Search Results (25,297)

Establishing a safe exposure level from epidemiological studies while providing direct hazard characterization in humans often faces uncertainty in causality, especially cross-sectional data. With advances in molecular epidemiology, it is reasonable to integrate identified intermediate biomarkers into health risk assessment. In this study, by considering the mediation of the oxidative stress marker malondialdehyde (MDA), we explored the exposure threshold of melamine on the early renal injury marker N-acetyl-β-D glucosaminidase (NAG). The benchmark dose (BMD) was derived from model averaging of the composite direct effect of melamine exposure and the indirect effect through the mediation of MDA on NAG levels. As illustrative examples, we analyzed 309 adult patients with calcium urolithiasis and 80 occupational workers for the corresponding exposure thresholds. The derived threshold was subpopulation-dependent, with the one-sided lower bound BMDL₁₀ for the patients with urolithiasis with (without) the mediator MDA for the patients with kidney stones and the occupational workers being 0.88 (0.96) $\mathsf{\mu }\mathrm{g}/\mathrm{k}\mathrm{g\_b}\mathrm{w}/\mathrm{d}\mathrm{a}\mathrm{y}$ and 22.82 (18.09) $\mathsf{\mu }\mathrm{g}/\mathrm{k}\mathrm{g\_b}\mathrm{w}/\mathrm{d}\mathrm{a}\mathrm{y}$, respectively. The derived threshold levels, considering the oxidative stress marker MDA, were consistent with those without adjusting for the mediation effect. However, the study outcomes were further supported by the suggested mechanism pathway. The threshold for the patients with urolithiasis was up to two orders lower than the current tolerable daily intake level of 200 $\mathsf{\mu }\mathrm{g}/\mathrm{k}\mathrm{g\_b}\mathrm{w}/\mathrm{d}\mathrm{a}\mathrm{y}$ recommended by the WHO (EFSA). Full article

Background: The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to viral entry and can cause cardiac injuries. Toll-like receptor 4 (TLR4) and NOD-, LPR-, and pyrin-domain-containing 3 (NLRP3) inflammasome are critical immune system components implicated in cardiac fibrosis. The spike proteins activate NLRP3 inflammasome through TLR4 or angiotensin-converting enzyme 2 (ACE2) receptors, damaging various organs. However, the role of spike proteins in cardiac fibrosis in humans and the interactions of spike proteins with NLRP3 inflammasomes and TLR4 remain poorly understood. Methods: We utilized scratch assays, Western blotting, and immunofluorescence to evaluate the migration, fibrosis signaling, mitochondrial calcium levels, reactive oxygen species (ROS) production, and cell morphology of cultured human cardiac fibroblasts (CFs) treated with spike (S1) proteins for 24 h with or without an anti-ACE2 neutralizing antibody, a TLR4 blocker, or an NLRP3 inhibitor. Results: S1 protein enhanced CFs migration and the expressions of collagen 1, α-smooth muscle actin, transforming growth factor β1 (TGF-β1), phosphorylated SMAD2/3, interleukin 1β (IL-1β), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). S1 increased ROS production but did not affect mitochondrial calcium content and cell morphology. Treatment with an anti-ACE2 neutralizing antibody attenuated the effects of S1 on collagen 1 and TGF-β1 expressions. Moreover, NLRP3 (MCC950) and NF-kB inhibitors, but not the TLR4 inhibitor TAK-242, prevented the S1-enhanced CFs migration and overexpression of collagen 1, TGF-β1, and IL-1β. Conclusion: S1 activates human CFs by priming NLRP3 inflammasomes through NF-κB signaling in an ACE2-dependent manner. Full article

