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Abstract Background To analyze the etiological distribution characteristics of drug-resistant epilepsy (DRE) in children, with the aim of providing valuable perspectives to enhance clinical practice. Methods In this retrospective study, clinical data were collected on 167 children with DRE who were hospitalized between January 2020 and December 2022, including gender, age of onset, seizure types, video electroencephalogram(VEEG) recordings, neuroimaging, and genetic testing results. Based on the etiology of epilepsy, the enrolled children were categorized into different groups. The rank-sum test was conducted to compare the age of onset for different etiologies. Results Of the 167 cases, 89 (53.3%) had a clear etiology. Among them, structural factors account for 23.4%, genetic factors for 19.2%, multiple factors for 7.2%, and immunological factors for 3.6%. The age of onset was significantly earlier in children with genetic causes than those with structural (P

Objective: The study analyzed the impact of urbanization on epidemiological characteristics of respiratory infectious disease in Tongzhou District, Beijing during 2014–2022 to provide reference for prevention and control priorities of respiratory infectious diseases during the innovative urbanization process in China. Methods: The incidence data of notifiable respiratory infectious diseases (NRIDs) in Tongzhou Beijing during 2014–2022 were summarized. The trend of incidence rate was analyzed by Joinpoint regression model, and entropy method was performed to construct the comprehensive index of urbanization (CIU) and generalized linear model was used to analyze the influence of CIU on the incidence rate of respiratory infectious diseases. Results: Totally 72616 NRIDs cases were reported in Tongzhou District during 2014–2022, and the incidence rate of NRIDs was higher during 2017–2019 (153/100 000) than during 2014–2016 (930/100 000) and during 2020–2022 (371/100 000), respectively (both P

Abstract Background This study aimed to investigate the relationship between chronotypes and aggression in adolescents. Methods A cross-sectional study was conducted on 755 primary and secondary school students aged 11–16 years in rural areas of Ningxia Province, China. The Chinese version of the Buss-Perry Aggression Questionnaire (AQ-CV) and the Chinese version Morningness-Eveningness Questionnaire (MEQ-CV) were used to assess the aggressive behavior and chronotypes of the study subjects. The Kruskal-Wallis test was then used to compare the differences in aggression among adolescents with different chronotypes, and Spearman correlation analysis to determine the relationship between chronotypes and aggression. Further linear regression analysis was used to investigate the effects of chronotype, personality traits, family environment, and class environment on adolescent aggression. Results There were significant differences in chronotypes between different age groups and different sexes. Spearman correlation analysis showed that the MEQ-CV total score was negatively correlated with the AQ-CV total score (r = -0.263) and score of each AQ-CV subscale. In Model 1, chronotypes were negatively associated with aggression when controlling for age and sex, and evening-type adolescents might be more likely to exhibit aggressive behavior (b = -0.513, 95% CI: [-0.712, -0.315], P

Background: To meet the growing global demand for rehabilitation services, the World Health Organization (WHO) launched Rehabilitation 2030. This study was commissioned by the WHO to investigate the integration degree of traditional Chinese medicine (TCM) in Chinese health system rehabilitation services and the demand for TCM rehabilitation in China. Methods: Twenty TCM rehabilitation experts and relevant government administrators were invited to complete the questionnaire between September 2019 and January 2022. The development of traditional, complementary, and integrative medicine (TCI) rehabilitation in China was assessed primarily based on six different health system components. Results: 26 policies, regulations, and national strategic plans related to TCI rehabilitation were issued by relevant government departments since 2002; notably, 14 policies related to TCI rehabilitation development were intensively introduced from 2016 to 2021. These policies cover the three main areas of financing, infrastructure development, and service delivery. The National Administration of Traditional Chinese Medicine's investment in TCM clinical capacity infrastructure and scientific research in 2019–2021 increased by 66% compared to 2010–2012, and the average number of TCM hospitals with rehabilitation departments in 2020 increased by 6.5% compared to 2018. The proportion of community health service centers providing TCM services in primary medical and health institutions has increased by 30.8% over the past 10 years. Conclusion: Long-term continuous policies, substantial financial investment, and expansion of the scope of TCI rehabilitation services in primary care institutions have effectively contributed to the rapid development of TCI rehabilitation. However, human resources and financing mechanisms for TCI rehabilitation need further improvement.

