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Aims Methods Results Conclusions Hydroxychloroquine (HCQ) is recommended for the long‐term treatment of rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus. Given the complex process of HCQ metabolism and individual physiological differences, the metabolic profile of HCQ after long‐term administration is unknown. This study aimed to establish a population pharmacokinetic model for long‐term HCQ treatment in patients with rheumatic diseases and to identify the factors influencing HCQ metabolism.This study included 274 HCQ whole‐blood trough concentration data points from 203 patients with rheumatic diseases, all of whom had taken HCQ for more than 6 months, with a median duration of 36 months. A nonlinear mixed‐effects model was derived to establish a population pharmacokinetic model, and potential influencing factors were investigated. Different covariates were used to simulate the optimal dose.The final model describing the HCQ blood concentration–time profile was a compartmental model with first‐order absorption. The estimated values for apparent clearance and volume of distribution were 16.4 L/h and 1220 L, respectively. The clearance of HCQ gradually increased with increasing dosing regimens and weight gain. Monte Carlo simulations were used to determine the optimal dosage regimens for patients with different body weights and drug durations. The simulation results revealed that an initial dose of 5 mg/kg was appropriate.We developed a population pharmacokinetic model for long‐term HCQ therapy in patients with rheumatic diseases. HCQ clearance from whole blood increased progressively with increasing duration of drug administration. [ABSTRACT FROM AUTHOR]

Labeled hyperspectral image (HSI) information is commonly difficult to acquire, so the lack of valid labeled data becomes a major puzzle for HSI classification. Semi-supervised methods can efficiently exploit unlabeled and labeled data for classification, which is highly valuable. Graph-based semi-supervised methods only focus on HSI local or global data and cannot fully utilize spatial–spectral information; this significantly limits the performance of classification models. To solve this problem, we propose an adaptive global–local feature fusion (AGLFF) method. First, the global high-order and local graphs are adaptively fused, and their weight parameters are automatically learned in an adaptive manner to extract the consistency features. The class probability structure is then used to express the relationship between the fused feature and the categories and to calculate their corresponding pseudo-labels. Finally, the fused features are imported into the broad learning system as weights, and the broad expansion of the fused features is performed with the weighted broad network to calculate the model output weights. Experimental results from three datasets demonstrate that AGLFF outperforms other methods. [ABSTRACT FROM AUTHOR]

What is Known and Objective. Voriconazole (VRC) increases the blood concentration of Tacrolimus (TAC). However, the patterns of changes in TAC trough concentration (TAC C0) and dose-adjustment regimens after VRC discontinuation have not been reported. We aimed to explore the changing pattern of TAC C0 after VRC discontinuation and provide strategies for TAC dose adjustment and blood concentration monitoring in renal transplant recipients. Methods. The clinical data of 46 renal transplant patients pre- and during VRC medication and VRC discontinuation were retrospectively recorded, including doses and concentrations 0 of TAC and VRC; biochemical indicators such as liver and kidney function; and CYP3A5, CYP3A4, and CYP2C19 gene types. Results and Discussion. After discontinuing VRC for 2–4 days, 81% of the patients returned to their initial TAC dose, although TAC C0 and TAC dose-adjusted trough concentration (C/D) were 2.43-fold and 3.35-fold higher, respectively, than pre-VRC administration. After 5–7 days, TAC C0 and C/D gradually recovered. TAC C/D was significantly higher after VRC discontinuation when the VRC trough concentration (VRC C0) was greater than 2.43 mg/L; CYP3A5, CYP3A4, and CYP2C19 genotypes and the administration of erythromycin did not affect the change in TAC C/D. What is New and Conclusion. TAC C/D remains elevated 2–4 days after discontinuing VRC compared to pre-VRC administration, with gradual recovery observed 5–7 days after VRC discontinuation. To avoid excessive blood TAC C0 , the initial TAC dose should not be immediately reinstated upon VRC discontinuation for 2–4 days. VRC C0 are a critical factor influencing the change in TAC C/D ratio after VRC discontinuation. [ABSTRACT FROM AUTHOR]

