Search Results (434)

Phytonutrient-enriched prebiotic mixtures (PEPs), composed of phytonutrients and prebiotics serving as substrates for gut microbes, are recognized for their potential to modulate gut microbial metabolic activity. However, direct evidence of enhanced effects following co-administration with probiotics remains limited. Using a three-phase design integrating ex vivo evaluation and clinical validation, we assessed how PEP components influence microbial responses and whether co-administration with probiotics enhances these effects. PEP components increased acetate, butyrate, total short-chain fatty acids (SCFAs), and lactate, with fiber-rich components showing the strongest effects (all q < 0.0001 relative to negative control). Co-treatment with probiotics further enhanced butyrate and total SCFAs in a dose-dependent manner. In a randomized clinical study, all groups showed increases in fecal metabolites, with the combined group exhibiting the greatest increases in butyrate (+6.0 µmol/g, ~1.5-fold, p < 0.05) and total SCFAs (+22.9 µmol/g, ~1.3-fold, p < 0.05). Participants with constipation-type stool patterns shifted toward normal stool types across all groups. These findings support the utility of combined PEP and probiotic interventions for enhancing microbiome-derived metabolic activity. Full article

Background: Critically ill patients experience rapid muscle wasting during their ICU stay. Ultrasound (US) and bioelectrical impedance analysis (BIA) are widely used to assess muscle mass; however, their accuracy may be affected by fluid balance alterations. This study aimed to compare the reliability of US and BIA in detecting muscle loss under varying fluid balance conditions in ICU patients. Methods: In this prospective observational study, adult ICU patients with an ICU stay of ≥7 days were evaluated on Days 1, 5, and 7. Muscle thickness was measured using US, and phase angle (PhA) using BIA. Cumulative fluid balance, C-reactive protein (CRP), and lactate levels were recorded. Patients were stratified according to cumulative fluid balance. Results: A total of 143 ICU patients were included in the final analysis. US demonstrated a progressive decrease in muscle thickness (−3.54% ± 10.90% from Day 1 to Day 5 and −7.56% ± 11.82% from Day 1 to Day 7 (both p < 0.0001)), whereas BIA showed no significant change in PhA. Positive fluid balance significantly reduced PhA compared with the negative balance group, p < 0.001, whereas no statistically significant effect on US measurements was detected. CRP > 200 mg/L was associated with greater US-detected muscle loss on Day 5, while lactate > 2.5 mmol/L was associated with lower PhA. Conclusions: Ultrasound reliably identified structural muscle wasting in critically ill patients, with no statistically significant effect of fluid balance detected in this cohort. Furthermore, ultrasound measurements were associated with inflammation-related muscle loss. In contrast, BIA was strongly influenced by hydration and perfusion status, limiting its ability to assess true muscle mass loss in the ICU setting. Full article

Background/Objectives: Immune checkpoints are critical regulatory pathways that maintain peripheral tolerance and prevent autoimmunity. Among these, the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis serves as a major inhibitory pathway that terminates T cell responses. While protein-based checkpoint blockade (ICB) targeting this axis has revolutionized clinical cancer therapy, its clinical efficacy is frequently limited by low response rates, immune-related adverse events (irAEs), and the emergence of adaptive resistance. To break through these bottlenecks, genetic interruption has emerged as a high-precision alternative to modulate the PD-1/PD-L1 pathway at the nucleotide level. Methods: A comprehensive systematic review of literature was performed across major databases (PubMed, Web of Science), with a focus on high quality studies published up to 2026. Results: Direct genomic disruption via CRISPR/Cas9 and post-transcriptional silencing through RNA interference can effectively neutralize inhibitory signaling at its source. Recent advances demonstrate that targeting upstream regulatory nodes—including metabolic checkpoints (e.g., lactate metabolism) and biophysical mechanisms (e.g., liquid–liquid phase separation)—provides superior transcriptional control over PD-L1. Furthermore, engineering CAR-T cells with multiplex gene editing (e.g., TCR/B2M/PD-1 knockout) or localized scFv secretion significantly enhances antitumor potency while reducing systemic toxicity. Innovations in organ-targeted lipid nanoparticles and stimuli-responsive biomimetic carriers further address the delivery barriers in solid tumors. Conclusions: Gene therapy provides a high-precision platform for PD-1/PD-L1 modulation, offering a viable strategy to overcome adaptive resistance. Future clinical application depends on the refinement of safer editing tools, such as base editing, and the standardization of intelligent delivery systems to ensure controllable and scalable cancer immunotherapy. Full article

