The effect of childhood trauma on moral cognition in patients with schizophrenia.

Objective: The aim of this study was to investigate whether a potential moral cognitive impairment (failure in understanding moral rules) exists in patients with schizophrenia (SCZ) and to explore the effect of childhood trauma (CT) on moral cognition in a group of patients with SCZ. Methods: A total of 99 patients with SCZ and 102 healthy controls (HCs) were included in this study. The Childhood Trauma Questionnaire-Short Form (CTQ) was administered to assess childhood trauma experiences in both groups, while the Moral Identity Measure (MIM) and the Moral Foundations Questionnaire (MFQ) were applied for a comparative evaluation of moral cognition across the two groups. The Positive and Negative Syndrome Scale (PANSS) was administered to assess the psychopathology. Results: Patients with schizophrenia had significantly greater CTQ scores than HCs (42.77 ± 13.50 vs. 29.11 ± 4.25, t=9.697, p<0.001). The prevalence of childhood trauma (χ 2 = 58.452, p<0.001) and history of aggressive behaviors (χ 2 = 23.565, p=0.001) among patients with SCZ were greater than that among HCs. In addition, the scores of moral cognition (MIM: 61.82 ± 15.12 vs. 70.88 ± 8.87, p=0.001; MFQ: 87.24 ± 22.30 vs. 112.62 ± 23.42, p=0.045) in the SCZ group was lower than that in the HC group after controlling for the influence of CT covariates. The MFQ score was negatively correlated with the CTQ score, the emotional abuse (EA) score, the physical abuse (PA) score and the physical neglect (PN) score in SCZ patients. Among HCs, the MFQ score was positively correlated with the CTQ score, as well as with the dimensions of physical abuse (PA) and emotional Neglect (EN). Multiple linear regression analyses revealed that impaired moral cognition performance was significantly predicted by the CTQ score (beta=-0.235, p=0.034, 95% CI -0.743 to -0.031) in patients with SCZ but was significantly predicted by years of education (beta=-0.392, p<0.001, 95% CI -4.783 to -1.876), alcohol use (beta=0.210, p=0.023, 95% CI 2.191 to 29.399) and the CTQ score (beta=0.184, p=0.046, 95% CI 0.019 to 1.928) in HCs. CTQ moderated the effect of SCZ on MFQ (B = 0.516); Simple tests revealed that the group effect on the MFQ was B=12.306 at the lower level(-1SD) and B = 54.089 at the higher level(+1SD) of the CTQ scores. Conclusions: SCZ patients exhibit impaired moral cognition. The contribution of CT to the presence of moral cognitive impairments seems to be independent of psychopathology.

Therapeutic Drug Monitoring for Sirolimus in Children with Vascular Anomalies: What Can We Learn from a Retrospective Study.

Objectives: Sirolimus (SRL), a mammalian target of rapamycin inhibitor, has been widely used to treat patients with vascular anomalies (VAs). The objectives of this study were to summarize the routine blood SRL monitoring data for VAs children, to investigate the factors contributing to the variable blood SRL concentrations and to evaluate the efficacy and safety of SRL therapy. Methods: VAs patients with routine blood SRL monitoring from July 2017 to April 2022 at the Department of Burns and Plastic Surgery, Children's Hospital of Nanjing Medical University were retrospectively collected. Clinical data were obtained from the hospital information system. Results: In total, 67 children (35 females) were enrolled. The therapeutic drug monitoring data showed that the range of measured blood trough concentrations (Ctrough) was 3.6-46.8 ng/mL. At the initial measurements, only 33% of patients were in the target concentration range (10-15 ng/mL). But this proportion became 54% at the last measurements. The whole blood-Ctrough-to-daily dose (Ctrough/Dose) ratio was significantly associated with age and body weight (BW). The patients' laboratory results did not change significantly after SRL treatment. Although the incidence of adverse events was relatively high (44.8%), most of them were mild and tolerable. 70.3% patients had total responses to SRL, whereas 29.7% children exhibited stable disease or progressive disease. No significant differences were found in Ctrough between the total response group and non-response group. Conclusions: This retrospective study revealed a high variability in SRL blood concentrations in Chinese children with VAs. Of note, pediatric patients with older age and a higher BW had a lower Ctrough/Dose ratio. It is a concern whether the range of 10-15 ng/mL is feasible for Chinese children based only on our study. Further studies recruiting more patients are required to redefine the target reference range for children with VAs.

Mega-dose decitabine conditioning and prophylactic donor lymphocyte infusion for patients with relapsed/refractory AML with active disease at the time of allogeneic haematopoietic cell transplantation: A multicenter prospective phase II study.

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/m2) 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.

Mitochondrial dysfunction in sepsis: mechanisms and therapeutic perspectives.

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.

CYP2C19 genotype and sodium channel blockers in lacosamide-treated children with epilepsy: two major determinants of trough lacosamide concentration or clinical response.

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.

CYP2C19 genotype and sodium channel blockers in lacosamide-treated children with epilepsy: two major determinants of plasma lacosamide concentration or treatment efficacy This study examined the impact of genetic factors and drug combinations on the effectiveness and plasma concentrations of lacosamide, an antiseizure medication, in patients under 18. Analyzing blood samples from 316 patients at the Children's Hospital of Nanjing Medical University, researchers discovered that genetic variations in the CYP2C19 (i.e. *2 and *3), along with metabolic capacity, and co-medication with sodium channel blockers, all influence plasma lacosamide concentration. Understanding these genetic influences could inform personalized dosing strategies, improving the medication's management for pediatric epilepsy patients.

Relationship between sun exposure and seasonal affective disorder symptoms in rural older people with different personalities: a cross-sectional study.

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.

Global burden of benign prostatic hyperplasia, urinary tract infections, urolithiasis, bladder cancer, kidney cancer, and prostate cancer from 1990 to 2021.

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.

A small step toward precision dosing of caffeine in preterm infants: An external evaluation of published population pharmacokinetic models.

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.

Distinct Immune Homeostasis Remodeling Patterns after HLA-Matched and Haploidentical Transplantation.

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.

Advancements in understanding substantia nigra hyperechogenicity via transcranial sonography in Parkinson's disease and its clinical implications.

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.

Clinical characteristics and risk stratification for late-onset herpes zoster following allogeneic hematopoietic stem cell transplantation.

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.

Expert consensus on the diagnosis and treatment of macrolide-resistant Mycoplasma pneumoniae pneumonia in children.

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.

Clinical features and prognostic model for viral encephalitis after allogeneic haematopoietic stem cell transplantation.

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.

Analysis of factors influencing pregnancy and its outcomes in women undergoing in vitro fertilization-embryo transfer/frozen embryo transfer cycles: A retrospective study.

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.

Polysaccharides from bile Arisaema exert an antipyretic effect on yeast-induced fever rats through regulating gut microbiota and metabolic profiling.

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.

Genetic evidence supporting potential causal roles of EIF4 family in breast cancer: a two-sample randomized Mendelian study.

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.

Development and application of a population pharmacokinetic model repository for caffeine dose tailoring in preterm infants.

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.

Clinical biomarker-based biological aging and risk of benign prostatic hyperplasia: A large prospective cohort study.

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.

Patient-reported symptom burden and circulating cytokines undergoing chemotherapy: a pilot study in patients with ovarian cancer.

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.