Aggressive pharmacokinetic (PK)/pharmacodynamic (PD) targets have shown better microbiological eradication rates and a lower propensity to develop resistant strains than conservative targets. We investigated whether meropenem blood levels, including aggressive PK/PD, were acceptable in terms of efficacy and safety using a meropenem regimen of 1 g infusion every 8 h over 3 h in patients undergoing continuous renal replacement therapy (CRRT) for septic acute kidney injury (AKI). Aggressive PK/PD targets were defined as the percentage of time that the free concentration (%fT) > 4 × minimal inhibitory concentration (MIC), the toxicity threshold was defined as a trough concentration >45 mg/L, and the percentage of achievement at each MIC was evaluated. The 100% fT > 4 × MIC for a pathogen with an MIC of 0.5 mg/L was 89%, and that for a pathogen with an MIC of 2 mg/L was 56%. The mean steady-state trough concentration of meropenem was 11.9 ± 9.0 mg/L and the maximum steady-state trough concentration was 29.2 mg/L. Simulations using Bayesian estimation showed the probability of achieving 100% fT > 4 × MIC for up to an MIC of 2 mg/L for the administered administration via continuous infusion at 3 g/24 h. We found that an aggressive PK/PD could be achieved up to an MIC of 0.5 mg/L with a meropenem regimen of 1 g infused every 8 h over 3 h for patients receiving CRRT for septic AKI. In addition, the risk of reaching the toxicity range with this regimen is low. In addition, if the MIC was 1–2 mg/L, the simulation results indicated that aggressive PK/PD can be achieved by continuous infusion at 3 g/24 h without increasing the daily dose. Full article

Recent studies have highlighted the therapeutic potential of stem cells for various diseases. However, unlike other tissues, brain tissue has a specific structure, consisting of synapses. These synapses not only transmit but also process and refine information. Therefore, synaptic regeneration plays a key role in therapy of neurodegenerative disorders. Neurexins (NRXNs) and neuroligins (NLGNs) are synaptic cell adhesion molecules that connect pre- and postsynaptic neurons at synapses, mediate trans-synaptic signaling, and shape neural network properties by specifying synaptic functions. In this study, we investigated the synaptic regeneration effect of human neural stem cells (NSCs) overexpressing NRXNs (F3.NRXN) and NLGNs (F3.NLGN) in a spinal cord injury model. Overexpression of NRXNs and NLGNs in the neural stem cells upregulated the expression of synaptophysin, PSD95, VAMP2, and synapsin, which are synaptic markers. The BMS scores indicated that the transplantation of F3.NRXN and F3.NLGN enhanced the recovery of locomotor function in adult rodents following spinal cord injury. Transplanted F3.NRXN and F3.NLGN differentiated into neurons and formed a synapse with the host cells in the spinal cord injury mouse model. In addition, F3.NRXN and F3.NLGN cells restored growth factors (GFs) and neurotrophic factors (NFs) and induced the proliferation of host cells. This study suggested that NSCs overexpressing NRXNs and NLGNs could be candidates for cell therapy in spinal cord injuries by facilitating synaptic regeneration. Full article

Xanthoxylin, a bioactive phenolic compound extracted from the traditional herbal medicine Penthorum Chinense Pursh, is renowned for its anti-inflammatory effects. While previous studies have highlighted the anti-inflammatory and antioxidant properties of Xanthoxylin, its precise mechanisms, particularly concerning immune response and organ protection, remain underexplored. This study aimed to elucidate the effects of Xanthoxylin on inflammation and associated signaling pathways in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced via intratracheal administration of LPS, followed by intraperitoneal injections of Xanthoxylin at doses of 1, 2.5, 5, and 10 mg/kg, administered 30 min post-LPS exposure. Lung tissues were harvested for analysis 6 h after LPS challenge. Xanthoxylin treatment significantly mitigated lung tissue damage, pathological alterations, immune cell infiltration, and the production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Additionally, Xanthoxylin modulated the expression of key proteins in the protein kinase B (Akt)/hypoxia-inducible factor 1-alpha (HIF-1α)/nuclear factor-kappa B (NF-κB) signaling pathway, as well as nuclear factor erythroid 2-related factor 2 (Nrf2) and oxidative markers such as superoxide dismutase (SOD) and malondialdehyde (MDA) in the context of LPS-induced injury. This study demonstrates that Xanthoxylin exerts protective and anti-inflammatory effects by down-regulating and inhibiting the Akt/HIF-1α/NF-κB pathways, suggesting its potential as a therapeutic target for the prevention and treatment of ALI or acute respiratory distress syndrome (ARDS). Full article

