搜索结果：profiles

Clostridioides difficile infection (CDI) remains a major global health threat due to the emergence of hypervirulent, multidrug-resistant lineages. However, the evolutionary dynamics and resistance-associated genomic profiles of strains circulating in underrepresented regions, such as Mexico, remain poorly characterized. Here, we present a comprehensive genomic and phylogenetic analysis of 77 Mexican C. difficile strains compared with 74 strains from other parts of the world. Using whole-genome sequencing and core-genome MLST, we identified 19 sequence types (STs) grouped across 3 clades, with hypervirulent ST01 dominating clade 2. Virulome analysis showed conserved toxin gene profiles (tcdA, tcdB and cdtAB) across strains, while clade-specific differences were observed in adhesion and survival genes. These variations, particularly pronounced in clade 2 strains from both global and Mexican collections, may contribute to enhanced persistence and transmissibility. Pangenome analysis of 151 genomes highlighted distinct genomic architectures. Clade 2, enriched in ST01 epidemic lineages, contained 5,480 genes (58% core, 42% accessory), showing a compact structure consistent with recent clonal expansion. In contrast, clade 1 displayed the highest diversity, with 8,584 genes (30% core, 70% accessory), indicative of an open and dynamic pangenome, while clade 4 showed a smaller, more conserved profile (4,784 genes, 63% core). These findings underscore the contrasting evolutionary strategies among clades. Notably, Mexican ST01 strains exhibited a distinct resistome, including the high prevalence of the vanG operon and the VanR T115A substitution (94% vs. 23% globally), as well as near-complete prevalence of the PnimBG mutation associated with reduced metronidazole susceptibility. This pattern may reflect local selective pressures associated with antimicrobial exposure. Phenotypic susceptibility testing of newly sequenced isolates showed that most ST01 strains remained susceptible to metronidazole and vancomycin despite carrying resistance-associated determinants. Our findings highlight the urgent need to recognize hypervirulent and resistant C. difficile lineages arising outside traditional surveillance regions. These Mexican strains not only reflect regional antibiotic usage patterns but also represent a potential reservoir of globally significant resistance traits. This work underscores the importance of integrating genomic surveillance across all continents to refine treatment protocols, prevent outbreaks and contain the spread of resistant CDI.

Poor adherence to oral antipsychotics is an important challenge in schizophrenia, highlighting long-acting injectables (LAIs) as an alternative. This study aimed to compare the clinical and demographic profiles of patients with schizophrenia with prior LAI exposure versus those maintained exclusively on oral antipsychotics. This cross-sectional, observational study enrolled eligible schizophrenia inpatients aged 18-65 diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria from June 2022 to October 2023. Participants were divided into two groups: those with prior LAI exposure and those who had maintained only oral antipsychotics. Demographic data, clinical history, and baseline laboratory parameters were collected. The primary outcome was the severity of psychotic symptoms, assessed using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Severity (CGI-S) Scale upon admission. A total of 70 patients were included in the final analysis, with 36 patients having a history of LAI and 34 on only oral treatment. Demographically, both groups were comparable across most characteristics. Baseline PANSS score and its subscales, CGI-S scores, and laboratory markers showed no statistical difference. However, the LAI group showed a significantly longer duration of illness (P = 0.017), more hospitalizations (P < 0.001), and greater prior exposure to first-generation antipsychotics (P < 0.001) with higher chlorpromazine equivalent doses (P < 0.001) compared to the oral-only group. This study highlights treatment patterns among Iranian schizophrenia patients, showing that patients on LAIs generally have a history of longer illness durations, more hospitalizations, and more expose to first generation antipsychotics. Further studies should be conducted to investigate the efficacy of early versus delayed initiation of LAI and their long-term outcomes.

