Neuropsychological (NP) tests are multi-domain in execution. Reliance on a single score representing specific domains obscures the detection of subtle cognitive changes and increases risk of inaccurate assessment. Rooted in the Boston Process Approach (BPA), the Framingham Heart Study (FHS) captures multi-dimensional errors and process features within and across NP tests. We examined these BPA variables in community-dwelling older adults. We analyzed data from 2363 dementia-free participants aged 60 and above. Exploratory and confirmatory factor analyses used Kemeny covariance structures. Measurement invariance was estimated across age, sex, and education groups. We assessed the impact of demographics on latent factors, and the ability of these factors to predict future conversion to all-cause dementia. We trained machine learning (ML) models to compare NP and BPA data. Participants were older adults (mean age 71.5 ± 8.7 years), primarily female (54.2%), and non-Hispanic White (96.5%). The bifactor model was the only model with adequate fit (CFI = 0.96, RMSEA = 0.03). General and specific factors captured ability for accurate and strategic responses, test-specific variance, and nuanced executive and semantic processes distributed across tests. Higher general ability and stronger verbatim story recall were associated with a reduced likelihood of developing all-cause dementia (general: OR = 0.15, 95% CI [0.12-0.86]; recall: OR = 0.24, 95% CI [0.23-0.90]) over a median of 5.2 years. With NP/BPA data, ML models identified >99% of 222 converters. This study highlights the strengths of NP/BPA data. Multidimensional cognitive features may enhance sensitivity to early changes predictive of incipient dementia.
Inter-basin water diversion projects are crucial for mitigating the spatial imbalance between water supply and demand. However, their operation is challenged by complex uncertainties arising from climate variability and hydrological fluctuations. To address these challenges, this study develops a multi-objective risk operation model and decision-making model for inter-basin water diversion projects. At the operational level, a multi-objective risk operation model is formulated to minimize both the total water shortage in water-receiving regions and the total transfer cost at pumping stations, while explicitly accounting for forecast uncertainties in source water availability. The model is solved by the Multi-Objective Mantis Search Algorithm (MOMSA) to generate a set of non-dominated solutions. At the decision level, a comprehensive risk decision-making model is established by integrating the Kemeny Median Indicator Ranks Accordance (KEMIRA) framework with the Best-Worst Method (BWM) for expert input and Data Envelopment Analysis (DEA) for dynamic weighting. The proposed framework is applied to the "One Gate Three Lines " project, a major water diversion project in China. The results show that non-dominated solutions under uncertainties effectively encompass the deterministic solution space. Compared with the deterministic case, the average water shortage rate reduces by 1.92 %, while the average transfer cost increased by CNY 63,300 due to uncertainty considerations. The risk decision-making model effectively captures multiscale risks and supports adaptive, risk-informed decision making for inter-basin water diversion operations under climate variability.
We evaluated a Remote Surgical Training model (ReST) in which the tutor operates a second da Vinci Xi console from an adjacent room while preserving integrated audio and the ability to take over control. A comparative feasibility study was conducted at RAIN (A. Cardarelli Hospital, Naples, Italy) between March 2021 and April 2023 using a porcine model. Thirty training sessions were analysed (15 ReST, 15 in-room dual-console controls). Trainee performance was assessed with the Global Evaluative Assessment of Robotic Skills (GEARS); post-session surveys captured perceptions, tutor-trainee agreement (weighted Cohen’s κ), priority rankings (Kemeny aggregation with τX) and satisfaction. GEARS internal consistency was acceptable (Cronbach’s α overall 0.805; control 0.837; ReST 0.768). No statistically significant differences were observed for the GEARS total score (Mann-Whitney U = 105, p = 0.595) or domains (p = 0.074–0.683). Tutor-trainee agreement was significant for three interaction items: ease of teaching/training (p = 0.004), ability to follow the trainee’s actions (p = 0.011) and overall interaction quality (p = 0.014). Priority rankings in both roles emphasised clarity of instruction and takeover capability, while physical proximity ranked lowest. Tutors and trainers reported high satisfaction in both groups; one trainee reported low satisfaction in the ReST group. Adjacent-room ReST with takeover capability was feasible in this porcine-model training setting and showed no observed performance decrement compared with conventional in-room dual-console training. These findings should not be interpreted as proof of equivalence or as validation of true long-distance teleproctoring; further work is required for larger samples, participant-level baseline adjustment, and longer-distance configurations.