$ \begin{align*} \left[\frac{f'''}{f'}-\frac{3}{2}\left(\frac{f''}{f'}\right)^{2}\right]^{k} = R(z). \end{align*} $ We investigate the uniqueness of meromorphic solutions of the above Schwarzian differential equation if the meromorphic solution $ f $ shares three values with any other meromorphic function.

BackgroundGiven that the combination of multiple antibodies in autoimmune encephalitis (AE) is rare and its clinical significance is unclear, this study aimed to investigate the clinical characteristics and significance of overlapping multiple anti-neuronal antibodies in patients with AE.MethodsWe conducted a retrospective analysis of the clinical characteristics, treatment, and prognostic details of 22 patients with multiple coexisting antibodies from multiple clinical centers in China.ResultsAmong the 276 patients who were AE antibody-positive, 22 (7.97%) had two or more antibodies. Among the 22 patients with coexisting AE-related antibodies, 14 patients (63.63%) were combined of cell surface and intracellular antibody, and the remaining 8 patients (36.36%) were detected to be cell surface antibody positive only. The main symptoms of the 22 patients in this cohort included fever, seizures, memory impairment, cognitive decline, and sleep disorders. Five (22.73%) patients had tumors, among whom four had small-cell lung cancers, and one had mediastinal tumors. A total of 20 patients were treated with steroids and intravenous immunoglobulin, and 18 showed varying degrees of symptomatic improvement after first-line immunotherapy. Three patients died of tumor progression or chemotherapy complications.ConclusionThe coexistence of multiple anti-neuronal antibodies in patients with AE may cause a superimposition and diversification of clinical manifestations. Combined paraneoplastic antibody positivity may be suggestive of an underlying malignancy.

BackgroundSarcopenia is the age-related loss of skeletal muscle mass and function; it is a risk factor for falls among older individuals. Few studies have focused on training such individuals to adopt a safe-landing strategy that would protect them from fall-related injuries. Ditangquan is a traditional Chinese martial art comprising movements that conform to the principles of safe landing. This study aims to investigate the effectiveness of Ditangquan in preventing fall-related injuries among older individuals with sarcopenia.MethodsA total of 70 participants (21 males and 49 females with sarcopenia) between 60 and 80 years of age were recruited from three local communities and randomly assigned to the Ditangquan exercise group (DG) or the control group (CG) in a 1:1 ratio. Three times a week for 24 weeks, both the DG and CG received an hour of conventional exercise and an hour of Ditangquan exercise based on safe landing. Primary outcomes were the modified falls efficacy scale (MFES), the number of falls, and fall injuries; the secondary outcome was the Timed Up & Go (TUG) test.ResultsThe DG had significantly fewer falls (1 vs. 8, P = 0.028) and fall injuries (0 vs. 6, P = 0.025) than the CG. Furthermore, at the end of the study, the DG had a significantly improved MFES (mean difference: 32.17 scores; 95% CI: 21.32, 43.02; P

Sarcopenia has become a key challenge for healthy aging in older adults. However, it remains unclear whether traditional Chinese medicine can effectively treat sarcopenia. This systematic review analyzes the current evidence for the effect of traditional Chinese medicine (TCM) on sarcopenia. We searched for articles regarding sarcopenia treated by TCM in Cochrane library, PubMed, SinoMed, Web of Science, Embase, and the China National Knowledge Infrastructure (from inception until 10 December 2021). Two researchers independently screened the literature in accordance with the inclusion and exclusion criteria designed by PICOS principles. The risk of bias was assessed by the Cochrane Risk of Bias (ROB) tool. The quality of evidence was assessed by the grading of recommendations, assessment, development, and evaluation (GRADE). Participants’ characteristics, interventions, and the relevant results of the included studies were extracted and synthesized in a narrative way. The total number of participants in the 21 included studies was 1,330. Most of the studies evaluated physical function (n = 20) and muscle strength (n = 18), and a small number of studies (n = 6) assessed muscle mass. Overall, it was found that TCM had a positive impact on muscle strength (grip strength, chair stand test) and physical function (6-m walking speed, timed up and go test, sit and reach) in patients with sarcopenia, inconsistent evidence of effects on muscle mass. However, the small sample size of the included studies led to imprecision in the results, and the presence of blinding of the studies, allocation concealment, and unreasonable problems with the control group design made the results low grade. Among these results, the quality of evidence for grip strength (n = 10) was of medium grade, and the quality of evidence related to the remaining indicators was of low grade. This systematic review showed that traditional Chinese Qigong exercises and Chinese herbal medicine have a positive and important effect on physical performance and muscle strength in older adults with sarcopenia. Future high-quality multicenter randomized controlled trials (RCTs) with large samples are needed to determinate whether acupuncture and other therapies are effective in treating sarcopenia.