Pyroptosis, a lytic and inflammatory form of programmed cell death, has emerged as a regulator of tumor immunity through its capacity to trigger localized cytokine storms (operationally defined in Section 3). This review examines the dual mechanisms by which macrophage pyroptosis-driven cytokine storms influence tumor progression. Pyroptosis is executed through canonical (caspase-1/nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3)-dependent) and non-canonical (caspase-4/5/11-dependent) pathways, both converging on cleavage of gasdermin D (GSDMD) to form membrane pores that release pro-inflammatory cytokines (interleukin-1 beta, IL-1&#x3b2;; interleukin-18, IL-18) and damage-associated molecular patterns (DAMPs). These primary signals initiate cascade amplification through chemokine and cytokine networks, recruit diverse immune cell populations, and establish distinct inflammatory microenvironments. The effects of pyroptotic cytokine storms show striking temporal and intensity dependence. Acute, moderate inflammatory responses activate anti-tumor immunity through induction of immunogenic cell death (ICD), dendritic cell maturation, and cytotoxic lymphocyte priming. Chronic, low-grade cytokine storms, in contrast, promote tumorigenesis through six interconnected mechanisms: genomic instability and epigenetic reprogramming, cancer stem cell enrichment, pro-angiogenic remodeling, pre-metastatic niche formation, establishment of an immunosuppressive microenvironment, and induction of epithelial-mesenchymal transition. This "double-edged sword" phenomenon depends on inflammation intensity, duration, spatial distribution, and tumor microenvironment (TME) characteristics. Clinical investigations indicate that pyroptosis-related biomarkers, including GSDMD, gasdermin E (GSDME), and inflammatory cytokine profiles, may support patient stratification and treatment-response prediction across multiple cancer types in patients with tumor-associated macrophages (TAMs)-rich tumors. Preclinical evidence from bioorthogonal chemical systems in murine models, together with mathematical modeling, has suggested that pyroptosis affecting approximately 10-15% of tumor cells may serve as a tentative threshold for initiating anti-tumor immunity. However, this value has been derived from a limited number of preclinical systems (primarily 4T1 mammary tumor models) and has not yet been validated in human tumors; it should therefore be interpreted as a working hypothesis rather than an established parameter. Current therapeutic strategies targeting this pathway include NLRP3 inhibitors, IL-1&#x3b2;/IL-18 blockers, and combination approaches with immune checkpoint inhibitors (ICIs). Looking forward, future research should prioritize: (i) quantitative in vivo mapping of macrophage pyroptosis using spatial multi-omics and intravital imaging; (ii) development of tumor-targeted, spatiotemporally controlled pyroptosis inducers (e.g., nano-delivery and bioorthogonal activation systems); (iii) rational combination with immune checkpoint inhibitors and epigenetic modulators; and (iv) establishment of pyroptosis-based biomarker panels to guide patient stratification and toxicity prediction in clinical trials. Achieving "controllable cytokine storms" through precise macrophage pyroptosis modulation represents a therapeutic paradigm that balances anti-tumor efficacy against inflammatory toxicity, with the potential to advance cancer immunotherapy toward precision inflammation regulation.

This study aims to evaluate and synthesize the best available evidence for improving the self-awareness of falls in elderly postoperative patients with osteoporotic vertebral compression fracture (OVCF), so as to provide a reference for clinical practice. This evidence summary was conducted in accordance with the reporting standards established by the Fudan University Center for Evidence-Based Nursing. Guided by the "6S" evidence pyramid model, we systematically searched relevant domestic and international databases and official websites to retrieve literature concerning the improvement of the self-awareness of falls in elderly postoperative patients with OVCF, covering the time frame from database inception to December 2025. Two researchers independently assessed the quality of all included literature, and subsequently performed evidence extraction, synthesis, and grading in strict compliance with established evidence-based criteria. A total of 15 studies were included, consisting of 1 clinical decision, 5 guidelines, 5 expert consensuses, 3 systematic reviews, and 1 evidence summary. From these, 28 best-evidence recommendations were identified and categorized into six domains: establishing a multidisciplinary team, fall-related assessment and screening, health education and guidance, osteoporosis self-management, rehabilitation therapy, and follow-up and evaluation. This study summarizes the best available evidence on improving the self-awareness of falls in elderly postoperative patients with OVCF, thereby providing guidance for clinical practice. However, high-quality direct evidence in this research field remains limited, and further rigorous studies are required to continuously update and enrich the evidence base. In clinical application, individualized intervention plans should be formulated based on personalized fall risk profiles and patient preferences, to effectively reduce fall incidence and prevent postoperative refractures.