Objective: Online patient education materials (OPEMs) are important resources for patients seeking health information. While the National Institutes of Health (NIH) and American Medical Association (AMA) recommend a sixth-grade readability level for OPEMs, commonly available material often exceeds such criteria. Large language models (LLMs), such as ChatGPT and Gemini, have emerged as tools for health education with potential applications in simplification of health material. This study assesses the utility of ChatGPT and Gemini in enhancing the readability of OPEMs for peripheral nerve surgeries. Methods: Eleven common peripheral nerve surgeries were used as online search terms. The first 20 unique search results were assessed; results were excluded if they did not include patient-facing material. ChatGPT and Gemini were instructed to rewrite the text of the OPEM at or below a sixth-grade reading level. Readability metrics were calculated for original OPEMs, alongside ChatGPT and Gemini rewrites. LLM responses were reviewed for accuracy/quality (five-point scale) and comprehensiveness (three-point scale) using predefined criteria. Results: A total of 220 websites were assessed. In total, 155 OPEMs met the inclusion criteria; 65 websites were excluded because they were academic journal articles or other provider-facing materials. The average Flesch-Kincaid grade level (FKGL) of OPEMs was 11.3, significantly greater than the NIH/AMA-sixth grade recommendations (p < 0.001). The average FKGL of ChatGPT rewrites was significantly lower than that of OPEMs (11.3 vs. 7.5, p < 0.001), as was the average FKGL of Gemini rewrites (11.3 vs. 5.6, p < 0.001). ChatGPT rewrites were of higher accuracy/quality (4.5/5.0 vs. 4.0/5.0, p < 0.001) and comprehensiveness (2.0/3.0 vs. 1.0/3.0, p < 0.001) relative to Gemini rewrites. Conclusions: The readability of online patient education materials for peripheral nerve surgery significantly exceeded NIH/AMA recommendations. ChatGPT and Gemini were able to significantly simplify the reading level of these OPEMs. LLMs may serve as tools to improve the readability of peripheral nerve surgery OPEMs.
The role of tumor-infiltrating B cells (TIL-Bs) in shaping anti-tumor responses in the context of immune checkpoint blockade remains incompletely understood. Here, we interrogate the humoral response in resected lung tumors from patients with non-small cell lung cancer (NSCLC) treated with neoadjuvant PD-1 blockade. We find that tumors orchestrate tertiary lymphoid structures with CD138+ plasma cells, from which we clone recombinant monoclonal antibodies (mAbs) using B cell receptors (BCRs) exhibiting somatic hypermutation and class switching. Several mAbs bind cell-surface citrullinated proteins, characteristic of cancer cells. Chimeric antigen receptor (CAR) T redirected with the soluble chain fragment variable (scFv) of our lead candidate antibody (PC-1) specifically target tumor cells and tumor-promoting myeloid cells in vivo without off-target activity. Moreover, ablation of the citrullination enzyme PADI2 in tumor-bearing mice eliminates reactivity to PC-1 and cytotoxic killing by the CAR. Our results implicate a therapeutic potential for tumor-infiltrating plasma cells that may be harnessed for cancer treatment.
Early detection remains the most powerful intervention in cutaneous oncology, yet it depends on accurate recognition across very different clinical contexts-from rare, rapidly progressive neuroendocrine tumors to common melanocytic lesions that patients first notice at home. This month's selected articles span this spectrum, highlighting practical dermoscopic clues for Merkel cell carcinoma, pragmatic surgical decision-making for anatomically constrained sites, and emerging approaches to melanoma risk stratification and public education. Together, they underscore a single message: better outcomes require both sharper clinical pattern recognition and clearer, more personalized risk communication.
