Search Results (8,258)

Background: Cefazolin is being increasingly used to treat central nervous system infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) to mitigate the side effects of existing anti-Staphylococcal drugs. This study aims to develop a cerebrospinal pharmacokinetic (PK) model to predict the cefazolin concentration in cerebrospinal fluid (CSF) and to individualize the dosing regimen for MSSA meningitis. Methods: A cerebrospinal PK model was developed based on the existing literature and used to estimate the probability of attaining PK/ pharmacodynamic (PD) targets. These targets were set as 100% time above the minimum inhibitory concentration (T > MIC) in CSF. The cerebrospinal PK/PD breakpoint was defined as the highest MIC at which target attainment probability in CSF was ≥90%. The mean CSF/serum ratio estimated from the literature was 0.0525 after a dose of 1–3 g (sampling time: 1–9 h after dose) in adult patients with suspected meningitis. This ratio was incorporated into this PK model based on a hybrid approach. Results: For patients with creatinine clearance (CL_cr) = 90 mL/min, the cerebrospinal PK/PD breakpoint MICs of continuous infusion regimens (6–12 g/day) reached 0.5 µg/mL, which can inhibit the growth of 90% of the MSSA population (MIC₉₀). Furthermore, for patients with renal dysfunction (CL_cr = 30 mL/min), a dose reduction (4 g/day) may be required to avoid excessive drug exposure. Conclusions: High-dose continuous infusion of cefazolin may be appropriate for MSSA meningitis in patients with normal renal function, while dose adjustments are needed for those with renal impairment. Full article

Triple-negative breast cancer (TNBC) accounts for about 10–15% of all breast cancers and is an aggressive disease with a poor prognosis. There is currently no standard treatment regimen for TNBC patients; thus, chemotherapy remains the main treatment. Anthracycline- and taxane-based regimens are the most widely used in a clinical setting, either alone or in combination with other chemotherapeutic agents, including poly (ADP-ribose) polymerase (PARP) inhibitors and platinum drugs. Platinum drugs have been used particularly in patients with BRCA1-mutated TNBC. Preclinical and clinical trials revealed that the response to PARP inhibition was directly correlated to the sensitivity to platinum chemotherapies. Inhibition of PARP enzymes has been shown to specifically target BRCA1 dysfunctional cells. Therefore, targeting breast cancer cells that possess genetic alterations that are absent in normal cells could be attained by the exploitation of synthetic lethality for the discovery of other candidate metals, i.e., ruthenium-derived compounds, as next-generation drugs for the treatment of TNBC. This prospective approach provides new insight into alternative treatments for breast cancers with BRCA1-associated TNBC. Full article

Background/Objectives: Late diagnosis and inefficient treatment regimens lead to poor prognosis, with a low 5-year survival rate for both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). New targeted therapeutic agents can be developed and introduced only by first discovering new driver oncogenes and with a thorough investigation of the known driver genes. The aim of the current study is to investigate the prevalence of alterations in the eight most frequently altered genes in lung cancer—BRAF, EGFR, KRAS, ALK, ROS1, HER2, PD-L1 and PIK3CA. Methods: Real-time polymerase chain reaction (RT-PCR) was used to detect KRAS and EGFR mutations, multiplex PCR and microarray hybridization for KRAS/BRAF/PIK3CA mutations. Immunohistochemical analysis was performed for the detection of ALK, HER2/NEU, ROS-1 and PD-L1 alterations. Results: Overall, 221/603 patients (36.65%) had at least one genetic alteration, of which 22 patients (3.65%) had two genetic alterations and two patients had more than two genetic alterations. Additionally, 50 patients were identified with one or more KRAS mutations (8.29%), 45 patients with EGFR mutations (7.46%), and 1.82% with PIK3CA mutations and 0.66% with BRAF mutations. Furthermore, 50% of the co-occurring alterations were either on KRAS and PIK3CA genes (3/6), on KRAS and BRAF genes (2/6, 33.33%) or on EGFR and PIK3CA genes (1/6, 16.67%), and 10.45% of the patients exhibited PD-L1 overexpression, 5.31% ALK rearrangements, and 2.36% HER2/NEU expression, with no ROS-1 rearrangements detected. Conclusions: Comprehensive testing for somatic alterations in EGFR, BRAF, KRAS, and PIK3CA is significant in guiding therapeutic decisions in lung cancer management. Such testing should be routinely conducted to establish a thorough genetic profile of lung cancers in a manner that is both time-efficient and cost-effective. Full article

