Search Results (955)

Background: We aimed to investigate the potential synergistic effect of ivacaftor combined with colistin against Pseudomonas aeruginosa and Klebsiella pneumoniae, and to elucidate the underlying molecular mechanisms through metabolomic analysis and its reproducibility in a murine model. Methods: Six colistin-susceptible and 2 colistin-resistant cystic fibrosis P. aeruginosa isolates, along with two colistin-resistant K. pneumoniae clinical isolates, were studied. Antimicrobial susceptibility was assessed by broth microdilution, and synergy by checkerboard assay. Metabolomic profiling was conducted via LC-HRMS with statistical analysis. A murine pneumonia model, induced by intranasal administration of colistin-resistant strains, was used to validate in vivo ivacaftor and colistin synergy after 24 h. Results: No previously described colistin resistance mutations were identified in P. aeruginosa strains, whereas K. pneumoniae carried mgrB variations. Ivacaftor restored colistin susceptibility at 16 mg/L concentration, and at 1–2 mg/L led to at least a twofold reduction in colistin MIC. Metabolomic analysis of colistin-resistant P. aeruginosa strains revealed that ivacaftor induced modifications in phosphoethanolamine groups of lipid A. However, no synergistic effects were observed in the short-term in vivo pneumonia model, regardless of the administration route. Conclusions: Ivacaftor exhibited no direct antimicrobial activity against P. aeruginosa and K. pneumoniae isolates in vitro but restored colistin susceptibility through synergistic interactions. The lack of synergy in the murine pneumonia model may reflect treatment time and challenges in standardizing in vivo conditions. These findings highlight the potential of ivacaftor as an adjunct to colistin therapy, warranting further investigation into its clinical applicability. Full article

Background/Objectives: While doxorubicin (DOX) and trastuzumab (TRZ) improve overall survival in women with breast cancer, these two anti-cancer drugs increase the risk of developing heart failure. As a novel and largely unexplored approach, our aim was to evaluate whether the prophylactic use of the sodium-glucose co-transporter 2 inhibitor empagliflozin (EMPA), with and without the angiotensin converting enzyme inhibitor perindopril (PER), is cardioprotective in preventing DOX + TRZ-mediated cardiotoxicity. Methods: In a chronic in vivo murine model, female mice received prophylactic treatment with PER (3 mg/kg), EMPA (10 mg/kg), or EMPA + PER via oral gavage for a total of 3 weeks as a run-in period prior to weekly administration of DOX + TRZ (8 mg/kg and 3 mg/kg, respectively) intraperitoneally for an additional 3 weeks (total of 6 weeks). Results: In mice treated with DOX + TRZ, the left ventricular ejection fraction (LVEF) decreased from 75 ± 2% at baseline to 40 ± 4% at week 6. Prophylactic treatment with either PER, EMPA, or EMPA+PER improved LVEF to 58 ± 3%, 66 ± 3%, and 67 ± 4% at week 6, respectively (p < 0.05). Histological analyses confirmed significant disruption of myofibrils, vacuolization, and loss of sarcomere integrity in the DOX + TRZ-treated mice. Prophylactic administration with PER, EMPA, or EMPA + PER, however, improved myofibril integrity at week 6 in mice receiving DOX + TRZ. Finally, although the Bax/Bcl-xL ratio was significantly elevated by 1.5-fold in mice treated with DOX + TRZ, this marker of apoptosis was attenuated by prophylactic treatment with either PER, EMPA, or EMPA + PER. Conclusions: Prophylactic administration of EMPA mitigated adverse cardiovascular remodeling in a chronic in vivo model of DOX + TRZ-mediated cardiotoxicity. Full article