Background and ObjectivesLow free triiodothyronine (FT3) is usually associated with worse functional outcome in critical illness; however, the information on thyroid dysfunction and autoimmune encephalitis (AE) is limited. This study aims to evaluate the clinical prognostic value of thyroid function and low-T3 syndrome in patients with multiple subtypes of AE. MethodsIn this retrospective study, we identified the hospital records of 319 candidate patients with AE admitted between January 2016 and December 2020. We then extracted the clinical features and outcomes. Modified Rankin scale (mRS) scores were used to evaluate the patients’ neurological function. The serum levels of FT3, free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were measured upon admission. Normal thyroid stimulating hormone level with FT3 below the lower limit of the reference interval (2.63 nmol/L) was defined as low-T3 syndrome.ResultsA total of 237 AE cases remained after screening. Among these, 57.81% (137/237) were men and the average age at onset was 41 y (interquartile range, 12–61 y). We found that 83.54% (198/237) of the patients had a good prognosis, and 16.46% (39/237) had a poor prognosis. Abnormal thyroid function was observed in 30.80% of these patients, with a relatively greater prevalence in the group with a poor prognosis (p < 0.001). The serum FT3 levels in the poor-prognosis group were significantly lower than those in the good-prognosis group (p < 0.001). Low-T3 syndrome occurred in 15.19% of AE cases and was more frequent in patients with poor prognosis (p < 0.001).ConclusionsAbnormal thyroid function in AE is frequent, and serum FT3 levels in patients with poor prognosis are significantly lower than in those with good prognosis. Low-T3 syndrome could be a potential candidate for predicting the prognosis of AE following future research.

Objective: We conducted a survey to assess vaccination coverage, vaccination willingness, and variables associated with vaccination hesitancy to provide evidence on coronavirus disease (COVID-19) vaccination strategies.Methods: This anonymous questionnaire study conducted a multicenter, cross-sectional survey of outpatients and inpatients with epilepsy (PWE) registered in epilepsy clinics, in 2021, in 10 hospitals in seven cities of Shandong Province.Results: A total of 600 questionnaires were distributed, and 557 valid questionnaires were returned. A total of 130 people were vaccinated against COVID-19. Among 427 unvaccinated participants, 69.32% (296/427) were willing to receive the COVID-19 vaccine in the future, and the remaining 30.68% (131/427) were unwilling to receive vaccination. Most (89.9%) of the participants believed that the role of vaccination was crucial in response to the spread of COVID-19. A significant association was found between willingness to receive the COVID-19 vaccine and the following variables: age, marital status, level of education, occupation, residence, seizure type, and seizure control after antiepileptic drug therapy. It is noteworthy that education level, living in urban areas, and seizure freedom were significantly related to willingness to receive COVID-19 vaccination.Conclusions: Vaccination is a key measure for the prevention and control of COVID-19, and most PWE are willing to be vaccinated. Vaccine safety, effectiveness, and accessibility are essential in combatting vaccine hesitation and increasing vaccination rates.