Background: Optimizing training load and recovery is crucial for achieving peak performance in competitive wrestling, a sport characterized by high physical, technical, and psychological demands. Methods: This study compared the effects of two different training programs—one emphasizing high-intensity interval training (HIIT) sessions and the other based on traditional volume-oriented training—on both competitive performance and autonomic regulation measured by heart rate variability (HRV). A total of 24 elite wrestlers were divided into two equal groups, each following a different weekly training regimen over a 3-month period. HRV was recorded using a wearable 3-channel ECG Holter before training, immediately after training, and during recovery phases (up to 2 h post-exercise). HRV parameters were analyzed to assess training-induced stress and recovery status. Competitive performance was evaluated using official national championship scores and ranking positions. Results: Both training programs improved competitive performance, the HIIT-based regimen induced greater short-term suppression of parasympathetic activity (RMSSD: −32% vs. −14%; HF power: −40% vs. −18%) and increased sympathetic dominance (LF/HF: +56% vs. +22%) after training. Wrestlers in the HIIT group achieved a mean competition score of 17.92 ± 4.50 points, compared to 15.08 ± 6.26 points in the volume-oriented group. These acute autonomic shifts may provide a higher readiness for intense and explosive actions, which is advantageous in short and dynamic matches. In contrast, the volume-oriented program induced smaller acute autonomic changes but showed a slower recovery to baseline. Conclusions: These findings suggest that HRV-derived measures can serve as sensitive indicators of training load tolerance, recovery capacity, and stress susceptibility in combat sports athletes. This study highlights the value of integrating HRV monitoring into the periodization of combat training to individualize the load, prevent overtraining, and optimize performance outcomes. Full article

Periodontitis is a chronic oral inflammatory disease whose treatment is often hindered by poor drug retention, prolonged therapeutic regimens, and the rise of antibiotic resistance. In this study, we developed a Hydrogel@ZIF-8@metronidazole (Hydrogel@ZIF-8@MNZ) nanocomposite dressing for targeted, sustained, and in situ antimicrobial therapy. This system integrates ZIF-8, a pH-responsive metal–organic framework, with the antimicrobial agent metronidazole (MNZ), encapsulated within a crosslinked hydrogel matrix to enhance stability and retention in the oral environment. Drug release studies demonstrated that MNZ release was significantly accelerated under acidic conditions (pH 5.0), mimicking the periodontal microenvironment. The Hydrogel@ZIF-8 composite achieved a maximum MNZ adsorption capacity of 132.45 mg·g⁻¹, with a spontaneous and exothermic uptake process best described by a pseudo-second-order kinetic model, suggesting chemisorption as the dominant mechanism. The nanoplatform exhibited strong pH-responsive behavior, with enhanced drug release under acidic conditions and potent dose-dependent bactericidal activity against Fusobacterium nucleatum (Fn). At the highest tested concentration, bacterial survival was reduced to approximately 30%, with extensive membrane disruption observed through live/dead fluorescence microscopy. In summary, the stimuli-responsive Hydrogel@ZIF-8@MNZ nanocomposite offers an intelligent and effective therapeutic strategy for periodontitis. By tailoring its action to the disease microenvironment, this platform enables sustained and localized antibacterial therapy, addressing major challenges in the treatment of chronic oral infections. Full article

