This white paper focuses on maintenance, monitoring and transfer of Ligand Binding Assays (LBAs) supporting vaccine immunogenicity studies and is part 3 of a series to harmonize method validation and bioanalysis. The objective of this series was identified during the drafting of the 2020 White Paper in Bioanalysis. The Workshop on Recent Issues in Bioanalysis (WRIB) produces the White Paper in Bioanalysis yearly, which is one of the high-profile articles published in the journal, providing detailed discussions and recommendations on Bioanalytical Method Development and Validation. Since 2017, participation by vaccine assay validation experts and regulators in the WRIB working groups has rapidly increased due to its unique format where industry leaders and regulators can meet and exchange ideas on topics of mutual interest. In early 2021, vaccine manufacturers approached WRIB to sponsor and support the authorship and publication of an overarching vaccine assay validation document based on the 2017-2020 discussions and consensus, starting with LBA, then followed by future papers on Molecular Diagnostics (MDx including both PCR and NGS), Biofunctional Assays (BFA) and Cell-Mediated Immunity (CMI) assays validation. Using the industry and WRIB vaccine network, a vaccine immunogenicity assay validation expert working group was assembled representing 16 global companies. The work on the first 3 white papers officially began in April 2021 focusing on vaccine immunogenicity ligand binding assays (Part 1 LBA Validation, Part 2 Assay Development, Part 3 Assay Lifecycle Management, Assay Maintenance, Monitoring and Transfer). In this publication (Part 3), the activities that are required to ensure consistency of assay performance following validation are discussed. In contrast to bioanalytical methods evaluating chemical and biological drugs (ICH-M10), there are no clear guidelines for methods supporting vaccine immunogenicity studies. Hence, the authors of this White Paper hope that this common effort will help close this regulatory gap. These harmonization white papers will collectively be pivotal for whole vaccine development process.
While emotions are socially shaped, research on academic emotions has neglected the potential influence of peer emotions. This study investigated whether students' boredom is influenced by their classroom friends' boredom and whether teacher-student relationship quality and cognitive ability moderate these influences. Participants were 3415 7th Grade students (Mage = 12.44(0.45); 49.69% females) from 27 Flemish schools. Longitudinal social network analyses demonstrated peer influence effects on academic boredom, controlling for selection and network effects. Teacher-student relationship quality and cognitive ability did not moderate this influence, but higher teacher-student relationship quality predicted less increases in boredom. Findings indicate that boredom can spread through classroom friendship networks, regardless of student ability, and that high-quality teacher-student relationships protect against increases in boredom.
Fixture congestion has emerged as one of the defining challenges of modern professional soccer, exposing players to repeated high-intensity demands with limited opportunities for recovery. Such cumulative exposure taxes multiple physiological systems and may lead to sustained biological strain throughout the competitive season. However, the integrated systemic impact of congested schedules remains incompletely characterized. We aimed to characterize the systemic physiological impact of cumulative competitive load across a full professional soccer season using an integrated biomarker framework. In this prospective longitudinal investigation, we employed the systemic degree of perturbation score, an adaptation of the molecular degree of perturbation, to circulating biochemical, hematological, and metabolic biomarkers obtained from professional soccer players across a full competitive season. Multi-dimensional analyses were employed to characterize systemic alterations associated with cumulative competitive load. A progressive increase in systemic perturbation was observed across the competitive season. The relative contribution of individual biomarkers shifted over time, with late-season phases characterized by more integrated muscular-inflammatory-metabolic profiles. Myoglobin and monocyte-related markers consistently contributed to systemic degree of perturbation values across competitive quarters, and network analyses demonstrated progressive changes in correlation architecture involving muscular, inflammatory, and metabolic mediators. These results provide a comprehensive view of the physiological burden imposed by a professional soccer season and describe a progressive integration of muscular, inflammatory, and metabolic responses under cumulative competitive load. This integrated perspective supports the potential utility of biomarker-based monitoring frameworks for characterizing seasonal biological strain in elite athletes.
