement. Google Trends analysis highlighted “causes” and “treatment” searches as highest in relative interest. The 10 most popular categories of concern were antibiotics, microbiome, vaccines, prevention, pelvic pain, sex, testing, symptoms, diet/lifestyle, and hormones. Conclusions: People living with rUTIs demonstrate key concerns and often seek information online, yet articles with high engagement often contain unreliable information. Healthcare professionals may consider counteracting misinformation by providing evidence-based information online about rUTIs. Full article