Background/Objectives: High-frequency ultrasonography (HFUS) has gained increasing attention in dermatology as a non-invasive imaging technique capable of visualizing cutaneous structures with high resolution. In cutaneous T-cell lymphomas (CTCL), including mycosis fungoides (MF)/Sézary syndrome (SS), HFUS may provide an objective method for assessing disease activity and monitoring treatment response. This study aimed to evaluate the clinical utility of HFUS in detecting therapy-induced changes in subepidermal low-echogenic band (SLEB) thickness. Methods: We conducted a prospective, single-center study between May 2021 and May 2025. Thirty-three patients with histologically confirmed MF (n = 31) or SS (n = 2) underwent HFUS at baseline and after 4–8 weeks of treatment. SLEB thickness was measured before (E1) and after early treatment (E2). Patients received systemic agents, phototherapy, or topical regimens. Statistical analysis included mixed-model ANOVA with repeated measures to assess SLEB changes, and post hoc tests were applied to explore the influence of therapy type, age, and gender. Results: Among 31 evaluable patients with MF, HFUS revealed a significant reduction in SLEB thickness after treatment (0.90 ± 1.10 mm vs. 0.69 ± 0.89 mm; F(1,29) = 8.88, p = 0.006, η² = 0.23). The type of early therapy (systemic vs. topical) did not significantly affect outcomes (p = 0.452). Age emerged as a relevant factor: patients ≥ 66 years exhibited higher baseline SLEB values and a significant reduction post-treatment (p < 0.001), whereas no comparable effect was observed in younger patients. Gender did not significantly influence SLEB changes. Conclusions: HFUS is a sensitive and clinically applicable imaging tool for monitoring treatment response in MF/SS. Reductions in SLEB thickness were observed across therapeutic modalities and aligned with early clinical improvement. HFUS may serve as a valuable adjunct to standard clinical and histopathological evaluation in the routine management of MF/SS. Full article

Background: hearing loss represents, today, one of the most significant health problems affecting the world’s population. This clinical condition, particularly manifest in adulthood, can arise or be aggravated by both the presence of specific pathologies and by taking multiple classes of drugs at the same time. Methods: to understand this relationship, the present non-interventional observational study aimed to investigate the relationship between worsening hearing abilities in 1651 patients aged between 18 and 99 years. In particular, the thorough history of patients allowed us to evaluate the pathological profiles, pharmacological profiles, and therapeutic regimens adopted. This allowed us to evaluate its association with self-reported hearing loss, assessed through the administration of the HHIE-S-It questionnaire. Furthermore, given the presence of multimorbidity, the possible correlation between self-reported hearing loss and the specific classes of drugs, categorized using the Anatomical Therapeutic Classification (ATC) system, was evaluated. Results: the results highlighted how patients taking drugs, both in mono- and polytherapy regimens, had higher hearing deficits than patients not taking drugs. Furthermore, an apparent dose–response effect, in which the risk of moderate to severe impairment progressively increased with the number of drugs taken, was also observed. Different classes of drugs, particularly those used for the treatment of diseases of the cardiovascular system, as well as drugs for acid-related disorders, were significantly linked to an increased risk of perceived hearing impairment. On the contrary, agents belonging to the antidiabetic category have proven to be drugs capable of offering a potential protective effect. Conclusion: this study highlighted how both the number of drugs taken and some specific categories of drugs can contribute to perceived hearing impairment. While this evidence highlights the importance of integrating audiological evaluation into the management of patients in polypharmacy, the cross-sectional nature of the design precludes the inference of causality. This evidence still favors safer and more personalized therapeutic strategies. Full article

Nutritional factors play a crucial role in many gynecological disorders, particularly those influenced by estrogen. Uterine fibroids are benign tumors that affect a large proportion of women of reproductive age, especially between 30 and 40 years. These lesions may cause significant symptoms, including pelvic pain, heavy menstrual bleeding, and infertility. In younger women, the onset of fibroids is often associated with familial and genetic predisposition, whereas in adulthood, hormonal influences linked to environmental factors and states of exogenous or endogenous hyperestrogenism are more frequently observed. In both contexts, supportive management through an appropriate diet may provide clinical benefit. Although the precise pathogenesis remains incompletely understood, hormonal, genetic, and environmental components—particularly hyperestrogenism—are considered key contributors to fibroid development. Current evidence suggests that consumption of saturated fats, particularly from red meat and full-fat dairy, may raise circulating estrogen concentrations and contribute to the development of fibroids. In contrast, diets abundant in fiber, fruits, and vegetables appear to exert a protective effect, potentially lowering fibroid risk. Obesity, through increased aromatization and consequent estrogen production, also represents an established risk factor. This narrative review aims to explore the role of nutritional determinants in the onset and progression of uterine fibroids, with a specific focus on the impact of individual nutrients, foods, and dietary patterns on clinical outcomes. Particular emphasis is placed on obesity and macronutrient composition (e.g., high-fat versus high-fiber dietary regimens) as potential modulators of circulating estrogen levels and, consequently, fibroid growth dynamics. Furthermore, the potential of nutritional strategies as complementary therapeutic approaches, capable of integrating established clinical practices, is examined. Full article