Breed-related differences in spermatological traits, morphometric characteristics and trace element status may influence reproductive performance in bucks during the breeding season. This study aimed to comparatively evaluate spermatological characteristics, body and testicular morphometric traits, and trace element concentrations in blood serum and seminal plasma of Honamli and Hair bucks during the breeding season. A total of 16 bucks (8 Honamli and 8 Hair), aged 2-4 years, were included. Semen samples were collected for spermatological evaluation, including mass activity, volume, pH, motility, concentration, plasma membrane and acrosome integrity (PMAI), viability and mitochondrial membrane potential. Seminal plasma was obtained by centrifugation for biochemical analysis. Blood samples were collected from the jugular vein after semen collection, centrifuged and the serum was separated. Trace element concentrations (Se, Zn, Cu, Ca, Mg, Fe and Co) were measured in blood serum and seminal plasma at the beginning and end of the study. Body, scrotal, and testicular morphometric measurements were also recorded. Honamli bucks exhibited significantly higher sperm motility (p&#xa0;<&#xa0;0.05), sperm concentration, PMAI and mitochondrial membrane potential compared with Hair bucks (p&#xa0;<&#xa0;0.001), while no significant differences were observed in semen volume, pH, mass activity or viability (p&#xa0;>&#xa0;0.05). Significant breed-related differences were found in body morphometric traits, including withers height (p&#xa0;<&#xa0;0.01), rump height (p&#xa0;<&#xa0;0.001), tail length (p&#xa0;<&#xa0;0.001), nose length (p&#xa0;<&#xa0;0.001) and ear length (p&#xa0;<&#xa0;0.05). Only scrotal circumference differed significantly between breeds (p&#xa0;<&#xa0;0.05). In blood, Ca, Mg, Zn, Se and Co showed significant time-dependent changes (p&#xa0;<&#xa0;0.001), while Fe also changed over time (p&#xa0;<&#xa0;0.01); breed effects were not significant (p&#xa0;>&#xa0;0.05). Furthermore, Ca increased in both breeds (p&#xa0;<&#xa0;0.001), Zn increased in Honamli and Hair (p&#xa0;<&#xa0;0.01 and p&#xa0;<&#xa0;0.05, respectively), Co decreased in both breeds (p&#xa0;<&#xa0;0.01) and Se increased only in Hair (p&#xa0;<&#xa0;0.001). Significant time &#xd7; breed interactions were found for Fe and Cu (p&#xa0;<&#xa0;0.05); Fe was higher in Honamli on the first day (p&#xa0;<&#xa0;0.05) and decreased only in this breed (p&#xa0;<&#xa0;0.001), whereas Cu increased only in Hair (p&#xa0;<&#xa0;0.05). In seminal plasma, Se, Fe and Cu changed over time (p&#xa0;<&#xa0;0.001), whereas Ca, Zn, Co and Mg remained unchanged (p&#xa0;>&#xa0;0.05); breed and time &#xd7; breed effects were not significant for any seminal plasma mineral (all p&#xa0;>&#xa0;0.05). In addition, Se increased in both breeds (Honamli: p&#xa0;<&#xa0;0.001; Hair: p&#xa0;<&#xa0;0.05), while Fe and Cu decreased in both breeds (Fe: p&#xa0;<&#xa0;0.01 and p&#xa0;<&#xa0;0.05; Cu: p&#xa0;<&#xa0;0.01 and p&#xa0;<&#xa0;0.001, respectively). Honamli and Hair bucks display distinct spermatological, morphometric and trace element profiles during the breeding season. These findings indicate that trace element dynamics strongly influence semen quality, suggesting their potential use as markers for sire selection and targeted reproductive management.