Abstract Background Host genetic factors affect the immune response to Mycobacterium tuberculosis (Mtb) infection as well as the progression of the disease. Epiregulin (EREG) belongs to the epidermal growth factor (EGF) family, which binds to the epidermal growth factor receptor (EGFR) to regulate the immune response of the host during infections. Our study aimed to compare EREG levels in tuberculosis (TB) patients and healthy controls and assess whether polymorphisms in EREG increase the risk of TB. Methods We used ELISA to determine the plasma EREG level from 30 healthy controls and 50 tuberculosis patients. By evaluating the EREG gene from 624 TB patients and 600 healthy controls, we determined the allelic and genotypic frequencies for association with susceptibility to TB infections in this group. Results This paper shows that the pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) groups showed a significantly higher plasma EREG level (1014 ± 733.9 pg/ml, 700.2 ± 676.6 pg/ml, respectively) than the healthy controls (277 ± 105.4 pg/ml). The rs2367707 polymorphism was associated with a higher risk of PTB and EPTB (P = 0.00051, P = 0.0012). Analyses of haplotype frequencies found that people with the haplotype CACAT had a higher risk of PTB and EPTB (P = 0.00031, OR = 1.43; P = 0.000053, OR = 1.65). Moreover, the rs6446993 polymorphism of the EREG gene was found to be associated with EPTB (P = 0.00087, OR = 1.54; 95% CI = 1.23–1.94). Conclusions Compared to that of healthy controls, the level of EREG in the plasma of TB patients increased significantly. Based on these data, we demonstrated that EREG polymorphisms are genetic factors for susceptibility to TB and various forms of TB.

Purpose: Autoimmune encephalitis (AE) is a heterogeneous neurological autoimmune disorder associated with cognitive and psychiatric symptoms. It can be divided into several subtypes based on autoantibodies. Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor encephalitis (AMPAR-E) is one of the recently discovered AE subtypes, usually manifesting limbic encephalitis and with a good prognosis. Considering AMPAR-E has been described for the first time, only a few cases with similar antibodies have been reported clinically. We aimed to clarify the clinical course and prognosis of the disease in the light of previous reports.Patients and Methods: We collected data on the diagnosis and treatment of six cases of AMPAR-E, diagnosed at the Qilu Hospital of Shandong University in the past 5 years. We retrospectively analyzed the clinical characteristics of the patients and performed a follow-up of the disease.Results: The patients often presented with limbic encephalitis, which sometimes coexisted with tumors. In addition, immunotherapy had a significant effect on the disease. The clinical outcome was related to factors such as the age of onset, timing of treatment, and presence of tumors.Conclusion: In conclusion, specific antibody tests should be performed as early as possible in suspected cases. Clinicians should actively administer immunotherapy and the management of the co-tumor. In addition, repeat antibody tests and image examinations following discharge from the hospital guide the maintenance protocol of immunotherapy.

Objective: This study aimed to investigate epidemiological characteristics, clinical manifestations, and long-term outcomes of patients with autoimmune encephalitis (AE) in the east of China.Methods: From January 2015 to December 2019, 226 potential AE patients were recruited from five clinical centers, and a total of 185 patients who met the diagnostic criteria were included in the study. We retrospectively reviewed clinical features, auxiliary examinations, details of treatments, and outcomes of AE, and identified risk factors of poor prognosis. Modified Rankin Scale scores were used to evaluate neurological function, and scores of 3–6 indicated a poor-prognosis.Results: Patients with five main subtypes of AE were enrolled in the study, as follows: anti-NMDAR (79), anti-LGI1 (55), anti-CASPR2 (30), anti-GABABR (16), and anti-AMPAR (5). Among 185 patients, 58.38% (108/185) were male and 41.62% (77/185) were female. The median age at disease onset was 41 years (interquartile range, 17–62). The most common clinical manifestations of AE were seizures (146, 78.92%) and memory deficit (123, 66.49%). A total of 95 (51.35%) patients had abnormal brain magnetic resonance imaging results. Electroencephalographic findings were abnormal in 131 (70.81%) patients, and 168 (90.81%) and 26 (14.05%) patients were treated with first- and second-line immunotherapies, respectively. All surviving patients were followed-up for at least 1 year (range 12–36 months). Good clinical outcomes were achieved in 117 (63.24%), while 68 (36.76%) patients had a poor prognosis. Further, 33 (17.84%) patients relapsed and 10 (5.41%) died within 1 year post-discharge. Older patients tended to have a poorer prognosis, and the occurrence of mental behavioral disorders, movement disorders, disturbance of consciousness, central hypoventilation, and tumors were overrepresented in the poor-prognosis group.Conclusions: AE is a treatable disease, and most patients have a good prognosis. There are differences in the clinical manifestations of patients with different AE subtypes. Some with AE will relapse, and long-term follow-up is of great significance for further research.