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental condition characterized by impairments in attention, inhibitory control, working memory, and executive functions, largely associated with dysfunction of prefrontal and frontoparietal networks. Limitations and variable tolerability of pharmacological treatments have motivated interest in nonpharmacological neuromodulatory approaches. Methods: This narrative review was conducted based on a structured search of the PubMed database to identify preclinical and clinical studies investigating the cognitive and neurobiological effects of transcranial photobiomodulation. Studies were selected using predefined keywords related to photobiomodulation, cognition, and ADHD, and included investigations assessing cognitive or neurophysiological outcomes. Results: Across studies, photobiomodulation targeting prefrontal regions was associated with improvements in sustained and selective attention, inhibitory control, working memory, and broader executive functions, accompanied by increased cortical oxygenation, enhanced mitochondrial metabolism, and functional reorganization of prefrontal and frontoparietal networks; preliminary studies in ADHD populations also suggest beneficial effects on attention and working memory. Limitations: The current literature is constrained by the limited number of ADHD-specific clinical studies, heterogeneity in stimulation parameters, variability in cognitive outcome measures, relatively small sample sizes, and limited long-term follow-up. Conclusion: Transcranial photobiomodulation represents a promising, safe, and biologically plausible nonpharmacological strategy for modulating cognitive dysfunctions associated with ADHD; however, well-controlled randomized clinical trials are required to confirm efficacy, define optimal protocols, and establish long-term outcomes. Full article

Since the elimination of smallpox, mpox (monkeypox) is the most medically significant orthopoxvirus infection. As a result of numerous regional, national and global outbreaks of MPXV (mpox virus), there is an abundance of new data available on the effects of the different viral clades on clinical obstetrical and perinatal outcomes when infection occurs in pregnancy. In addition, there have been additional placentas from cases of congenital MPXV infection available for study. These recent data indicate that there are prominent differences between viral strains and their effects on the fetus, with MPXV Clade I strains (Ia, Ib) having the greatest risk for an adverse outcome in pregnancy, and Clade II strains (IIa, IIb) having far less risk. In particular, the ongoing outbreak of MPXV Clade Ib in the DRC indicates that there is a significant risk for adverse perinatal outcomes associated with infection in pregnancy, especially during the first trimester. These outcomes include spontaneous abortion, stillbirth, neonatal death and congenital mpox. The placenta in cases of congenital infection demonstrates abundant virus in the chorionic villi, with prominent involvement of Hofbauer cells. Similar to smallpox, transplacental transmission and adverse pregnancy outcomes are an important feature of certain strains of this orthopoxvirus infection when occurring in pregnant women. Full article

Background/Objectives: Poor bone quality is strongly associated with adverse surgical events. Although dual-energy X-ray absorptiometry (DXA) remains the gold standard for bone mineral density (BMD) assessment, logistical barriers may limit its preoperative application. The Endplate Bone Quality (EBQ) score is an MRI-derived metric quantifying subchondral bone quality at the vertebral endplate with demonstrated predictive value for cage subsidence following lumbar interbody fusion. However, EBQ has been measured exclusively at the operative level in surgical cohorts. This study aimed to assess level-specific EBQ scores across the entire lumbar spine and compare distributions across age, sex and osteoporosis subgroups. Methods: A single-institution retrospective review of T1-weighted lumbar MRI studies from patients evaluated for lower back pain from 2020 to 2025 was performed. EBQ was independently scored by two blinded raters at each disc space from L1–L2 to L5–S1 using 3 mm endplate ROIs normalized to a CSF ROI at L3. Interrater reliability was assessed via ICC, Pearson correlation, and RMSE. Patients were stratified by age (≤60 vs. >60 years), sex, and osteoporosis status, and subgroup comparisons were performed for overall and level-specific EBQ score. Results: A total of 96 patients with an average age of 61.0 ± 9.42 years were included in this study. The majority of patients included were female (87.5%), and 18.8% had been diagnosed with osteoporosis. EBQ scores demonstrated a progressive caudal increase across all subgroups from L2–L3 to L5–S1. Overall interrater reliability was acceptable (ICC = 0.76), with level-specific ICCs ranging from 0.70 to 0.83. No significant differences were observed between age or sex subgroups. Osteoporotic patients demonstrated significantly higher EBQ at L1–L2, L2–L3, and overall (all p < 0.05), with no significant differences at L3–L4 through L5–S1. Conclusions: This study provides normative, level-specific EBQ reference data throughout all levels of the lumbar spine. The increase in EBQ scores seen among caudal levels and reduced osteoporotic discriminatory power support the importance of level-specific context when interpreting EBQ thresholds. These findings may support future studies evaluating threshold development for EBQ. Full article

