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The incidence of herpes zoster (HZ) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is significantly higher than that of the general public. Although routine antiviral prophylaxis is recommended, late-onset HZ has been highlighted, yet limited information is known about its clinical features and predictors. Here, we conducted a retrospective nested case-control study to identify patients with late-onset HZ, defined as a diagnosis of HZ after 1 year of transplantation, among allo-HSCT recipients between 2012 and 2017 at Peking University People's Hospital. Three controls were matched for each patient. A total of 201 patients developed late-onset HZ. Age over 20 years, absence of neutrophil engraftment by 14 days, mental disorders, immunosuppressant use at 1 year, and a peripheral CD4+/CD8+ ratio ≥0.5 at 1 year were independent risk factors, among which the CD4+/CD8+ ratio demonstrated good discriminative power for predicting late-onset HZ. For patients with a CD4+/CD8+ ratio <0.5, patient age, neutrophil engraftment time, mental disorders, and immunosuppressant use were potential risk factors. A stratification algorithm was accordingly established, classifying the transplant recipients into three risk groups. Whether the algorithm could facilitate the administration of posttransplant antiviral prophylaxis merits further validation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In our previous study, bile Arisaema was elucidated to have a significant anti-febrile effect, but the pharmacodynamic material basis of this effect remains uncertain. Herein, we found that the soluble polysaccharide fraction from bile Arisaema presents a remarkable antipyretic effect through balancing the gut microbiota and regulating metabolic profiling. Bile Arisaema polysaccharide (BAP) was characterized for its monosaccharide composition with arabinose, galactose, glucose, mannose and xylose (0.028:0.072:0.821:0.05:0.029, molar ratios) and amino acid composition with arginine, threonine, alanine, glycine, serine, proline and tyrosine (109.33, 135.78, 7.22, 8.86, 21.07, 4.96, 12.31 μg/mg). A total of 50 peptides were identified from BAP using Ltq-Orbitrap MS/MS. The oral administration of 100 mg/kg BAP significantly increased the antipyretic effect in yeast-induced fever rats by comparing the rectal temperature. Mechanistically, the inflammation and disorders of neurotransmitters caused by fever were improved by treatment with BAP. The western blotting results suggested that BAP could suppress fever-induced inflammation by down-regulating the NF-κB/TLR4/MyD88 signaling pathway. We also demonstrated that BAP affects lipid metabolism, amino acid metabolism and carbohydrate metabolism and balances the gut microbiota. In summary, the present study provides a crucial foundation for determining polysaccharide activity in bile Arisaema and further investigating the underlying mechanism of action., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Patients with relapsed/refractory acute myeloid leukaemia (R/R AML), especially those who failed in novel target agents are related to dismal survival. We developed a multi-institutional, single-arm, prospective phase II trial, to investigate intensified conditioning with 'Mega-Dose' decitabine (MegaDAC) following allogeneic haematopoietic cell transplantation (allo-HCT) for R/R AML. From 2019 to 2023, 70 heavily treated R/R AML patients in active disease were consecutively enrolled. Significantly, every patient (n = 18) harbouring specific mutations exhibited no response to their best available target agents (BATs). Moreover, 74.3% of the enrolled patients did not reach remission following venetoclax-based regimens. All patients underwent intravenous decitabine (400 mg/m 2 ) along with busulfan and cyclophosphamide. Median follow-up was 26 months (8-65) after HCT. All engrafted patients achieved MRD negativity post-HCT, with a median 3.3-log reduction in recurrent genetic abnormalities. The regimen was well tolerated, without irreversible grades III-IV toxicity peri-engraftment. The estimated 2-year CIR was 29.6% (18.4%-41.7%) and the est-2-year NRM was 15.5% (7.8%-25.5%). The est-2-year LFS, OS, and GRFS were 55.0% (43.5%-69.4%), 58.6% (47.0%-73.0%), and 42.9% (31.9%-57.6%), respectively. Multivariate analysis showed that pre-HCT drug exposures had no significant impact on primary outcomes. MegaDAC is highlighted as an effective and safe option for R/R AML in the new era of targeted therapies., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: Evidence suggests that environmental support, personality traits, and psychological factors can influence seasonal changes in human mood and behavior, particularly in rural middle-aged women and older people. This study aimed to quantify the associations between personality traits, seasonal affective disorder symptoms, and sun exposure in rural older people., Methods: This study is a cross-sectional analytical study, the participants were 300 rural older persons from 12 natural villages and 5 geriatric service centers in 4 different cities in Jiangxi Province, China. The Eysenck Personality Questionnaire (EPQ), the Personal Inventory of Depression and Seasonal Affective Disorder (PIDS-SA-SimpChi), and the Sunlight Exposure Scale were used to conduct follow-up interviews throughout the year. Spatial analysis was performed using ArcGIS and Geodetic Probes. The data were analyzed using SPSS 21 and Amos 23.0 mediated models., Results: Rural older people with low sun exposure exhibited higher personality trait scores (p < 0.001). Personality traits were directly associated with seasonal affective disorder symptoms(p < 0.01); Sun exposure mediated this effect in rural older people (p < 0.05)., Conclusion: High-scoring personalities are more typical of rural older people with low sun exposure, and there is a greater risk of emotional and behavioral instability. Latitudinal differences are not a determinant of SAD. Increased sun exposure is associated with symptom relief. The promotion of light therapy devices in rural areas with low sunlight is warranted., (© 2024. The Author(s).)

Background: The widespread clinical use of lacosamide (LCM) has revealed significant individual differences in clinical response, with various reported influencing factors. However, it remains unclear how genetic factors related to the disposition and clinical response of LCM, as well as drug-drug interactions (DDIs), exert their influence on pediatric patients with epilepsy., Objectives: To evaluate the impact of genetic variations and DDIs on plasma LCM concentrations and clinical response., Design: Patients with epilepsy treated with LCM from June 2021 to March 2023 in the Children's Hospital of Nanjing Medical University were included in the analysis., Methods: The demographic information and laboratory examination data were obtained from the hospital information system. For the pharmacogenetic study, the left-over blood specimens, collected for routine plasma LCM concentration monitoring, were used to perform genotyping analysis for the selected 26 single nucleotide polymorphisms from 14 genes. The trough concentration/daily dose ( C 0 /D) ratio and efficacy outcomes were compared., Results: Patients achieved 90.1% and 68.9% responder rates in LCM mono- and add-on therapy, respectively. The genetic variant in the CYP2C19 *2 (rs4244285) was associated with a better responsive treatment outcome (odds ratio: 1.82; 95% confidence interval: 1.05-3.15; p  = 0.031). In monotherapy, 36% of patients were CYP2C19 normal metabolizers (NMs), 49% were intermediate metabolizers (IMs), and 15% were poor metabolizers (PMs) carrying CYP2C19 *2 or *3. Of note, the C 0 /D ratios of IMs and PMs were 9.1% and 39.6% higher than those of NMs, respectively. Similar results were in the add-on therapy group, and we also observed a substantial decrease in the C 0 /D ratio when patients were concomitant with sodium channel blockers (SCBs)., Conclusion: This study was the first to confirm that CYP2C19 *2 or *3 variants impact the disposition and treatment response of LCM in children with epilepsy. Moreover, concomitant with SCBs, particularly oxcarbazepine, also decreased plasma LCM concentration., (© The Author(s), 2024.)

Background: The burden of common urologic diseases, including benign prostatic hyperplasia (BPH), urinary tract infections (UTI), urolithiasis, bladder cancer, kidney cancer, and prostate cancer, varies both geographically and within specific regions. It is essential to conduct a comprehensive and precise assessment of the global burden of urologic diseases., Methods: We obtained data on incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) for the aforementioned urologic diseases by age, sex, location, and year from the Global Burden of Disease (GBD) 2021. We analyzed the burden associated with urologic diseases based on socio-demographic index (SDI) and attributable risk factors. The trends in burden over time were assessed using estimated annual percentage changes (EAPC) along with a 95% confidence interval (CI)., Results: In 2021, BPH and UTI were the leading causes of age-standardized incidence rate (ASIR) and age-standardized prevalence rate (ASPR), with rates of 5531.88 and 2782.59 per 100,000 persons, respectively. Prostate cancer was the leading cause of both age-standardized mortality rate (ASMR) and age-standardized DALYs rate (ASDR), with rates of 12.63 and 217.83 per 100,000 persons, respectively. From 1990 to 2021, there was an upward trend in ASIR, ASPR, ASMR, and ASDR for UTI, while urolithiasis showed a downward trend. The middle and low-middle SDI quintile levels exhibited higher incidence, prevalence, mortality, and DALYs related to UTI, urolithiasis, and BPH, while the high and high-middle SDI quintile levels showed higher rates for the three cancers. The burden of these six urologic diseases displayed diverse age and sex distribution patterns. In 2021, a high body mass index (BMI) contributed to 20.07% of kidney cancer deaths worldwide, while smoking accounted for 26.48% of bladder cancer deaths and 3.00% of prostate cancer deaths., Conclusions: The global burden of 6 urologic diseases presents a significant public health challenge. Urgent international collaboration is essential to advance the improvement of urologic disease management, encompassing the development of effective diagnostic screening tools and the implementation of high-quality prevention and treatment strategies., (© 2024. The Author(s).)