This paper investigates the nonlinear dynamics of Transmission Control Protocol and Active Queue Management (TCP/AQM) networks, including the local stability and periodic bifurcation. The parameter of transportation delay affects the stability of the dynamical systems. One of the purposes of our work is to determine the delay stable interval of the transportation network. It is found that there is only one critical value of network delay by the τ decomposition technique. When the delay passes the critical point, the system performs Hopf bifurcation with a pair of symmetry with purely imaginary roots (PIR). In addition, the other purpose is to consider the stability of bifurcating periodic solutions. Combining with τ-decomposition strategy and central manifold theory, the issues of delay stable interval and stability of Hopf bifurcation are all tackled. Finally, numerical examples are illustrated to show the accuracy and effectiveness of the proposed method.

Therapies against hepatitis B virus (HBV) have improved in recent decades; however, the development of individualized treatments has been limited by the lack of individualized infection models. In this study, we used human induced pluripotent stem cell (hiPSC) to generate a functional liver organoid (LO) that inherited the genetic background of the donor, and evaluated its application in modeling HBV infection and exploring virus–host interactions. To establish a functional hiPSC-LO, we cultured hiPSC-derived endodermal, mesenchymal, and endothelial cells with a chemically defined medium in a three-dimensional microwell culture system. Based on cell-cell interactions, these cells could organize themselves and gradually differentiate into a functional organoid, which exhibited stronger hepatic functions than hiPSC derived hepatic like cell (HLC). Moreover, the functional LO demonstrated more susceptibility to HBV infection than hiPSC-HLC, and could maintain HBV propagation and produce infectious virus for a prolonged duration. Furthermore, we found that virus infection could cause hepatic dysfunction of hiPSC-LOs, with down-regulation of hepatic gene expression, induced release of early acute liver failure markers, and altered hepatic ultrastructure. Therefore, our study demonstrated that HBV infection in hiPSC-LOs could recapitulate virus life cycle and virus induced hepatic dysfunction, suggesting that hiPSC-LOs may provide a promising individualized infection model for the development of individualized treatment for hepatitis. Keywords: Liver organoid, hiPSC, Hepatitis B virus, Virus-host interactions

Summary: Radio frequency identification (RFID) is a cost-effective and durable method to trace and track individual objects in multiple contexts by wirelessly providing digital signals; RFID is thus widely used in many fields. Here, we implement this concept to biological tissues by producing a compact RFID chip-incorporated organoid (RiO). The 0.4 mm RFID chips are reproducibly integrated inside the self-assembling organoids from 10 different induced pluripotent stem cell (iPSC) lines from healthy and diseased donors. We use the digitalized RiO to conduct a phenotypic screen on a pool of RiO, followed by detection of each specific donor in situ. Our proof-of-principle experiments demonstrated that a severely steatotic phenotype could be identified by RFID chip reading and was specific to a genetic disorder of steatohepatitis. Given evolving advancements surrounding RFID technology, the digitalization principle outlined here will expand organoid medicine potential toward drug development, precision medicine, and transplant applications. : Cell Biology; Stem Cells Research; Bioengineering Subject Areas: Cell Biology, Stem Cells Research, Bioengineering