With the escalating complexity of composite contamination in industrial wastewater, exploring high-efficiency and robust photocatalysts has become a research hotspot in environmental remediation. Herein, five isostructural rare-earth metal-organic frameworks (RE-MOFs, LCUH-128-132) were solvothermally assembled via the coordination of anthracene chromophore ligand 9,10-anthracenedicarboxylic acid (H2ADC) with five rare-earth metal ions (RE = Y, Eu, Gd, Tb, Dy). Remarkably, LCUH-129 (Eu-MOF) presents outstanding multifunctional photocatalytic activity without any additional photosensitizers or cocatalysts. It delivers a Cr(VI) reduction rate constant of 0.49 min-1, along with RhB and MB degradation rate constants of 0.23 min-1 and 0.026 min-1, respectively. The anthracene moiety serves as a light antenna to efficiently capture visible light; photogenerated electrons are rapidly transferred to rare-earth catalytic centers via ligand-to-metal charge transfer, which effectively inhibits electron-hole recombination. Radical trapping experiments and EPR characterization verify that ·OH, ·O2- radicals, and photogenerated electrons dominate the pollutant elimination processes. Furthermore, LCUH-129 exhibits excellent recyclability. This work affords a facile strategy for fabricating high-performance RE-MOF photocatalysts and reveals their promising prospects in the practical remediation of water composite pollution.
Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent and heritable of neurodevelopmental disorders. To characterize the genetic variants contributing to this heritability, we studied families with members affected by ADHD. Genome-wide array data were obtained on two cohorts: NHGRI Family Cohort (359 nuclear families,1538 individuals) and NCR Family Cohort (25 multigenerational and 132 nuclear families, 631 members). A meta-analysis of family-based association tests (FBAT) of the two cohorts identified three genome-wide significant associations, one upstream from TFRC, and two that were intronic to GSDME and to TRIM31, with the last gene previously implicated in ADHD. Genes associated with ADHD (MAGMA, gene-based association P < 0.05) overlapped with genes implicated in ADHD by prior case/control genome-wide association studies. Meta-analyses of the linkage signals identified one significant linkage region (LOD > 3) on 19p13.2-13.11 that encompassed a genome-wide significant variant in the FBAT of the NHGRI Family Cohort (rs55741253, P = 2.68 × 10- 8). Additionally, two of the five linkage regions that reached a LOD > 2 in our meta-analysis replicated significant linkages from prior studies (prior studies reporting 13 linkages with LOD > 3.0; hypergeometric test of overlapping linkage signals, P < 0.01). Using neuroimaging data from the NCR cohort, we found genes associated with ADHD overlapped with genes associated with the brain's total surface area and a feature of functional connectivity, reflecting the interaction between the brain's default mode and task positive networks. Such work begins to delineate the neural substrates of the discovered genetic associations with familial ADHD.
The impact and mechanisms of PROK1 on macrophages in pancreatic cancer (PC) progression was investigated. PROK1 and PROKR2 expression in PC patients were detected by immunohistochemistry and Western blot. TIMER database analyzed correlation between PROK1/PROKR2 and macrophage infiltration in PC. PROK1 influence on macrophage M2 phenotypic conversion and PI3K/AKT pathway activity were investigated by detecting CD206, IL-10, Arg-1, p-PI3K/PI3K and p-AKT/AKT via immunofluorescence and Western blot. PROK1 in macrophages on viability, migration and invasion of PC cells was appraised by CCK-8, wound healing and Transwell assays. Immunoprecipitation verified the interaction between PROK1 and PROKR2. Western blot explored regulation of PROK1 and PROKR2 on PI3K/AKT pathway activity and macrophage M2 phenotypic conversion. In vivo study was executed by constructing xenograft tumor models. PROK1 and PROKR2 overexpression in PC patients was associated with macrophage infiltration, advanced TNM stage, lymph node and distant metastasis. PROK1 silencing suppressed macrophage M2 phenotypic conversion and PI3K/AKT pathway activity, as it reduced CD206, IL-10, Arg-1, p-PI3K/PI3K, and p-AKT/AKT. PROK1 silencing in M2 macrophages attenuated PC cell viability, migration and invasion. PROK1 interacted with PROKR2 to activate PI3K/AKT pathway in macrophages. PROK1 elevated CD206, IL-10 and Arg-1 in M2 macrophages, which was reversed by PROKR2 silencing. In vivo, PROK1 in macrophages enhanced PC growth and expression of CD206, IL-10, Arg-1, p-PI3K/PI3K and p-AKT/AKT in xenograft tumors, which was abrogated by PROKR2 silencing. PROK1 induced macrophage M2 phenotype conversion to promote PC progression by activating the PI3K/AKT pathway via interacting with PROKR2.