Protein biomarkers are increasingly recognized as indicators of metabolic status, immune response, and reproductive performance in cattle. However, comparative data among different breeds commonly raised in Indonesia remain limited. This study aimed to compare the specific proteins in follicular fluid (FF) of Bali and Brahman cows. Samples from FF (n&#x2009;=&#x2009;20 pairs of ovarium) were analyzed for identification of specific proteins using LC-HRMS analysis. Proteomic analysis revealed distinct breed-specific FF profiles, with 16 proteins uniquely identified in Bali cattle and 23 proteins in Brahman. Bali FF was enriched with proteins associated with protease inhibition, coagulation regulation, extracellular matrix remodeling, and cytoskeletal dynamics, including CORO1C, ZER1, YARS1, and L3MBTL3. In contrast, Brahman FF showed enrichment of proteins involved in lipid oxidation, one-carbon metabolism, and peroxisomal activity, notably ACOX2, BHMT, and KIAA0586. Here, we present the proteomic characterization of FF from Bali and Brahman cattle, where several bioactive proteins are candidate proteins potentially associated with reproductive processes. These findings highlight the potential of protein biomarkers in guiding cattle breeding and management strategies in tropical regions.

Parkinson's disease (PD) is closely associated with abnormal &#x3b1;-synuclein propagation along the gut-brain axis and progressive dopaminergic neuronal loss. Traditional oral preparations suffer from weak gastrointestinal resistance, rapid degradation and poor gut-brain axis regulation. Here, we constructed a gastrodia elata polysaccharide-functionalized dual-network GEPH hydrogel via thiol-maleimide click crosslinking. GEPH possesses favorable biocompatibility, regular porous microstructure and tailored rheological properties suitable for gastrointestinal delivery, showing outstanding erosion resistance and structural stability in simulated intestinal fluid. It achieves in situ gelation in the gastrointestinal tract and maintains 24&#xa0;h long-term retention after oral administration. GEPH modulates gut microbiota composition and metabolite profiles, repairs intestinal barrier and neuronal injury in PD mice such as Corynebacterium, CAG_95, and Akkermansia, while regulated metabolite abundance such as 3-methyl-4-cis-hydroxy-2-butenal, Nicotinic acid, Linolenate. By regulating the TLR4/NF-&#x3ba;B pathway and gut-brain axis, it inhibits abnormal aggregation and spread of intestinal and cerebral &#x3b1;-synuclein, alleviates neuroinflammation and neuronal apoptosis, protects dopaminergic neurons and ameliorates motor dysfunction. This study proposes GEPH as a new type of oral functionalized dual-network hydrogel formulation that regulates the gut-brain axis, promoting the clinical application of a new strategy for oral drug administration for gastrointestinal prevention and treatment of PD.

