Few studies have assessed work restrictions and unfitness to work simultaneously, particularly on large populations, and evidence on their main influencing factors remains limited. To assess prevalence and risk factors of work restrictions and unfitness to work. We included all visits conducted in occupational health departments of the Cher, over two consecutive years. Visits had to have a conclusion: fitness to work, temporary work restrictions, permanent work restrictions, and unfitness to work. Mixed multinomial models with individual random effects were used. Among the 71,848 occupational health visits, 62,436 had a conclusion. Most (90.6%, 95 CI 90.4 to 90.8%) were fit to work, 3.2% (3.1 to 3.3%) had temporary restrictions, 4.9% (4.7 to 5.1%) had permanent restrictions, and 1.3% (1.2 to 1.4%) were unfit to work. The risk of temporary restrictions was multiplied by 1.69 (1.16 to 2.48) in workers over 55 vs < 25 years old; by 1.74 (1.42 to 2.14) in workers with disabilities; by 1.30 (1.07 to 1.58) for workers with 10-20 vs < 5 years of seniority; and by 1.57 (1.22 to 2.01) in companies with 50-199 vs < 10 workers. The risk of permanent restrictions was multiplied by 2.24 (1.68 to 2.97) in workers over 55 yo; by 1.86 (1.57 to 2.21) in workers with disabilities; by 1.47 (1.05 to 2.06) for qualified workers; by 1.24 (1.05 to 1.46) for workers with 10-20 years of seniority; and by 1.30 (1.07 to 1.58) for workers in companies with 50-199 employees. The risk of unfitness to work decreased with increasing seniority in the company, while a significant interaction between sex and sector of activity was observed for temporary restrictions. Nearly one worker out of ten were unfit to work or had restrictions. The main risk factors for both unfit to work and restrictions were older age, women, and return-to-work visits; whereas lower seniority and smaller companies were risk factors for unfit to work, and longer seniority and bigger companies were risk factors for restrictions.
The June 2023 Supreme Court decision against affirmative action and the November 2024 US election impacted American universities and companies nationwide, many of which have ended their diversity, equity, inclusion (DEI) programs. This review was undertaken to assess the impact of these events, if any, on DEI publications in plastic surgery. It also examines the core issues-barriers to minorities, equity, a leaky pipeline, and racial concordance. Six plastic surgery journals were queried from January 2024 to December 2025 using the search term "diversity." The recommendations and keywords were evaluated. Sixty articles were identified. Publications commonly evaluated racial and gender compositions of plastic surgery trainees, academic surgeons, websites, presentations, and publications. Frequent keywords included: diversity, inclusion, mentorship, equity, underrepresented, disparity, barriers, and a leaky pipeline. The publications uniformly made recommendations in favor of DEI initiatives. The recruitment and sponsorship of underrepresented applicants was a common theme. The plastic surgery literature almost exclusively supports DEI initiatives. However, recent federal lawsuits underscore the risk of continuing racial preferences, which have been ruled unconstitutional by the US Supreme Court. Many keywords and recommendations contrast sharply with the US Supreme Court decision. Moreover, an unrecognized shift in demographics has taken place over the last 4 decades. Whites are now underrepresented in medical schools compared with the US population. It has not been demonstrated that Blacks or Hispanics are underrepresented because of barriers. The evidence shows that there are simply fewer Black and Hispanic applicants entering the pipeline, as opposed to a "leaky pipeline." Racial concordance - aligning providers and patients by race - cannot be condoned. The need for continued pro-DEI publications that overlook the constitutionality and legality of their recommendations warrants reconsideration.