This study examined access to water, food, and nutrition programs among marginalized communities in Southern Punjab, Pakistan, and their effects on nutrition. Both qualitative and quantitative data were used in this study. We held two focus group discussions (one with 10 males and one with 10 females) and conducted in-depth interviews with 15 key stakeholders, including 20 mothers and 10 healthcare providers. A survey of 235 households was carried out to evaluate water and food insecurity, with the data analyzed using Wilcoxon’s rank-sum test, t-test, and Pearson’s chi-square test. The results revealed that 90% of households experienced moderate-to-severe water insecurity, and 73% faced moderate-to-severe food insecurity. Household water and food insecurity were positively correlated with each other (correlation coefficient = 0.205; p = 0.004). Greater household water (p = 0.028) and food insecurity (p < 0.001) were both associated with higher perceived stress. Furthermore, lower socioeconomic status was strongly related to higher levels of water (p < 0.001) and food insecurity (p < 0.001). Qualitative findings highlight the impact of colonial and post-colonial policies, which have resulted in water injustice, supply issues, and corruption in water administration. Women face significant challenges in fetching water, including stigma, harassment, and gender vulnerabilities, leading to conflicts and injuries. Water scarcity and poor quality adversely affect sanitation, hygiene, and breastfeeding practices among lactating mothers. Structural adjustment policies have exacerbated inflation and reduced purchasing power. Respondents reported a widespread lack of dietary diversity and food quality. Nutrition programs face obstacles such as the exclusion of people with low social and cultural capital, underfunding, weak monitoring, health sector corruption, and the influence of formula milk companies allied with the medical community and bureaucracy. This study concludes that addressing the macro-political and economic causes of undernutrition should be prioritized to improve nutrition security in Pakistan. Full article

Osteoarthritis (OA) is a prevalent, degenerative joint disease, with knee OA being particularly common and impactful. This systematic review and meta-analysis aimed to assess the efficacy of eggshell membrane (ESM) supplementation in improving joint functionality and reducing pain in individuals with knee OA. A comprehensive search was conducted across PubMed, Scopus, Web of Science, and Cochrane Database up to July 2024, following PRISMA guidelines. Seven randomized controlled trials (RCTs) met the inclusion criteria, with five included in the meta-analysis. The studies compared ESM to a placebo, evaluating outcomes based on assessment tools such as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Visual Analogue Scale (VAS), and Knee Injury and Osteoarthritis Outcome Score (KOOS). Results indicated that ESM significantly reduced pain and improved functionality, with notable improvements in total WOMAC score (effect size −0.34; 95% CI: −0.56 to −0.13; p < 0.001) and pain subscale (SMD −0.23; 95% CI: −0.42 to −0.04; p < 0.02). The findings support ESM as a promising adjunctive treatment for knee OA, offering a safe, natural supplement to enhance quality of life. Further high-quality RCTs are needed to confirm these results and explore the long-term effects and mechanisms of ESM. Full article

Reconstructive and regenerative medicine are critical disciplines dedicated to restoring tissues and organs affected by injury, disease, or congenital anomalies. These fields rely on biomaterials like synthetic polymers, metals, ceramics, and biological tissues to create substitutes that integrate seamlessly with the body. Personalized implants and prosthetics, designed using advanced imaging and computer-assisted techniques, ensure optimal functionality and fit. Regenerative medicine focuses on stimulating natural healing mechanisms through cellular therapies and biomaterial scaffolds, enhancing tissue regeneration. In bone repair, addressing defects requires advanced solutions such as bone grafts, essential in medical and dental practices worldwide. Bovine bone scaffolds offer advantages over autogenous grafts, reducing surgical risks and costs. Incorporating antimicrobial properties into bone substitutes, particularly with metals like zinc, copper, and silver, shows promise in preventing infections associated with graft procedures. Silver nanoparticles exhibit robust antimicrobial efficacy, while zinc nanoparticles aid in infection prevention and support bone healing; 3D printing technology facilitates the production of customized implants and scaffolds, revolutionizing treatment approaches across medical disciplines. In this review, we discuss the primary biomaterials and their association with antimicrobial agents. Full article

