The ULTRA trial evaluated the impact of ultra-early and short-term tranexamic acid (TXA) treatment in patients with subarachnoid hemorrhage (SAH) and found no clinical benefit at six months. This post-hoc analysis examines whether TXA improves quality of life (QoL) at three and six months. The ULTRA trial was a randomized, controlled, multicenter study conducted from July 2013 to July 2019. Patients received either TXA or standard care. This analysis included patients who completed at least one QoL questionnaire. The primary endpoint was QoL, assessed using the EQ-5D-3L questionnaire at three and six months. Linear mixed models adjusted for confounders were used to analyze the association between TXA and QoL. Of the 955 ULTRA patients, approximately 25% died, and 63% completed at least one QoL questionnaire. At three months, the TXA group had a mean EQ-5D index score of 0.75 versus 0.71 in the control group (p = 0.11) and a mean EQ-5D Visual Analogue Scale (VAS) score of 89 versus 86 (p = 0.10). At six months, the mean EQ-5D index score was 0.84 in the TXA group compared to 0.82 in the control group (p = 0.23), and the mean VAS was 92 in the TXA group compared to 89 in the control group (p = 0.13). Ultra-early and short-term TXA did not result in a significant improvement in QoL at three or six months in patients with SAH. Given the lack of benefit on both clinical outcome and QoL, routine use of TXA is not recommended. Netherlands Trial Register: NTR3272. gov: NCT02684812.
Triple Negative Breast Cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC), which is associated with a very poor prognosis. It is a broad category of tumors with a variety of biological, clinical, and morphological characteristics. FOXM1 is a pivotal transcription factor that modulates proliferation-associated genes through complex protein-DNA and protein-protein interactions, making it a highly attractive target in cancer therapy. However, existing small-molecule inhibitors often suffer from limited specificity and efficacy. In this study, we designed, synthesized, and evaluated novel series of 2-aminothiazole derivatives (C1-C15) as potential FOXM1 inhibitors. Molecular docking and molecular dynamics (MD) simulations were employed to investigate the binding interactions of these compounds with the FOXM1 DNA-binding domain (FOXM1-DBD). Structural analysis highlighted the importance of crucial residues, including Asn283, His287, and Arg286, in mediating inhibitory activity. Among the synthesized compounds, C11 exhibited remarkable structural alignment and interaction patterns with FOXM1-DBD, comparable to the reference inhibitor FDI-6. In vitro studies using TNBC cell lines (MDA-MB-231, BT-549, and BT-20) demonstrated that compound C11 significantly outperformed FDI-6 in potency. Western blot analysis revealed that C11 effectively suppressed FOXM1 transcriptional activity at concentrations of 10 µM in BT-549 cells and 20 µM in MDA-MB-231 cells. These findings underscore the potential of C11 as a potent FOXM1 inhibitor and highlight its promise for further development in TNBC therapy.
Executive function assessment is central in clinical practice and research, and the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) is widely used in adults. However, its nine-factor structure has rarely been evaluated with contemporary factor-analytic standards, prompting this study to examine its factorial validity and propose a psychometrically robust alternative. Adult participants completed the French version of the BRIEF-A, including a university student sample (N = 775) and a community adult sample (N = 1599). Factorial validity was examined using confirmatory and exploratory factor analyses, conducted on manifest items. A split-sample cross-validation procedure was applied to item-level analyses to identify a reduced item configuration reflecting the latent structure. None of the traditional BRIEF-A factor structures reported in the literature demonstrated acceptable model fit, whether analyses were based on individual items or parceled scores. In contrast, a six-factor, 24-item solution emerged, showing strong model fit, accounting for approximately 50% of the variance, and replicating across samples. The 24-item configuration provides a parsimonious representation of response patterns associated with adult executive functioning compared with the original 70-item organization. These findings concern the latent structure of BRIEF-A responses and do not constitute an alternative instrument. Future studies should examine the factorial structure of the BRIEF-A in clinical populations to further assess the robustness and generalizability of these findings.