Emotional labor in interpreting has been examined primarily within the boundaries of interpreted encounters, leaving the periods surrounding such encounters underexplored. This gap is particularly significant in outsourced interpreting, where interpreters operate under a dual authority structure. Interpreters have to deal with intensified occupational stress and emotional dissonance as they are simultaneously accountable to language companies and commissioning institutions. How interpreters manage their emotional responses across the full temporal trajectory of an outsourced contract remains insufficiently understood. This study examines the emotional labor of 52 professional Chinese-English interpreters during the 19th Hangzhou Asian Games in 2023 using a sequential explanatory mixed-methods design. The author, embedded in the cohort as both researcher and interpreter, adopted an autoethnographic approach. Sentiment analysis was conducted over group chats along with frequency and TF-IDF analyses to identify emotion-signifying markers. Semi-structured interviews were conducted with two purposively selected interpreters representing contrasting emotional trajectories, with findings used to contextualize and interrogate the sentiment patterns. Sentiment scores were lowest during the Games period (2.48), consistent with heightened emotional dissonance under dual institutional supervision. The use of mitigating expressions peaked during this period, suggesting widespread surface acting in interpreter-language company interactions. Sentiment scores peaked on the final day of the Games (7.90), reflecting behavioral patterns consistent with deep acting and professional inculcation. Interview data revealed that interpreters experiencing emotional dissonance during interpreting subsequently disclosed genuine emotions to trusted peers in inter-interpreting settings as a coping and resource-replenishment strategy, while carefully managing their self-presentation toward the language company throughout. Outsourced interpreting imposes compounded emotional labor demands extending well beyond interpreted encounters. This study introduces the distinction between intra-interpreting and inter-interpreting settings as a conceptual framework for mapping this temporal ecology, and demonstrates that interpreters engage in both visible and invisible forms of emotional labor to mitigate the negative effects of power asymmetry on their well-being and professional practice.
In the biopharmaceutical sector, characterized by rapid technological change and intense market competition, external knowledge search (EKS) has become a strategic necessity to overcome the limitations of closed innovation. However, while EKS is widely studied in developed economies, its underlying mechanisms remain underexplored in emerging biopharmaceutical sectors. This cross-sectional study examines how EKS affects innovation performance (IP) in Iranian biopharmaceutical firms, testing the mediating role of knowledge integration capability (KIC) and the moderating effect of R&D intensity, while controlling for firm size and age. Data were collected using a validated questionnaire completed by 92 senior executives (CEOs, R&D, and Business Development managers) from 44 Iranian biopharmaceutical companies. The model was analyzed using partial least squares structural equation modeling (PLS-SEM) in SmartPLS. EKS significantly enhances both IP (β = 0.462, P < 0.001) and KIC (β = 0.239, P < 0.003). KIC positively influences IP (β = 0.437, P < 0.001) and partially mediates the EKS-IP relationship (indirect effect β = 0.104, P = 0.02). R&D intensity showed no significant moderating effect (β = 0.198, P = 0.10). The model explains 40.5% of IP variance (R² = 0.405). Firm size (β = 0.009, P = 0.924) and age (β = 0.030, P = 0.792) had no significant effects. The impact of EKS on IP depends more on a firm's KIC than on its R&D intensity. This study advances open innovation theory by clarifying how external knowledge is effectively translated into innovation outcomes within an emerging biopharmaceutical context.
To evaluate the reproducibility of quantitative plaque characterization between energy-integrating detector (EID)-CT and photon-counting detector (PCD)-CT, identify reconstruction settings yielding the lowest variability, and model sample-size requirements for trial planning. Patients who underwent coronary CT angiography on dual-source EID-CT and PCD-CT within 30 days were screened retrospectively. EID-CT data were reconstructed using quantitative (Qr40) and vascular (Bv40) kernels, while PCD-CT data were reconstructed with Bv36/40/44 and Qr36/40/44 kernels and quantum iterative reconstruction strengths 2-4. For each plaque component (total, low-attenuation, fibrotic, and calcified), volumes were computed using fixed and adaptive Hounsfield-unit thresholds using an automated deep-learning-based plaque-quantification platform and spatially co-registered. Inter-scanner standard deviation (SD) was calculated, and optimal reconstruction pairs were used for power modeling. Thirty-eight patients (age 68.0 [64.0-72.5] years, 30 men) and 77 vessels were included. Inter-scanner correlations were very strong for total (r = 0.85-0.95), fibrotic (r = 0.74-0.94), and calcified plaque (r = 0.92-0.98), and strong for low-attenuation plaque volumes (r = 0.71-0.85). Mean bias ranged from 8.2 to 164.4 mm³ for total plaque volume. Applying the optimal reconstruction pair (Qr40EID-CT vs. Bv36PCD-CT), inter-scanner SDs were 0.14 (vessel-based) and 0.12 (patient-based). At 80% power and α = 0.05, the estimated sample sizes to detect 5% and 10% changes in total plaque volume were 116 and 29 vessels or 92 and 23 patients per group. Quantitative coronary plaque volumes demonstrated high inter-scanner consistency between EID-CT and PCD-CT under optimized conditions. The dual-level power-modeling framework translates inter-scanner variability into actionable sample-size estimates for study design. Question Quantitative coronary plaque volumes are increasingly used as surrogate biomarkers, yet variability between energy-integrating and photon-counting CT remains a major concern. Findings Harmonized reconstruction settings achieved high inter-scanner consistency with low variability when optimized reconstruction settings and automated plaque quantification are applied. Clinical relevance Standardized coronary plaque quantification across CT technologies enables reliable use of quantitative plaque endpoints, supporting mixed-platform longitudinal trials.