This study evaluated the effects of dietary S-abscisic acid (S-ABA) supplementation on reproductive performance and piglet growth in multiparous sows under commercial farming conditions. A total of 65 Landrace × Yorkshire multiparous sows were allocated to one of three dietary treatments: a basal diet (control); a basal diet supplemented with 1 ppm S-ABA; or a basal diet supplemented with 10 ppm S-ABA. The experimental period was set from weaning through the subsequent weaning (approximately 147 days), encompassing the non-pregnant, gestation, and lactation phases. Reproductive performance parameters, including the number of piglets born, the number of piglets weaned, and piglet body weight at birth and at weaning, were recorded, in addition to general health observations of sows and piglets. 1 ppm S-ABA supplementation significantly increased the number of piglets born compared to control (p < 0.05). Both 1 ppm and 10 ppm S-ABA supplementation resulted in a significantly higher number of piglets weaned (p < 0.05) and average piglet weaning weight (p < 0.01) compared with control, with no apparent differences in measured piglet survival outcomes among treatment groups. No additional benefits were observed when the supplementation level was increased from 1 ppm to 10 ppm. These findings suggest that dietary S-ABA supplementation at low inclusion levels may positively influence sow reproductive performance and piglet growth under practical feeding conditions. Full article

Home healthcare has recently been promoted in response to the increase in vulnerable people, such as elderly patients who can have difficulty accessing clinics and hospitals in Japan. A characteristic specific to home healthcare is that laboratory tests using specimens are conducted by transport from home to laboratory centers or by point-of-care testing at home. In this case, several issues can lead to inaccurate test values. This narrative literature review summarizes issues in the preanalytical process, a critical phase for ensuring the accuracy of laboratory tests. Specimen collection may not always be smooth in the pathological conditions of some elderly patients and/or in the non-clinic/hospital environments. The preservation of specimens, considering prolonged pre-centrifugation time and storage temperature, can alter the values of various analytes, including blood glucose, potassium, and lactate dehydrogenase. In addition, hemolytic phenomenon caused by insufficient specimen collection, vibration during specimen transport, and excessive milking during fingertip blood sampling can also be an issue. Awareness of the preanalytical process in testing specimens is important for obtaining accurate laboratory tests in home healthcare settings. This comprehensively summarized paper will be helpful in securing test quality and patient care. Full article

Background/Objectives: Standard mechanical compression applied during screening mammography is a primary barrier that reduces patient compliance. Current guidelines attempt to standardize compression based solely on the one-dimensional “breast thickness” measured by the device. This study aimed to investigate the effects of three-axis anatomical breast dimensions, applied compression force, menstrual cycle phases, and BI-RADS breast density patterns on pain scores during mammography within a comprehensive biomechanical model. Methods: This retrospective cohort study included 443 female patients who underwent routine screening or diagnostic mammography. Patients with a history of breast implants, lactation, or prior breast surgery that could alter tissue biomechanics were excluded. Maximum pain scores (1–10 on a Visual Analog Scale [VAS]) were recorded. Transverse, anteroposterior, and superoinferior breast biometric measurements for each patient were calculated using advanced radiological workstations. Data were analyzed using One-Way ANOVA and Multiple Linear Regression (OLS) models. Results: The mean age of the participants was 49.7 ± 9.4 years, the mean applied compression force was 62.4 ± 10.3 N, and the mean pain score was 2.03 ± 2.12 (range: 1–10). The multiple linear regression analysis was statistically significant overall (F = 2.516, p = 0.015). Having a BI-RADS Type D (extremely dense) breast pattern was identified as the strongest independent factor associated with an increased pain score (p = 0.082, coefficient = 1.219). Age showed a trend toward a negative effect on pain (p = 0.072), while compression force showed a trend toward a positive effect (p = 0.067). Conversely, breast thickness (p = 0.231) and the three-dimensional mean breast size index (p = 0.568) demonstrated no independent predictive power. The menstrual cycle phase did not reach independent significance in the multivariate regression model (p = 0.117); however, non-parametric univariate analysis revealed a significant difference in pain across hormonal groups (Kruskal–Wallis H = 10.04, p = 0.039), with actively menstruating and luteal-phase women reporting higher pain than menopausal women. Conclusions: The pain experienced during mammography depends on the internal fibroglandular architecture (elasticity and stiffness) of the tissue rather than its external volumetric dimensions. Notably, neither device-measured breast thickness nor manually calculated three-dimensional breast dimensions independently predicted pain, challenging the widespread assumption that breast size drives mammographic discomfort. “One-size-fits-all” or thickness-based compression strategies should be abandoned in routine practice. Instead, “personalized compression” protocols that prioritize patient comfort without compromising image quality should be developed, particularly for younger patients and those with BI-RADS Type D, and to a lesser extent Type C, density patterns. Full article