Background: Several population pharmacokinetic (PopPK) models of caffeine in preterm infants have been published, but the extrapolation of these models to facilitate model-informed precision dosing (MIPD) in clinical practice is uncertain. This study aimed to comprehensively evaluate their predictive performance using an external, independent dataset., Methods: Data used for external evaluation were based on an independent cohort of preterm infants. Currently available PopPK models for caffeine in preterm infants were identified and re-established. Prediction- and simulation-based diagnostics were used to assess model predictability. The influence of prior information was assessed using Bayesian forecasting., Results: 120 plasma samples from 76 preterm infants were included in the evaluation dataset. Twelve PopPK models of caffeine in preterm infants were re-established based on our previously published study. Although two models showed superior predictive performance, none of the 12 PopPK models met all the clinical acceptance criteria of these external evaluation items. Besides, the external predictive performances of most models were unsatisfactory in prediction- and simulation-based diagnostics. Nevertheless, the application of Bayesian forecasting significantly improved the predictive performance, even with only one prior observation., Conclusions: Two models that included the most covariates had the best predictive performance across all external assessments. Inclusion of different covariates, heterogeneity of preterm infant characteristics, and different study designs influenced predictive performance. Thorough evaluation is needed before these PopPK models can be implemented in clinical practice. The implementation of MIPD for caffeine in preterm infants could benefit from the combination of PopPK models and Bayesian forecasting as a helpful tool., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Sepsis is a severe medical condition characterized by a systemic inflammatory response, often culminating in multiple organ dysfunction and high mortality rates. In recent years, there has been a growing recognition of the pivotal role played by mitochondrial damage in driving the progression of sepsis. Various factors contribute to mitochondrial impairment during sepsis, encompassing mechanisms such as reactive nitrogen/oxygen species generation, mitophagy inhibition, mitochondrial dynamics change, and mitochondrial membrane permeabilization. Damaged mitochondria actively participate in shaping the inflammatory milieu by triggering key signaling pathways, including those mediated by Toll-like receptors, NOD-like receptors, and cyclic GMP-AMP synthase. Consequently, there has been a surge of interest in developing therapeutic strategies targeting mitochondria to mitigate septic pathogenesis. This review aims to delve into the intricate mechanisms underpinning mitochondrial dysfunction during sepsis and its significant impact on immune dysregulation. Moreover, we spotlight promising mitochondria-targeted interventions that have demonstrated therapeutic efficacy in preclinical sepsis models., (© 2024. The Author(s).)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a widely used treatment for a variety of hematopoietic disorders, and also provides a valuable platform for investigating the development of donor-derived immune cells in recipients post-HSCT. The immune system remodels from the donor to the recipient during allo-HSCT. However, little is known about the cell profile alterations as donor homeostasis rebalances to recipient homeostasis following HSCT. Here, multi-omics technology is applied at both the single cell and bulk sample levels, as well as spectrum flow cytometry and fluorescent transgenic mouse models, to dissect the dynamics of the rebalanced homeostatic immune system in recipients after allo-HSCT. The data reveal that all immune subpopulations observed in donors are successfully restored in recipients, though with varying levels of abundance. The remodeling of immune homeostasis exhibits different patterns in HLA-matched and haploidentical HSCT, highlighting distinct biases in T cell reconstitution from the central and peripheral pathways. Furthermore, ZNF683 is critical for maintaining the persistence and quiescence of CD8 T-cell in haploidentical HSCT. The research can serve as a foundation for developing novel strategies to induce immune tolerance., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Mycoplasma pneumoniae (M. pneumoniae) is a significant contributor to community-acquired pneumonia among children. Since 1968, when a strain of M. pneumoniae resistant to macrolide antibiotics was initially reported in Japan, macrolide-resistant M. pneumoniae (MRMP) has been documented in many countries worldwide, with varying incidence rates. MRMP infections lead to a poor response to macrolide antibiotics, frequently resulting in prolonged fever, extended antibiotic treatment, increased hospitalization, intensive care unit admissions, and a significantly higher proportion of patients receiving glucocorticoids or second-line antibiotics. Since 2000, the global incidence of MRMP has gradually increased, especially in East Asia, which has posed a serious challenge to the treatment of M. pneumoniae infections in children and attracted widespread attention from pediatricians. However, there is still no global consensus on the diagnosis and treatment of MRMP in children., Methods: We organized 29 Chinese experts majoring in pediatric pulmonology and epidemiology to write the world's first consensus on the diagnosis and treatment of pediatric MRMP pneumonia, based on evidence collection. The evidence searches and reviews were conducted using electronic databases, including PubMed, Embase, Web of Science, CNKI, Medline, and the Cochrane Library. We used variations in terms for "macrolide-resistant", "Mycoplasma pneumoniae", "MP", "M. pneumoniae", "pneumonia", "MRMP", "lower respiratory tract infection", "Mycoplasma pneumoniae infection", "children", and "pediatric"., Results: Epidemiology, pathogenesis, clinical manifestations, early identification, laboratory examination, principles of antibiotic use, application of glucocorticoids and intravenous immunoglobulin, and precautions for bronchoscopy are highlighted. Early and rapid identification of gene mutations associated with MRMP is now available by polymerase chain reaction and fluorescent probe techniques in respiratory specimens. Although the resistance rate to macrolide remains high, it is fortunate that M. pneumoniae still maintains good in vitro sensitivity to second-line antibiotics such as tetracyclines and quinolones, making them an effective treatment option for patients with initial treatment failure caused by macrolide antibiotics., Conclusions: This consensus, based on international and national scientific evidence, provides scientific guidance for the diagnosis and treatment of MRMP in children. Further studies on tetracycline and quinolone drugs in children are urgently needed to evaluate their effects on the growth and development. Additionally, developing an antibiotic rotation treatment strategy is necessary to reduce the prevalence of MRMP strains., (© 2024. The Author(s).)

Background: Considerable interindividual variability for the pharmacokinetics of caffeine in preterm infants has been demonstrated, emphasizing the importance of personalized dosing. This study aimed to develop and apply a repository of currently published population pharmacokinetic (PopPK) models of caffeine in preterm infants to facilitate model-informed precision dosing (MIPD)., Research Design and Methods: Literature search was conducted using PubMed, Embase, Scopus, and Web of Science databases. Relevant publications were screened, and their quality was assessed. PopPK models were reestablished to develop the model repository. Covariate effects were evaluated and the concentration-time profiles were simulated. An online simulation and calculation tool was developed as an instance., Results: Twelve PopPK models were finally included in the repository. Preterm infants' age and body size, especially the postnatal age and current weight, were identified as the most clinically critical covariates. Simulated blood concentration-time profiles across these models were comparable. Caffeine citrate-dose regimen should be adjusted according to the age and body size of preterm infants. The developed online tool can be used to facilitate clinical decision-making., Conclusions: The first developed repository of PopPK models for caffeine in preterm infants has a wide range of potential applications in the MIPD of caffeine.

Translational control plays a crucial role in the regulation of apoptosis, with the EIF4 family serving as one of the mRNA translation factors that modulate the process of mRNA translation based on mRNA characteristics. To address this potential causal role of EIF4 family proteins and breast cancer, Mendelian randomization was employed. The study incorporated four sets of genetics instrumental variables, namely EIF4E, EIF4B, EIF4A, and EIF4EBP2. The outcome variables selected for analysis were the BCAC consortium, which included estrogen receptor positive (ER+) and estrogen receptor negative (ER-) samples. To assess the potential violations of the MR assumption, the primary MR analysis employed inverse variance weighted (IVW), and several sensitivity analyses were conducted. The findings of the two-sample MR analysis indicate that EIF4E has an adverse effect on breast cancer risk (p = 0.028). However, the evidence for the relationship between EIF4E and ER status of breast cancer suggests a weak association with ER+ breast cancer (p = 0.054), but not with ER- breast cancer (p > 0.05). The study findings indicate that EIF4A is not causally linked to the risk of ER+ breast cancer, but is significantly associated with an elevated risk of ER- breast cancer (p = 0.028). However, the evidence is inadequate to support the effects of EIF4B and EIF4EBP2 on breast cancer (p > 0.05). Our results suggest that EIF4 may be a potential factor in the occurrence and development of breast cancer, which may lead to a better understanding of its causes and prevention., (© 2024. The Author(s).)