The population of Vietnam remains underrepresented in global genomic databases. Here, we present VN1K, a resource of multi-omics and phenotypic information for 1011 unrelated Vietnamese individuals. We present high-depth short-read whole-genome sequencing data for all samples along with various -omics datasets. Using a high-sensitivity variant detection pipeline, which includes a pangenome graph reference and a deep-learning framework, we identify approximately 42 million variants with 7 million short insertions/deletions and 90 thousand structural variants. VN1K also features a whole-genome methylation profile based on long read sequencing. We create a genotype imputation panel with high accuracy on the Vietnamese population, allowing us to identify variants with significantly different allele frequencies in the Vietnamese population compared to other populations. We establish the functional relevance of some of these variants, particularly those in genes associated with genetic disorders, immune diseases, and drug responses, by integrating the allele frequency differences with known genotype-phenotype associations and clinical annotations. Further, we map various loci related to hepatitis B virus infection, triglyceride levels, LDL-C levels, serum glucose levels, HbA1c levels, and levels of two liver enzymes (ALT and AST). The VN1K dataset is accessible via genome.vinbigdata.org, an integrated platform with both linear and graph-based genome browsers.
While numerous preclinical models emphasize the therapeutic promise of in vitro-induced Tregs (iTregs) for managing inflammatory diseases and promoting tolerance, their translation to clinical use is limited by concerns over phenotypic and functional instability, largely due to an epigenetic profile distinct from thymic Tregs. To address this, we generated and expanded iTregs in the presence of Vitamin C, known to activate TET enzymes that demethylate critical gene regions such as FOXP3. Antigen-specific Tregs were derived from allogeneic co-cultures of monocyte-derived dendritic cells and naïve T cells. After 7 days, allo-Tregs were isolated by FACS and further expanded for 3 weeks with IL-2, TGF-β, rapamycin, with or without Vitamin C supplementation. iTregs treated with Vitamin C displayed heightened FOXP3 expression and sustained high levels of suppressive markers (PD-L1, CD39, TIGIT, and CTLA-4), as well as chemokine receptors linked to allograft homing (CCR4, CCR5, and CXCR3). These cells also demonstrated enhanced allospecific suppression of CD4 + and CD8 + T cell proliferation, even in the presence of pro-inflammatory cytokines. Notably, this proinflammatory milieu did not trigger the production of intracellular cytokines IL-17 and IFN-γ by allo-iTregs, confirming their sustained phenotypic and functional stability. Advanced analysis demonstrated that allo-iTregs possess a unique profile, setting them apart from conventional T cells. Pyrosequencing of the FOXP3 TSDR revealed reduced CpG methylation in Vitamin C-treated iTregs (60.9% at day 21 and 43.5% at day 28) compared to untreated allo-iTregs (85.9% at day 21 and 80.5% at day 28) and naïve T cells (92.8%). In addition, transcriptomic analysis demonstrated that the core Treg transcriptional signature remained largely intact with Vitamin C treatment, irrespective of cytokine exposure, whereas the major transcriptional changes were associated with activation, proliferation, and cell cycle regulation. In summary, Vitamin C enhances both the phenotypic and functional stability of allospecific iTregs, even under proinflammatory conditions, correlating with increased TSDR demethylation, while preserving the transcription of key Treg genes. These results suggest that Vitamin C-treated allospecific iTregs are superior candidates for immunotherapy strategies to promote long-term tolerance in transplant recipients.