Noninvasive imaging techniques are playing an increasingly significant role in dermatologic diagnosis, risk evaluation, and the monitoring of therapeutic outcomes. In the August issue of the Journal, we highlight how dermoscopy, onychoscopy, trichoscopy, and line-field confocal optical coherence tomography (LC-OCT) can refine clinical decision-making across acral melanocytic lesions, onycholysis, primary cicatricial alopecia, and hyperkeratotic actinic keratoses. These papers show that imaging is most useful when tailored to anatomical and clinical context, advancing standardized and clinically actionable imaging approaches.
Itch is a common and challenging symptom in dermatology, present in various conditions from idiopathic cases to chronic inflammatory diseases, systemic disease associations, and treatment-related eruptions in oncology and immunology. This month's selected articles focus on the treatment options of chronic pruritus, prurigo nodularis, and the impact of immunomodulatory therapies. Overall, these studies emphasize that pruritus often involves more than just the skin, requiring multidisciplinary care.
Targeted therapeutic advances in autoimmune blistering diseases have renewed attention to diagnostic precision, disease classification, and clinically relevant subgroups. In this issue, we focus on two aspects of this evolving field: recent developments in the diagnostics of autoimmune blistering diseases and the clinical features of checkpoint inhibitor-associated autoimmune blistering diseases and their treatment options. These contributions illustrate how therapeutic innovation, diagnostic progress, and recognition of emerging clinical contexts are closely interconnected.
To assess the proportion of unresectable colorectal liver metastasis (CRLM) patients meeting liver transplant (LT) criteria and define their outcomes following hepatic artery infusion pump (HAIP) chemotherapy. The TransMet RCT demonstrates improved survival with combined LT and systemic versus systemic therapy alone; however, systemic therapy might not be the best control. This study assesses outcomes in similarly selected patients treated with HAIP. We identified unresectable CRLM patients treated with HAIP between 2006-2016. Modified TransMet/SECA-II selection criteria were applied, including pre-treatment with at least 1st line chemotherapy before HAIP placement. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier methods from HAIP placement. Of 483 patients identified, 23 (4.8%) were LT-eligible. Median age was 52 years (range:37,73). Primary tumors were right-sided in 6 (23%) and rectal in 12 (52%). Eight (38%) patients were KRASmut. Median CRLM size and number were 28 mm (range:9,92) and 11 (range:4,38). Median pre-HAIP chemotherapy cycles were 8 (range:3,20), and most patients were on 1st (15,65%) or 2nd (7,30%) line therapy. Conversion to resection occurred in 18 (78%) patients after a median of 5 (range:1,20) HAIP chemotherapy cycles. With a median follow-up time of 98 (95%CI:96,NR) months, median OS was 61 (95%CI:36,92) months, and 5-year OS was 53% (95%CI:36,79). Median PFS was 13 (95%CI:10,22) months. In this cohort, less than 5% of unresectable CRLM patients were LT-eligible. After treatment with HAIP chemotherapy, overall 5-year survival was 53%, similar to a recent LT randomized trial (5-year OS 57%).