Despite soccer's popularity in Egypt, no comprehensive epidemiological studies have examined injury distribution by playing position. To characterize the injury profile of Egyptian professional soccer players and assess differences by playing position. Cohort study; Level of evidence, 2. A prospective cohort study was conducted across 12 soccer clubs in the Egyptian professional league during the 2022 to 2023 season. Player exposure was recorded using a standardized form. Injuries were documented by medical staff. Data were collected on player demographics, injury profile, and diagnostic modalities. Associations between categorical injury variables and position were assessed using chi-square tests with Cram&#xe9;r V, followed by post hoc analysis using adjusted residuals. Among 384 male players, midfielders were the largest group (38.5%), followed by forwards (27.9%), defenders (22.1%), and goalkeepers (11.5%). There were 422 time-loss injuries (incidence: 2.36/1000 player-hours). Goalkeepers were taller (182 &#xb1; 5 cm) and heavier (74.5 &#xb1; 3.9 kg) than defenders (178 &#xb1; 4 cm; 70.2 &#xb1; 5.1 kg), midfielders (175 &#xb1; 3 cm; 67.2 &#xb1; 4.8 kg), and forwards (175 &#xb1; 4 cm; 67.1 &#xb1; 5.5 kg); all P < .001. Exposure hours differed by position (P = .007): goalkeepers, 403.7 &#xb1; 112.9 h; defenders, 405.1 &#xb1; 108.5 h; midfielders, 447.3 &#xb1; 106.7 h; and forwards, 411.8 &#xb1; 108.9 h. Injury incidence showed no positional variation (P = .07): goalkeepers, 2.54 (IQR, 2.1-3.2); defenders, 2.38 (IQR, 2.2-3.2); midfielders, 2.19 (IQR, 1.9-3.1); and forwards, 2.38 (IQR, 2.1-3.2) per 1000 h. Goalkeepers sustained more nervous system/soft tissue injuries, upper limb/head injuries, contact injuries, first-time training injuries, and minimal degree injuries, and were more often diagnosed by imaging. Among outfield players, defenders were taller and heavier, midfielders had more overstretch injuries with shorter layoffs, and forwards had more severe injuries. Outfield injuries relied more on clinical assessment (36.1%). Our study showed that injury patterns among Egyptian professional soccer players vary significantly by playing position. While muscle/tendon and lower limb injuries are common overall, the 4 positions exhibit distinct anthropometric, injury mechanism, site, severity, and diagnostic profiles. These findings recommend position-specific injury prevention and rehabilitation in Egyptian professional soccer.

Salispina (Salispinaceae, Rhipidiales), a mangrove-associated oomycete, is characterized by uniquely forming aculeolate sporangia. In this study, six Salispina strains were isolated from fallen mangrove leaves collected in coastal sites in the Philippines. A combined strategy of morphology, morphometric analyses, physiology, and multilocus phylogeny assigned the isolates as Salispina lobata (USTCMS 1612, USTCMS 1613, USTCMS 1617) and Salispina hoi (USTCMS 1614, USTCMS 1615, USTCMS 1616). Multilocus phylogenetic analyses consistently assigned the isolates into two strongly supported clades corresponding to the two species. Despite the clear phylogenetic separation, both species exhibited extensive overlaps in sporangial morphology (i.e., shape and spine distribution) across culture conditions. Morphometric principal component analyses revealed broadly overlapping morphospaces, with culture conditions exhibiting a stronger influence on sporangial size than species identity. Agar-grown cultures frequently developed enlarged, lobate to irregular, and extensively aculeolate sporangia, whereas globose to obpyriform forms with apical spines predominated in water cultures. Temperature and salinity growth profiles were broadly overlapping between the two species, showing optimal growth at 30 &#xb0; C and tolerance to moderate salinity levels. These findings demonstrate culture-dependent phenotypic plasticity in Salispina and highlight the importance of integrative taxonomy for delimiting closely related oomycete species with overlapping morphological traits.

First-line (1L) bendamustine plus rituximab (BR) leads to high response rates in follicular lymphoma (FL), but maintaining durable remissions remains challenging. We report the 3-year follow-up from arm 3 of the phase 1b/2 EPCORE NHL-2 trial (NCT04663347) of epcoritamab, a subcutaneously administered CD3&#xd7;CD20 bispecific antibody, combined with BR in patients with newly diagnosed FL. Twenty-five patients received epcoritamab plus BR, followed by epcoritamab monotherapy for up to 2 years. At a median follow-up of 41.3 months, the best overall response and CR rates were both 96%. The median time to CR was 1.5 (range 1-6) months. At 3 years, 87% of responders maintained CR. High CR rates were observed across subgroups, including 100% of patients with bulky disease (&#x2265;7&#x2009;cm), 93% with Follicular Lymphoma International Prognostic Index score &#x2265;3, and 100% with bone marrow involvement. The three-year progression-free survival and overall survival rates were 83% and 96%, respectively. Three patients progressed within 24 months of initiating treatment. Long-term data were consistent with prior reports and the known safety profiles of the individual agents, with no high-grade cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome events. Infections occurred in 92% of patients; COVID-19 was the most common (84%). Overall, 1L FL treatment with epcoritamab plus BR resulted in deep, durable responses beyond 3 years with a consistent safety profile. These results compare favorably with BR alone, although they require confirmation in further studies, and highlight the versatility of epcoritamab in combination with various standards of care and in improving outcomes in FL.