Technological advances provide new approaches to improving oncology care. Research indicates that supportive technological tools can benefit children with cancer, and integrating technology into exercise-based interventions may enhance physical activity and reduce fatigue. The FORTEe clinical trial incorporated a motion tracking device (Pixformance) within a broader, individualised exercise intervention for children and young adults (CAYA) with cancer. The device used an inbuilt camera, avatar-led demonstrations, and real-time feedback on exercise form. This FORTEe sub-study explored the perspectives of CAYA with cancer and exercise and healthcare professionals (EHCP) on using this motion tracking technology. CAYA aged 4-21 years and EHCP from five participating centres were eligible. Experiences and perceptions were explored through semi-structured interviews with CAYA and an anonymous online survey for EHCP. The CAYA interviews and open-ended text from the EHCP survey were analysed using an inductive content analysis approach. Ninety CAYA (mean age 11.1 ± 3.7 years; 44.4% female) participated in interviews and 33 EHCP completed the survey. CAYA found the device a novel and useful addition to conventional training, appreciating its variety of exercises and real-time guidance. Some technical issues affected motion detection consistency. EHCP recognised benefits for supervised exercise but highlighted challenges with transport and offline use. CAYA also suggested adding gamification features such as rewards, avatar customisation, and competition. The motion tracking device was well received by both CAYA and EHCP. Findings suggest this technology could complement conventional exercise interventions and provide insights for optimising efficiency, motivation, and user experience in clinical settings. ClinicalTrials.gov (NCT05289739).
Pelvic fractures pose significant surgical challenges due to complex anatomy and proximity to neurovascular structures. This study evaluated the clinical efficacy of artificial intelligence (AI)-assisted Holosight robotic percutaneous screw fixation compared to conventional fluoroscopy-guided internal fixation for pelvic fractures. A retrospective cohort analysis was conducted on 89 patients with pelvic fractures treated between September 2016 and December 2024. Patients were divided into two groups: those who underwent robot-assisted percutaneous screw fixation (Robot group, n = 68) and those who received conventional fluoroscopy-guided screw fixation (Control group, n = 21). In selected cases within the robot group, AI was utilized for preoperative screw trajectory planning. Clinical outcomes including operative time, intraoperative blood loss, fluoroscopy frequency, guidewire insertion attempts, Majeed functional scores, and fracture healing time were compared between groups. The robot-assisted group demonstrated significantly shorter operative time (P < 0.01), reduced intraoperative blood loss (P < 0.01), fewer fluoroscopic exposures (P < 0.01), and fewer guidewire insertion attempts (P < 0.01) compared to the control group. No statistically significant differences were observed in Majeed functional scores between the two groups (P > 0.05). Robot-assisted percutaneous screw fixation for pelvic fractures offers superior surgical precision and reduced invasiveness compared to conventional methods. The integration of AI-based preoperative planning enhances screw trajectory accuracy, potentially reducing the risk of neurovascular injury. While the clinical benefits are promising, larger prospective multicenter trials are warranted to validate these findings.
During contour rotary tillage on sloping terrain, the migration characteristics of the straw-root-soil complex directly affects the effectiveness of straw return and soil sustainability, but the underlying mechanisms remain unclear, hindering the development of specialized rotary tillage equipment. This study uses a self-developed bench test platform for rotary tillage on sloped terrain in hilly and mountainous regions and tracer method to systematically investigate the effects of slope gradient (5°, 10°, 15°), blade shaft rotational speed (200-300 r/min), forward farming speed (0.2-1.0 km/h), and straw content (0.4-1.2 kg/m²) on the migration characteristics of soil aggregates. The test results demonstrate that the forward farming speed is the most effective controllable parameter for suppressing the horizontal and lateral displacement of soil complexes. Increasing the speed from 0.2 km/h to 1.0 km/h can reduce the lateral displacement of straw by 65.3%. An increase in the rotational speed of the blade shaft intensifies the migration of the complex mass, with a notably increased displacement toward the downhill side under steep slope conditions (15°). The slope gradient is the dominant natural factor driving the asymmetric movement of the complex along the lower side of the slope. When the slope increases from 5° to 15°, the lateral displacement of the straw increases by 166%. Straw mulching effectively mitigates tillage-induced soil erosion. When the straw content increases from 0.4 kg/m² to 1.2 kg/m², the lateral soil displacement is reduced by 37.7% to 51.9%. Through orthogonal experiments and response surface analysis, the hierarchical order of the factors influencing soil complex transport was determined. In terms of soil lateral displacement, the primary influencing factor is the slope gradient. With respect to soil horizontal displacement, the dominant factor is the forward farming speed. Corresponding regression prediction models were developed. This study provides the first systematic evaluation of the transport mechanisms governing the straw-root-soil complex on sloped terrain under contour rotary tillage conditions, thereby establishing a theoretical foundation for designing specialized tillage equipment for hillside agriculture and performing quality control in the incorporation of crop residue.