Background: Diffusion tensor imaging (DTI) studies have demonstrated white matter (WM) abnormalities in patients with temporal lobe epilepsy (TLE). However, alterations in the topological properties of the WM structural network in patients with TLE remain unclear. Graph theoretical analysis provides a new perspective for evaluating the connectivity of WM structural networks. Methods: DTI was used to map the structural networks of 18 patients with TLE (10 males and 8 females) and 29 (17 males and 12 females) age‐ and gender‐matched normal controls (NC). Graph theory was used to analyze the whole‐brain networks and their topological properties between the two groups. Finally, partial correlation analyses were performed on the weighted network properties and clinical characteristics, namely, duration of epilepsy, verbal intelligence quotient (IQ), and performance IQ. Results: Patients with TLE exhibited reduced global efficiency and increased characteristic path length. A total of 31 regions with nodal efficiency alterations were detected in the fractional anisotropy_ weighted network of the patients. Communication hubs, such as the middle temporal gyrus, right inferior temporal gyrus, left calcarine, and right superior parietal gyrus, were also differently distributed in the patients compared with the NC. Several node regions showed close relationships with duration of epilepsy, verbal IQ, and performance IQ. Conclusions: Our results demonstrate the disruption of the WM structural network in TLE patients. This study may contribute to the further understanding of the pathological mechanism of TLE. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic presents challenges for healthcare systems globally, especially in vulnerable populations such as pediatric hematopoietic stem cell transplant (HSCT) recipients. This study examines the clinical characteristics and outcomes of COVID-19 infection in pediatric HSCT recipients within one year post-HSCT.Methods: Retrospective analysis was conducted on data from 247 pediatric patients. None of them had received SARS-CoV-2 vaccination or had prior infection. SARS-CoV-2 infection was confirmed using RT-PCR testing. COVID-19 disease severity was categorized according to established guidelines. Demographic, clinical, laboratory, imaging and treatment data were collected.Results: The median age of the cohort was 7± 3.7 years, with thalassemia major as the predominant underlying disease. Allogeneic HSCT was performed in the majority of cases, with haploidentical donors being the most common source of grafts. Nearly half of the patients developed COVID-19, with significantly higher infection rates observed in recipients over 100 days compared to recipients within 100 days post-HSCT (40.1% vs 21.7%, p< 0.05, Fisher's Exact test). Fever (n=107, 43.2%) and cough (n=88, 35.6%) were the most common symptoms. While most patients had mild disease and did not require specific anti-viral treatment, a significant proportion required hospitalization (n=34, 13.8%). Various treatments were employed hospitalized patients, including Paxlovid (n=19, 55.9%), methylprednisolone (n=7, 20.6%), IL-6 antibody (n=2, 5.9%), mesenchymal stem cells (n=3, 8.8%), and exosomes nebulization therapy (n=2, 5.9%). Despite multidisciplinary approaches, one patient died from severe respiratory failure. However, overall survival of all patients remained high (99.53%; CI 96.72– 99.93%), indicating favorable outcomes in pediatric HSCT recipients with COVID-19.Conclusion: This study provides insights into clinical features, therapeutic measures, and outcomes of pediatric HSCT recipients following COVID-19 infection in a large HSCT center in China. These findings contribute to our understanding of COVID-19 in this population and inform strategies to mitigate the impact the pandemic's impact on their care. [ABSTRACT FROM AUTHOR]