External insults can cause immune activation in immune cells, resulting in persistent molecular changes that can lead to innate immune memory changes in these cells. This study investigated the potential for cellular reprogramming in response to Cutibacterium acnes in keratinocytes. We exposed normal human epidermal keratinocytes (NHEKs) obtained by mammoplasty (denoted as NHEK-B) or abdominoplasty (denoted as NHEK-A) to C acnes, followed by stimulation with Pam3CSK4 to assess immune activation and cellular responses. In NHEK-B cells, C acnes and Pam3CSK4 treatment induced trained immunity-type responses, higher expression of selected immune target genes, and a diminished response compared with trained and Pam3CSK4-induced NHEK-A cells. Total transcriptome analysis delineated regional differences, with the activation of immune-related pathways in NHEK-B cells and alterations in keratinocyte differentiation processes in NHEK-A cells. We detected differences in metabolic regulation, and utilizing pharmacological inhibitors, we demonstrated the necessity of the optimal regulation of histone acetylation and DNA methylation for the changes mentioned earlier. This study demonstrated that C acnes triggers innate immune memory processes in keratinocytes, characterized by signaling, epigenetic, and metabolic reprogramming that influences cellular responses to subsequent stimuli. The observation that analogous insults might elicit skin region-specific responses offers insights into the etiology and mechanisms underlying common inflammatory skin diseases.
Hepatic artery infusion chemotherapy (HAIC) has shown survival benefits in unresectable intrahepatic cholangiocarcinoma (IHC). The optimal timing of HAIC remains uncertain. This study compares outcomes with HAIC when used as first-line treatment compared with as second-line treatment in patients with advanced IHC. A total of 722 patients with biopsy-proven IHC treated from 2000 to 2018 were evaluated. Patients undergoing upfront resection or with metastatic disease beyond regional lymph nodes were excluded. Overall survival (OS) was calculated from the date of diagnosis using Kaplan-Meier methods. To assess the impact of timing of HAIC on survival, multi-state models using parametric Cox regression and separate cause-specific hazard models were used to estimate mean survival time from diagnosis. A total of 336 patients eligible for HAIC were analyzed: 137 received first-line HAIC and 199 received first-line systemic chemotherapy (SYS). The median OS of all patients was 22 months (95% confidence interval [CI] 20-25), and HAIC given at any time was associated with reduced all-cause mortality by 34% (hazard ratio [HR] 0.66; 95% CI 0.52-0.84). Of 199 patients who received first-line SYS, 59 received second-line HAIC, 73 received second-line SYS, and 67 did not receive further treatment. Multi-states analyses revealed that first-line HAIC was associated with a mean survival time of 33 months, compared with 36 months for second-line HAIC and 22 months for those who received second-line SYS. HAIC is associated with a survival benefit whether administered in the first-line or second-line setting, supporting its use as an effective treatment option in unresectable IHC.
Hepatic artery infusion pump chemotherapy (HAIC) improves colorectal liver metastasis (CRLM) outcomes, but treatment-associated biliary sclerosis (BS) is a major complication. This study evaluates the incidence of and risk factors for BS after HAIC for CRLM. This was a single-center retrospective analysis including all patients with CRLM treated with floxuridine between 2000 and 2022. The primary outcome was BS, intractable hyperbilirubinemia, and/or biliary stricture not caused by cancer progression requiring percutaneous or endoscopic stenting or drainage. BS was analyzed using competing risk methods where death was the competing event. Between 2000 and 2022, a total of 2239 patients received HAIC for CRLM, 48% (n=1067) received adjuvant HAIC and 52% (n=1172) were unresectable. There were 128 (6% at 60 months) BS events, and rates did not differ between adjuvant (n=66) and unresectable (n=62) groups (60-month estimate: 6% [95% confidence interval (CI) 5-8] vs 6% [95% CI 4-7]; p=0.362). Operative variables, variant hepatic arterial anatomy, non-gastroduodenal artery cannulation, and extrahepatic perfusion were not associated with BS. In adjuvant cases, BS risk increased with each cycle (hazard ratio [HR] 1.123, p=0.003) and every 100 mg of cumulative floxuridine (HR 1.087, p<0.001) controlling for concurrent colorectal resection and variant vessel ligation. Among unresectable patients, each cycle (HR 1.087, p<0.001) and every 100 mg of cumulative floxuridine (HR 1.054, p<0.001) increased BS risk, controlling for race and concurrent colorectal resection. The incidence of BS after HAIC for CRLM is 6% after 60 months and does not differ in the adjuvant and unresectable setting due to meaningful differences in survival. Cumulative floxuridine dose and number of HAIC cycles were independently associated with increased BS risk.