Healthcare technologies are increasingly reshaping how diseases are detected, monitored, treated, and managed across healthcare systems. Advances in artificial intelligence (AI), digital health, remote monitoring, advanced medical devices, and data-driven clinical infrastructures are creating important opportunities to improve prevention, diagnostic accuracy, personalisation of care, workflow efficiency, and long-term healthcare sustainability within the framework of predictive, preventive, personalized, and participatory medicine (4P Medicine). However, despite growing technological sophistication and investment, many innovations fail to achieve scalable and sustainable implementation in real-world clinical environments. This narrative review critically examines the systemic factors that condition the successful translation of healthcare technologies into routine clinical practice, with particular emphasis on the European and Spanish contexts. Rather than focusing exclusively on technological performance, the review analyses the broader regulatory, organisational, financial, ethical, and governance challenges that shape implementation. Key areas discussed include technology transfer, regulatory frameworks, health data governance, and the organisational challenges associated with implementing AI-driven healthcare technologies. The central argument of this review is that the real-world impact of healthcare innovation depends less on technological capability itself than on the capacity of healthcare systems to support validation, regulation, implementation, workforce adaptation, interoperability, and long-term governance. Consequently, the principal challenge for contemporary healthcare systems is no longer simply how to develop new technologies, but how to integrate them safely, equitably, and sustainably into routine clinical practice.
Bacterial fruit blotch (BFB), caused by Acidovorax citrulli, is a devastating seed-borne disease of cucurbit crops. The chemical form of nitrogen fertilizer is a key factor modulating host plant defense and pathogen virulence. In this study, we investigated the effects of three nitrogen regimes on watermelon resistance to BFB by assessing disease severity, seedling biomass, stem vascular morphology, expression of defense-related genes, and in planta growth of A. citrulli. Our results showed that sole ammonium nitrogen application led to a significantly higher disease index compared with nitrate nitrogen alone or a 1:1 nitrate-ammonium mixture. Moreover, nitrate nitrogen application enhanced watermelon seedling growth, calcium uptake, development of stem vascular tissue, and expression of disease resistance-related genes. Temporal dynamics revealed that A. citrulli populations in cotyledons were initially lower under sole ammonium but surpassed nitrate and mixed nitrogen treatments at later infection stages. Furthermore, the expression of type III secretion system genes hrpG and hrpE in A. citrulli from watermelon cotyledons initially decreased and then increased over time, with this fluctuating expression pattern accelerating as the ammonium proportion in the fertilizer increased. This finding suggests that A. citrulli establishes infection more rapidly in watermelon seedlings under sole application of ammonium nitrogen. Together, nitrate nitrogen mitigates BFB severity in watermelon, whereas sole ammonium exacerbates disease likely via combined effects of weakened plant vigor, altered tissue nutrition, and accelerated pathogen infection. This study offers a theoretical foundation for nutrient-based management of watermelon BFB.
To evaluate outcomes of phacoemulsification plus Tanito microhook (TMH) trabeculotomy and assess differences by incision extent, glaucoma severity, and baseline medications classes. Retrospective cohort of 880 open-angle glaucoma eyes (119 exfoliation glaucoma, 761 primary open-angle glaucoma) undergoing phaco-TMH. Success was defined using the American Academy of Ophthalmology (AAO) minimally invasive glaucoma surgery (MIGS) endpoint for cataract-combined procedures ( ≥ 1 medication reduction without intraocular pressure [IOP] increase, or ≥20% IOP reduction to ≤21 mmHg) with no additional glaucoma surgery, hypotony, or loss of light perception. Prespecified alternative IOP-defined success definitions were also evaluated. Outcomes were stratified by incision extent ( < 6 and ≥6 clock hours), baseline glaucoma severity (early, moderate, advanced), and baseline medications classes (0-1, 2, ≥3). Time-to-failure was evaluated using Kaplan-Meier analysis and multivariable Cox proportional hazards models adjusted for surgical year and baseline covariates. Mean (SD) IOP decreased from 17.2 (4.9) mmHg at baseline to 13.1 (3.5) at 12 months and 13.1 (3.9) at 24 months, and medications decreased from 2.6 (1.3) to 2.0 (1.3) at 12 and 24 months. Two-year cumulative success was 59.0% (95% CI, 54.4 to 63.2) by AAO MIGS criteria. In the multivariable Cox model, ≥6 clock hours was not significantly associated with surgical failure compared with <6 clock hours (adjusted HR, 1.14; 95% CI, 0.85 to 1.53; P = 0.367). Higher baseline medication burden was associated with worse success across IOP-defined criteria. In patients undergoing phacoemulsification combined with TMH trabeculotomy, IOP and medication burden improved through 2 years. Surgical success did not differ by incision extent or baseline glaucoma severity, whereas higher baseline medication burden was associated with worse IOP-defined success.