Incident clearance time (ICT) is impacted by several factors, including crash injury severity. The strategy of most transportation agencies is to allocate more resources and respond promptly when injuries are reported. Such a strategy should result in faster clearance of incidents, given the resources used. However, injury crashes by nature require extra time to attend to and move crash victims while restoring the highway to its capacity. This usually leads to longer incident clearance duration, despite the higher amount of resources used. This finding has been confirmed by previous studies. The implication is that the relationship between ICT and injury severity is complex as well as correlated with the possible presence of unobserved heterogeneity. This study investigated the impact of injury severity on ICT on Louisiana’s urban interstates by adopting a random-parameter bivariate modeling framework that accounts for potential correlation between injury severity and ICT, while also investigating unobserved heterogeneity in the data. The results suggest that there is a correlation between injury severity and ICT. Importantly, it was found that injury severity does not impact ICT in only one way, as suggested by most previous studies. Also, some shared factors were found to impact both injury severity and ICT. These are young drivers, truck and bus crashes, and crashes that occur during daylight. The findings from this study can contribute to an improvement in safety on Louisiana’s interstates while furthering the state’s mobility goals. Full article

Background: Fractures of the distal radius are among the most common bone injuries, and their frequency is constantly increasing, leading to an elevated need for subsequent rehabilitation. This growing need has led to the emergence of online content aimed at providing guidance on rehabilitation. Nonetheless, unreviewed online content raises concerns about its reliability; therefore, the objective of this study was to evaluate the quality, reliability, and comprehensiveness of online videos concerning rehabilitation following a distal radius fracture. Methods: A total of 240 YouTube videos were screened, identifying 33 videos that met the inclusion criteria. These selected videos were evaluated by five independent experts from various professional groups, using the Global Quality Scale, the DISCERN reliability tool, and the JAMA Benchmark Score, as well as a structured set of questions to assess their comprehensiveness and coverage of pertinent aspects. Results: The observers’ assessment of the Global Quality Scale exhibited a broad spectrum of viewpoints, indicating considerable variability in evaluations. In most cases, therapy aligned well with the diagnosed condition, and most raters deemed the indication and instruction in the videos acceptable. A proportion of 87% of the videos was deemed suitable for home training by at least three raters. However, a concerning trend emerged, as potential risks and pitfalls were scarcely addressed. Conclusions: The moderate overall quality of the videos and the divergence in expert opinions highlight the need for a regulatory authority to ensure adherence to guidelines and maintain high-quality content. Additionally, our results raise concerns about the applicability of established assessment tools in this context. Full article

Soccer referees are at risk of injury due to the physical demands of their role. This study evaluated the impact of the 24-week FIFA 11+ Referees training program on the quality of change of direction (COD) maneuvers in elite soccer referees. Eighty-one male referees were randomly assigned to either the 11+ referee group (n = 40) or a control group (n = 41). The intervention group replaced their usual warm-up routines with the FIFA 11+ program, while the control group continued their standard training. Both groups were assessed using the cutting movement assessment score (CMAS) before and after the intervention. The results demonstrated significant improvements in CMAS scores for the 11+ referee group at all tested angles (45°, 70°, and 90°), with the most notable improvements observed at 90° angles. These findings indicate that the FIFA 11+ Referees program enhances COD maneuver quality, which is critical for injury prevention. Implementing this program may therefore improve movement quality and reduce injury risks among soccer referees. Further research should explore the program’s long-term efficacy and applicability across different populations and injury factors. Full article

Introduction: Accidental caustic burns of the esophagus in children represent a significant global health challenge, often necessitating esophageal reconstruction. The aim of this study is to compare the efficacy and morbidity related to esophagus replacement with colonic and gastric tube transplants in a pediatric population followed for caustic stenosis. Methods: This retrospective study was conducted at a tertiary pediatric surgery unit for children treated from January 1989 to December 2022. We compared colonic and gastric tube esophageal replacement. Short term (within 30 days) and mid-term outcomes and complications were reviewed. Statistical evaluation was considered using a Chi-square test for categorical data analysis. Results: A total of 124 children with caustic esophageal burns were included. Among them, 23 (18.5%) had a gastric tube transplant for esophagus replacement and 101 (81.5%) a colonic transplant. During surgical intervention, we found a significantly higher risk of complications when using a colonic transplant (34%, p < 0.001). There was no significant statistical difference in postoperative short term and mid-term complications between the two techniques. Twenty-six (26%) of the children required a reoperation, with a higher risk in the gastric tube transplant group (p < 0.001). Endoscopic dilatation after surgery was also performed on a higher number of children who had received a gastric tube transplant (p = 0.005). Overall, 97.6% recovered full normal oral feeding. Conclusions: We found that colonic and gastric tube replacement are both good options for pediatric esophageal replacement after a caustic injury and show effectiveness over time. Gastric tube transplants carried a slightly higher risk of reoperations and a higher number of dilatations post-surgery. However, our groups are not really comparable, due to the much higher number of colonic transplants. Both surgical options have to be considered during surgery, and the choice depends on the anatomy of the patient. Our future research will focus on assessing long term quality of life and the potential risk of neoplastic complications. Full article