The objective of this study was to identify independent prognostic factors of viral encephalitis (VE) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) and establish a prognostic model to identify post-transplant VE patients with a greater likelihood of mortality. Among 5380 patients in our centre from 2014 to 2022, 211 patients who developed VE after allo-HSCT were reviewed in this retrospective study. Prognostic factors were selected, and a prognostic model was constructed using Cox regression analysis. The model was subsequently validated and estimated using the area under the receiver operating characteristic curve (AUC), a calibration plot and decision curve analysis (DCA). Glasgow Coma Scale score <9, lesions >3 lobes on magnetic resonance imaging and severe thrombocytopenia were identified as independent prognostic risk factors for VE patients who underwent allo-HSCT. The prognostic model GTM (GTM is an abbreviation for a model composed of three risk factors: GCS score <9, severe thrombocytopenia [platelet count <20 000 per microliter], and lesions >3 lobes on MRI) was established according to the regression coefficients. The validated internal AUC was 0.862 (95% confidence interval [CI], 0.773-0.950), and the external AUC was 0.815 (95% CI, 0.708-0.922), indicating strong discriminatory ability. Furthermore, we constructed calibration plots that demonstrated good consistency between the predicted outcomes and the observed outcomes. DCA exhibited high accuracy in this system, leading to potential benefits for patients., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

The relationship between clinical outcomes and various factors influencing pregnancy was analyzed to provide reference data for patients and clinicians when selecting embryo transfer protocols. This was a retrospective study of 1309 transfer cycles between June 1, 2018, and May 1, 2023, in the Reproductive Medicine Center. Univariate analysis was performed on various factors that may have affected pregnancy outcomes, and further regression analysis was performed on those factors found by univariate analysis to correlate positively with clinical pregnancy outcomes. Finally, the embryo transfer schemes were compared based on the analysis results. The results showed that the stage of embryonic development significantly affected pregnancy outcomes after transplantation (P < .01, 95% confidence interval: 2.554 [1.958-3.332]). There was no significant difference in the pregnancy rate between 1 high-quality blastocyst transfer and 2 cleavage-stage embryos or blastocyst transfer (64.22% vs 70.11%, P = .439); however, the rate of multiple pregnancies after 1 high-quality blastocyst transfer was close to the rate of natural conception. These data show that the transfer of single high-quality blastocysts can significantly reduce the multiple pregnancy rate while ensuring an ideal pregnancy rate, which can be used as a reference for planning the first transplantation in patients with good prognoses., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Vaccination strategies that can induce a broad spectrum immune response are important to enhance protection against SARS-CoV-2 variants. We conducted a randomized, double-blind and parallel controlled trial to evaluate the safety and immunogenicity of the bivalent (5×10 10 viral particles) and B.1.1.529 variant (5×10 10 viral particles) adenovirus type-5 (Ad5) vectored COVID-19 vaccines administrated via inhalation. 451 eligible subjects aged 18 years and older who had been vaccinated with three doses inactivated COVID-19 vaccines were randomly assigned to inhale one dose of either B.1.1.529 variant Ad5 vectored COVID-19 vaccine (Ad5-nCoVO-IH group, N=150), bivalent Ad5 vectored COVID-19 vaccine (Ad5-nCoV/O-IH group, N=151), or Ad5 vectored COVID-19 vaccine (5×10 10 viral particles; Ad5-nCoV-IH group, N=150). Adverse reactions reported by 37 (24.67%) participants in the Ad5-nCoVO-IH group, 28 (18.54%) in the Ad5-nCoV/O-IH group, and 26 (17.33%) in the Ad5-nCoV-IH group with mainly mild to moderate dry mouth, oropharyngeal pain, headache, myalgia, cough, fever and fatigue. No serious adverse events related to the vaccine were reported. Investigational vaccines were immunogenic, with significant difference in the GMTs of neutralizing antibodies against Omicron BA.1 between Ad5-nCoV/O-IH (43.70) and Ad5-nCoV-IH (29.25) at 28 days after vaccination (P=0.0238). The seroconversion rates of neutralizing antibodies against BA.1 in Ad5-nCoVO-IH, Ad5-nCoV/O-IH, and Ad5-nCoV-IH groups were 56.00%, 59.60% and 48.67% with no significant difference among the groups. Overall, the investigational vaccines were demonstrated to be safe and well tolerated in adults, and was highly effective in inducing mucosal immunities in addition to humoral and cellular immune responses defending against SARS-CoV-2 variants.Trial registration: Chictr.org identifier: ChiCTR2200063996.

Amidst rising Parkinson's disease (PD) incidence in an aging global population, the need for non-invasive and reliable diagnostic methods is increasingly critical. This review evaluates the strategic role of transcranial sonography (TCS) in the early detection and monitoring of PD. TCS's ability to detect substantia nigra hyperechogenicity offers profound insights into its correlation with essential neuropathological alterations-namely, iron accumulation, neuromelanin depletion, and glial proliferation-fundamental to PD's pathophysiology. Our analysis highlights TCS's advantages, including its non-invasiveness, cost-effectiveness, and ease of use, positioning it as an invaluable tool for early diagnosis and continual disease progression monitoring. Moreover, TCS assists in identifying potential risk and protective factors, facilitating tailored therapeutic strategies to enhance clinical outcomes. This review advocates expanding TCS utilization and further research to maximize its diagnostic and prognostic potential in PD management, contributing to a more nuanced understanding of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Jiang, Zhu, Zhuo and Liu.)

Membranous nephropathy (MN) is a rare complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). MN patients may develop nephrotic syndrome or even kidney failure, which greatly affects their quality of life and prognosis. However, current knowledge regarding MN after allo-HSCT is limited. Thus, a multicenter nested case‒control study was conducted. Patients who had been diagnosed with MN after allo-HSCT were retrospectively identified at 8 HSCT centers. A total of 51 patients with MN after allo-HSCT were included. The median age of MN patients after allo-HSCT was 38 years, and the median duration from HSCT to MN was 18 months. The use of HLA-matched donors (P = 0.0102) and peripheral blood as the graft source (P = 0.0060) were identified as independent predisposing risk factors for the onset of MN after allo-HSCT. Compared to those in the control group, the incidence of extensive chronic graft-versus-host disease was greater in the MN patients (P = 0.0002). A total of 31 patients developed nephrotic syndrome. Patients receiving combination treatments of corticosteroids and immunosuppressants appeared to have better outcomes. In conclusion, MN is a rare but occasionally severe complication following HSCT and may require active treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Patients with steroid-resistant or relapsed immune thrombocytopenia (ITP) suffer increased bleeding risk and impaired quality of life. Baricitinib, an oral Janus-associated kinases (JAK) inhibitor, could alleviate both innate and adaptive immune disorders without inducing thrombocytopenia in several autoimmune diseases. Accordingly, an open-label, single-arm, phase 2 trial (NCT05446831) was initiated to explore the safety and efficacy of baricitinib in ITP. Eligible patients were adults with primary ITP who were refractory to corticosteroids and at least one subsequent treatment, and had platelet counts below 30 × 10 9 /L at enrolment. Participants received baricitinib 4 mg daily for 6 months. The primary endpoint was durable response at the 6-month follow-up. A total of 35 patients were enrolled. Durable response was achieved in 20 patients (57.1%, 95% confidence interval, 39.9 to 74.4), and initial response in 23 (65.7%) patients. For patients responding to baricitinib, the median time to response was 12 (IQR 6-20) days, and the median peak platelet count was 94 (IQR 72-128) × 10 9 /L. Among the 27 patients undergoing extend observation, 12 (44.4%) remained responsive for a median duration of approximately 20 weeks after baricitinib discontinuation. Adverse events were reported in 11 (31.4%) patients, including infections in 6 (17.1%) patients during the treatment period. Treatment discontinuation due to an adverse event was reported in 2 (5.7%) patients. Evidence from this pilot study suggested that baricitinib might be a novel candidate for the armamentarium of ITP-modifying agents. Future studies are warranted to validate the safety, efficacy, and optimal dosing of baricitinib in patients with ITP., (© 2024 Wiley Periodicals LLC.)