The enrichment of gluten-free fresh pasta with commercial cricket flour (Acheta domesticus) was investigated as a strategy to improve nutritional and technological quality. Pasta formulations containing 0%, 5.8%, and 10% cricket flour were studied. Cricket flour significantly increased protein and mineral content while reducing lipids and carbohydrates. Protein determined by amino acid count, rather than total nitrogen analysis, avoided overestimation due to chitin. Cooking trials revealed shorter optimal cooking times and lower water absorption in enriched samples, while cooking loss remained within acceptable limits. Textural analysis showed reduced firmness in uncooked pasta, although cooking minimized differences among formulations. Cricket flour imparted a darker hue to uncooked pasta that diminished after cooking, consistent with pigment leaching and degradation. Starch digestibility profiles showed moderate effects depending on enrichment level. Protein digestibility remained high (>&#x2009;80%), and amino acid profiling demonstrated improved lysine content. Consumers expressed doubt or negativity toward uncooked samples with 10% cricket flour but responded favorably to 0% and 5.8% formulations. After cooking, all samples received mainly positive evaluations. Overall, A. domesticus flour proved to be a promising ingredient for enhancing protein quality and sustainability of gluten-free fresh pasta while maintaining acceptable technological performance.

Companion animal shelters represent underexplored settings for One Health antimicrobial resistance (AMR) surveillance. This study investigated the recovery, antimicrobial resistance, and genomic features of Enterococcus spp. from shelter dogs and cats in the United Arab Emirates (UAE). Rectal swabs were collected from 230 shelter animals, including 129 dogs and 101 cats, across five shelters in four UAE emirates/cities. Enterococcus isolates were recovered using selective culture and identified by MALDI-TOF MS. Confirmed Enterococcus faecalis and Enterococcus faecium isolates underwent antimicrobial susceptibility testing using Vitek-2. Multidrug-resistant (MDR) and linezolid-resistant isolates were subjected to whole-genome sequencing (WGS) for multilocus sequence typing, resistome analysis, single-nucleotide polymorphism-based phylogeny, phenotype-genotype concordance assessment, and virulence-associated gene profiling. Enterococcus spp. were recovered from 122/230 animals (53.0%; 95% confidence interval: 46.6-59.4), with higher recovery in dogs (71.3% (92/129)) than cats (29.7% (30/101)). Overall, E. faecalis accounted for 63/122 isolates (51.6%) and E. faecium for 59/122 isolates (48.4%). Phenotypic resistance was most frequent for tetracycline (51.6%), erythromycin (30.3%), ciprofloxacin (27.2%), high-level streptomycin (20.5%), and high-level gentamicin (9.8%). All isolates were susceptible to ampicillin, vancomycin, teicoplanin, and tigecycline. MDR was detected in 25/122 isolates (20.5%) and was more frequent among E. faecalis than E. faecium. Linezolid resistance was detected in two isolates recovered from two dogs, one male and one female, housed in the same shelter. WGS of 25 MDR or linezolid-resistant isolates revealed diverse sequence types, including dominant E. faecalis ST16, shelter-associated SNP clusters, and multiple resistance determinants, including erm(B), tet(L), tet(M), aminoglycoside resistance genes, quinolone resistance-associated mutations, and plasmid-predicted optrA in three E. faecalis isolates. Virulence-associated genes were more prominent in E. faecalis, particularly the endocarditis- and biofilm-associated pilus genes involved in adhesion and biofilm formation, together with a putative exoenzyme-associated factor potentially contributing to host interaction and bacterial fitness. Shelter dogs and cats in the UAE carried E. faecalis and E. faecium with phenotypic AMR, MDR profiles, and diverse genomic resistance determinants. The detection of linezolid resistance and plasmid-predicted optrA supports inclusion of shelter companion animals in regional One Health AMR surveillance.