Low-frequency radar waves, particularly in the P-band, present a significant stealth challenge due to the inherent trade‑offs among strong absorption, broad bandwidth, and ultra-thin thickness. These limitations arise from the conflict between structural thickness and wavelength, impedance-matching difficulties, and weakened loss mechanisms. To overcome these constraints, a new strategy for synergistic enhancement of the local field and electromagnetic loss field of metamaterials has been proposed. By employing metasurface structures for local‑field enhancement, strong absorption is achieved at ultra-thin thicknesses. Furthermore, dielectric, magnetic, conduction, and structural resonance losses are integrated to enable strong, broadband absorption. Herein, a double-layer metasurface array is designed and integrated onto a polydimethylsiloxane/flake carbonyl iron high‑loss dielectric substrate. The resulting composite exhibits exceptional performance in the 1.77-2.85 GHz range at a thickness of only 3.78 mm (~ 0.022 λ), with an absorption rate exceeding 90%, and the absorption rate within the 1-6 GHz range can exceed 60%. It also demonstrates good mechanical flexibility and stability. The proposed local‑field enhancement principle provides a new route to bypass the quarter-wavelength limitation of traditional absorbers, while its ultra-thin, broadband, and flexible integrable features highlight its potential for efficient conformal integration on complex curved surfaces.
Although sex differences in the epidemiology and clinical expression of schizophrenia (SZ) are well established, sex differences in cognition during the chronic stage of SZ remains controversial and merits further investigation. We aimed to examine sex differences in executive function and working memory within a longitudinal family study of SZ, hypothesizing that sex effects would be negligible. A total of 266 participants, including 113 individuals with SZ, 58 unaffected first-degree relatives (SZR), and 95 healthy controls (HC), were assessed twice over one year using a comprehensive neuropsychological battery. Mixed one-way analyses of covariance were performed to compare these participant groups, accounting for sex. No significant sex differences were found in performance on executive functioning and working memory tasks across SZ and SZR (p > 0.05). This performance pattern was also maintained for HC. However, the SZ group performed significantly worse than other two groups in most tasks (p < 0.0001; η²p = 0.09 to 0.14). The present results support previous evidence reporting the absence of sex differences in higher-order cognition in schizophrenia and provide new evidence that there are no sex effects in these domains in unaffected relatives of individuals with SZ.
High-dose intravenous vitamin C was associated with increased harm in adults with sepsis requiring vasopressors in the large international LOVIT trial. This population pharmacokinetic sub-study of LOVIT aimed to characterise the pharmacokinetics of vitamin C and explore associations with patient characteristics and outcomes. Patients who enrolled in the LOVIT trial were randomized to receive 50 mg/kg vitamin C every 6 hours for 96 hours or placebo. Blood samples were collected on study Days 1, 3, and 7 for plasma vitamin C quantification. Population pharmacokinetic modeling was performed, with relevant patient and treatment-related factors tested as covariates. Internal validation was conducted using bootstrap resampling (n = 1000). Univariable and multivariable analyses explored associations between 28-day mortality and patient characteristics, as well as the relationship between vitamin C exposure and severity of illness. A total of 464 samples from 161 patients who were randomized to vitamin C were analysed. The median age was 64 (interquartile range [IQR] 56-72) years, weight 82 (IQR, 70-94) kg, and APACHE II score 24 (IQR, 18-29); 65.2% were male. A one-compartment model best described the data, with clearance (CL) significantly influenced by CKD-EPI eGFR and APACHE II score. Population mean estimates for clearance and volume of distribution were 3.37 L/h and 45.06 L, respectively. The model was internally validated and demonstrated to be robust and stable. Although greater vitamin C exposure was observed among non-survivors versus survivors (median 1900.5 [IQR 1191.8-2548.2] vs 1017.8 [IQR 630-1836.7] mg·h/L; p < 0.001), only age (odds ratio [OR] 1.063; 95% confidence interval [CI] 1.024-1.104, p = 0.001) and APACHE II score (OR 1.079; 95% CI 1.005-1.158, p = 0.036) were independently associated with 28-day mortality. Severity of illness was also predictive of vitamin C exposure. Vitamin C pharmacokinetics are highly variable between individuals. Some of this variability can be explained by changes in glomerular filtration and APACHE II score as a measure of illness severity. Although non-survivors had greater vitamin C exposure than survivors, exposure was not independently associated with mortality.