Objective: To analyze the fluctuations of patient-reported outcomes (PROs) and their relationships with cytokines in the peripheral blood of patients undergoing chemotherapy for ovarian cancer (OC)., Methods: PROs burden was prospectively measured by the M.D. Anderson Symptom Inventory-Ovarian Cancer (MDASI-OC) at baseline before chemotherapy, on a daily basis during and post-chemotherapy days (PCD) 7, 14, and 20. Cytokines were collected at baseline, days prior to hospital discharge and PCD 20. Pearson correlation was used to explore the associations between PROs and cytokines levels in peripheral blood., Results: The top 8 rated symptoms were compared between the neoadjuvant chemotherapy (NACT) group (n=20) and the postoperative adjuvant chemotherapy (PAC) group (n=7). Before chemotherapy, the mean scores of fatigue and lack of appetite in the NACT group were higher than those in the PAC group. After chemotherapy, pain, nausea, vomiting, disturbed sleep, lack of appetite, and constipation increased to peak during PCD 2-6; while, fatigue and numbness or tingling remained at high levels over PCD 2-13. By PCD 20, disturbed sleep and fatigue showed a significant increase in mean scores, particularly in the NACT group; while, other symptom scores decreased and returned to baseline levels. Additionally, the longitudinal fluctuations in pain, fatigue, and lack of appetite were positively associated with circulating levels of interleukin-6 and interferon gamma (p<0.05)., Conclusion: MDASI-OC was feasible and adaptable for demonstrating the fluctuations of symptom burden throughout chemotherapy course. Moreover, symptoms changing along with cytokines levels could provide clues for exploring mechanism underlying biochemical etiology., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2025. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Background: Nipah virus is a zoonotic paramyxovirus responsible for disease outbreaks with high fatality rates in south and southeast Asia. However, knowledge of the potential geographical extent and risk patterns of the virus is poor. We aimed to establish an integrated spatiotemporal and phylogenetic database of Nipah virus infections in humans and animals across south and southeast Asia., Methods: In this geospatial modelling analysis, we developed an integrated database containing information on the distribution of Nipah virus infections in humans and animals from 1998 to 2021. We conducted phylodynamic analysis to examine the evolution and migration pathways of the virus and meta-analyses to estimate the adjusted case-fatality rate. We used two boosted regression tree models to identify the potential ecological drivers of Nipah virus occurrences in spillover events and endemic areas, and mapped potential risk areas for Nipah virus endemicity., Findings: 749 people and eight bat species across nine countries were documented as being infected with Nipah virus. On the basis of 66 complete genomes of the virus, we identified two clades-the Bangladesh clade and the Malaysia clade-with the time of the most recent common ancestor estimated to be 1863. Adjusted case-fatality rates varied widely between countries and were higher for the Bangladesh clade than for the Malaysia clade. Multivariable meta-regression analysis revealed significant relationships between case-fatality rate estimates and viral clade (p=0·0021), source country (p=0·016), proportion of male patients (p=0·036), and travel time to health-care facilities (p=0·036). Temperature-related bioclimate variables and the probability of occurrence of Pteropus medius were important contributors to both the spillover and the endemic infection models., Interpretation: The suitable niches for Nipah virus are more extensive than previously reported. Future surveillance efforts should focus on high-risk areas informed by updated projections. Specifically, intensifying zoonotic surveillance efforts, enhancing laboratory testing capacity, and implementing public health education in projected high-risk areas where no human cases have been reported to date will be crucial. Additionally, strengthening wildlife surveillance and investigating potential modes of transmission in regions with documented human cases is needed., Funding: The Key Research and Development Program of China., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Graft failure is a fatal complication following allogeneic stem cell transplantation where a second transplantation is usually required for salvage. However, there are no recommended regimens for second transplantations for graft failure, especially in the haploidentical transplant setting. We recently reported encouraging outcomes using a novel method (haploidentical transplantation from a different donor after conditioning with fludarabine and cyclophosphamide). Herein, we report updated outcomes in 30 patients using this method. The median time of the second transplantation was 96.5 (33-215) days after the first transplantation. Except for one patient who died at +19d and before engraftment, neutrophil engraftments were achieved in all patients at 11 (8-24) days, while platelet engraftments were achieved in 22 (75.8%) patients at 17.5 (9-140) days. The 1-year OS and DFS were 60% and 53.3%, and CIR and TRM was 6.7% and 33.3%, respectively. Compared with the historical group, neutrophil engraftment (100% versus 58.5%, p < 0.001) and platelet engraftment (75.8% versus 32.3%, p < 0.001) were better in the novel regimen group, and OS was also improved (60.0% versus 26.4%, p = 0.011). In conclusion, salvage haploidentical transplantation from a different donor using the novel regimen represents a promising option to rescue patients with graft failure after the first haploidentical transplantation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: In this study, we aimed to evaluate the combined diagnostic value of procalcitonin (PCT), C-reactive protein (CRP), and serum amyloid A (SAA) in sepsis caused by urinary tract infection., Method: A total of 80 patients with urosepsis who were hospitalized were included in the study group, and 80 patients with urinary tract infection without sepsis were included in the control group. We collected the PCT, SAA, and CRP levels of patients following admission. Subsequently, we conducted a comparative analysis to assess the specificity, accuracy, and sensitivity of combined diagnostic approaches in contrast to individual diagnostic methods for blood PCT, SAA, and CRP., Results: The levels of PCT, SAA, and CRP in the study group were significantly higher than those in the control group, and the differences were statistically significant (P < 0.01). Multi-factor logistic regression analysis revealed that the levels of PCT (P = 0.003) and SAA (P = 0.014) were associated with urosepsis. The sensitivity of PCT was 87.133% and the specificity was 93.066%, which were higher than that of SAA and CRP. The specificity of the combined detection of the three was 95.670%, which was higher than that of PCT, SAA, and CRP alone. Correlation analysis revealed that PCT had a significant positive correlation with CRP and SAA (P < 0.01), and a weak correlation with white blood cell count (WBC) and fibrinogen (FIB) (P = 0.03 for WBC, P = 0.04 for FIB)., Conclusion: PCT, SAA, and CRP indicators in patients with urosepsis are significantly elevated, and all three are valuable in the diagnosis of urosepsis. PCT alone has good diagnostic efficiency for urosepsis, and a certain correlation with other inflammatory factors. The diagnostic efficacy of the three indicators in combination is better than that of any one of the three, and is worthy of widespread clinical application., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo-geneic hematopoiesis stem cell transplantation (allo-HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome., Methods: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF-normal (CSF-) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis., Results: Compared to those in the CSF-negative group, the conventional cytology positive and MFC+ groups had comparable 8-year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia-free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS., Conclusion: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Dysfunctional bone marrow (BM) endothelial progenitor cells (EPCs) with high levels of reactive oxygen species (ROS) are responsible for defective hematopoiesis in poor graft function (PGF) patients with acute leukemia or myelodysplastic neoplasms post-allotransplant. However, the underlying mechanism by which BM EPCs regulate their intracellular ROS levels and the capacity to support hematopoiesis have not been well clarified. Herein, we demonstrated decreased levels of peroxisome proliferator-activated receptor delta (PPARδ), a lipid-activated nuclear receptor, in BM EPCs of PGF patients compared with those with good graft function (GGF). In vitro assays further identified that PPARδ knockdown contributed to reduced and dysfunctional BM EPCs, characterized by the impaired ability to support hematopoiesis, which were restored by PPARδ overexpression. Moreover, GW501516, an agonist of PPARδ, repaired the damaged BM EPCs triggered by 5-fluorouracil (5FU) in vitro and in vivo. Clinically, activation of PPARδ by GW501516 benefited the damaged BM EPCs from PGF patients or acute leukemia patients in complete remission (CR) post-chemotherapy. Mechanistically, we found that increased expression of NADPH oxidases (NOXs), the main ROS-generating enzymes, may lead to elevated ROS level in BM EPCs, and insufficient PPARδ may trigger BM EPC damage via ROS/p53 pathway. Collectively, we found that defective PPARδ contributes to BM EPC dysfunction, whereas activation of PPARδ in BM EPCs improves their hematopoiesis-supporting ability after myelosuppressive therapy, which may provide a potential therapeutic target not only for patients with leukemia but also for those with other cancers., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests. All co-author shave seen and approved this version of the manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Significant pharmacokinetic (PK) differences exist between different forms of valproic acid (VPA), such as syrup and sustained-release (SR) tablets. This study aimed to develop a population pharmacokinetic (PopPK) model for VPA in children with epilepsy and offer dose adjustment recommendation for switching dosage forms as needed. The study collected 1411 VPA steady-state trough concentrations (C trough ) from 617 children with epilepsy. Using NONMEM software, a PopPK model was developed, employing a stepwise approach to identify possible variables such as demographic information and concomitant medications. The final model underwent internal and external evaluation via graphical and statistical methods. Moreover, Monte Carlo simulations were used to generate a dose tailoring strategy for typical patients weighting 20-50 kg. As a result, the PK characteristics of VPA were described using a one-compartment model with first-order absorption. The absorption rate constant (k a ) was set at 2.64 and 0.46 h -1 for syrup and SR tablets. Body weight and sex were identified as significant factors affecting VPA's pharmacokinetics. The final PopPK model demonstrated acceptable prediction performance and stability during internal and external evaluation. For children taking syrup, a daily dose of 25 mg/kg resulted in the highest probability of achieving the desired target C trough , while a dose of 20 mg/kg/day was appropriate for those taking SR tablets. In conclusion, we established a PopPK model for VPA in children with epilepsy to tailor VPA dosage when switching between syrup and SR tablets, aiming to improve plasma VPA concentrations fluctuations., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Serum biomarkers play an important role in the early diagnosis and prognosis of HCC. Because a certain percentage of HCC patients are negative for alpha-fetoprotein (AFP) , the diagnosis of AFP-negative HCC is essential to improve the detection rate of HCC., Aim: To establish an effective model for diagnosing AFP-negative HCC based on serum tumour biomarkers., Methods: A total of 180 HCC patients were enrolled in this study. The expression levels of GP73, des-γ-carboxyprothrombin (DCP), CK18-M65, and CK18-M30 were detected by a fully automated chemiluminescence analyser. The variables were selected by logistic regression analysis. Several models were constructed using stepwise backward logistic regression. The performance of the models was compared using the C statistic, integrated discrimination improvement, net reclassification improvement, and calibration curves. The clinical utility of the nomogram was assessed using decision curve analysis (DCA)., Results: The results showed that the expression levels of GP73, DCP, CK18-M65, and CK18-M30 were significantly greater in AFP-negative HCC patients than in healthy controls ( P < 0.001). Multivariate logistic regression analysis revealed that GP73, DCP, and CK18-M65 were independent factors for diagnosing AFP-negative HCC. By comparing the diagnostic performance of multiple models, we included GP73 and CK18-M65 as the model variables, and the model had good discrimination ability (area under the curve = 0.946) and good goodness of fit. The DCA curves indicated the good clinical utility of the nomogram., Conclusion: Our study identified GP73 and CK18-M65 as serum biomarkers with certain application value in the diagnosis of AFP-negative HCC. The diagnostic nomogram based on CK18-M65 combined with GP73 demonstrated good performance and effectively identified high-risk groups of patients with HCC., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: Chronological age (CAge), biological age (BAge), and accelerated age (AAge) are all important for aging-related diseases. CAge is a known risk factor for benign prostatic hyperplasia (BPH); However, the evidence of association of BAge and AAge with BPH is limited. This study aimed to evaluate the association of CAge, Bage, and AAge with BPH in a large prospective cohort., Method: A total of 135,933 males without BPH at enrolment were extracted from the UK biobank. We calculated three BAge measures (Klemera-Doubal method, KDM; PhenoAge; homeostatic dysregulation, HD) based on 16 biomarkers. Additionally, we calculated KDM-BAge and PhenoAge-BAge measures based on the Levine method. The KDM-AAge and PhenoAge-AAge were assessed by the difference between CAge and BAge and were standardized (mean = 0 and standard deviation [SD] = 1). Cox proportional hazard models were applied to assess the associations of CAge, Bage, and AAge with incident BPH risk., Results: During a median follow-up of 13.150 years, 11,811 (8.690%) incident BPH were identified. Advanced CAge and BAge measures were associated with an increased risk of BPH, showing threshold effects at a later age (all P for nonlinearity <0.001). Nonlinear relationships between AAge measures and risk of BPH were also found for KDM-AAge ( P  = 0.041) and PhenoAge-AAge ( P  = 0.020). Compared to the balance comparison group (-1 SD < AAge < 1 SD), the accelerated aging group (AAge > 2 SD) had a significantly elevated BPH risk with hazard ratio (HR) of 1.115 (95% CI, 1.000-1.223) for KDM-AAge and 1.180 (95% CI, 1.068-1.303) for PhenoAge-AAge, respectively. For PhenoAge-AAge, subgroup analysis of the accelerated aging group showed an increased HR of 1.904 (95% CI, 1.374-2.639) in males with CAge <50 years and 1.233 (95% CI, 1.088-1.397) in those having testosterone levels <12 nmol/L. Moreover, AAge-associated risk of BPH was independent of and additive to genetic risk., Conclusions: Biological aging is an independent and modifiable risk factor for BPH. We suggest performing active health interventions to slow biological aging, which will help mitigate the progression of prostate aging and further reduce the burden of BPH., Competing Interests: The authors declare that they have no conflict of interest., (© 2024 The Author(s). Aging Medicine published by Beijing Hospital and John Wiley & Sons Australia, Ltd.)