Cordyceps chanhua (Hypocreales: Cordycipitaceae) is a renowned entomopathogenic fungus used as herbal medicine in China. It has been developed as a biopesticide. Previous studies by our research group found that the expression level of the responsive gene Ccebp2163 in C. chanhua was significantly upregulated under induction by the insect hormone the 20-hydroxyecdysone (20E). To improve fungal virulence, an optimized Agrobacterium tumefaciens-mediated transformation system was established for C. chanhua. The 20E-responsive gene Ccebp2163 was overexpressed in C. chanhua, and its insecticidal activity of the 20E-responsive gene Ccebp2163-mediated C. chanhua against larvae of G. mellonella. The minimum inhibitory concentration of hygromycin against C. chanhua was determined to be 300 μg/mL, with 1/2 CZP identified as the suitable transformation medium. Optimized parameters were: Agrobacterium resuspension OD660 = 0.15, co-culture temperature 20 °C, co-culture duration 60 h, acetosyringone concentration 200 μM, and spore suspension concentration 1 × 104 conidia/mL. The transformants expressing Ccebp2163 exhibited an approximately 16-fold increase in gene expression levels. The overexpression (OE) of Ccebp2163 did not significantly affect the morphology, growth rate, or sporulation capacity of C. chanhua, but it enhanced the spore germination rate. Bioassays using the larval dipping method on G. mellonella revealed that the survival rate of larvae treated with OE-Ccebp2163 was significantly lower than that of the WT group. OE-Ccebp2163 suppressed the upregulation of 20E concentration in the host during the mid to late stages of infection. OE-Ccebp2163 infection significantly altered the gut microbiota structure of G. mellonella, with notable changes in the abundance of Proteus, Enterococcus, Salmonella, Commensalibacter, Enterobacter, and Vagococcus. Klebsiella was detected in large quantities exclusively during the mid-infection stage of OE-Ccebp2163. These alterations indicate that gut bacteria responded pronouncedly to Ccebp2163 at mid-infection, with gradual community restoration later.
Tertiary lymphoid structures (TLSs) are associated with improved responses to immune checkpoint blockade across solid tumours1,2, but how they impact the phenotypic properties of tumour-specific T cells remains unclear. Here we found, across 24 treatment-naive renal cell carcinoma (RCC) tumours, that TLS-containing tumours are more heavily infiltrated by exhausted CD8+ T cells and have a reduced terminal exhaustion transcriptional program compared with TLS- tumours. Specificity screening of 554 T cell clonotypes expanded within the microenvironment of 6 RCC tumours revealed 82 TCRs that were reactive against tumour cells and/or RCC antigens. A subset of tumour-specific T cell clonotypes (12%) was enriched within TLSs, and these expressed an increased program of stem-like progenitor exhaustion, associated with favourable anti-tumour immunity. However, in 60 independent RCC tumours, macrophages within tumour margins of TLS-containing tumours had an inferred immunosuppressive phenotype and were colocalized with exhausted putative tumour-reactive T cells in a subgroup that was further analysed, therefore supporting this mode of immune evasion as a counterbalance to T cell immune pressure. Our data reveal that TLSs are reservoirs of tumour-specific T cells with stem-like progenitor features that could be leveraged by T cell immunotherapies.