There is a high prevalence of poor sleep quality and low energy availability (EA) in athletes during phases of intensive training, which poses significant risks for overreaching, improper recovery, and compromised training adaptations. To mitigate these risks, there is a need to explore the relationship between EA and sleep quality. To determine the interrelationships between EA and sleep quality, we assessed EA and sleep quality (sleep durationhrs, sleep debthrs, percent and hours of: slow-wave sleep (SWShrs/%), and rapid-eye movement (REMhrs/%)). The participants included 26 elite male (n = 10; 83.8 ± 8.6 kg; BMI: 24.1 ± 1.9 kg/m2) and female (n = 16; 68.0 ± 5.6 kg; BMI: 22.5 ± 1.6 kg/m2) collegiate swimmers (aged 18-22 years). The descriptive data collected included age, weight, height, training data, and body composition measures. Using a wearable device and a dietary recording cell phone application, the collection of EA was matched to sleep data over a two-week period of heavy training. Pearson correlations were utilized to determine relationships between variables. When effects of sex were observed, linear regression analyses were utilized to control for sex-differences. Among all swimmers, 69% exhibited sub-optimal EA (<45 kcal/kg FFM/d). Male swimmers exhibited greater EA and SWS versus females (p < 0.05). EA was positively correlated with REMhrs (R = 0.64; p= 0.001) but not related to sleep debthrs. Regression analyses revealed that when controlling for sex, EA positively predicted SWShrs (R2 = 0.448; F = 9.35, p < 0.001), where higher EA predicted longer SWS durations. Controlling for sleep durationhrs, EA positively predicted REMhrs (R2 = 0.425; F = 8.509, p < 0.002) and negatively predicted sleep debthrs (R2 = 0.261; F = 4.055, p < 0.031), such that higher EA was predictive of longer durations of REM, and fewer hours of sleep debt. There was a trend toward a correlation between EA and sleep durationhrs in all swimmers (R = 0.33; p = 0.06). Higher EA was significantly associated with greater REM and SWS durations, and with lower sleep debt in elite male and female college swimmers. Although cause and effect were not established, these findings provide preliminary evidence that adequate EA may support better sleep quality in elite collegiate swimmers. If this is confirmed, our results may suggest that athletes should get adequate sleep and consume adequate calories to support energy expenditure needs and optimize training and recovery. Future research should explore the underlying mechanisms and whether low EA causally impacts sleep quality.
Breast cancer patients often experience significant psychological distress. This study examined distress trajectories from diagnosis to 6 months post-treatment and explored differences across demographic, medical, and psychosocial subgroups. In this prospective cohort study, 528 patients with breast cancer were recruited between 1 December 2023 and 31 December 2024. Assessments were conducted at baseline (at diagnosis, T0), after the first treatment (T1), mid-treatment (T2), at treatment completion (T3), and at three (T4) and six months (T5) post-treatment. Growth mixture modeling (GMM) was used to identify distinct trajectories of psychological distress. Multinomial logistic regression analysis was performed to examine associations between patient-related factors and trajectory membership. Three psychological distress trajectories were identified: a high-distress remission group (17.05%), a moderate-stable distress group (11.93%), and a low-fluctuating distress group (71.02%). Multivariable analyses showed that higher educational attainment, breast-conserving surgery, early disease stage, partial self-management ability, and strong social support were associated with membership in the moderate-stable or low-fluctuating groups (p < 0.05). Employment, health insurance coverage, avoidant medical coping style, and higher baseline anxiety and depression scores were concurrently associated with membership in the high-distress remission group (p < 0.05). Although psychological distress generally decreased over time, 71.02% of patients followed a low-fluctuating trajectory, 11.93% maintained moderate distress with potential risk of persistence, and 17.05% showed high initial distress that remitted substantially within 6 months. Continuous monitoring and early psychosocial support are recommended, particularly for patients with moderate- or high-risk trajectories.
Viruses often hijack host developmental programs to promote infection, but the mechanistic links between reproductive regulation and antiviral immunity remain incompletely understood. Here, we identify a virus-triggered hierarchical degradation cascade that links antiviral immunity and fertility regulation in rice. We show that the rice grassy stunt virus (RGSV) effector P3 transcriptionally activates P3IP1, a RING-type E3 ubiquitin ligase. P3IP1 ubiquitinates and destabilizes the receptor-like cytoplasmic kinase RLCK22, which functions as a scaffold to stabilize the floral MADS-box transcription factors MADS1 and MADS15. The loss of RLCK22 results in decreased MADS1/15 protein levels, accompanied by reduced pollen viability and increased susceptibility to viral infection. Genetic and biochemical analyses support the existence of a regulatory module involving P3IP1, RLCK22, and MADS1/15. Mutants of mads1, mads15, or rlck22 exhibit overlapping molecular and antiviral phenotypes, including altered pollen viability and impaired transcriptional responses to RGSV. Our findings uncover a virus-inducible E3-RLCK-MADS axis linking post-translational regulation of development and defense, providing new insight into how pathogens manipulate plant fitness through targeted protein degradation.