Background: At present, liver transplantation (LT) is one of the best treatments for hepatocellular carcinoma (HCC). Accurately predicting the survival status after LT can significantly improve the survival rate after LT, and ensure the best way to make rational use of liver organs., Aim: To develop a model for predicting prognosis after LT in patients with HCC., Methods: Clinical data and follow-up information of 160 patients with HCC who underwent LT were collected and evaluated. The expression levels of alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin, Golgi protein 73, cytokeratin-18 epitopes M30 and M65 were measured using a fully automated chemiluminescence analyzer. The best cutoff value of biomarkers was determined using the Youden index. Cox regression analysis was used to identify the independent risk factors. A forest model was constructed using the random forest method. We evaluated the accuracy of the nomogram using the area under the curve, using the calibration curve to assess consistency. A decision curve analysis (DCA) was used to evaluate the clinical utility of the nomograms., Results: The total tumor diameter (TTD), vascular invasion (VI), AFP, and cytokeratin-18 epitopes M30 (CK18-M30) were identified as important risk factors for outcome after LT. The nomogram had a higher predictive accuracy than the Milan, University of California, San Francisco, and Hangzhou criteria. The calibration curve analyses indicated a good fit. The survival and recurrence-free survival (RFS) of high-risk groups were significantly lower than those of low- and middle-risk groups ( P < 0.001). The DCA shows that the model has better clinical practicability., Conclusion: The study developed a predictive nomogram based on TTD, VI, AFP, and CK18-M30 that could accurately predict overall survival and RFS after LT. It can screen for patients with better postoperative prognosis, and improve long-term survival for LT patients., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes, inflammation and fibrosis play an important role in its progression. Histone lysine crotonylation (Kcr) was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the study of sodium crotonate (NaCr) and histone Kcr in kidney diseases. However, the effects of NaCr and NaCr-induced Kcr on DKD remain unclear. In this study, db/db mice and high glucose-induced human tubular epithelial cells (HK-2) were used respectively, and exogenous NaCr and crotonoyl-coenzyme A (Cr-CoA) as intervention reagents, histone Kcr and DKD-related indicators were detected. The results confirmed that NaCr had an antidiabetic effect and decreased blood glucose and serum lipid levels and alleviated renal function and DKD-related inflammatory and fibrotic damage. NaCr also induced histone Kcr and histone H3K18 crotonylation (H3K18cr). However, NaCr and Cr-CoA-induced histone Kcr and protective effects were reversed by inhibiting the activity of Acyl-CoA synthetase short-chain family member 2 (ACSS2) or histone acyltransferase P300 in vitro. In summary, our data reveal that NaCr may mitigate DKD via an antidiabetic effect as well as through ACSS2 and P300-induced histone Kcr, suggesting that Kcr may be the potential molecular mechanism and prevention target of DKD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Sporadic parathyroid adenoma (PA) is the most common cause of hyperparathyroidism, yet the mechanisms involved in its pathogenesis remain incompletely understood., Methods: Surgically removed PA samples, along with normal parathyroid gland (PG) tissues that were incidentally dissected during total thyroidectomy, were analysed using single-cell RNA-sequencing with the 10× Genomics Chromium Droplet platform and Cell Ranger software. Gene set variation analysis was conducted to characterise hallmark pathway gene signatures, and single-cell regulatory network inference and clustering were utilised to analyse transcription factor regulons. Immunohistochemistry and immunofluorescence were performed to validate cellular components of PA tissues. siRNA knockdown and gene overexpression, alongside quantitative polymerase chain reaction, Western blotting and cell proliferation assays, were conducted for functional investigations., Results: There was a pervasive increase in gene transcription in PA cells (PACs) compared with PG cells. This is associated with high expression of histone-lysine N-methyltransferase 2A (KMT2A). High KMT2A levels potentially contribute to promoting PAC proliferation through upregulation of the proto-oncogene CCND2, which is mediated by the transcription factors signal transducer and activator of transcription 3 (STAT3) and GATA binding protein 3 (GATA3). PA tissues are heavily infiltrated with myeloid cells, while fibroblasts, endothelial cells and macrophages in PA tissues are commonly enriched with proinflammatory gene signatures relative to their counterparts in PG tissues., Conclusions: We revealed the previously underappreciated involvement of the KMT2A‒STAT3/GATA3‒CCND2 axis and chronic inflammation in the pathogenesis of PA. These findings underscore the therapeutic promise of KMT2A inhibition and anti-inflammatory strategies, highlighting the need for future investigations to translate these molecular insights into practical applications., Highlights: Single-cell RNA-sequencing reveals a transcriptome catalogue comparing sporadic parathyroid adenomas (PAs) with normal parathyroid glands. PA cells show a pervasive increase in gene expression linked to KMT2A upregulation. KMT2A-mediated STAT3 and GATA3 upregulation is key to promoting PA cell proliferation via cyclin D2. PAs exhibit a proinflammatory microenvironment, suggesting a potential role of chronic inflammation in PA pathogenesis., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background and Aims: Accurate preoperative prediction of microvascular invasion (MVI) and recurrence-free survival (RFS) is vital for personalised hepatocellular carcinoma (HCC) management. We developed a multitask deep learning model to predict MVI and RFS using preoperative MRI scans., Methods: Utilising a retrospective dataset of 725 HCC patients from seven institutions, we developed and validated a multitask deep learning model focused on predicting MVI and RFS. The model employs a transformer architecture to extract critical features from preoperative MRI scans. It was trained on a set of 234 patients and internally validated on a set of 58 patients. External validation was performed using three independent sets (n = 212, 111, 110)., Results: The multitask deep learning model yielded high MVI prediction accuracy, with AUC values of 0.918 for the training set and 0.800 for the internal test set. In external test sets, AUC values were 0.837, 0.815 and 0.800. Radiologists' sensitivity and inter-rater agreement for MVI prediction improved significantly when integrated with the model. For RFS, the model achieved C-index values of 0.763 in the training set and ranged between 0.628 and 0.728 in external test sets. Notably, PA-TACE improved RFS only in patients predicted to have high MVI risk and low survival scores (p < .001)., Conclusions: Our deep learning model allows accurate MVI and survival prediction in HCC patients. Prospective studies are warranted to assess the clinical utility of this model in guiding personalised treatment in conjunction with clinical criteria., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cyclosporine A (CsA) is a widely used immunosuppressive drug with a narrow therapeutic index and large individual differences. Its therapeutic and toxic effects are closely related to blood drug concentrations, requiring routine therapeutic drug monitoring (TDM). The current main methods for TDM of CsA are enzyme multiplied immunoassay technique (EMIT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). However, few study on the method comparison of the EMIT and LC-MS/MS for the measurement of whole blood CsA concentration in children has been reported. In this study, we developed a simple and sensitive LC-MS/MS assay for the determination of CsA, and 657 cases of CsA concentrations were determined from 197 pediatric patients by a routine EMIT assay and by the validated in-house LC-MS/MS method on the same batch of samples, aimed to address the aforementioned concern. Consistency between the two assays was evaluated using linear regression and Bland-Altman analysis. The linear range of LC-MS/MS was 0.500-2000 ng/mL and that of the EMIT was 40-500 ng/mL, respectively. Overall, the correlation between the two methods was significant (r-value ranging from 0.8842 to 0.9441). Unsatisfactory consistency was observed in the concentrations < 40 ng/mL (r = 0.7325) and 200-500 ng/mL (r = 0.6851). Bland-Altman plot showed a mean bias of -18.0 % (±1.96 SD, -73.8 to 37.8 %) between EMIT and LC-MS/MS. For Passing-Bablok regression between EMIT and LC-MS/MS did not differ significantly (p > 0.05). In conclusion, the two methods were closely correlated, but the CsA concentration by LC-MS/MS assay was slightly higher than that by EMIT method. Switching from the EMIT assay to the LC-MS/MS method was acceptable, and the LC-MS/MS method will receive broader application in clinical settings due to its better analytical capabilities, but the results need to be further verified in different laboratories., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The proton-electron coupling effect induces rich spectrums of electronic states in correlated oxides, opening tempting opportunities for exploring novel devices with multifunctions. Here, via modest Pt-aided hydrogen spillover at room temperature, amounts of protons are introduced into SmNiO 3 -based devices. In situ structural characterizations together with first-principles calculation reveal that the local Mott transition is reversibly driven by migration and redistribution of the predoped protons. The accompanying giant resistance change results in excellent memristive behaviors under ultralow electric fields. Hierarchical tree-like memory states, an instinct displayed in bio-synapses, are further realized in the devices by spatially varying the proton concentration with electric pulses, showing great promise in artificial neural networks for solving intricate problems. Our research demonstrates the direct and effective control of proton evolution using extremely low electric field, offering an alternative pathway for modifying the functionalities of correlated oxides and constructing low-power consumption intelligent devices and neural network circuits.