Background/Objectives: Although neoadjuvant chemotherapy (NAC) is not universally recommended for resectable pancreatic ductal adenocarcinoma (PDAC), NAC with gemcitabine plus S-1 (NAC-GS) has become a commonly used regimen for resectable PDAC in Japan. Furthermore, the impact of achieving textbook outcomes (TO) in patients receiving NAC-GS remains unclear. Methods: This retrospective study included 265 patients who were diagnosed with resectable PDAC at our institution between January 2009 and December 2023. Patients were categorized into two groups: the NAC-GS group (n = 81; 2019–2023) and the upfront surgery (UFS) group (n = 164; 2009–2018). After comparing the clinical outcomes between groups, multivariate analyses for survival were performed. Additionally, outcomes stratified by the achievement of the modified TO were analyzed in the NAC-GS group. Results: The completion rate of NAC-GS was 90.1%. Patients in the NAC-GS group exhibited significantly longer survival than those in the UFS group (2-year recurrence-free survival: 61.4% vs. 37.9%, p < 0.01; 2-year overall survival: 83.2% vs. 61.2%, p < 0.01). Multivariate analyses identified lymph node metastasis, NAC-GS induction, and completion of adjuvant chemotherapy as factors significantly associated with improved survival. Moreover, among patients who received NAC-GS, those who achieved modified TO demonstrated significantly longer survival than those who did not. Conclusions: This study demonstrated the clinical efficacy of NAC-GS in patients with resectable PDAC. Induction of NAC-GS was significantly associated with improved long-term outcomes. In multidisciplinary treatment strategies for PDAC, achieving a modified TO may lead to improved survival of patients undergoing NAC-GS. Full article

Background: End-stage renal disease (ESRD) presents a substantial and growing global health challenge, where hemodialysis serves as an essential life-sustaining therapy for countless individuals. Despite its physiological necessity, the demanding treatment regimen can profoundly impact mental health and overall well-being, though gender-specific data and correlates within the Saudi population remain insufficiently explored. Methods: This cross-sectional study aimed to investigate this gap by assessing the prevalence of anxiety and depression, evaluating health-related quality of life (HRQoL), and analyzing associations with gender and treatment duration in a cohort of 250 hemodialysis patients from multiple centers in Madinah, Saudi Arabia. Validated instruments, namely, the Hospital Anxiety and Depression Scale (HADS) and the 36-Item Short Form Health Survey (SF-36), were employed. Results: The findings revealed a significant psychological burden, with 38% of patients exhibiting anxiety and 32% depression, with females disproportionately affected. HRQoL scores were severely diminished across all domains compared to healthy population norms. Furthermore, a longer dialysis vintage demonstrated a significant positive correlation with worsening psychological scores and a decline in physical HRQoL. Conclusions: These results underscore the critical need for a paradigm shift in standard care, advocating for the systematic integration of routine mental health screenings and the development of tailored, gender-sensitive psychosocial interventions to mitigate this considerable burden. Full article