Gestational diabetes mellitus (GDM) refers to glucose intolerance, insulin sensitivity, and beta islet cell dysfunction during pregnancy. GDM pathogenesis is associated with hypertension, impaired placental and renal function, oxidative stress, and increased circulating CD4+ T cells. There are limited animal models to explore GDM pathology and treatment. This study sought to determine a role for GDM placental CD4+ T cells to parallel manifestations of the GDM phenotype in pregnant athymic nude rats. GDM placental CD4+ T cells (GDM T cells) were isolated upon delivery and injected into pregnant nude rats on gestational day (GD) 12. Mean arterial pressure and markers of renal injury, proteinuria, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin, were assessed on GD19. Glucose, insulin tolerance, and glucose tolerance tests were also performed. Renal and pancreatic tissues were stained using Periodic acid Schiff and hematoxylin and eosin, respectively. A one-way ANOVA was used for statistical analysis. Adoptive transfer of GDMT cells increased blood pressure (120.8 ± 2.2 mmHg, p < 0.05) compared to controls (105.4 ± 2.8 mmHg) and normotensive Tcell recipients (96.3 ± 3.9 mmHg). Metformin or MitoTEMPO attenuated this response. GDM T cell recipients had elevated blood glucose (p < 0.05) and impaired glucose tolerance and insulin sensitivity, which improved with metformin or MitoTEMPO treatment. Renal injury was more severe in GDM T cell recipients, but attenuated with metformin or MitoTEMPO. Pancreatic morphology showed reduced beta islet numbers in GDM T cell recipients. GDM CD4+ T cells contribute to hypertension, glucose intolerance, and renal dysfunction, improved byMitoTEMPO. These findings supports optional therapeutics that support mitochondrial function during pregnancy.
Soybean stay-green associated virus (SoSGV) is an emerging begomovirus associated with severe disease in soybean crops in East Asia. This study investigated its evolutionary relationships, population structure, recombination history, adaptive signal, and candidate host-interaction features using integrated phylogenetic, population genetic, natural selection, and structural modeling analyses of 54 complete genome sequences. Maximum-likelihood and Bayesian phylogenetic analyses recovered SoSGV as a distinct monophyletic lineage, with strong support in the maximum-likelihood analysis (96% bootstrap support). Population genetic analysis revealed high haplotype diversity (Hd = 0.962), moderate nucleotide diversity (π = 0.022), and a negative Tajima's D value (D = - 1.49, p < 0.05), a pattern consistent with recent demographic expansion but not, by itself, proof of emergence timing. Recombination screening identified two robust coat protein-associated events (best p = 1.95 × 10⁻⁷ and 1.91 × 10⁻¹⁴), and sliding-window similarity analysis independently supported the resulting mosaic structure. Natural selection analyses detected adaptive signal in the V2 gene; MEME identified episodic selection at residues 35 and 36 (p < 0.1), while complementary methods supported additional method-dependent signals. ColabFold predicted a moderate-confidence V2 structure (mean pLDDT = 73.36). Protein docking identified a plausible V2-SKP1-related interface comprising 39 contacting residues, while a short 10 ns molecular dynamics simulation indicated preliminary structural compatibility rather than biological validation. These findings support the hypothesis that recombination contributed to SoSGV diversification and that V2 may interact with SKP1-related host proteins.
1. Why is this study needed?Little is known about the quality-of-life of caregivers of disabled-older-adult in China. The Care-related Quality of Life instrument (CarerQol) is designed to measure informal caregivers’ quality of life. This instrument requires validation in these populations to determine its suitability and identification of potentially modifiable predictors that may improve informal caregivers’ quality-of-life (CRQoL).2. What is the key problem/issue/question this manuscript addresses?This study examined whether the CarerQol was a reliable and valid instrument in informal caregivers of disabled older adults in China. We also examined which factors were associated with CarerQol scores.3. What is the main point of your study?The Chinese CarerQol can be used to capture CRQoL among informal caregivers of disabled older adults in China, providing information that complements generic health measures and inform caregiver support.4. What are your main results and what do they mean?The CarerQol instrument performed well with no clear ceiling or floor effects. Known-group analyses supported the expected direction, with larger effect-sizes for factors closely related to CarerQol domains (such as depressive symptoms, caregiving burnout, and care willingness). Most correlations met our a priori expectation of at least moderate strength, supporting convergent validity. A worse financial situation, heavier caregiving burden, and lower care willingness were associated with lower CarerQol scores. These findings suggest that the CarerQol is a suitable instrument for measuring quality-of-life across Chinese informal caregivers of disabled older adults. We also highlight modifiable predictors of CRQoL, including strengthening financial support, service support, and caregiver guidance programs.