Graft-versus-host disease (GVHD), an immunological disorder that arises from donor T cell activation through recognition of host alloantigens, is the major limitation in the application of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Traditional immunosuppressive agents can relieve GVHD, but they induce serious side effects. It is highly required to explore alternative therapeutic strategy. Human amniotic epithelial stem cells (hAESCs) were recently considered as an ideal source for cell therapy with special immune regulatory property. In this study, we evaluated the therapeutic role of hAESCs in the treatment of GVHD, based on our previous developed cGMP-grade hAESCs product. Humanized mouse model of acute GVHD (aGVHD) was established by injection of huPBMCs via the tail vein. For prevention or treatment of aGVHD, hAESCs were injected to the mice on day -1 or on day 7 post-PBMC infusion, respectively. We showed that hAESCs infusion significantly alleviated the disease phenotype, increased the survival rate of aGVHD mice, and ameliorated pathological injuries in aGVHD target organs. We demonstrated that hAESCs directly induced CD4 + T cell polarization, in which Th1 and Th17 subsets were downregulated, and Treg subset was elevated. Correspondingly, the levels of a series of pro-inflammatory cytokines were reduced while the levels of the anti-inflammatory cytokines were upregulated in the presence of hAESCs. We found that hAESCs regulated CD4 + subset polarization in a paracrine mode, in which TGFβ and PGE2 were selectively secreted to mediate Treg elevation and Th1/Th17 inhibition, respectively. In addition, transplanted hAESCs preserved the graft-versus-leukemia (GVL) effect by inhibiting leukemia cell growth. More intriguingly, hAESCs infusion in HSCT patients displayed potential anti-GVHD effect with no safety concerns and confirmed the immunoregulatory mechanisms in the preclinical study. We conclude that hAESCs infusion is a promising therapeutic strategy for post-HSCT GVHD without compromising the GVL effect. The clinical trial was registered at www.clinicaltrials.gov as #NCT03764228., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Developing new pharmaceuticals is a costly and time-consuming endeavor fraught with significant safety risks. A critical aspect of drug research and disease therapy is discerning the existence of interactions between drugs and proteins. The evolution of deep learning (DL) in computer science has been remarkably aided in this regard in recent years. Yet, two challenges remain: (i) balancing the extraction of profound, local cohesive characteristics while warding off gradient disappearance and (ii) globally representing and understanding the interactions between the drug and target local attributes, which is vital for delivering molecular level insights indispensable to drug development. In response to these challenges, we propose a DL network structure, MolLoG, primarily comprising two modules: local feature encoders (LFE) and global interactive learning (GIL). Within the LFE module, graph convolution networks and leap blocks capture the local features of drug and protein molecules, respectively. The GIL module enables the efficient amalgamation of feature information, facilitating the global learning of feature structural semantics and procuring multihead attention weights for abstract features stemming from two modalities, providing biologically pertinent explanations for black-box results. Finally, predictive outcomes are achieved by decoding the unified representation via a multilayer perceptron. Our experimental analysis reveals that MolLoG outperforms several cutting-edge baselines across four data sets, delivering superior overall performance and providing satisfactory results when elucidating various facets of drug-target interaction predictions.

Background: Acute kidney injury (AKI) is a common clinical syndrome with high morbidity and mortality rates. The use of pluripotent stem cells holds great promise for the treatment of AKI. Urine-derived stem cells (USCs) are a novel and versatile cell source in cell-based therapy and regenerative medicine that provide advantages of a noninvasive, simple, and low-cost approach and are induced with high multidifferentiation potential. Whether these cells could serve as a potential stem cell source for the treatment of AKI has not been determined., Aim: To investigate whether USCs can serve as a potential stem cell source to improve renal function and histological structure after experimental AKI., Methods: Stem cell markers with multidifferentiation potential were isolated from human amniotic fluid. AKI severe combined immune deficiency (SCID) mice models were induced by means of an intramuscular injection with glycerol. USCs isolated from human-voided urine were administered via tail veins. The functional changes in the kidney were assessed by the levels of blood urea nitrogen and serum creatinine. The histologic changes were evaluated by hematoxylin and eosin staining and transferase dUTP nick-end labeling staining. Meanwhile, we compared the regenerative potential of USCs with bone marrow-derived mesenchymal stem cells (MSCs)., Results: Treatment with USCs significantly alleviated histological destruction and functional decline. The renal function was rapidly restored after intravenous injection of 5 × 10 5 human USCs into SCID mice with glycerol-induced AKI compared with injection of saline. Results from secretion assays conducted in vitro demonstrated that both stem cell varieties released a wide array of cytokines and growth factors. This suggests that a mixture of various mediators closely interacts with their biochemical functions. Two types of stem cells showed enhanced tubular cell proliferation and decreased tubular cell apoptosis, although USC treatment was not more effective than MSC treatment. We found that USC therapy significantly improved renal function and histological damage, inhibited inflammation and apoptosis processes in the kidney, and promoted tubular epithelial proliferation., Conclusion: Our study demonstrated the potential of USCs for the treatment of AKI, representing a new clinical therapeutic strategy., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Tubulointerstitial fibrosis (TIF) is a critical pathological feature of chronic renal failure (CRF), with oxidative stress (OS) and hypoxic responses in renal proximal tubular epithelial cells playing pivotal roles in disease progression. This study explores the effects of Modified Zhenwu Tang (MZWT) on these processes, aiming to uncover its potential mechanisms in slowing CRF progression., Methods: We used adenine (Ade) to induce CRF in rats, which were then treated with benazepril hydrochloride (Lotensin) and MZWT for 8 weeks. Assessments included liver and renal function, electrolytes, blood lipids, renal tissue pathology, OS levels, the hypoxia-inducible factor (HIF) pathway, inflammatory markers, and other relevant indicators. In vitro, human renal cortical proximal tubular epithelial cells were subjected to hypoxia and lipopolysaccharide for 72 h, with concurrent treatment using MZWT, FM19G11, and N-acetyl-l-cysteine. Measurements taken included reactive oxygen species (ROS), HIF pathway activity, inflammatory markers, and other relevant indicators., Results: Ade treatment induced significant disruptions in renal function, blood lipids, electrolytes, and tubulointerstitial architecture, alongside heightened OS, HIF pathway activation, and inflammatory responses in rats. In vivo, MZWT effectively ameliorated proteinuria, renal dysfunction, lipid and electrolyte imbalances, and renal tissue damage; it also suppressed OS, HIF pathway activation, epithelial-mesenchymal transition (EMT) in proximal tubular epithelial cells, and reduced the production of inflammatory cytokines and collagen fibers. In vitro findings demonstrated that MZWT decreased apoptosis, reduced ROS production, curbed OS, HIF pathway activation, and EMT in proximal tubular epithelial cells, and diminished the output of inflammatory cytokines and collagen., Conclusion: OS and hypoxic responses significantly contribute to TIF development. MZWT mitigates these responses in renal proximal tubular epithelial cells, thereby delaying the progression of CRF., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