Allergic contact dermatitis (ACD) is a frequent inflammatory skin disease with limited therapeutic options. While neuronal Transient Receptor Potential Ankyrin 1 (TRPA1) has been implicated in ACD, the role of keratinocyte TRPA1 remains unclear. We investigated whether allergen binding to keratinocyte TRPA1 drives cytotoxicity, cytokine release and inflammatory amplification. We combined in vivo oxazolone-induced hypersensitivity in wild-type and Trpa1 knockout mice with pharmacological inhibition by HC-030031, in vitro assays using TRPA1-expressing Chinese hamster ovary (CHO) cells and primary keratinocytes, RNAscope localisation in human and murine skin, cytokine profiling and in silico docking analyses of allergen-TRPA1 interactions. TRPA1 deletion or antagonism markedly reduced oxazolone-induced ear swelling, vascular responses and histopathology. Strong contact sensitisers (2,4-dinitrochlorobenzene [DNCB], 2,4-dinitrofluorobenzene [DNFB], oxazolone and formaldehyde) activated TRPA1, inducing Ca2+ influx, cytotoxicity and IL-1α release, effects absent in Trpa1-deficient cells and inhibited by HC-030031. RNAscope confirmed keratinocyte TRPA1 expression in human and mouse skin. Docking revealed allergen-specific binding modes, where covalent cysteine modification and A-loop stabilisation correlated with potency. Consistent with these observations allergen-induced ROS, which also target the cysteine cluster of TRPA1, may further lower the channel's activation threshold and thereby amplify allergen-driven cytotoxicity. Keratinocyte TRPA1 integrates direct allergen binding with ROS-mediated sensitisation to drive cytotoxicity and IL-1α release. This dual mechanism helps explain sensitiser potency and positions TRPA1 antagonism as a promising therapeutic approach in ACD, while providing a framework for chemical risk assessment.
Major advances have broadened the therapeutic landscape of inflammatory skin diseases. In psoriasis, alongside the tyrosine kinase 2 (TYK2) inhibitor deucravacitinib, the United States Food and Drug Administration (FDA) has approved the first oral interleukin-23 (IL-23) receptor antagonist peptide, icotrokinra. In atopic dermatitis, new data have emerged on stapokibart, an interleukin-4 receptor alpha subunit (IL-4Rα) inhibitor introduced in China. In hidradenitis suppurativa, glucagon-like peptide-1 receptor agonists (GLP-1 RA) are also gaining increasing attention as adjunctive therapy.
In an era of antimicrobial resistance (AMR), identifying alternatives to conventional antibiotics in livestock farming is vital for veterinary medicine and public health. Due to the constant exposure to pathogens and the need for optimal productivity, maintaining gut homeostasis is essential in poultry. Therefore, investigating antimicrobial alternatives that can support gut health is of key importance. Host defense peptides (HDPs) have been identified as promising candidates due to their beneficial effects on the gut; however, there is still much to clarify regarding the individual peptides' mechanism of action. In the present study, the HDP cecropin A (CecA) was applied to chicken-derived ex vivo ileal explant cultures to examine its impact on immune response and tight junction (TJ) protein expression. CecA was applied at 3.125 and 6.25 µg/mL concentrations, either alone (Cec-low and Cec-high) or in polyinosinic-polycytidylic acid (Poly I:C, 50 µg/mL)-induced inflammatory conditions (PI:C + Cec-low and PI:C + Cec-high). The experiment revealed that CecA had no impact on cell viability, as reflected by unchanged metabolic activity and extracellular lactate dehydrogenase activity. Regarding the immune state, Cec-high and PI:C + Cec-high increased the production of interleukin (IL)-2, whereas IL-6 concentration was decreased by PI:C + Cec-low treatment. Furthermore, Cec-high elevated the intracellular expression of the TJ protein claudin-3. In conclusion, CecA displayed immunomodulatory activity in chicken intestinal cells and supported epithelial integrity without exerting cytotoxic effects.