Maturity Onset Diabetes of the Young (MODY) is a type of genetically inherited diabetes. As it generally arises in early adulthood, it can affect pregnant women with significant neonatal outcomes. Our study aimed to conduct a systematic review on pregnancy management and outcomes of all subtypes of MODY, browsing the Cochrane, EMBASE and PubMed databases to find clinical studies on the topic. They were last searched on June 29, 2025. The inclusion criteria for our review were: published articles, available in their full-text version, about MODY, reporting data about its management during pregnancy and neonatal outcomes, in English language, specifying therapeutic approaches used. The exclusion criteria were: study designs reported below, written in other languages, not present in above mentioned databases. The risk of bias was assessed through the ROBIS tool. Our systematic review analyzed data on 1408 live births of 1183 pregnant women, and found specific guidelines for the management of pregnant women affected with GCK-MODY and HNF1A-MODY, but none on rarer subtypes. Thus, indications on pregnancy management and outcomes of rarer MODYs were identified through an additional literature review, and its findings were summarized in Table 1. Our systematic review was limited by the lack of data on rarer subtypes of MODY and the specific keywords and databases selected. However, our work lays an important step in the direction of much-needed clinical data and recommendations in treating rare MODY subtypes during pregnancy, towards healthy offspring delivery and growth. A further literature review was carried out to identify any data on other subtypes of MODY and their neonatal outcomes, and the findings were summarized in Table 1. No funding was needed to carry out the present systematic review. PROSPERO registration number: CRD420251062633.
Women with endometriosis are at increased risk of severe postoperative pain due to nociceptive sensitization. While multimodal analgesia reduces opioid use, the added value of objective nociception monitoring remains unclear. This study evaluated whether NOL®-guided opioid titration improves perioperative outcomes within a standardized multimodal regimen. In this prospective, randomized, single-blinded trial, premenopausal women undergoing laparoscopic surgery for suspected endometriosis or adenomyosis were assigned to NOL®-guided analgesia or standard care based on clinical assessment. All patients received a standardized multimodal protocol. The primary outcome was total perioperative opioid consumption. Secondary outcomes included postoperative pain scores (NRS) and PACU length of stay. Exploratory analyses assessed the association between preoperative pain (Mankoski Pain Scale, MPS) and postoperative outcomes. A total of 111 patients were analyzed (NOL®: n = 54; control: n = 57). Total perioperative opioid consumption did not differ significantly between groups (adjusted mean difference = 14 μg for Fentanyl and 52 μg for Remifentanil; p = 0.8). Surgery duration was an independent predictor of opioid use (p < 0.001) and PACU length of stay (p = 0.01), whereas treatment group had no significant effect. Postoperative pain scores were comparable between groups at all time points. NOL®-derived metrics were not associated with opioid consumption or pain. Higher preoperative MPS scores independently predicted higher pain scores in the late PACU phase. NOL®-guided opioid titration did not reduce perioperative opioid consumption or improve early postoperative outcomes compared with standard multimodal analgesia in women undergoing laparoscopic surgery for endometriosis.