Background: Most immunologically “cold” tumors do not respond durably to checkpoint blockade because tumor antigen (TA) release and presentation are insufficient to prime effective T-cell immunity. While prior work demonstrated synergy between cisplatin and a TLR7/8/9 agonist (CR108) in 4T1 tumors, the underlying mechanism—particularly whether chemotherapy functions as a broad antigen-releasing agent enabling TLR-driven immune amplification—remained undefined. Methods: Using murine models of breast (4T1), melanoma (B16-F10), and colorectal cancer (CT26), we tested multiple chemotherapeutic classes combined with CR108. We quantified intratumoral and systemic soluble TAs, antigen presentation and cross-priming by antigen-presenting cells, tumor-infiltrating lymphocytes, and cytokine production by flow cytometry/ICS. T-cell receptor β (TCRβ) repertoire dynamics in tumor-draining lymph nodes were profiled to assess amplitude and breadth. Tumor microenvironment remodeling was analyzed, and public datasets (e.g., TCGA basal-like breast cancer) were interrogated for expression of genes linked to TA generation/processing and peptide loading. Results: Using cisplatin + CR108 in 4T1 as a benchmark, we demonstrate that diverse chemotherapies—especially platinum agents—broadly increase the repertoire of soluble tumor antigens available for immune recognition. Across regimens, chemotherapy combined with CR108 increased T-cell recognition of candidate TAs and enhanced IFN-γ⁺ CD8⁺ responses, with platinum agents producing the largest expansions in soluble TAs. TCRβ sequencing revealed increased clonal amplitude without loss of repertoire breadth, indicating focused yet diverse antitumor T-cell expansion. Notably, therapeutic efficacy was not predicted by canonical damage-associated molecular pattern (DAMP) signatures but instead correlated with antigen availability and processing capacity. In human basal-like breast cancer, higher expression of genes involved in TA generation and antigen processing/presentation correlated with improved survival. Conclusions: Our findings establish an antigen-centric mechanism underlying chemo–TLR agonist synergy: chemotherapy liberates a broadened repertoire of tumor antigens, which CR108 then leverages via innate immune activation to drive potent, T-cell-mediated antitumor immunity. This framework for rational selection of chemotherapy partners for TLR7/8/9 agonism and support clinical evaluation to convert “cold” tumors into immunologically responsive disease. Full article

Introduction: After total pancreatectomy, patients inevitably develop pancreatogenic diabetes with marked glycemic variability and high risk of malnutrition due to both endocrine and exocrine insufficiency. Weight loss and malnutrition can occur even in those with adequate dietary intake and plausible pancreatic enzyme replacement. We hypothesized that glycemic variability is associated with nutritional decline. Methods: We retrospectively analyzed 14 patients who underwent continuous glucose monitoring (CGM) after total pancreatectomy. Nutritional status was assessed using the Geriatric Nutritional Risk Index (GNRI), and patients were classified into malnutrition-risk progression or nutrition-maintaining groups. Then, we evaluated glycemic indices, dietary intake, anthropometry, and pancreatic enzyme replacement therapy (PERT). Results: Insulin use, PERT dose, and dietary intake were approximately comparable between groups. In contrast, the malnutrition-risk progression group showed significantly higher mean glucose and time above range, and lower time in range (TIR). Importantly, TIR consistently showed an inverse association with malnutrition-risk progression across models adjusted for clinical covariates, including time since pancreatectomy, primary diagnosis, insulin regimen, and pancrelipase dose. These findings indicate that the observed relationship between lower TIR and worsening GNRI was independent of dietary intake and adequacy of enzyme replacement therapy, underscoring TIR as a clinically meaningful indicator of nutritional decline in this population. Conclusions: Hyperglycemia and reduced TIR were significantly associated with worsening GNRI after total pancreatectomy, independent of dietary intake or PERT. CGM-based glycemic metrics may help identify patients at risk of malnutrition and guide postoperative management. Full article