Summary: Early endoderm progenitors naturally possess robust propagating potential to develop a majority of meter-long gastrointestinal tracts and are therefore considered as a promising source for therapy. Here, we demonstrated the reproducible generation of human CDX2+ posterior gut endoderm cells (PGECs) from five induced pluripotent stem cell clones by manipulating FGF, TGF, and WNT signaling. Transcriptome analysis suggested that putative PGECs harbored an intermediate signature profile between definitive endoderm and organ-specific endoderm. We found that combinatorial EGF, VEGF, FGF2, Chir99021, and A83-01 treatments selectively amplify storable PGECs up to 1021 cell scale without any gene transduction or feeder use. PGECs, compared with induced pluripotent stem cells, showed stable differentiation propensity into multiple endodermal lineages without teratoma formation. Furthermore, transplantation of PGEC-derived liver bud organoids showed therapeutic potential against fulminant liver failure. Together, the robustly amplified PGECs may be a promising cellular source for endoderm-derived organoids in studying human development, modeling disease, and, ultimately, therapy. : In this article, Takebe, Taniguchi, and colleagues derived a unique population of CDX2+ posterior endoderm progenitors (PGECs) from human pluripotent stem cells that are highly expandable and storable in a chemically defined condition. CDX2+ endoderm progenitors can form multiple endodermal organoids. Transplantation of human liver bud organoids from robustly propagated PGECs rescued lethal liver failure of immunodeficient mice. Keywords: progenitors, posterior gut endoderm cells, organoid, liver bud, transplant, human, pluripotent stem cells, iPSC, CDX2, intestine

Abstract Background Mature human hepatocytes are critical in preclinical research and therapy for liver disease, but are difficult to manipulate and expand in vitro. Hepatic stem cells (HpSCs) may be an alternative source of functional hepatocytes for cell therapy and disease modeling. Since these cells play an import role in regenerative medicine, the precise characterization that determines specific markers used to isolate these cells as well as whether they contribute to liver regeneration still remain to be shown. Method In this study, human HpSCs were isolated from human primary fetal liver cells (FLCs) by flow cytometry using CDCP1, CD90, and CD66 antibodies. The isolated CDCP1+CD90+CD66– HpSCs were cultured on dishes coated with type IV collagen in DMEM nutrient mixture F-12 Ham supplemented with FBS, human γ-insulin, nicotinamide, dexamethasone, and l-glutamine for at least 2 weeks, and were characterized by transcriptomic profiling, quantitative real-time PCR, immunocytochemistry, and in-vivo transplantation. Results The purified CDCP1+CD90+CD66– subpopulation exhibited clonal expansion and self-renewal capability, and bipotential capacity was further identified in single cell-derived colonies containing distinct hepatocytes and cholangiocytes. Moreover, in-vivo liver repopulation assays demonstrated that human CDCP1+CD90+CD66– HpSCs repopulated over 90% of the mouse liver and differentiated into functional hepatocytes with drug metabolism activity. Conclusions We identified a human hepatic stem/progenitor population in the CDCP1+CD90+CD66– subpopulation in human FLCs, indicating CDCP1 marker could potentially be utilized to identify and isolate HpSCs for further cytotherapy of liver disease.

Binge Eating Disorder (BED), considered a public health problem because of its impact on psychiatric, physical, and social functioning, merits much attention given its elevation to an independent diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Similar with substance use disorders, some neuropsychological and personality constructs are potentially implicated in the onset and development of BED, in which poor decision-making has been suggested to facilitate overeating and BED. The objective of this study was to investigate the associations between decision-coping patterns, monetary decision-making, and binge-eating behavior in young adults. A sample of 1013 college students, equally divided into binge-eating and non-binge-eating groups according to the scores on the Binge Eating Scale (BES), were administered multiple measures of decision-making including the Melbourne Decision-Making Questionnaire (MDMQ), the Delay-discounting Test (DDT), and the Probability Discounting Test (PDT). Compared with the non-binge-eating group, the binge-eating group displayed elevated scores on maladaptive decision-making patterns including Procrastination, Buck-passing, and Hypervigilance. Logistic regression model revealed that only Procrastination positively predicted binge eating. These findings suggest that different dimensions of decision-making may be distinctly linked to binge eating among young adults, with Procrastination putatively identified as a risk trait in the development of overeating behavior, which might promote a better understanding of this disorder.