Patient-reported outcomes (PROs) after total knee arthroplasty (TKA) are well-documented in Western populations, but long-term recovery and its determinants in multiethnic Asian populations remain poorly understood. We aimed to characterise 5-year WOMAC recovery after TKA and to identify patient, clinical, and surgical factors associated with the odds of improvement at each consecutive postoperative interval in a multiethnic Asian cohort. This registry-based cohort study used prospectively collected data from a tertiary hospital in Singapore. We included 4964 consecutive cases with osteoarthritis undergoing primary TKA between December 1, 2008, and December 31, 2023. The primary outcomes were changes in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total and subscale scores, measured at baseline and at 6 months, 1, 2, and 5 years postoperatively. The mean (SD) total WOMAC score improved from 38.6 (15.1) at baseline to 7.5 (9.2) at 5 years. The greatest improvement occurred within the first 6 months (mean change, 27.6 points; P value < .001). In multivariable interval-specific analyses, older age (≥ 75 years; OR 0.55, 95% CI 0.39-0.79) and the presence of one or more comorbidities (OR 0.83, 95% CI 0.71-0.96) were independently associated with lower odds of long-term improvement. Interval-specific associations with ethnicity were also observed for pain and stiffness. In this large, multi-ethnic Asian cohort, TKA was associated with substantial and durable WOMAC improvements, primarily within the first 6 months. Interval-specific predictors of improvement were dominated by patient-level factors, notably age, comorbidity, and ethnicity, while surgical variables showed limited association. These findings support the potential value of patient-centred risk stratification and culturally responsive perioperative care in optimising long-term outcomes.
Processing binaural cues is crucial for many acoustic communication tasks, and understanding the neural mechanisms of binaural sound processing gives important insights into how receivers localize signalers, which in anurans is a key component of mate selection. We characterized the binaural interaction component (BIC) of the auditory brainstem response (ABR) by collecting monaural and binaural ABRs using click stimuli with varying interaural time difference (ITD) and interaural level difference (ILD) in male and female Cope's gray treefrogs (Hyla chrysoscelis). We hypothesized that the latency of the BIC peaks would increase with larger ITDs and ILDs. We also hypothesized that females would show a stronger relationship between binaural cues and BIC characteristics than males because of the greater importance of directional hearing for females. We characterized two prominent BIC peaks, DN1 and DN2. Both BIC peak latencies had a positive relationship with ITD, but there was no effect of ITD on peak amplitudes. The amplitude and latency of the BIC peaks were not affected by variation in ILD. There were no sex or body size effects on ABR or BIC characteristics. Our findings demonstrate that the BIC is driven primarily by ITD in H. chrysoscelis. This is the first study to characterize the BIC in an amphibian, which expands the comparative understanding of the neural mechanisms of binaural hearing in vertebrates.