Agitation is a common and distressing phenomenon across neurocognitive disorders (NCD). It is linked to decreased quality of life of the person with NCD, cognitive and functional decline, increased health-care utilization and institutionalization rates, and substantial burden for family carers and care professionals. Its management is particularly challenging. The objective of this International Psychogeriatric Association's (IPA) task force was to synthesize recent advances in nomenclature and assessment, epidemiology, progression, etiology, detection, impact, approaches to managing agitation; and to make recommendations to guide IPA's next 10-year strategy. A multidisciplinary expert workgroup met multiple times virtually and during the 2024 IPA Congress in person to discuss the current scientific and clinical practice landscape for agitation in NCD. The group integrated evidence about validated behavioral measures, biomarkers, digital monitoring, psychosocial and environmental interventions, and pharmacological options. Agitation is attributed to disruptions in fronto-limbic circuitry with contributions from neuroimmune dysregulation, neurotransmitter alterations, and mitochondrial dysfunction, and various psychosocial and environmental factors. Psychosocial and environmental strategies can reduce agitation, though magnitude and durability of responses vary. Pharmacological options can have short-term benefits but carry risks that require strict patient selection, counseling, monitoring and medication stewardship. Approved medications based on controlled clinical trials remain limited. Care and support in agitation in NCD should involve the implementation of person-centered, rights-based psychosocial and environmental approaches, with time-limited pharmacological adjuncts as second-line. Key evidence gaps include head-to-head and longer-term trials, active safety surveillance, validated agitation measures, and equity-focused implementation across settings and cultures.
To characterize the CT imaging features of normal parathyroid glands validated by ultrasonography (US) and intraoperative findings. This retrospective analysis used prospectively collected data from patients who underwent total thyroidectomy for benign or malignant thyroid nodules between February 1, 2023, and January 1, 2024. Patients were excluded if they had lateral neck node metastasis, renal disease, Graves' disease, biochemical parathyroid dysfunction, age < 19 or > 80 years, or insufficient imaging data. Normal parathyroid glands were defined as glands visualized on preoperative US and intraoperatively identified as non-enlarged glands without gross pathological abnormalities. Patients who underwent preoperative thyroid CT were included. CT images were independently reviewed by two radiologists to evaluate gland size, location, attenuation, and dynamic enhancement patterns. Interobserver agreement for attenuation measurements was assessed using intraclass correlation coefficients (ICC). Thirty-eight patients with 117 normal parathyroid glands confirmed by US-intraoperative correlation were included. Inferior glands showed a higher CT identification rate than superior glands (94.4% vs. 87%), although the difference was not statistically significant. Superior glands were consistently located at the tracheoesophageal groove, whereas inferior glands demonstrated greater positional variability (p < 0.001). Most glands (96.6%) showed arterial enhancement followed by washout on venous-phase imaging and exhibited lower attenuation than the thyroid gland. Interobserver agreement was excellent (ICC, 0.95-0.96). Normal parathyroid glands demonstrated characteristic anatomical distribution and dynamic enhancement patterns on CT in this highly selected surgical cohort. Further validation in broader and independent populations is warranted. Question The CT appearance of normal parathyroid glands has not been well established. Findings Normal parathyroid glands demonstrated characteristic arterial enhancement with washout on venous-phase and lower attenuation than the thyroid gland on CT. Superior parathyroid glands demonstrate a relatively constant location at the tracheoesophageal groove, whereas inferior glands show greater positional variability. Clinical relevance Familiarity with the normal CT appearance of parathyroid glands may help avoid confusion with other enhancing cervical lesions.
Tacrolimus therapeutic drug monitoring after kidney transplantation is primarily guided by the pre-dose concentration (C0), assuming it reflects overall drug exposure. At the same time, the tacrolimus concentration-to-dose ratio (C0/dose) has emerged as a marker associated with clinical outcomes after transplantation, suggesting that differences in peak (maximum concentration [Cmax]) and total tacrolimus exposure (area under the concentration-time curve from 0 to 24 h [AUC0-24h]) may not be fully captured by C0 alone. In 534 kidney transplant recipients followed for up to 13 months post-transplantation, 635 tacrolimus pharmacokinetic profiles with corresponding C0 values were analyzed. The C0/dose category was defined using the C0/dose ratio and classified as fast (<1.05 ng·mL⁻1·mg⁻1, n = 344), intermediate (1.05-1.53, n = 127), or slow (≥1.54, n = 164). Analyses were restricted to measurements with C0 between 5.0 and 6.0 ng/mL to compare Cmax and AUC0-24h across C0/dose categories and tacrolimus formulations (immediate release vs extended release) using linear mixed-effects models. Sensitivity analyses evaluated C0-adjusted Cmax and AUC0-24h in the full cohort (4271 pharmacokinetic profiles) and assessed consistency when Cmax was predicted using population pharmacokinetic models. Despite comparable C0 levels, the fast C0/dose category was associated with substantially higher tacrolimus doses and had higher peak concentration and total exposure. Under immediate-release tacrolimus, Cmax and AUC0-24h were 30 and 18% higher, respectively, compared with the slow category. Under extended-release tacrolimus, differences were more pronounced, with 86% higher Cmax (estimate: 1.86, 95% confidence interval 1.61-2.13) and 46% higher AUC0-24h (estimate: 1.45, 95% confidence interval 1.35-1.55). The intermediate category showed a smaller but consistent increase in exposure. Higher Cmax and AUC0-24h relative to C0 in fast metabolizers remained consistent in the full cohort and when Cmax was model predicted. Tacrolimus C0 alone incompletely reflects the full pharmacokinetic profile and may miss clinically relevant peak-related toxicity. The C0/dose ratio may help identify patients with disproportionate exposure, in whom more individualized therapeutic drug monitoring beyond C0 monitoring is recommended.