Measures of dynamic constructs in everyday life, captured in intensive longitudinal data (ILD), may function differently across clustering dimensions, leading to measurement noninvariance. Cross-classified factor analysis (CCFA) has been used to test invariance across people and time, but additional dimensions remain largely unexplored. Situational characteristics-both perceived and objective aspects-may affect responses, making them an informative clustering dimension beyond time for measurement invariance investigations in ILD. Using ILD from 225 participants with up to 50 observations each, we applied the CCFA approach to test the measurement invariance of vigor across people and time and, newly, to examine situational characteristics as an alternative clustering dimension. Profiles of perceived situations for clustering observations were derived via latent profile analysis, complemented by more objective situational aspects: location, accompanying people, and main activity. For the vigor items, the measurement parameters varied substantially across participants, indicating noninvariance. While invariance held across time and objective situational properties, measurement parameters varied markedly across perceived situations. These findings highlight the need to move beyond time as a clustering dimension and, crucially, consider people's situation perception when evaluating measurement invariance in ILD. The proposed CCFA usage can be copied to incorporate further clustering dimensions in future research.

The FDA's Guidance for an industry evaluating drug effects on the ability to operate a motor vehicle describes the need to evaluate drug-induced neurobehavioral impairment. However, the guidance does not provide instruction or the means to implement the analysis. The proposed Construct provides a means to operationalize the evaluation of adverse event datasets for this disorder. A noninterventional pharmacoepidemiologic methods development study using routinely collected health data. Preferred terms for the Construct were derived by mapping the domains of concern cited by the Guidance to the corresponding MedDRA terms. Additional terms were derived from the MedDRA preferred terms cited in the warning section of labels from drugs with a warning about driving or operating machinery. The performance of the Construct was evaluated by comparing adverse events for the FDA Adverse Event Reporting System (FAERS) database for drugs considered to be of high risk versus low risk for this condition using descriptive statistics and a nonparametric test. A Construct of PTs (neurobehavioral impairment term list; NITL) was obtained after identification of 55 drugs with the Warning in their FDA-approved label for driving or operating machinery based on drug-induced neurobehavioral impairment. Additional terms not covered in the labels were derived from the five domains of interest cited in the Guidance for a total of 52 PTs. Comparison of the difference in the proportion of FAERS reports with the NITL terms in drugs with and without the relevant labeling was nominally significant (p&#x2009;<&#x2009;0.0001; Kruskal-Wallis ChiSquare approximation). A MedDRA-based Construct was generated for the selection of adverse events related to drug-induced neurobehavioral impairment. The Construct discriminated high- from low-risk drugs based on publicly available adverse event profiles. Further evaluation with clinical trial data will be needed to facilitate its use for signal detection in safety analysis. A method to operationalize the analysis of drug-induced CNS functional impairment This article describes how one may operationalize the FDA's guidance to assess whether a drug causes CNS functional impairment, including (but not limited to) the ability to drive or operate machinery. A set of terms was derived from FDA labels with a warning for this disorder, to ensure face validity, as well as from the FDA Guidance on this topic. A comparison of real-world reports from the FDAs reporting system, FAERS, demonstrated, that the construct developed here was able to differentiate drugs that notably have this feature (neural impairment) from those with less or none.