This study examines Millennial business students’ expectations of organizational career systems (OCS) to inform the design of work environments that attract and retain Millennial employees. It explores preferred OCS features, the role of personal value orientations (PVO), and potential cross-national differences. Data were collected through a cross-national survey of 284 business students in Canada and Germany. Variance analyses and group comparisons were used to assess differences in OCS expectations, and ordinary least squares regression examined the influence of PVO on preferences for four OCS features: internal recruitment, recognition of group contributions, formal promotion processes, and tenure-based advancement. The results show that Millennial business students favor OCS that emphasize recognition of group contributions and transparent, formal procedures, while placing less importance on internal recruitment and tenure-based advancement. PVO significantly predict these preferences: self-transcendence values are positively associated with preferences for formal procedures, whereas conservation values relate positively to tenure-based advancement. Canadian respondents exhibit slightly stronger preferences for formal procedures, group recognition, and tenure than German respondents, although overall cross-national differences remain modest. The study’s reliance on a convenience sample and self-reported data limits generalizability, highlighting the need for more diverse samples and qualitative approaches. By linking career system expectations to underlying personal values rather than generational labels, this study provides theoretical insight and practical guidance for designing fair and transparent OCS aligned with the career expectations of Millennial respondents. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) and high-grade follicular lymphoma (FL) are aggressive B-cell malignancies predominantly affecting older adults. R-CHOP remains the frontline standard of care, with frail and elderly patients requiring attenuated regimens such as R-mini-CHOP. Real-world comparative data in elderly and Hispanic populations remain limited. We aimed to evaluate outcomes of R-mini-CHOP versus R-CHOP in elderly patients and to explore potential differences by ethnicity. Methods: Single-center retrospective analysis of adult patients older than 70 years with DLBCL and high-grade FL, treated between January 2014 and June 2025. Clinical characteristics, treatment responses, and survival outcomes were analyzed. The overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Results: A total of 136 patients were included (72 R-mini-CHOP; 64 R-CHOP). Patients receiving R-mini-CHOP were older (median 82 vs. 74 years) and had higher-risk features. Overall response rates were 88.7% and 92.6% in the R-mini-CHOP and R-CHOP groups, respectively. Two-year OS was 79.3% for R-mini-CHOP and 76.7% for R-CHOP. Median OS and PFS were not reached in either group. Elevated lactate dehydrogenase (LDH) was associated with an inferior response. We identified a trend toward better response with R-CHOP in Hispanic patients, although this was not statistically significant. Conclusions: In this real-world cohort, R-mini-CHOP achieved response and survival outcomes comparable to R-CHOP despite worse baseline characteristics. These findings support the use of dose-attenuated therapy in frail and elderly patients and suggest that equitable access to care may mitigate ethnic disparities in outcomes. Full article

Ewing sarcoma (ES) is the second most common primary bone malignancy in children and adolescents and remains one of the most lethal pediatric cancers. Found in more than 85% of patients with ES, EWSR1::FLI1 results from the t(11;22)(q24;q12) chromosomal translocation. This fusion encodes an aberrant transcription factor that dysregulates gene expression and drives oncogenic transformation. Although this oncogene was identified over three decades ago, therapeutic progress has been limited, in part due to the lack of robust and permissive animal models. Prior efforts to generate transgenic mouse models have been unsuccessful, and while zebrafish have emerged as a promising system, a tissue context capable of supporting EWSR1::FLI1-driven tumorigenesis has not been defined. Here, we report that tissue-specific expression of EWSR1::FLI1 in zebrafish induces tumor formation that recapitulates the histologic and molecular hallmarks of human ES, including small round blue cell morphology and characteristic biomarker expression. Tumors were driven by the col2a1a promoter and resulted in ~70% incidence of notochord tumors within the first 72–96 h. Of the surviving fish, ~5% developed CD99-positive small round blue cell tumors at ~9 months post-fertilization. This work establishes a stable tissue-specific transgenic model of ES, providing a powerful in vivo platform to investigate disease pathogenesis and evaluate novel therapeutic strategies. Full article