The bovine gut microbiota is crucial for many physiological functions, but how microbial interactions and related metabolic processes shift during pregnancy and lactation remains poorly understood. This study utilized fecal samples from 18 Bunaji (White Fulani) cows as a model to examine the gut microbial composition and structure across lactation, pregnancy, and the dry phase using 16S rRNA gene sequencing. Community composition analysis, alpha and beta diversity, LEfSe and correlation analyses were performed to explore the relationship between these reproductive stages, gut microbiota, and concentrations of short-chain fatty acids (SCFAs). Based on the Shannon and Simpson alpha diversity indices, no significant differences among the groups were found. However, beta diversity analysis revealed clear distinctions in microbial community structures between the groups. The most abundant microbial phyla across all three groups were the Bacillota (55–60%) and Bacteroidota (25–33%). At both the family and genus levels, cellulose-degrading bacteria such as Oscillospiraceae, Bacteroidaceae, Sphingobacteriaceae, Intestinimonas, Bacteroides, and Acetivibrio were prevalent across lactating, pregnant, and dry cows. Fifteen genera, including Intestinimonas, Bacteroides, Aristaeella, and Acinetobacter, were identified as potential biomarkers due to their significantly different abundances (p < 0.05) among the groups based on LEfSe. Notably, Spearman’s correlation analysis (p < 0.05) showed significant associations between the levels of specific microbial taxa and SCFA concentrations. In conclusion, although the core gut microbiota was similar across the groups, significant variations in microbial composition were detected. Additionally, these microbial profiles were associated with variations in fecal SCFA levels, indicating a potential interaction between them. Full article

Background/Objectives: Although COVID-19 is generally more severe in males, data on sex-specific differences in the predictive value of commonly used inflammatory biomarkers remain limited. The study aimed to evaluate the sex-specific prognostic performance of selected biomarkers during the Alpha variant wave. Methods: In single-center study, univariate and multivariable regressions analyses, along with receiver operating characteristic curve (ROC) analyses, were performed to assess the association of acute-phase proteins, cytokines, and white blood cell indices (at admission and 7 days later) and disease severity and mortality in patients with severe-to-critical COVID-19. Results: At admission, the combined assessment of ferritin and D-dimer predicted disease severity in both sexes; however, optimal cut-off values and diagnostic performance (specificity and sensitivity) differed between males and females. In males, neutrophil and lymphocyte counts provided additional clinically relevant predictive value. Seven days after admission, the combination of ferritin, D-dimer, and fibrinogen in males, and ferritin, as an independent predictor within a model including lactate dehydrogenase, in females demonstrated strong predictive performance for severe-to-critical COVID-19. At this time-point, lymphocyte count in males was also identified as an independent predictor of disease severity. Notably, C-reactive protein and neutrophil count correlated with mortality in males with severe-to-critical disease. Conclusions: Severe COVID-19 is predicted by distinct acute-phase proteins and shared, sex-specific biomarkers, but with distinct cut-offs and predictive accuracy. In males, white blood cell indices also serve as independent predictors. Furthermore, prognostic utility changes of these biomarkers over the course of the disease, suggesting sex-specific and time-dependent role in COVID-19 pathogenesis. Full article

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by complement-mediated hemolytic anemia and thrombosis. The first treatments approved were complement 5 inhibitors (C5is), eculizumab and ravulizumab. Recently approved treatments include pegcetacoplan, iptacopan, danicopan (as an add-on to a C5i), and crovalimab. Methods: A systematic literature review (SLR) was conducted to identify clinical evidence on all available treatments. Outcomes evaluated were hemoglobin and lactate dehydrogenase (LDH) levels, transfusion avoidance, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores, and safety. Results: In total, 133 records met the inclusion criteria. Of these, 54 records reporting on 11 Phase 3 trials and 2 extension studies are summarized. Eight trials and one extension study evaluated complement inhibitor (CI)-naïve patients, three trials evaluated CI-experienced patients with residual anemia, and one extension study evaluated both groups. In both patient groups, all treatments led to improved outcomes. Conclusions: This SLR is the first to provide an overview of clinical trials assessing the efficacy and safety of all currently approved PNH treatments, which could help inform clinical decisions. Although some head-to-head trials are available, direct comparative evidence remains limited for several comparators, necessitating an indirect treatment comparison (ITC) to assess the efficacy and safety across the treatment landscape. Full article