This study aimed to identify subgroups of health-related quality of life (HRQoL) and examine predictors of latent class membership among low- and high-income cancer survivors using latent class analysis (LCA). We analyzed data from the Korea National Health and Nutrition Examination Survey (2013-2020), including 1075 cancer survivors. HRQoL patterns were identified using LCA based on the EuroQol five-dimension questionnaire. Analyses were conducted separately for low- and high-income groups to examine income-stratified HRQoL patterns. Sociodemographic characteristics and chronic disease status were included as covariates in the latent class models to examine predictors of class membership within each income group. Income-stratified LCAs suggested differential HRQoL patterns. Three latent HRQoL classes were identified in the low-income group: Good HRQoL, Pain and Mobility Impairment, and Poor HRQoL. In the high-income group, two classes were identified: Good HRQoL and Pain and Mobility Impairment. While education was a common predictor in both groups, other predictors varied by income level. In the low-income group, older age, unemployment, and multimorbidity were significantly associated with impaired HRQoL classes, whereas female sex predicted membership in the Pain and Mobility Impairment class in the high-income group. These findings highlight differences in HRQoL patterns and associated factors across income-stratified groups of cancer survivors, underscoring the limitations of relying solely on average HRQoL scores in survivorship care. Survivorship strategies should be tailored to the differential HRQoL patterns and associated predictors identified within each income group, thereby promoting more targeted and equitable care for cancer survivors. Health-related quality of life (HRQoL) is a key measure for understanding cancer survivors’ well-being after cancer. However, most studies use a single total score of HRQoL, which can mask important differences across physical, psychological, and social aspects. Considering its multidimensional nature, examining patterns across HRQoL domains can provide a more comprehensive understanding of survivors’ well-being. Moreover, since socioeconomic status—especially income—strongly influences HRQoL, it is important to explore how these patterns differ by income level. Therefore, this study examined HRQoL patterns among low- and high-income Korean cancer survivors and identified factors related to each pattern. Three patterns were found among low-income survivors—Good HRQoL, Pain and Mobility Impairment, and Poor HRQoL—and two among high-income survivors—Good HRQoL and Pain and Mobility Impairment. Education was associated with better HRQoL patterns in both groups, but other predictors differed. Among low-income survivors, older age, unemployment, and multiple chronic diseases were linked to poorer HRQoL patterns. Among high-income survivors, women were more likely to belong to the Pain and Mobility pattern. These findings highlight the need for survivorship strategies that address heterogeneity across income-stratified groups, promoting equitable and comprehensive care for cancer survivors, even when overall HRQoL scores appear satisfactory.
In this study, a novel series of chromene-based derivatives was rationally designed as potential VEGFR-2 inhibitors based on key structural and pharmacophoric features required for antiangiogenic activity. Accordingly, twelve chromene derivatives (13a-e, 15a-e, and 17a-b) were successfully synthesized and structurally characterized. The synthesized compounds were evaluated in vitro for their cytotoxic activity against human cancer cell lines (MCF-7, HepG-2, and HCT-116), in addition to normal WI-38 and WISH cells. Among the tested compounds, compound 13a demonstrated the most potent and selective antiproliferative activity, exhibiting low micromolar IC50 values and favorable selectivity indices. Enzymatic assays confirmed its VEGFR-2 inhibitory activity (IC50 = 1.666 ± 0.025 µM), comparable to the reference drug sorafenib. Mechanistic investigations revealed that compound 13a effectively inhibited cancer cell migration in a wound healing assay, highlighting its potential antiangiogenic properties. Furthermore, compound 13a induced significant G0/G1 cell cycle arrest in MCF-7 cells and triggered apoptosis, as evidenced by Annexin V/PI staining. To support the experimental findings, Density Functional Theory (DFT) calculations confirmed favorable structural stability and electronic properties. Molecular docking studies demonstrated strong binding interactions within the VEGFR-2 ATP-binding site. These results were further validated by 200 ns molecular dynamics simulations, MM-GBSA binding free energy calculations, Protein-Ligand Interaction Fingerprints (Pro-LIF), Principal Component Analysis of Trajectories (PCA-T), and Free Energy Landscape (FEL) analyses, confirming the dynamic stability and favorable energetics of the VEGFR-2-13a complex. Overall, this integrated experimental and computational study identifies compound 13a as a promising VEGFR-2-targeted anticancer lead warranting further preclinical investigation.
BACKGROUND This retrospective study aimed to radiographically compare injectable platelet-rich fibrin (I-PRF)-enriched bone graft matrix (sticky bone) with conventional particulate grafting during lateral sinus lift procedures performed simultaneously with implant placement in patients exhibiting insufficient posterior maxillary residual bone height. MATERIAL AND METHODS Twenty-four systemically healthy, non-smoking patients who underwent lateral sinus lift surgery between January 2014 and June 2023 were included. Patients were retrospectively allocated into groups according to grafting material: conventional particulate bone graft (group 1, n=12) and I-PRF-enriched bone graft matrix (sticky bone) (group 2, n=12). Radiographic bone height measurements were obtained using panoramic radiographs acquired preoperatively, immediately postoperatively, and at 6 months postoperatively. Measurements were conducted using calibrated digital software. Inter- and intragroup comparisons were analyzed via paired and independent samples t-tests, using a statistical significance threshold of P<0.05. RESULTS Immediate postoperative bone gain was significantly higher in group 1 than in group 2 (11.94 mm vs 10.15 mm; P<0.05). However, bone resorption at 6 months was significantly greater in group 1 than in group 2 (2.61 mm vs 1.07 mm; P<0.05). Bone loss percentage also was significantly higher in group 1 than in group 2 (16.50% vs 7.74%; P<0.05), indicating superior bone preservation in group 2. CONCLUSIONS Although conventional grafting resulted in greater initial bone gain, I-PRF-enriched bone graft matrix demonstrated significantly reduced bone resorption at 6 months. Sticky bone may provide a clinical advantage in bone preservation after sinus lift procedures.