The rapid development of society and economy has resulted in a substantial increase in energy consumption, consequently exacerbating pollution issues. Current research predominantly focuses on energy-saving and emission reduction in road transportation within individual cities or the three major economic regions of China:the Yangtze River Delta, the Pearl River Delta, and the Beijing-Tianjin-Hebei Region. However, there is a dearth of studies addressing the southeastern coastal economic region. Located at the heart of China's southeastern coastal economic development, the provinces of Guangdong, Fujian, and Zhejiang unavoidably face challenges associated with energy consumption and emissions while pursuing economic growth. To address these challenges, this study employed a LEAP model to construct various scenarios for road transportation in the key coastal cities of Guangdong, Fujian, and Zhejiang from 2015 to 2035. These scenarios included a baseline scenario (BAU), an existing policy scenario (EPS), and an improved policy scenario (MPS). The MPS and EPS encompassed vehicle structure optimization (VSO), improved fuel economy (IFE), and reduced annual average mileage (RDM). By simulating and evaluating these scenarios, the energy-saving and emission reduction potentials of road transportation in the key coastal cities were assessed. The results indicated that, in the primary scenario, the MPS exhibited the most significant improvements in energy-saving, carbon reduction, and pollutant reduction effects. By 2035, the MPS achieved a remarkable 75% energy-saving rate compared to that in the baseline scenario, accompanied by reductions of 68%, 59%, 66%, 70%, and 64% in CO 2 , CO, NO x , PM 2.5 , and SO 2 emissions, respectively. In the secondary scenario, the improved scenario of enhancing fuel economy achieved a notable 30% reduction in energy consumption. Additionally, the scenarios involving vehicle structure adjustment (yielding reductions of 36%, 30%, 36%, 26%, and 40%) and annual average mileage reduction (resulting in reductions of 37%, 37%, 36%, 37%, and 36%) demonstrated significant reductions in CO 2 , CO, NO x , PM 2.5 , and SO 2 emissions.

Patients with triple-negative breast cancer (TNBC) have a poor prognosis due to the lack of effective molecular targets for therapeutic intervention. Here we found that the long noncoding RNA (lncRNA) MILIP supports TNBC cell survival, proliferation, and tumorigenicity by complexing with transfer RNAs (tRNA) to promote protein production, thus representing a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, and MILIP silencing suppressed TNBC cell viability and xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its established role in repressing p53 in other types of cancers. Mechanistic investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1α1) and formed an RNA-RNA duplex with the type II tRNAs tRNALeu and tRNASer through their variable loops, which facilitated the binding of eEF1α1 to these tRNAs. Disrupting the interaction between MILIP and eEF1α1 or tRNAs diminished protein synthesis and cell viability. Targeting MILIP inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identify MILIP as an RNA translation elongation factor that promotes protein production in TNBC cells and reveal the therapeutic potential of targeting MILIP, alone and in combination with other types of protein synthesis inhibitors, for TNBC treatment., Significance: LncRNA MILIP plays a key role in supporting protein production in TNBC by forming complexes with tRNAs and eEF1α1, which confers sensitivity to combined MILIP targeting and protein synthesis inhibitors., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: The recent discovery of emerging relapsing fever group Borrelia (RFGB) species, such as Borrelia miyamotoi, poses a growing threat to public health. However, the global distribution and associated risk burden of these species remain uncertain. We aimed to map the diversity, distribution, and potential infection risk of RFGB., Methods: We searched PubMed, Web of Science, GenBank, CNKI, and eLibrary from Jan 1, 1874, to Dec 31, 2022, for published articles without language restriction to extract distribution data for RFGB detection in vectors, animals, and humans, and clinical information about human patients. Only articles documenting RFGB infection events were included in this study, and data for RFGB detection in vectors, animals, or humans were composed into a dataset. We used three machine learning algorithms (boosted regression trees, random forest, and least absolute shrinkage and selection operator logistic regression) to assess the environmental, ecoclimatic, biological, and socioeconomic factors associated with the occurrence of four major RFGB species: Borrelia miyamotoi, Borrelia lonestari, Borrelia crocidurae, and Borrelia hermsii; and mapped their worldwide risk level., Findings: We retrieved 13 959 unique studies, among which 697 met the selection criteria and were used for data extraction. 29 RFGB species have been recorded worldwide, of which 27 have been identified from 63 tick species, 12 from 61 wild animals, and ten from domestic animals. 16 RFGB species caused human infection, with a cumulative count of 26 583 cases reported from Jan 1, 1874, to Dec 31, 2022. Borrelia recurrentis (17 084 cases) and Borrelia persica (2045 cases) accounted for the highest proportion of human infection. B miyamotoi showed the widest distribution among all RFGB, with a predicted environmentally suitable area of 6·92 million km 2 , followed by B lonestari (1·69 million km 2 ), B crocidurae (1·67 million km 2 ), and B hermsii (1·48 million km 2 ). The habitat suitability index of vector ticks and climatic factors, such as the annual mean temperature, have the most significant effect among all predictive models for the geographical distribution of the four major RFGB species., Interpretation: The predicted high-risk regions are considerably larger than in previous reports. Identification, surveillance, and diagnosis of RFGB infections should be prioritised in high-risk areas, especially within low-income regions., Funding: National Key Research and Development Program of China., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Older patients with constipation are at higher risk for inadequate bowel preparation, but there are currently no targeted strategies. This study aims to develop an abdominal vibration combined with walking exercise (AVCWE) program and assess its feasibility among older patients with constipation., Methods: Phase I: Using the Delphi technique, eight experts across three professional fields were consulted to develop the AVCWE program. The experts evaluated and provided recommendations on demonstration videos and detailed descriptions of the preliminary protocol. Phase II: A single-arm feasibility study of the AVCWE program was conducted on 30 older patients with constipation undergoing colonoscopy at a tertiary hospital in China. A 10-point exercise program evaluation form and several open-ended questions were used to gather feedback from participants regarding the program. In both phases, content analysis was used to critically analyze and summarize qualitative suggestions for protocol modifications., Results: Based on feedback from the expert panel, the AVCWE program developed in Phase I included two procedures during laxative ingestion: at least 5,500 steps of walking exercise and two cycles of moderate-intensity abdominal vibration (each cycle consisted of 10 min of vibration and 10 min of rest). The feasibility study in Phase II showed high positive patient feedback scores for the program, ranging from 9.07 ± 0.74 to 9.73 ± 0.52., Conclusion: The AVCWE program was developed by eight multidisciplinary experts and was well accepted by 30 older patients with constipation. Study participants believed that this program was simple, safe, appropriate, and helpful for their bowel preparation. The findings of this study may provide valuable information for optimizing bowel preparation in older patients with constipation., (Copyright © 2024 Copyright: © 2024 Saudi Journal of Gastroenterology.)