Invasive fungal infections (IFIs) are among the most severe complications in recipients of hematopoietic stem cell transplantation (HSCT) recipients and in patients with hematological malignancies. An increasing number of uncommon fungal infections have been reported in this era of antifungal prophylaxis. Coprinopsis cinerea is a rare pathogen that causes opportunistic infections in the immunocompromised patients, including HSCT recipients and is associated with very high mortality rates. Herein, we present a successfully treated pediatric HSCT patient with breakthrough pulmonary IFI caused by Coprinopsis cinerea despite posaconazole, prophylaxis using multidisciplinary approaches. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), a progressive disorder, has become a global health problem and is now the main cause of dementia. The aetiology of AD is complex and remains elusive making effective AD treatment difficult. Current drugs for AD only improve symptoms but do not interfere with pathogenic mechanisms. Three main hypotheses have been brought forward regarding AD aetiology, one of them being the 'inflammation hypothesis'. A number of studies have demonstrated that inflammation plays a critical role in AD. Self-limiting neuroinflammation is considered beneficial to AD, whereas chronic inflammation aggravates brain injury and neuronal death. Transforming growth factor β 1(TGF-β1) is an anti-inflammatory cytokine with neuroprotective properties. Smad proteins are downstream molecules of TGF-β signalling. They are cytoplasmic transcription factors that can regulate targeted gene expression. In AD, impairments of TGF-β1/Smad pathways have been observed. Moreover, microglia, astrocytes, inflammasomes, and insulin resistance also have been implicated in AD pathogenesis. Elucidating the molecular mechanisms underlying AD pathogenesis is a fundamental step toward designing new treatment options. In this review, we detail the changes in TGF-β1/Smad pathways in AD and hope this will facilitate further research on AD treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Cytokines are small molecules that modify the response of the human body to external signals. Tumor Necrosis Factor was found in 1975 and its main activity was assumed to be lethal for cancer cells and to be able to kill tumors, hence the name. Research over the last 35 years has shown that this is not really the case. This review illuminates what caused this misunderstanding and answers the question if there is any connection at all between the cytokine Tumor Necrosis Factor and cancer. Tumor Necrosis Factor was one of the first cytokines described in the literature as a soluble mediator of cytotoxicity to tumors. Over the years, more extensive research that tried to employ Tumor Necrosis Factor in cancer treatments showed nevertheless that it mainly functioned as a proinflammatory cytokine. However, this did not stop the search for the holy grail of cancer research: A cytokine that could act as a one-stop treatment for solid tumors and lymphomas. This review will summarize the long experimental history of Tumor Necrosis Factor that caused the initial observations of a tumor necrotizing cytokine that could serve as a potential cancer treatment and discuss the current state of research into this side of the activities of Tumor Necrosis Factor. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea syndrome (OSAS) has become a major worldwide public health concern, given its global prevalence. It has clear links with multiple comorbidities and mortality. Cognitive impairment is one related comorbidity causing great pressure on individuals and society. The clinical manifestations of cognitive impairment in OSAS include decline in attention/vigilance, verbal–visual memory loss, visuospatial/structural ability impairment, and executive dysfunction. It has been proven that chronic intermittent hypoxia (CIH) may be a main cause of cognitive impairment in OSAS. Inflammation plays important roles in CIH-induced cognitive dysfunction. Furthermore, the nuclear factor kappa B and hypoxia-inducible factor 1 alpha pathways play significant roles in this inflammatory mechanism. Continuous positive airway pressure is an effective therapy for OSAS; however, its effect on cognitive impairment is suboptimal. Therefore, in this review, we address the role inflammation plays in the development of neuro-impairment in OSAS and the association between OSAS and cognitive impairment to provide an overview of its pathophysiology. We believe that furthering the understanding of the inflammatory mechanisms involved in OSAS-associated cognitive impairment could lead to the development of appropriate and effective therapy. [ABSTRACT FROM AUTHOR]