The transition phase often causes athletes to lose the benefits of warm-up, so this study aimed to assess the effects of two re-warm-up protocols and a control condition without re-warm-up on 100 m freestyle performance and the kinematic variables (stroke length (SL), stroke rate (SR), and stroke index (SI)), subjective perception of effort (RPE), and physiological variables (heart rate (HR), temperature (T), and blood lactate concentration (La⁻)). Twenty competitive-level swimmers completed a dryland and water warm-up, followed by a 30 min transition phase and a 100 m freestyle simulation. Over 30 min, each swimmer randomly performed one of three re-warm-up protocols: control (remaining seated), dryland (explosive exercises), and water (race-pace series). The three experimental re-warm-up protocols affected 100 m freestyle performance (p = 0.019; η²p = 0.189). Post hoc comparisons showed that dryland was faster than control (−0.68%, p = 0.009), whereas no significant difference was observed between water and control (−0.52%, p = 0.234). No significant differences were observed between conditions for SR, SL, RPE, or La⁻, whereas peak HR was lower in the control. Although water did not significantly improve performance, swimmers reported more favourable sensations during the trial. In conclusion, the dryland protocol significantly improved 100 m freestyle performance, whereas the water protocol did not produce significant performance benefits under the present conditions. Full article

The cell density effect, defined as reduced cell-specific productivity above a critical cell density, remains a major limitation in virus manufacturing processes. While medium exchange prior to infection has been reported to mitigate this effect, the role of spent medium during the early phase of infection is poorly understood. Here, we show that spent medium conditioned by high-density HEK293 cultures inhibits infection with recombinant vesicular stomatitis virus (rVSV), even when infection is performed at low cell density. The strength of inhibition increased with the density and conditioning time of the donor culture and resulted in slower replication kinetics, thereby delaying the optimal harvest time and potentially reducing overall yield. Notably, the inhibitory effect was reversible when the virus was added to cells maintained in fresh medium, indicating that inhibition is mediated by the medium rather than intrinsic changes in the cells. We excluded pH effects within 7.1–8.0, nutrient depletion, and lactate/ammonium accumulation as primary causes. Removal of cell debris and extracellular vesicles by filtration (down to 0.02 µm) and size-based retention down to 3 kDa did not restore infection, and AUC indicated no major differences in particle distributions between fresh and conditioned media. Together, our data suggest an unidentified <3 kDa inhibitor in spent medium that partially suppresses rVSV infection and slows replication kinetics. Full article

Tyrosol, a phenolic compound derived from olive products, exhibits anti-inflammatory, neuroprotective, and cardiometabolic properties, whereas creatine is a well-established ergogenic aid with documented benefits for muscular performance and emerging evidence for cognitive support. This 5-week randomized, double blind, placebo-controlled trial examined the effects of Tyrosol, creatine, their combination, and placebo on resistance and aerobic exercise performance and psychomotor vigilance in healthy adults. Participants (n = 48; 18–50 years) consumed their assigned supplement for 4 weeks, after which changes in upper and lower body strength, submaximal resistance performance, aerobic capacity, lactate responses, plyometric performance, and acute cognitive function were assessed. The Tyrosol + Creatine condition produced the most consistent improvements in upper body resistance performance, particularly for higher load, higher volume bench press work. In contrast, neither the Tyrosol-alone group, the creatine-alone group, nor the placebo group achieved this effect, which suggests there is a synergistic effect between Tyrosol and creatine. No significant effects were observed for intermediate resistance loads, isometric lower body strength, grip strength, aerobic endurance, lactate responses, plyometric outcomes, or acute psychomotor vigilance. Collectively, these findings support the use of short-term co-supplementation with Tyrosol and low-dose creatine (without a loading phase) as a potentially beneficial strategy to enhance upper-body training quality in specific tests and improve upper-body strength endurance. Full article