Introduction: Ubiquinol–cytochrome c reductase core protein II (UQCRC2) encodes a core subunit of the mitochondrial electron transport chain (ETC) complex III (CIII). Biallelic pathogenic variants in UQCRC2 have been associated with mitochondrial disease characterized by lactic acidosis, developmental delay, hepatopathy, and episodic metabolic decompensation. Methods: We reviewed the biochemical phenotypes of 14 individuals possessing UQCRC2 variants, including two novel cases. We performed biochemical studies of mitochondrial respiration and oxidative phosphorylation (OXPHOS) complex measurements in patient-derived fibroblasts. Results: We report reduced CIII activity in a majority of individuals possessing variants in UQCRC2, as well as biochemical findings consistent with impaired mitochondrial energy metabolism, though impairments in mitochondrial respiration were variable. The two previously unreported, unrelated patients possessing the likely pathogenic missense variant c.361T>C, p.Tyr121His in UQCRC2 in trans with a 16p12.2 microdeletion encompassing UQCRC2 showed milder phenotypes, less severe metabolic decompensations, and no long-term neurological impairments. Both individuals display reduced CIII activity and mitochondrial respiratory dysfunction. Discussion: These data expand the current understanding of genotypes associated with UQCRC2-associated mitochondrial disease to include the novel 16p12.2 microdeletion. These data also highlight the consistent biochemical phenotype associated with UQCRC2-associated mitochondrial disease, and the need for consistent biochemical and respiratory assessment of individuals possessing UQCRC2 variants to further our understanding of this phenotype. Full article

Background: The updated Schwartz and CKiDU25 bedside (SCr-based) formulae for the estimated glomerular filtration rate (eGFR) in children are defined by a constant term (with the latter formula dependent upon age and sex) multiplied by the ratio of patient’s height (m) to SCr (mg/dL). However, the Schwartz formula can severely underestimate the measured GFR (mGFR) at higher mGFR levels. Methods: For a single-center cohort of 92 pediatric kidney transplant recipients, we statistically determined if the log{eGFR} at 1 mo and 6 mo post-transplant might further depend upon patient demographics or height, indicating the inadequacy of these formulae for properly predicting the mGFR. We also determined how the log{SCr} at 1 mo and 6 mo post-transplant might depend upon patient demographics and height, helping to corroborate any arrived-at improved functional form for the eGFR. Results: Overall, our cohort received good-quality donor kidneys; however, both eGFR formulae calculated that the percentage of recipients with an eGFR < 60 mL/min/1.73 m² at 1 mo and 6 mo post-transplant was 26–28%. Furthermore, neither the updated Schwartz nor the CKiDU25 bedside formulae adequately controlled for the influence of patient height on SCr; in fact, the patient height squared was superior to its unidimensional value at accounting for the sharp increase in SCr that normally occurs as children grow from infancy to young adulthood (p < 0.000001 at mo1, p = 0.000003 at mo6 for the updated Schwartz bedside formula; p = 0.0009 at mo1, p = 0.005 at mo6 for the CKiDU25 bedside formula). The log{SCr} was also best fitted by a linear regression model that controlled for the log{patient height squared} (p < 0.000001 at both mo1 and mo6). Conclusions: A statistically more accurate eGFR formula should be based on using a power function (power > 1) for patient height rather than its unidimensional value. Full article

Background: Responders to the September 11, 2001, WTC attacks experience high rates of PTSD, and existing treatments often lead to high dropout and low care use. Objectives: This randomized, double-blind, sham-controlled trial assesses the feasibility and acceptability of transcutaneous auricular vagus nerve stimulation (taVNS) as a potential PTSD treatment for 9/11 responders. Methods: A total of 32 WTC responders aged 18+ with PTSD, recruited via the World Trade Center Health Program, participated; those with current psychosis, unstable medical conditions, or recent trial involvement were excluded. Participants were randomly assigned to taVNS or sham groups and asked to use the device for 15 min daily for 8 weeks, with staff and participants blinded. Primary outcomes included recruitment, adherence, retention, and feedback. Secondary outcomes examined changes in depression (PHQ-9), anxiety (GAD-7), and sleep (PSQI). Data were analyzed with mixed-effects models focusing on PTSD and mental health symptoms. Results: The taVNS group showed modest PTSD improvement, with a 10-point CAPS-5 reduction in 40% of stimulation participants versus 28.5% sham; no significant differences in self-reported symptoms were found. Discussion: Daily taVNS over eight weeks is feasible and acceptable, warranting larger studies to detect differences and identify subgroups with greater benefit. Trial registration: “taVNS to Reduce PTSD Symptoms in WTC Responders” (NCT05212714); registered 9 September 2021. Full article