Background and Purpose: Understanding the pathogenesis of temporal lobe epilepsy (TLE) is essential for its diagnosis and treatment. The study aimed to explore regional homogeneity (ReHo) and changes in effective connectivity (EC) between brain regions in TLE patients, hoping to discover potential abnormalities in certain brain regions in TLE patients. Methods: Resting‐state functional magnetic resonance data were collected from 23 TLE patients and 32 normal controls (NC). ReHo was used as a feature of multivariate pattern analysis (MVPA) to explore the ability of its alterations in identifying TLE. Based on the results of the MVPA, certain brain regions were selected as seed points to further explore alterations in EC between brain regions using Granger causality analysis. Results: MVPA results showed that the classification accuracy for the TLE and NC groups was 87.27%, and the right posterior cerebellum lobe, right lingual gyrus (LING_R), right cuneus (CUN_R), and left superior temporal gyrus (STG_L) provided significant contributions. Moreover, the EC from STG_L to right fusiform gyrus (FFG_R) and LING_R and the EC from CUN_R to the right occipital superior gyrus (SOG_R) and right occipital middle gyrus (MOG_R) were altered compared to the NC group. Conclusion: The MVPA results indicated that ReHo abnormalities in brain regions may be an important feature in the identification of TLE. The enhanced EC from STG_L to FFG_R and LING_R indicates a shift in language processing to the right hemisphere, and the weakened EC from SOG_R and MOG_R to CUN_R may reveal an underlying mechanism of TLE. [ABSTRACT FROM AUTHOR]

Purpose: This study used the graph-theory approach, degree centrality (DC) to analyze whole-brain functional networks at the voxel level in children with ASD, and investigated whether DC changes were correlated with any clinical variables in ASD children. Methods: The current study included 86 children with ASD and 54 matched healthy subjects Aged 2– 5.5 years. Next, chloral hydrate induced sleeping-state functional magnetic resonance imaging (ss-fMRI) datasets were acquired from these ASD and healthy subjects. For a given voxel, the DC was calculated by calculating the number of functional connections with significantly positive correlations at the individual level. Group differences were tested using two-sample t-tests (p < 0.01, AlphaSim corrected). Finally, relationships between abnormal DCs and clinical variables were investigated via Pearson's correlation analysis. Results: Children with ASD exhibited low DC values in the right middle frontal gyrus (MFG) (p < 0.01, AlphaSim corrected). Furthermore, significantly negative correlations were established between the decreased average DC values within the right MFG in ASD children and the total ABC scores, as well as with two ABC subscales measuring highly relevant impairments in ASD (ie, stereotypes and object-use behaviors and difficulties in language). Conclusion: Taken together, the results of our ss-fMRI study suggest that abnormal DC may represent an important contribution to elucidation of the neuropathophysiological mechanisms of preschoolers with ASD. [ABSTRACT FROM AUTHOR]

The dynamic description of neural networks has attracted the attention of researchers for dynamic networks may carry more information compared with resting-state networks. As a non-invasive electrophysiological data with high temporal and spatial resolution, magnetoencephalogram (MEG) can provide rich information for the analysis of dynamic functional brain networks. In this review, the development of MEG brain network was summarized. Several analysis methods such as sliding window, Hidden Markov model, and time-frequency based methods used in MEG dynamic brain network studies were discussed. Finally, the current research about multi-modal brain network analysis and their applications with MEG neurophysiology, which are prospected to be one of the research directions in the future, were concluded. [ABSTRACT FROM AUTHOR]