Background/Objectives: Herpes zoster is caused by varicella-zoster virus reactivation, which often leads to a chronic pain condition named postherpetic neuralgia (PHN). Patients with immunosuppressive conditions face a heightened risk of developing PHN. This study aims to identify factors contributing to PHN development in immunosuppressive patients. Methods: This retrospective cohort study was conducted involving 219 immunosuppressive patients from two centers and split into training and test cohorts. Participants were divided into PHN (n = 88) and acute phase pain (ACP, n = 131) groups. Univariate and multivariate logistic regression analyses were used to identify clinical predictors of PHN. A nomogram was constructed to predict PHN risk by integrating significant predictors. The discrimination, calibration and clinical usefulness of the nomogram were evaluated. Results: Multivariate analysis revealed metabolic syndrome, older age, higher lactate dehydrogenase (LDH), and higher neutrophil-to-lymphocyte ratio (NLR) as significant PHN predictors. The nomogram showed good discrimination in both training (AUC of 0.83 [95% CI 0.77–0.90] with a specificity of 0.78, sensitivity of 0.87, NPV of 0.90, and PPV of 0.73) and test cohorts (AUC of 0.85 [95% CI 0.75–0.96] with a specificity of 0.82, sensitivity of 0.85, NPV of 0.89, and PPV of 0.76). Clinical decision curve analysis confirmed the practical utility of the nomogram. Conclusions: The nomogram incorporating age, metabolic syndrome, LDH, and NLR are useful in estimating PHN risk among immunosuppressed patients. Full article

The responsiveness of the stress axis is fundamental for maintaining health and sustaining productive performance; however, the effect of modulating this stress axis with bovine appeasing substance and its effects on biochemical, immunological, oxidative parameters and uterine involution have not been determined, which are the objectives of this experiment. To elucidate these questions, Holstein cows, from the prepartum to lactation period in a cross-ventilation system, received an application of a bovine appeasing substance (treated group) and a 0.9% saline solution (control group) at the time of calving, and blood samples were collected on calving day and on days 3, 7, 14 and 21 postpartum for analysis. Modulation of the stress axis by bovine appeasing substance increased magnesium levels on days 7 and 14 postpartum, with a reduction in fructosamine levels on days 3, 7, 14, and 21 postpartum. A reduction in ferritin levels, an acute-phase protein, and a reduction in interleukin 1 beta and interleukin 6 were also observed, demonstrating an anti-inflammatory effect in cows of the treated group. Creatine kinase activity decreased on day 21 postpartum in cows treated with bovine appeasing substances. An increase in cholinesterase activity on day 7 and a marked decrease on day 21 postpartum in treated cows were observed compared to the control. This was accompanied by a reduction in beta-hydroxybutyrate levels on day 7 and a reduction in reactive oxygen species levels on day 14 in animals of the treated group, indicating modulation of ketogenesis and reduced oxidation through an anti-inflammatory effect. Mean uterine thickness was also affected by the bovine appeasing substance, with a lower mean thickness on day 21 postpartum in treated cows. Modulation of the stress axis by the bovine appeasing substance reduces inflammation, improving energy dynamics and reducing oxidation, thus facilitating tissue repair associated with postpartum uterine involution in dairy cows. Full article

This study aimed to evaluate the trends in physiological and metabolic parameters—such as heart rate (HR), respiratory rate (RR), hematological parameters, blood lactate, and serum enzymes (LDH, AST, and CK)—in seven regularly trained working dogs during the protection phase of the IGP1 Working Trial. HR and RR measurements, along with blood samples, were collected at rest (upon arrival at the field), immediately after exercise, and 10 min post-exercise. Statistical analysis revealed significantly higher HR, RR, RBC, hemoglobin (Hb), hematocrit (Hct), and blood lactate values both immediately and 10 min after exercise compared to rest. Creatine kinase (CK) concentrations were significantly higher 10 min post-exercise compared to rest and immediately after exercise. Additionally, a positive correlation was found between blood lactate levels and HR and RR throughout the monitoring period. Preliminarily, these findings suggest that the protection phase of the IGP1 trial involves a mixed energy metabolism, comprising both anaerobic (alactic and lactic) and aerobic pathways. The results also highlight the usefulness of blood lactate and heart rate measurements as practical indicators for assessing fitness and physiological response in working dogs during IGP1 activities. Full article