The 2x2 Demonstrator, a prototype for the Deep Underground Neutrino Experiment (DUNE) liquid argon (LAr) Near Detector, was exposed to the Neutrinos from the Main Injector (NuMI) neutrino beam at Fermi National Accelerator Laboratory (Fermilab). This detector is a prototype of a new modular design for a liquid argon time-projection chamber (LArTPC), comprising a two-by-two array of four modules, each further segmented into two optically isolated LArTPCs. The 2x2 Demonstrator features a number of pioneering technologies, including a low-profile resistive field shell to establish drift fields, native 3D ionization pixelated imaging, and a high-coverage dielectric light readout system. The 2.4-tonne active mass detector is flanked upstream and downstream by supplemental solid-scintillator tracking planes, repurposed from the MINERvA experiment, which track ionizing particles exiting the argon volume. The antineutrino beam data collected by the detector over a 4.5 day period in 2024 include over 30,000 neutrino interactions in the LAr active volume—the first neutrino interactions reported by a DUNE detector prototype. During its physics-quality run, the 2x2 Demonstrator operated at a nominal drift field of 500 V/cm and maintained good LAr purity, with a stable electron lifetime of approximately 1.25 ms. This paper describes the detector and supporting systems, summarizes the installation and commissioning, and presents the initial validation of collected NuMI beam and off-beam self-triggers. In addition, it highlights observed interactions in the detector volume, including candidate muon antineutrino events. Full article

This study analyzes the relationship between personal values and (un)ethical behavior in organizations, and the moderating role of perceived ethical climate. We integrate Schwartz’s theory of personal values with the Victor and Cullen model of ethical climate, following the recent reformulation proposed by Weber and Opoku-Dakwa, thereby offering a novel perspective not previously explored in empirical research. Relying on the Person–Organization Fit model, we test whether perceived ethical climate (specifically Egoism and Principled dimensions) moderates the relationship between personal values (Self-Transcendence and Self-Enhancement) and (un)ethical behavior, operationalized by Counterproductive Work Behavior (CWB) and Organizational Citizenship Behavior (OCB). To this end, we conducted a semi-longitudinal study involving a heterogeneous sample of workers from different organizations (Wave 1: N = 212; Wave 2: N = 84). The analyses supported that personal values and ethical climate are associated with (un)ethical behavior. Furthermore, significant interaction effects between ethical climate and personal values predicting CWB and OCB were found. This study contributes to a better understanding and management of ethical behavior, providing a theoretical contribution and plausible practical guidelines from a person-in-context approach. Limitations and challenges of this work are discussed. Full article

Entrustable professional activities (EPAs) define key tasks expected of physicians. The entrustment levels that US pediatric gastroenterology (GI) fellowship program directors (FPDs) expect of graduating fellows remain unclear. This study aimed to identify the minimum entrustment levels FPDs expect for graduation and for safe and effective practice. We conducted a secondary analysis of GI data from a national multispecialty cross-sectional survey. FPDs reported the minimum entrustment level for fellows expected for graduation, whether they would graduate a fellow not meeting this level, and the minimum level for practice. A minimum entrustment level was defined as a level where at least 80% of FPDs would not allow a lower rating. Most FPDs did not require level 5 (unsupervised practice) for graduation or for practice. Instead, level 4 (indirect supervision with discussion of complex cases) was the most commonly required minimum for GI EPAs. When adjusted for FPD willingness to graduate fellows even if they did not meet the expected minimum, the level was 3 (direct supervision for complex cases) across all GI-specific EPAs. These findings underscore the potential need for ongoing mentorship, professional development, and continuing medical education after GI fellowship, particularly in the early practice period. Full article