Hepatic artery infusion (HAI) chemotherapy improves hepatic recurrence rates and survival for patients with colorectal liver metastases (CRLM) in the adjuvant setting. Dose reductions of HAI floxuridine (FUDR) are common due to hepatotoxicity. The impact of these dose adjustments on patient outcomes is unclear. This study retrospectively analyzed patients who underwent adjuvant HAI pump placement for CRLM between January 2000 and October 2017. The study enrolled only patients intended to receive six cycles of FUDR. Hepatic recurrence and overall survival (OS) were correlated with the number of FUDR cycles and dose density, defined as the actual FUDR dose received divided by the expected total during six cycles. The study identified 344 patients who met the inclusion criteria. Of these 344 patients, 173 received up to four cycles of FUDR and 171 received > 4 cycles. The median dose density was 0.42 (range, 0.17-1.13). Competing risk analysis of the two groups showed no difference in risk for liver recurrence (p = 0.357). Neither the cycles of FUDR received (hazard ratio [HR], 0.93; p = 0.237) nor the FUDR dose density (HR, 1.26; p = 0.631) was associated with hepatic recurrence in the univariable analysis. Dose density was not associated with improved OS (HR, 1.35; p = 0.486), although in the multivariable analysis, increased FUDR cycles were associated with improved OS (HR, 0.86; p = 0.005). In adjuvant HAI therapy for CRLM, neither the number of FUDR cycles nor the dose density of FUDR is associated with hepatic recurrence.
The February issue of the IJD reflects the growing complexity of managing chronic inflammatory skin diseases in the era of targeted therapies. Covering atopic dermatitis, psoriasis, and hidradenitis suppurativa, the featured papers address clinically relevant questions related to treatment safety, disease-associated comorbidities, and long-term therapeutic outcomes. Key topics include vaccination strategies in patients receiving Janus kinase inhibitors, ocular complications associated with atopic dermatitis, malignancy considerations in biologic-treated psoriasis, long-term efficacy and safety of selective tyrosine kinase 2 (TYK2) inhibition, and dose optimization of biologic therapy in hidradenitis suppurativa. Together, these contributions highlight a shift toward personalized, risk-aware management strategies that balance sustained efficacy with long-term safety in chronic inflammatory dermatoses.
This study compares the psychometric properties of eight EQ-5D-5L bolt-ons in the general populations from two culturally distinct countries: China (CN) and the Netherlands (NL). As part of the EQ-DAPHNIE project, cross-sectional online surveys were conducted in 2024 with quota-based samples approximating the adult population from CN and the NL. Participants completed EQ-5D-5L, eight bolt-ons (vision, hearing, breathing, sleep, tiredness, social relationships, self-confidence, and cognition/memory), and sociodemographic and health-related questions. Psychometric assessments included ceiling, convergent/divergent validity, structural validity, known-groups validity, and explanatory power. The ceiling of the EQ-5D-5L was higher in CN (45%) than NL (32%). In both countries, vision, tiredness, and sleep bolt-ons reduced the ceiling the most, while breathing had the least effect. Tiredness and self-confidence bolt-ons demonstrated stronger associations with the core dimensions. Several bolt-ons significantly improved known-groups validity. In CN, hearing showed stronger known-groups discrimination across age groups, while self-confidence had the greatest impact in NL. The core dimensions explained more variance in EQ VAS in NL (37%) than CN (25%). In both countries, tiredness and self-confidence contributed most to increasing the variance explained. Principal component analysis (PCA) confirmed a seven-factor structure, with all bolt-ons loading separately from the core dimensions. In country-specific PCAs, no major differences were observed between CN and NL. While certain bolt-ons demonstrated robust psychometric properties in both countries, others showed greater context dependence. These findings add to the growing body of evidence supporting the development of the experimental EQ-5D Bolt-on Toolbox.