Cadaveric temporal bones (CTBs) for otologic instruction have become increasingly expensive and scarce. Simulators offer a potentially cost-effective alternative to cadaveric specimens but must possess material characteristics similar to those of cadaveric specimens to be of value. This study evaluated otolaryngologists' interactions with additively manufactured (AM) analogs of cadaveric cortical and trabecular temporal bone and assessed how these interactions correlated with otologic experience. Solid and porous photopolymer samples with unique geometry profiles were created from multiple materials using a Stratasys J750 inkjet 3D printer (Stratasys Ltd., Rehovot, Israel). Surveys using a customized version of the Michigan Standard Simulation Scale Experience (MiSSES) were administered to otolaryngology trainees, otologists, and pediatric otolaryngologists to evaluate AM temporal bone (AMTB) analogs and a CTB. Kendall's tau was used to compare Likert-scale responses to training year and level of otologic experience. Cronbach's &#x3b1; for interrater reliability was calculated based on training. To account for multiple comparisons from correlations, p-values were adjusted using the Benjamini-Hochberg false discovery rate. Nineteen responses from thirteen otolaryngology trainees, two otologists, and four pediatric otolaryngologists with extensive otologic experience were included. All participants consistently rated both AMTB analogs positively for fidelity to cadaveric bone. Increasing surgical experience, as measured by both training year and completed mastoidectomies, was associated with higher survey scores for the AM analogs; however, after adjusting for multiple comparisons, there was no statistically significant association between training year or mastoidectomy experience and survey responses. Otologic training simulators must possess structural and material properties that closely match those of the human temporal bone. All respondents validated both solid and porous AM bony analogs, with a non-significant trend toward higher satisfaction with increasing surgical experience. This study provides the basis for constructing CT-based AMTB models that provide high-fidelity haptic feedback for otologic training.

Static cold storage of cardiac allografts at 4-8&#x2009;&#xb0;C or 10&#x2009;&#xb0;C has yielded promising heart transplant outcomes compared with ice storage. However, direct comparisons between these 2 preservation temperatures are lacking. This dual-center study is the first to compare adult heart transplant outcomes using allografts preserved at 10&#x2009;&#xb0;C versus 4-8&#x2009;&#xb0;C static cold storage. All single-organ, donation-after-brain-death adult heart transplants performed at 2 high-volume centers between January 2020 and April 2025 were retrospectively analyzed. Multiorgan, adult congenital, and donation-after-circulatory-death cases were excluded. A 3:1 nearest-neighbor propensity score matching was applied using a standardized mean difference <20% to create balanced cohorts. Firth logistic regression and quantile regression were used to evaluate categorical and continuous outcomes in unmatched and matched cohorts. Among 365 recipients, 113 received allografts preserved at 10&#x2009;&#xb0;C and 252 at 4-8&#x2009;&#xb0;C. The 10&#x2009;&#xb0;C group had higher donor and recipient risk profiles, including older donors (37 [28-43] versus 31 [24-39] years; P=0.004), greater donor-recipient sex mismatch, and more frequent donor undersizing by predicted heart mass ratio. Recipients in this cohort were older and had more re-sternotomies and higher serum creatinine levels at transplant. Patients in the 4-8&#x2009;&#xb0;C group were more often listed as Status 2. After matching, 10&#x2009;&#xb0;C preservation was associated with less primary graft dysfunction (2 [2.9%] versus 19 [14.6%]; P=0.008), less left and right ventricular dysfunction, reduced new intraaortic balloon pump use, and improved 1-year survival (95.7% versus 86.2%; P=0.02). Other outcomes, including cardiac indices and posttransplant length of stay, were not significantly different between groups. Preservation of cardiac allografts at 10&#x2009;&#xb0;C may yield superior early graft function compared with 4-8&#x2009;&#xb0;C static cold storage. However, further prospective studies are required to delineate the optimal donor heart preservation temperature.