The main goal of this paper is to examine variations in the political attitudes of elites in Chile concerning two key dimensions: socioeconomic attitudes (concerning redistribution, taxation, and state provision of services) and sociocultural attitudes (concerning immigration, LGBTQ+ rights, gender equality, and democratic values). I propose a framework that underscores the potential impact of the source of elite power-whether economic, political, or cultural-in shaping differences in political attitudes. Additionally, I suggest that patterns of intergenerational persistence and mobility (e.g., being born into an elite family) may contribute to variations in attitudes among elite individuals. To test the study's expectations, I use survey data collected between 2019 and 2020 from a sample of 416 individuals belonging to Chile's economic, political, and cultural elites. Using multiple correspondence analysis (MCA), findings reveal substantial variation in political attitudes among elite individuals, with socioeconomic and sociocultural orientations strongly aligned. Explanatory analyses using multivariate regression models reveal that variations in attitudes among elite individuals are largely shaped by their elite type and social origins, with members of the economic elite and those from elite origins displaying the most conservative and inegalitarian views on both dimensions. Moreover, significant attitudinal tensions are observed between inheritors and newcomers, not only across the elites as a whole but also within the economic, political, and cultural elite groups.
Di(2-ethylhexyl) phthalate (DEHP) is a widely used industrial plasticizer, raising global concerns due to its potential endocrine-disrupting effects and environmental persistence. Human exposure to DEHP primarily occurs through the ingestion of contaminated food and water, inhalation of airborne particles, and dermal contact with products containing DEHP. Understanding the toxicological mechanisms of DEHP is essential for evaluating its health risks and developing effective strategies to mitigate its adverse effects. In this study, we conducted long-term exposure experiments to DEHP using both an animal model and in vitro system to investigate the complex interplay among DNA methylation, hyperactivation of macroautophagy/autophagy, mitochondrial dysfunction, and lipid accumulation induced by DEHP. The results revealed that DEHP exposure induced the degradation of DNMT1 (DNA methyltransferase 1) by enhancing its interaction with the autophagy-related protein SQSTM1 (sequestosome 1). DNMT1 degradation resulted in decreased methylation of the promoter regions of genes associated with autophagosome formation, subsequently increasing their expression. The resulting demethylation excessively activated autophagy, contributing to mitochondrial dysfunction and lipid accumulation in the liver. This study uncovered a previously unrecognized interplay among hyperactivation of autophagy, mitochondrial dysfunction, and lipid accumulation in the context of DEHP exposure. These findings enhanced our understanding of DEHP's toxicity and underscored concerns about the long-term health effects of environmental pollutants, particularly regarding metabolic diseases.
This study analysed the effects of four parameters (current intensity, rising time, maintenance duration, and falling time) of ramped galvanic vestibular stimulation (GVS) on vestibular perception. Based on these findings, an optimal waveform for inducing roll sensation was designed and applied to a virtual reality (VR) flight simulator. Current intensity and rising time significantly affected perceived strength and annoyance, whereas maintenance duration affected only annoyance, and falling time showed no significant effects. Application of the recommended waveform in a VR flight simulator significantly increased presence and reduced simulator sickness compared with the no-GVS condition. By combining four parameters that constitute the GVS waveform (current intensity, rising time, maintenance duration, and falling time) the recommended waveform for inducing the stimulation of roll sensation was identified. When integrated with a VR flight simulator video, this GVS stimulation enhanced the sense of presence and reduced simulator sickness.