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive therapeutic intervention that is typically used for many years to treat chronic pain in patients who are refractory to pain medications. However, evidence of the efficacy of TENS treatment for neuropathic pain is lacking in humans. To further understand the efficacy of TENS under various intervention conditions and illuminate the current circumstance and future research directions, we systematically reviewed animal studies investigating the efficacy of TENS in relieving pain in neuropathic pain rodent models. We searched the Cochrane Library, EMBASE, MEDLINE (via PubMed), and Web of Science and identified 11 studies. Two meta-analyses were performed. The first meta-analysis showed that a single TENS treatment was capable of temporarily ameliorating neuropathic pain when compared to control groups with a significant effect (standardized mean difference: 1.54; 95% CI: 0.65, 2.42; p = 0.0007; I 2 = 58%). Significant temporary alleviation in neuropathic pain intensity was also observed in the meta-analysis of repetitive TENS (standardized mean difference: 0.85; 95% CI: 0.31, 1.40; p = 0.002; I 2 = 75%). Subgroup analysis showed no effect of the timing of the application of TENS (test for subgroup difference, p = 0.47). Leave-one-out sensitivity analyses suggested that no single study had an outsized effect on the pooled estimates, which may partly prove the robustness of these findings. Other stratified analyses were prevented by the insufficient number of included studies. Overall, current data suggest that TENS might be a promising therapy to ameliorate neuropathic pain. However, the high risk of bias in the included studies suggests that cautions must be considered when interpreting these findings and it is not reasonable to directly generalize the results obtained from animal studies to clinical practice. Future studies should pay more attention to improving the quality of study design and reporting, thereby facilitating the understanding of mechanisms underlying TENS treatment, reducing more potentially unsuccessful clinical trials, and optimizing the efficacy of TENS for people with neuropathic pain. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis is a rare but life-threatening complication in patients who received hematopoietic stem cell transplantation. Early identification and intervention are essential to prevent severe complications. Case Presentation: We report two pediatric patients who developed tuberculosis after receiving hematopoietic stem cell transplantation for thalassemia major among 330 recipients between January 2012 and August 2019. Patient A presented with pulmonary tuberculosis and patient B presented with lymph node tuberculosis mimicking post-transplantation lymphoproliferative disorder associated with Epstein–Barr virus reactivation. Patient B's condition was deteriorated, and shortly after the initiation of anti-tuberculosis therapy, the patient was found to have disseminated pulmonary tuberculosis. Patient B was also found to have tuberculous granulomas, an uncommon manifestation of tuberculosis causing severe airway obstruction. Both patients developed critical respiratory failure and required mechanical ventilation; however, they recovered with almost full resolution of pulmonary lesions after multiple treatment adjustments. Conclusion: Tuberculosis must be carefully evaluated in all pediatric patients that receive hematopoietic stem cell transplantation, regardless of the identification of other pathogens. Prophylactic tuberculosis therapy should be considered for high-risk pediatric hematopoietic stem cell transplantation recipients from tuberculosis-endemic regions. [ABSTRACT FROM AUTHOR]

Background: Although functional brain connectivity in anxiety-related disorders has been studied, brain connectivity in non-clinical populations with high trait anxiety has been rarely reported. Whether structural brain connectivity changes in young healthy individuals with high trait anxiety remains unknown. Methods: Thirty-eight young healthy individuals with high anxiety levels and 34 healthy subjects with low anxiety levels who were matched by age, gender, and educational level were recruited. Diffusion tensor images were acquired to analyze white matter connectivity. A two-sample t -test was used for group comparison of weighted networks and graph properties. Results: Different connections were detected in fractional anisotropy- and fiber number-weighted networks. These connections were widely distributed in various regions, where relative significance was located in the inter-hemispheric frontal lobe, the frontal-limbic lobe in the right intra-hemisphere, and the frontal-temporal lobe in the ipsilateral hemisphere. However, no significant difference was found in fiber length-weighted network and in graph properties among the three networks. Conclusions: The structural connectivity of white matter may be a vulnerability marker. Hence, healthy individuals with high trait anxiety levels are susceptible to anxiety-related psychopathology. The findings may help elucidate the pathological mechanism of anxiety and establish interventions for populations susceptible to anxiety disorders. [ABSTRACT FROM AUTHOR]