One of the challenges in accessing cross-border clinical trials involving international participants in Europe is language diversity, with 32 official languages in the European continent. Some patients have reported being excluded from trials owing to their native language, and in certain studies, language has been used as an eligibility criterion for participation. Considering that pediatric studies in Europe are not conducted in all countries, cross-border access to clinical trials may represent the only therapeutic opportunity for children living with rare diseases for which no approved treatment exists. This study aimed to assess the use of language as an eligibility criterion in pediatric clinical trial protocols conducted in Europe (2007-2024) and published in the Clinicaltrials.gov database. It evaluated the frequency and context of language requirements and whether these were scientifically justified. The overall objective was to identify potential sources of language-based discrimination that may prevent cross-border access to pediatric clinical trials. The 32 official languages of the European continent were used as keywords to search the eligibility criteria of 1,754 pediatric clinical trial protocols for studies conducted in Europe between 2007 and 2024 and registered in the largest clinical trial registry, ClinicalTrials.gov, via an Application Programming Interface. Acceptable scientific justifications to use language as an eligibility criterion were defined as being (1) related to specific therapeutic areas that required language or cognitive assessments in communication with the health professionals, who do not speak the patient's language or (2) related to the use of patient- or caregiver-reported outcome measures that had only been validated in specific languages. The majority of the study protocols (95.2%) did not include any reference to European official languages in the eligibility criteria. Of the 85 study protocols that did include language requirements, only 23 (27.1%) had a scientific justification for the use of this criterion. The most frequent European languages required as eligibility criteria were English (20%) and French (16.5%). A minority of European paediatric studies (4.8%) included language in eligibility criteria in the study protocols, but of those that did, most offered no reasonable explanation for the restriction. To prevent language-based discrimination within the European regulatory framework, we recommend that ethics committees should require justification for any language-based eligibility criteria. Additionally, including dedicated sections on cross-border access in clinical trial protocols will help ensure the provision of appropriate resources such as translations, interpreters, travel, and accommodation when recruiting international participants. Pediatric clinical trials are needed to find safe and effective treatments for children. However, language requirements that are not scientifically necessary may prevent some children from taking part. In Europe, some families have reported that their child could not join a clinical trial because they did not speak a required language. This study examined 1,754 pediatric clinical trial studies conducted in Europe between 2007 and 2024, using data from a large database termed ClinicalTrials.gov. The researchers looked for any mention of language in the study entry rules (the criteria used to decide who can participate). They found that only a small number of trials (4.8%) mentioned language. However, when a language requirement was included, it was often not clearly justified. In only 27% of studies it was a scientific reason, for example, when tests required a specific language or relied on speech or understanding. English and French were the most commonly required languages. The study also identified other requirements that could limit participation, such as needing access to a mobile phone, Internet, or enrollment in a specific national health system. These factors may make it harder for international families or those with fewer resources to participate. The authors recommend that ethics committees carefully review language requirements and require a clear scientific reason before approving them. They also suggest that study plans include a section explaining how children from different language backgrounds and countries can be included.
Approach bias modification (ApBM) aims to target maladaptive approach tendencies toward substance-related cues and has increasingly been examined as an adjunctive intervention for substance use disorders, including nicotine use. However, although participants' subjective experiences of ApBM are likely to influence both its effectiveness and successful implementation, they have rarely been systematically investigated. This study aimed to explore both proximate and long-term subjective training experiences reported by participants from 2 previously conducted randomized controlled trials of ApBM for smoking cessation. Training experiences were explored across 2 delivery modalities (virtual reality and smartphone app) and compared with those reported in matched sham training conditions. Participants were invited to provide open-ended feedback immediately following the intervention and up to 7 weeks after study entry (proximate feedback), as well as again 4 years later (long-term feedback). Thematic analysis was conducted to identify core themes, complemented by exploratory frequency and descriptive quantitative analyses comparing ApBM and sham conditions. In total, 87 (ApBM: n=45; sham: n=42) of the 178 participants included in the randomized controlled trials provided proximate (7-week follow-up) feedback, and 63 (ApBM: n=33; sham: n=30) provided long-term (4-year follow-up) feedback; 104 participants contributed feedback at least once. Four overarching themes were identified, with the fourth emerging only in long-term reflections: (1) perceived treatment effects, spanning beneficial changes and a perceived lack of effects; (2) mechanisms of action, including presumed working mechanisms and impeding factors; (3) feedback on the training and study experience; and (4) attribution of effects to training-specific or external factors. Overall, participants engaged extensively in reflecting on potential mechanisms underlying the training, their relation to therapeutic outcomes, and opportunities for improving future interventions. Exploratory frequency analyses indicated that participants in the ApBM group more often suggested improvements to the training, whereas participants in the sham condition more frequently reported impeding factors, particularly difficulties understanding the training rationale. Quantitative training evaluations were generally more favorable for ApBM than for sham training, as reflected in a significantly higher overall evaluation score. In particular, ApBM received higher ratings for its perceived effectiveness in reducing smoking and its applicability to everyday situations. This study provides novel insights into how ApBM for smoking is experienced both shortly after training and years later. To our knowledge, this is the first study in the context of cognitive bias modification, including ApBM, to examine subjective experiences over a multiyear time frame. The findings highlight the importance of participants' understanding of the training rationale and underscore the value of incorporating participants' perspectives into the development and evaluation of ApBM interventions.