Animal-based measures, such as detecting inflammation in areas like the tail, ears, teats, coronary band, heels and claws (Swine Inflammation and Necrosis Syndrome, SINS), are used to monitor animal health and welfare. When parameters deviate from the established range, these measures enable prompt action to adjust husbandry practices, feeding regimens and management strategies. In addition to environmental factors, genetics have been shown to play a key role in inflammation and necrosis processes, and selection can reduce the severity of the disease. This study examined whether different breeds of AI boar exhibit different signs of SINS and how these signs are associated with SINS in their offspring when they are suckling piglets and weaners. Initially, 286 AI boars of 7 breeds from a German artificial insemination center were evaluated for SINS. The following parameters were assessed: tail base, tail tip, ears, skin, scrotum, coronary bands, heels and claws. Subsequently, 23 Pietrain and Duroc boars were used in combination with a Topigs DL sow line. The progeny of the AI boars was evaluated as suckling and weaned piglets, with the assessment framework encompassing SINS traits. The results revealed significant differences between the breeds and lines, as well as a strong correlation between the SINS phenotypes of the AI boars and the SINS scores of their offspring. The offspring of the 25% most extreme boars exhibited a 17% variation in SINS scores. This association was particularly evident when comparing the boars’ tail base. However, the development of the boars’ heels and claws was found to be significantly influenced by mechanical environmental factors and not associated with the piglets’ scores. These findings imply that heritable, endogenous processes, as proposed for SINS, also visibly impact the phenotype of the AI boar. This study’s fundamental premise suggests that pre-selecting AI boars could mitigate the occurrence of SINS and enhance piglet health and welfare. Full article

Background/Objectives: Children with myelomeningocele (MMC) often experience lower extremity muscular contractures, which can impact their functional mobility. While standing programs have demonstrated benefits for children with other neuromuscular conditions, there is limited evidence on their use in ambulatory children with MMC who have joint deformities. This single-subject design study examined the impact of a home-based standing program on two ambulatory children with MMC, focusing on lower extremity muscle flexibility, functional movement quality, gait velocity, and participation in daily activities. Methods: Two children participated in a multi-phase single-subject (ABABA) withdrawal design beginning with the baseline phase and then alternating between the intervention and withdrawal phases. The intervention consisted of 60-minute standing sessions, five days a week, using a sit-to-stand stander (STSS) with support and supervision from a physical therapist (PT) and the parent. Primary outcomes included goniometric passive range of motion (PROM) and 10-Meter Walk Test (10 MWT). Secondary outcomes included the Pediatric Neuromuscular Recovery Scale (Peds NRS) and the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT). Results: Improvements in hip and knee muscle flexibility were observed during the intervention phases, with some loss during the withdrawal phase. Functional movement quality improved in both children. Gait velocity and participation in daily activity scores remained stable during intervention phases. Parental feedback reflected increased independence and high engagement with the home program. One child discontinued due to a heel injury, highlighting the need for individualized support. Conclusions: Personalized standing programs may improve muscle flexibility and functional movement quality in ambulatory children with MMC. Further research is warranted to determine the optimal dosing regimen, ensure safety, and assess long-term functional outcomes. Full article

Colorectal cancer (CRC) is the second most prevalent cancer globally and remains a significant cause of cancer-related mortality. The limited efficacy and toxicities of conventional therapies underscore the urgent need for novel treatments. Lonidamine (LND), a synthetic indazole-3-carboxylic acid derivative, possesses anticancer properties, yet its clinical use is limited by toxic side effects. Apigenin (AP), a naturally occurring flavonoid present in a variety of fruits and vegetables, has been observed to enhance the efficacy of conventional chemotherapy regimens while mitigating associated side effects. In this study, we explored the potential synergistic anticancer effects and mechanisms of combining LND with AP in colon cancer cell lines MC38 and CT26. The results showed that LND and AP in combination synergistically inhibited the growth of colon cancer cells. In vitro, the combination therapy inhibited cell migration, induced cell cycle arrest in the G2/M phase, and promoted apoptosis by downregulating Bcl-2 and upregulating Bax expression. It disrupted glycolysis by reducing HK2 and GLUT1 expression, resulting in decreased glucose consumption and lactate production. Additionally, our findings suggested that the co-administration led to nucleotide depletion and disrupted NAD⁺ metabolism. The synergistic anticancer effect of LND combined with AP was also validated in MC38 tumor-bearing mice. These findings provide preliminary evidence that the combination of LND and AP may exert beneficial effects against CRC. Full article