Neuroimaging studies have shown that autism spectrum disorders (ASDs) may be associated with abnormalities in brain structures and functions at rest as well as during cognitive tasks. However, it remains unclear if functional connectivity (FC) of all brain neural networks is also changed in these subjects. In this study, we acquired functional magnetic resonance imaging scans from 93 children with ASD and 79 matched healthy subjects. Group independent component analysis was executed for all of the participants to estimate FC. One-sample t -tests were then performed to obtain the networks for each group. Group differences in the different brain networks were tested using two-sample t -tests. Finally, relationships between abnormal FC and clinical variables were investigated with Pearson's correlation analysis. The results from one-sample t -tests revealed nine networks with similar spatial patterns in these two groups. When compared with the controls, children with ASD showed increased connectivity in the right dorsolateral superior frontal gyrus and left middle frontal gyrus (MFG) within the occipital pole network. Children with ASD also showed decreased connectivity in the left gyrus rectus, left middle occipital gyrus, right angular gyrus, right MFG and right inferior frontal gyrus (IFG), orbital part within the lateral visual network (LVN), the left IFG, right precuneus, and right angular gyrus within the left frontoparietal (cognition) network. Furthermore, the mean FC values within the LVN showed significant positive correlations with total score of the Childhood Autism Rating Scale. Our findings indicate that abnormal FC extensively exists within some networks in children with ASD. This abnormal FC may constitute a biomarker of ASD. Our results are an important contribution to the study of neuropathophysiological mechanisms in children with ASD. [ABSTRACT FROM AUTHOR]

Antibiosis and resource competition are major drivers shaping the assembly, diversity and functioning of microbial communities. While it is recognized that competition is sensitive to environmental conditions, it is unclear to what extent this mediated by the availability of different carbon resources.Here, we used a model laboratory system to directly test this by exploring how carbon resource richness and identity shape resource competition and antibiosis between plant probiotic Bacillus amyloliquefaciens and phytopathogenic Ralstonia solanacearum bacteria. We found that while sugars typically promoted B. amyloliquefaciens growth, organic and amino acids increased the production of both bacillaene and macrolactin antibiotics and the direct inhibition of R. solanacearum. In contrast, when multiple different carbon resources were available, B. amyloliquefaciens could efficiently grow and produce antibiotics at the same time.Together, these results suggest that high carbon resource richness allows concurrent expression of growth‐ and antibiosis‐related traits, potentially altering bacterial competitive dynamics and plant growth promotion in microbial communities. A plain language summary is available for this article. [ABSTRACT FROM AUTHOR]

Background: Abnormalities in prespecified and empirical white matter tracts in young patients with anxiety-related disorders have been reported in some diffusion tensor imaging (DTI) studies. However, with few literatures examining the association between the integrity of whole brain white matter and trait anxiety levels in the non-clinical populations, whether white matter changes arise in young healthy individuals with high trait anxiety remains unknown. Methods: We examined whole brain white matter alterations in young healthy individuals with high anxiety but without history of neurological or psychiatric disorders via DTI technology. Group comparison of tract-based spatial statistics (TBSS) was performed to investigate the microstructural diffusion alterations in 38 high anxious subjects in comparison with 34 low anxious subjects matched with age, gender, and degree of education. These analyses controlled for depression to establish specificity to trait anxiety. Results: Young healthy subjects with high trait anxiety had significantly decreased fractional anisotropy (FA) values in multiple clusters, including corona radiate (CR), anterior thalamic radiation (ATR), inferior fronto-occipital fasciculus (IFOF), bilaterally, body, genu, and splenium of corpus callosum (CC) and forceps minor, compared with low trait anxious subjects. For the abnormal FA regions, the other diffusion metrics were also altered slightly. Conclusions: Non-clinical individuals with high anxiety already have white matter alterations in the thalamus-cortical circuit and some emotion-related areas that were widely reported in anxiety-related disorders. The altered white matter may be a vulnerability marker in individuals at high risk of clinical anxiety. These findings can deepen our understanding of the pathological mechanism of anxiety and further support the need for preventive interventions in high anxiety individuals. [ABSTRACT FROM AUTHOR]