Background and Aims: To assess patient comfort, wound healing, and scarring at the 6-month follow-up of split-skin graft donor sites treated with Ba-Hao burn ointment (BHBO) gauze, a compound preparation of traditional Chinese medicine since 1970s, compared with petrolatum gauze., Methods: Thirty patients admitted to the Department of Burns of the First Affiliated Hospital of Anhui Medical University between September 2021 and September 2022 participated in this randomized, prospective, self-control clinical study. After harvesting the split skin, donor sites were divided into two parts along the midline. BHBO gauze was applied to half of the donor wounds, and petrolatum gauze was applied to the other half. The wound healing time, pain scores on the postoperative Days 3, 6, and 9, and Vancouver Scar Scale (VSS) score at the 6-month follow-up were assessed., Results: The wound healing time was significantly shorter in the BHBO group than in the control group (10.07 ± 1.48 days vs. 11.50 ± 1.74 days, p  < 0.001). On postoperative Days 3 and 6, the pain scores quantified by visual analog scores were significantly lower in the BHBO group than in the control group (5.33 ± 1.54 and 4.17 ± 1.51, respectively vs. 7.57 ± 1.41 and 5.20 ± 1.47, respectively). The difference in the visual analog scale score on postoperative Day 9 between the groups was not significant ( p  > 0.05). Microbiological assessment revealed the absence of bacterial contamination in both groups. At the 6-month follow up, the VSS score was significantly lower in the BHBO group (6.67 ± 1.92) than in the control group (9.57 ± 1.55)., Conclusion: BHBO resulted in faster donor-site healing, reduced postoperative pain, and improved scar quality at the 6-month follow-up than petrolatum gauze alone., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Herpes zoster (HZ) refers to the rash appearing on dermatomes due to varicella zoster virus (VZV) reactivation. The incidence of HZ is significantly higher in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients than in non-HSCT recipients. Although acyclovir prophylaxis is routinely administered to every allo-HSCT recipient for 1 year after transplantation, some individuals eventually develop late-onset HZ after completing prophylaxis. Little information is known about the clinical features of HZ after prophylactic antiviral treatment discontinuation, and an effective predictive model of late-onset HZ needs to be established. A total of 3366 patients who had received allo-HSCT from 2012 to 2017 were included in our study, among whom 201 developed HZ after 1 year (late-onset HZ). We designed a nested case-control study to identify potential predictors of late-onset HZ. Finally, we established a predictive model using binary logistic regression analysis. Age (p < .001), use of immunosuppressants at +1 year (p < .001), CD4-CD8 ratio at +1 year (p < .001), certain mental disorders (depression, anxiety, insomnia and adjustment disorder) (p < .001), engraftment time of neutrophils (p < .001), and CD8 + cell count at +30 days (p < .001) were independent predictors of late-onset HZ. A risk grading system was established based on regression coefficients. Discrimination and calibration analysis indicated that the model had good performance. We also identified several predictive factors of the incidence of HZ-related complications. This is the first scoring system for predicting the incidence of late-onset HZ after allo-HSCT. This model can be applied to identify individuals at high risk of late-onset HZ in the early period after receiving allo-HSCT., (© 2023 Wiley Periodicals LLC.)

The presence of donor-specific antibodies (DSA) are associated with graft failure either following human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation or after organ transplantation. Although targeting B cells and plasma cells have been used for desensitization, there have been reports of failure. T-follicular helper (Tfh) cells assist B cells in differentiating into antibody-secreting plasma cells. We used haploidentical allograft as a platform to investigate the possibility of targeting Tfh cells to desensitize DSA. The quantities of circulating Tfh (cTfh) cell subsets in allograft candidates were abnormal, and these cells, including the cTfh2 and cTfhem cell subsets, were positively related to the production of anti-HLA antibodies. Ex vivo experiments showed that the cTfh cells of anti-HLA antibody-positive allograft candidates could induce B cells to differentiate into DSA-producing plasmablasts. The immune synapse could be involved in the assistance of cTfh cells to B cells in antibody production. In vitro experiments and in vivo clinical pilot studies indicated that targeting cTfh cells with sirolimus can inhibit their auxiliary function in assisting B cells. Ex vivo and in vivo studies demonstrated the effect of sirolimus and rituximab on DSA desensitization compared with either sirolimus or rituximab alone (60%, 43.75%, and 30%, respectively). Our findings provide new insight into the role of Tfh cells in the pathogenesis of DSA production in HLA-mismatched transplant candidates. Our data also indicate that targeting Tfh cells is a novel strategy for DSA desensitization and combination of sirolimus and rituximab might be a potential therapy. The prospective cohort of this study is registered at http://www.chictr.org.cn as #ChiCTR-OPC-15006672.

The ectonucleotidase CD39 has been regarded as a promising immune checkpoint in solid tumors. However, the expression of CD39 by tumor-infiltrating CD8 + T cells as well as their potential roles and clinical implications in human gastric cancer (GC) remain largely unknown. Here, we found that GC-infiltrating CD8 + T cells contained a fraction of CD39 hi cells that constituted about 6.6% of total CD8 + T cells in tumors. These CD39 hi cells enriched for GC-infiltrating CD8 + T cells with features of exhaustion in transcriptional, phenotypic, metabolic and functional profiles. Additionally, GC-infiltrating CD39 hi CD8 + T cells were also identified for tumor-reactive T cells, as these cells expanded in vitro were able to recognize autologous tumor organoids and induced more tumor cell apoptosis than those of expanded their CD39 int and CD39 - CD8 + counterparts. Furthermore, CD39 enzymatic activity controlled GC-infiltrating CD39 hi CD8 + T cell effector function, and blockade of CD39 efficiently enhanced their production of cytokines IFN-γ and TNF-α. Finally, high percentages of GC-infiltrating CD39 hi CD8 + T cells correlated with tumor progression and independently predicted patients' poor overall survival. These findings provide novel insights into the association of CD39 expression level on CD8 + T cells with their features and potential clinical implications in GC, and empowering those exhausted tumor-reactive CD39 hi CD8 + T cells through CD39 inhibition to circumvent the suppressor program may be an attractive therapeutic strategy against GC., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Integrating CYP2D6 genotyping and therapeutic drug monitoring (TDM) is crucial for guiding individualized atomoxetine therapy in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this retrospective study was (1) to investigate the link between the efficacy and tolerability of atomoxetine in children with ADHD and plasma atomoxetine concentrations based on their CYP2D6 genotypes; (2) to offer TDM reference range recommendations for atomoxetine based on the CYP2D6 genotypes of children receiving different dosage regimens. This retrospective study covered children and adolescents with ADHD between the ages of 6 and <18, who visited the psychological and behavioral clinic of Children's Hospital of Nanjing Medical University from June 1, 2021, to January 31, 2023. The demographic information and laboratory examination data, including CYP2D6 genotype tests and routine TDM of atomoxetine were obtained from the hospital information system. We used univariate analysis, Mann-Whitney U nonparametric test, Kruskal-Wallis test, and the receiver operating characteristic (ROC) curve to investigate outcomes of interest. 515 plasma atomoxetine concentrations of 385 children (325 boys and 60 girls) with ADHD between 6 and 16 years of age were included for statistical analysis in this study. Based on genotyping results, >60% of enrolled children belonged to the CYP2D6 extensive metabolizer (EM), while <40% fell into the intermediate metabolizer (IM). CYP2D6 IMs exhibited higher dose-corrected plasma atomoxetine concentrations by 1.4-2.2 folds than those CYP2D6 EMs. Moreover, CYP2D6 IMs exhibited a higher response rate compare to EMs (93.55% vs 85.71%, P = 0.0132), with higher peak plasma atomoxetine concentrations by 1.67 times than those of EMs. Further ROC analysis revealed that individuals under once daily in the morning (q.m.) dosing regimen exhibited a more effective response to atomoxetine when their levels were ≥ 268 ng/mL (AUC = 0.710, P < 0.001). In addition, CYP2D6 IMs receiving q.m. dosing of atomoxetine were more likely to experience adverse reactions in the central nervous system and gastrointestinal system when plasma atomoxetine concentrations reach 465 and 509 ng/mL, respectively. The findings in this study provided promising treatment strategy for Chinese children with ADHD based on their CYP2D6 genotypes and plasma atomoxetine concentration monitoring. A peak plasma atomoxetine concentration higher than 268 ng/mL might be requisite for q.m. dosing. Assuredly, to validate and reinforce these initial findings, it is necessary to collect further data in controlled studies with a larger sample size., (© 2024. The Author(s).)

Objectives: CD4 + T cell helper and regulatory function in human cancers has been well characterised. However, the definition of tumor-infiltrating CD4 + T cell exhaustion and how it contributes to the immune response and disease progression in human gastric cancer (GC) remain largely unknown., Methods: A total of 128 GC patients were enrolled in the study. The expression of CD39 and PD-1 on CD4 + T cells in the different samples was analysed by flow cytometry. GC-infiltrating CD4 + T cell subpopulations based on CD39 expression were phenotypically and functionally assessed. The role of CD39 in the immune response of GC-infiltrating T cells was investigated by inhibiting CD39 enzymatic activity., Results: In comparison with CD4 + T cells from the non-tumor tissues, significantly more GC-infiltrating CD4 + T cells expressed CD39. Most GC-infiltrating CD39 + CD4 + T cells exhibited CD45RA - CCR7 - effector-memory phenotype expressing more exhaustion-associated inhibitory molecules and transcription factors and produced less TNF-α, IFN-γ and cytolytic molecules than their CD39 - CD4 + counterparts. Moreover, ex vivo inhibition of CD39 enzymatic activity enhanced their functional potential reflected by TNF-α and IFN-γ production. Finally, increased percentages of GC-infiltrating CD39 + CD4 + T cells were positively associated with disease progression and patients' poorer overall survival., Conclusion: Our study demonstrates that CD39 expression defines GC-infiltrating CD4 + T cell exhaustion and their immunosuppressive function. Targeting CD39 may be a promising therapeutic strategy for treating GC patients., Competing Interests: The authors declare that they have no conflict of interest., (© 2024 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)