B cell-targeting chimeric antigen receptor (CAR) T cell therapy has shown efficacy in autoimmune diseases but is limited by toxicity, complex manufacturing, and high cost. Umbilical cord blood (UCB)-derived CAR-natural killer (CAR-NK) cells offer an alternative "off-the-shelf" platform with a potentially superior safety profile. We developed a UCB-derived CD19-targeting CAR-NK product incorporating the 4-1BB costimulatory domain (CD19-BBz) and evaluated its safety and efficacy in refractory systemic lupus erythematosus (SLE). This study was registered at ClinicalTrials.gov (ClinicalTrials.gov: NCT06421701). In this phase 1, open-label, dose-escalation study, five patients with refractory SLE received lymphodepletion chemotherapy followed by infusion of allogeneic CD19-BBz CAR-NK cells. Dosing followed a step-up regimen, with the highest total dose being 1.35 × 109 cells-2.2- to 3.3-fold lower than the highest doses previously reported for CAR-NK therapy in SLE. Treatment was exceptionally well tolerated. No grade ≥2 cytokine release syndrome and no neurotoxicity or graft-versus-host disease occurred. All patients achieved profound B cell depletion, with nadir circulating B cell levels ranging from 0.16 to 1.44 cells/μL. All patients achieved an SLE Responder Index-4 response by month 1. The lupus low disease activity state was attained in all patients by month 9, and 80% (4/5) met the definition of remission in SLE by the last follow-up (median, 12 months). Reconstituted B cells displayed a sustained naive-dominant repertoire. Low-dose UCB-derived CD19-BBz CAR-NK cell therapy demonstrated an excellent safety profile and induced robust, durable clinical responses in refractory SLE. This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0501300).
To identify serum lipid biomarkers for acute pulmonary embolism (APE) and evaluate their diagnostic value, and to investigate the impact of glycerol monolaurate (GML) and glycerol monooleate (GMO) on cytotoxic T cell function. A total of 436 subjects, including APE, healthy controls, and patients with related diseases, were enrolled. Serum samples were subjected to pseudotargeted lipidomics to screen differential lipid species. Targeted LC-MS/MS analysis was used to validate the GML and GMO levels. Flow cytometry was used to assess cytotoxic T cell markers such as granzyme B, perforin, and granulysin. In vitro experiments examined the inhibitory effect of GML and GMO on Notch1 signaling and cytotoxic protein expression in T cells. ROC curve analyses were performed to evaluate the diagnostic performance of lipid biomarkers. Pseudotargeted lipidomics identified 203 upregulated and 57 downregulated serum lipids in APE versus controls. Targeted LC-MS/MS confirmed significantly elevated serum GML and GMO in APE compared with healthy controls and other diseases. Serum GML and GMO were correlated with clinical risk stratification. ROC analyses showed high sensitivity and specificity for GML and GMO individually. Cytotoxic T cells from APE patients exhibited decreased granzyme B, perforin and granulysin. In vitro, GML and GMO reduced Notch1 and granzyme B expression in T cells. Elevated serum GML and GMO could serve as effective diagnostic biomarkers for APE, correlating with disease severity. They were likely to impair cytotoxic T cell function by downregulating Notch1 signaling and cytotoxic proteins, suggesting their involvement in APE pathogenesis.