Cutaneous gene therapy has the potential to treat a wide range of skin disorders, but effective delivery remains limited by the skin's barrier properties and immune surveillance. Here, we identify AAVrh32.33 as a potent vector for targeting dermal stromal compartments. Following systemic administration in mice, AAVrh32.33 mediated robust and durable transgene expression, with preferential targeting of dermal fibroblasts and hair follicle bulge cells. Expression peaked at one month and persisted for up to two years, highlighting its suitability for chronic conditions. To reduce immunogenicity, a dominant CD8+ T cell epitope was disrupted, generating the IDPΔ variant. This modification attenuated peptide-specific T cell responses while preserving stromal transduction. In human skin explants, IDPΔ achieved high levels of gene expression, primarily in dermal fibroblasts and precursors, confirming translational relevance. Finally, vectors encoding CCL17, CCL20, and CCL22 demonstrated localized targeted therapeutic gene delivery in both healthy and inflamed skin, underscoring the feasibility of using this platform to reshape local immune responses. Together, these findings establish AAVrh32.33 and IDPΔ as promising platforms for durable cutaneous gene therapy, with direct applications in diseases such as vitiligo where long-term modulation of the dermal microenvironment is essential.
Postpartum hemorrhage (PPH) remains a leading cause of maternal morbidity and mortality globally, particularly in women with antepartum hemorrhage (APH). Current risk assessment methods lack standardized predictive tools that are both simple and reliable for clinical application. We conducted a secondary analysis of a prospectively collected cohort of 100 pregnant women presenting with APH at ≥28 weeks' gestation at a tertiary care centre in northern India. Multivariable logistic regression was used to identify significant predictors of PPH. A point-based clinical risk score was then developed based on the multivariable model and internally validated using bootstrap techniques with 1000 replicates. PPH occurred in 30% of patients (n=30). Multivariable analysis identified four independent predictors of PPH: maternal age (adjusted odds ratio [OR] 1.29 per year; 95% confidence interval [CI] 1.10-1.51; p=0.002), gravidity (OR 2.11 per unit; 95% CI 1.00-4.43; p=0.049), gestational age at delivery (OR 0.64 per week; 95% CI 0.44-0.94; p=0.021), and antepartum blood transfusion (OR 2.44; 95% CI 1.02-5.84; p=0.045). The prediction model demonstrated excellent discrimination with an area under the receiver operating characteristic (ROC) curve of 0.86 (95% CI 0.80-0.92) and good calibration (slope 0.95). Bootstrap internal validation yielded an optimism-corrected AUC of 0.84. The resulting four-factor risk score stratified patients into four risk categories with PPH rates ranging from 4% (low risk) to 100% (very high risk). The four-variable score provides an accurate, easily applicable tool with excellent predictive performance. The score is a promising tool that, pending external validation, may facilitate early identification of high-risk patients and improve maternal outcomes. Further research should focus on external validation of this tool in diverse populations and its integration into clinical practice.
Glioblastoma is an aggressive primary brain tumor marked by rapid growth, invasiveness, poor prognosis, and an over 90 % tumor recurrence rate. Current radiation and chemotherapy treatments are limited by non-selectivity and toxicity, creating a need for safer complementary treatments. Historically, natural health products (NHPs) have been used medicinally across cultures for their anti-inflammatory and antioxidant effects. More recently, they have gained recognition for their selective, non-toxic properties in cancer treatment, suggesting their potential as adjuncts to conventional therapies. Black maitake (Grifola frondosa) extract, a well-tolerated NHP with known immunomodulatory properties, has demonstrated anticancer effects in breast cancer models. This study investigates the ability of Black Maitake Odaira Extract - Prothera (BMOE; a trade name of the extract manufactured by Shogun Maitake Canada, London, ON) to induce cell death in the U-87 MG glioblastoma cell line using 2D and 3D models, alone and in combination with the standard chemotherapy: temozolomide (TMZ). Apoptosis was assessed via Hoechst 33,342, annexin V, and propidium iodide staining, along with morphological analyses. Mitochondrial depolarization was measured using TMRM, cell migration was assessed via wound-healing assays, and structural integrity was evaluated using 3D spheroids. BMOE, alone and with TMZ, induced dose-dependent apoptosis, mitochondrial depolarization, and impaired glioblastoma cell migration. BMOE also disrupted 3D spheroid structures and promoted nuclear condensation, consistent with apoptotic processes. Most notably, BMOE significantly enhanced the anti-cancer effects of TMZ. These findings support the potential of BMOE as a complementary therapy that enhances the efficacy of current glioblastoma treatments.