To examine the relationship between oral handicap, clinical characteristics, psychosocial status, and quality of life in patients with systemic sclerosis (SSc). This cross-sectional study included 99 patients with SSc. Oral handicap was assessed using the Mouth Handicap in Systemic Sclerosis Scale (MHISS). Social appearance anxiety, anxiety/depression symptoms, resilience, and quality of life were evaluated using the Social Appearance Anxiety Scale, Hospital Anxiety and Depression Scale, Brief Resilience Scale, and World Health Organization Quality of Life-BREF (WHOQOL-BREF), respectively. Statistical and hierarchical multiple regression analyses were also performed. Oral handicap was associated with female sex (rho = 0.220, p = 0.029) and diffuse cutaneous SSc subtype (rho =  - 0.482, p < 0.001). Oral handicap showed strong positive correlations with the facial and total modified Rodnan Skin Score (rho = 0.851 and rho = 0.737; both p < 0.001). Positive associations were also observed for gastrointestinal (GI) involvement, calcinosis, telangiectasia, Scl-70 positivity, and digital ulcers (p < 0.002 for all). MHISS scores were positively correlated with anxiety, depression, and social appearance anxiety, and negatively correlated with all WHOQOL-BREF domains (p < 0.001 for all). In the regression analyses, mRSS (β = 0.484, p < 0.001), GI involvement (β = 0.210, p = 0.006), and anxiety scores (β = 0.183, p = 0.036) remained independently associated with oral impairment. The clinical model explained an additional 54% of variance, with a further 5% contributed by psychosocial variables. Oral impairment in SSc reflects both clinical disease burden and psychosocial distress, underscoring its multifactorial nature.
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder, often characterized by challenges in social interaction, repetitive behaviors, and restricted interests in work. Early diagnosis is critical for effective intervention, but current methods often rely on subjective behavioral assessments that can delay identification. This underscores the need for reliable biomarkers that can facilitate earlier detection of ASD. Biomarkers are primarily proteins in nature, found in blood, saliva, or other tissues, and have the potential to enhance diagnostic accuracy and speed. They can reveal underlying neurobiological changes associated with ASD, providing objective data to support clinical findings. The search for altered levels of certain amino acids and neurotransmitters and specific genetic biomarkers such as single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs) has gained momentum, driven by the need for more definitive early diagnostic tools. Neuroinflammatory and neuroimaging biomarkers through MRI and fMRI have also shown promise for early detection of ASD. Recent advancements in biosensor technology have significantly improved the prospects for biomarker discovery in ASD. Innovations in nanotechnology and microfluidics have enabled the development of highly sensitive and specific biosensors that can trace minute quantities of biomarkers. These devices allow for non-invasive sampling and real-time monitoring, making early screening more feasible and accessible for young children. This review article mainly focuses on how the integration of these biosensor and biomarker technologies could transform the early detection of ASD, ultimately facilitating timely interventions and improving patients' outcomes.
To evaluate the diagnostic performance of four-dimensional flow MRI alone and in combination with spleen volume and splenic extracellular volume fraction (ECV) for identifying high-risk esophageal variceal (HRV) in patients with liver cirrhosis. A total of 58 cirrhosis patients who underwent four-dimensional flow MRI and endoscopy were prospectively recruited and were divided into HRV group (n = 25) and non-HRV (NHRV) group (n = 33). The hemodynamic parameters of the portal vein (PV), superior mesenteric vein (SMV), and splenic vein (SV) derived from four-dimensional flow MRI for identifying HRV were analyzed and compared with spleen volume and splenic ECV. Then a combined model for identifying HRV was constructed by using the least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression analysis with stepwise forward. The peak velocity and maximum pressure gradient of the PV, SMV, and SV, as well as the total volume of the SMV, were significantly greater in the HRV group than in the NHRV group. The SV peak velocity had the highest AUROC for identifying HRV and was comparable to the spleen volume and splenic ECV. The combined model incorporating these three indicators showed superior performance with an AUC of 0.945, outperforming individual imaging indicators and other laboratory-based models. Four-dimensional flow MRI is a valuable noninvasive technique for detecting HRV in cirrhosis patients. The combined model incorporating SV peak velocity, spleen volume, and splenic ECV provided an accurate prediction of HRV, which may help avoid unnecessary screening endoscopy. The combined model incorporating spleen vein peak velocity derived by 4D flow MRI, spleen volume, and spleen ECV performed better than individual imaging indicators and laboratory-based models, which may help to avoid unnecessary screening endoscopy and aid in clinical decision-making. Noninvasive assessment of the risk of HRV in cirrhosis remains crucial but inadequate. Four-dimensional flow MRI can effectively identify HRV in patients with cirrhosis. Combining SV peak velocity, splenic volume, and ECV effectively identifies HRV.