Early-age masonry structures require temporary support until they achieve full strength. Nevertheless, there is a limited understanding of the properties of freshly laid masonry and the design of newly constructed, unsupported masonry walls. This situation has led to numerous instances of structural damage and injuries to workers, prompting conservative construction bracing techniques. This paper presents comprehensive experimental studies on early-age mortar cubes and masonry prisms to assess the effects of curing time on the compressive properties of masonry assemblies, which is necessary for the design of temporary bracing. The change in modulus of elasticity and compressive strength of masonry prisms and mortar with curing time has been experimentally assessed. The results indicate that the compressive strength of freshly cast mortar cubes is relatively insignificant until approximately 24 h after construction, when it was observed to increase logarithmically. Regarding the performance perspective, the compressive strength of early-age masonry prisms is inconsiderable, less than 15% of full strength during the first day after construction. By contrast, regarding the life safety perspective, the compressive properties of a mortar joint within a masonry assembly (which is of more practical interest) appear to have no effect on the failure strength of concrete masonry prisms over the range of ages tested. The failure modes of the early-age mortar cubes and early-age masonry prism samples depend on the curing time, and different failure modes occurred before and after the start of the primary hydration phase, which is 20.8 h after construction. It is anticipated that the proposed research will provide valuable material properties leading to efficient design of control devices (e.g., temporary bracing) and improved guidelines for concrete-block masonry construction. Full article

Since the role of the menisci in knee stability, proprioception, and homeostasis has been well established, significant efforts have been made to repair meniscal tears, resulting in excellent clinical outcomes and a reduction in the progression of knee osteoarthritis (OA). However, varying failure rates have been reported, raising questions regarding the healing potential in cases of complex injuries, poorly vascularized and degenerated areas, and generally in the presence of unfavorable biological characteristics. Therefore, over the last few decades, different strategies have been described to increase the chances of meniscal healing. Biological augmentation of meniscal repair through various techniques represents a safe and effective strategy with proven clinical benefits. This approach could reduce the failure rate and expand the indications for meniscal repair. In the present study, we thoroughly reviewed the available evidence on meniscal repair surgery and summarized the main techniques that can be employed to enhance the biological healing potential of a meniscal lesion. Our aim was to provide an overview of the state of the art on meniscal repair and suggest the best techniques to reduce their failure rate. Full article

Mesenchymal stromal cells (MSCs) can be isolated from various tissues of healthy or patient donors to be retransplanted in cell therapies. Because the number of MSCs obtained from biopsies is typically too low for direct clinical application, MSC expansion in cell culture is required. However, ex vivo amplification often reduces the desired MSC regenerative potential and enhances undesired traits, such as activation into fibrogenic myofibroblasts. Transiently activated myofibroblasts restore tissue integrity after organ injury by producing and contracting extracellular matrix into scar tissue. In contrast, persistent myofibroblasts cause excessive scarring—called fibrosis—that destroys organ function. In this review, we focus on the relevance and molecular mechanisms of myofibroblast activation upon contact with stiff cell culture plastic or recipient scar tissue, such as hypertrophic scars of large skin burns. We discuss cell mechanoperception mechanisms such as integrins and stretch-activated channels, mechanotransduction through the contractile actin cytoskeleton, and conversion of mechanical signals into transcriptional programs via mechanosensitive co-transcription factors, such as YAP, TAZ, and MRTF. We further elaborate how prolonged mechanical stress can create persistent myofibroblast memory by direct mechanotransduction to the nucleus that can evoke lasting epigenetic modifications at the DNA level, such as histone methylation and acetylation. We conclude by projecting how cell culture mechanics can be modulated to generate MSCs, which epigenetically protected against myofibroblast activation and transport desired regeneration potential to the recipient tissue environment in clinical therapies. Full article