Out-of-hospital cardiac arrest (OHCA) is associated with poor outcomes and presents a considerable treatment challenge. Here, we investigated the association of prior beta-blocker treatment with outcomes in patients with OHCA. We enrolled consecutive OHCA patients with return of spontaneous circulation (ROSC). Beta-blocker plasma concentrations were measured upon admission and analyzed in relation to the number of defibrillations required to achieve ROSC, initial cardiac rhythm and in-hospital mortality. Among 207 enrolled patients (median age 68 years, 71% male, 45% shockable rhythm), 65 (31.4%) had detectable beta-blocker plasma concentrations. Detectable beta-blocker concentrations were not associated with the likelihood of an initial shockable rhythm (adjusted odds ratio [OR] 0.99 [95% confidence interval [CI], 0.52-1.91]; P = 0.99), number of defibrillations (adjusted incidence rate ratio 0.93 [95% CI 0.63-1.37], P = 0.72) or doses of epinephrine (adjusted mean 7.4 vs. 6.7 mg, P = 0.29) and amiodarone (adjusted mean 99.3 vs. 93.9 mg, P = 0.83) administered to achieve ROSC. When analyzed as a continuous variable, beta-blocker concentration on admission was not associated with in-hospital death (adjusted OR 0.85 [95% CI 0.67-1.08]; P = 0.18). However, patients with plasma concentrations above the median had lower odds of death compared to those with undetectable levels or those below the median (adjusted OR 0.36 [95% CI 0.13-0.96]; P = 0.042). In OHCA patients with ROSC, detectable beta-blocker plasma concentrations on admission were not associated with defibrillation requirements or initial cardiac rhythm. While any detectable beta-blocker level was not associated with overall mortality, levels above the median were associated with lower odds of death in this cohort. These results are hypothesis-generating and warrant confirmation in larger independent cohorts.
Since Andrew Jameton introduced the term "moral distress" (MD) in 1984, the concept has attracted extensive attention in the healthcare literature. Much of this work emphasizes the costs of MD-for instance, psychological pain, work dissatisfaction, and burnout-while some highlights its potential benefits, including motivating self-improvement and institutional reform. We survey these assessments and argue that the bulk of them share a common limitation: they evaluate MD purely instrumentally, in terms of its painfulness and consequences, rather than its character as a moral experience. This instrumental framing, we contend, obscures MD's core moral significance and invites misguided interventions. In particular, it neglects the question of when MD is a fitting response to one's situation, and thus justified on intrinsic rather than instrumental grounds. We suggest that MD is fitting when one is genuinely constrained from meeting a moral requirement, and that fitting MD is significant in its own right.
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We report an 11-year-old boy with chronic kidney disease (CKD) stage 3 due to right multicystic dysplastic kidney and contralateral dysplasia who developed poststreptococcal acute glomerulonephritis (PSAGN) that rapidly progressed to kidney failure despite intensive immunosuppressive treatment. He presented with oliguria, macrohematuria, heavy proteinuria, hypocomplementemia, and an elevated antistreptolysin O titer. Initial kidney biopsy revealed diffuse endocapillary proliferation with prominent C3 deposition, subepithelial humps, and positive staining for nephritis-associated plasmin receptor (NAPlr), consistent with PSAGN. Kidney dysfunction persisted despite the administration of methylprednisolone pulse therapy, prednisolone, cyclosporine, and mycophenolate mofetil. A second biopsy at 4 months revealed focal segmental glomerulosclerosis, diffuse foot process effacement, and negative staining for NAPlr, suggesting transition from a glomerular inflammatory process to a hyperfiltration-driven structural injury. Comprehensive genetic analysis did not identify any pathogenic variants associated with bilateral dysplastic kidney. Peritoneal dialysis was initiated on day 182, and living donor kidney transplantation was performed 10 months after nephritis onset, with favorable early outcomes. This case highlights that PSAGN superimposed on CKD with reduced nephron mass may result in rapid kidney function deterioration despite aggressive treatment.