A full-length cDNA coding for hydroperoxide lyase (CsHPL) was isolated from cucumber fruits of No. 26 (Southern China type) and No.14-1 (Northern China type), which differed significantly in fruit flavor. The deduced amino acid sequences of CsHPL from both lines show the same and significant similarity to known plant HPLs and contain typical conserved domains of HPLs. The recombinant CsHPL was confirmed to have 9/13-HPL enzymatic activity. Gene expression levels of CsHPL were measured in different organs, especially in fruits of different development stages of both lines. The HPL activities of fruit were identified basing on the catalytic action of crude enzyme extracts incubating with 13-HPOD (13-hydroperoxy-(9Z,12E)-octadecadienoic acid) and 13-HPOD + 9-HPOD (9-hydroperoxy-(10E,12Z)-octadecadienoic acid), and volatile reaction products were analyzed by GC-MS (gas chromatography-mass spectrometry). CsHPL gene expression in No. 26 fruit occurred earlier than that of total HPL enzyme activity and 13-HPL enzyme activity, and that in No. 14-1 fruit was consistent with total HPL enzyme activity and 9-HPL enzyme activity. 13-HPL enzyme activities decreased significantly and the 9-HPL enzyme activities increased significantly with fruit ripening in both lines, which accounted for the higher content of C6 aldehydes at 0–6 day post-anthesis (dpa) and higher content of C9 aldehydes at 9–12 dpa.

OBJECTIVES: We aim to obtain the intra-subject coefficient of variability of a highly variable antidepressant agomelatine in humans, and propose an adjusted bioequivalence assessment strategy. METHODS: A single-dose, randomized crossover design was conducted in four periods (reference administered thrice, placebo administered once) separated by seven days. A validated LC-MS/MS assay was used to measure drug concentrations in serial blood samples. RESULTS: The intra-subject coefficient of variability was calculated using the residual variance of ANOVA analysis, and the results for Cmax and AUC0-t was 78.34% and 43.52%, respectively, in Chinese healthy subjects. The sample size required for standard BE study were 124(192, 340) if the expected deviation between the reference and generic products was set to 0 (5%, 10%). CONCLUSIONS: Agomelatine meets the criteria for highly variable drug in Chinese healthy male subjects, and the traditional BE criteria for agomelatine needs to be adjusted to alleviate the resource and ethical burden of using a large numbers of subjects in clinical trials. Our clinical data on the intra-subject variability of agomelatine PK in Chinese healthy population enables to adjust bioequivalence (BE) assessment approach for agomelatine based on the RSABE approaches recommended by regulatory agencies. TRIAL REGISTRATION: ChiCTR.org ChiCTR-TTRCC-13003835.

We obtain some results on the transcendental meromorphic solutions of complex functional difference equations of the form ∑λ∈Iαλ(z)(∏j=0nf(z+cj)λj)=R(z,f∘p)=((a0(z)+a1(z)(f∘p)+ ⋯ +as(z) (f∘p)s)/(b0(z)+b1(z)(f∘p)+ ⋯ +bt(z)(f∘p)t)), where I is a finite set of multi-indexes λ=(λ0,λ1,…,λn), c0=0,cj∈ℂ∖{0} (j=1,2,…,n) are distinct complex constants, p(z) is a polynomial, and αλ(z) (λ∈I), ai(z) (i=0,1,…,s), and bj(z) (j=0,1,…,t) are small meromorphic functions relative to f(z). We further investigate the above functional difference equation which has special type if its solution has Borel exceptional zero and pole.

Abstract: Mitochondrial damage is an important cause of heart dysfunction after severe burn injury. However, the pathophysiological process remains unclear. This study aims to examine the mitochondrial dynamics in the heart and the role of μ-calpain, a cysteine protease, in this scenario. Rats were subjected to severe burn injury treatment, and the calpain inhibitor MDL28170 was administered intravenously 1 h before or after burn injury. Rats in the burn group displayed weakened heart performance and decreased mean arterial pressure, which was accompanied by a diminishment of mitochondrial function. The animals also exhibited higher levels of calpain in mitochondria, as reflected by immunofluorescence staining and activity tests. In contrast, treatment with MDL28170 before any severe burn diminished these responses to a severe burn. Burn injury decreased the abundance of mitochondria and resulted in a lower percentage of small mitochondria and a higher percentage of large mitochondria. Furthermore, burn injury caused an increase in the fission protein DRP1 in the mitochondria and a decrease in the inner membrane fusion protein OPA1. Similarly, these alterations were also blocked by MDL28170. Of note, inhibition of calpain yielded the emergence of more elongated mitochondria along with membrane invagination in the middle of the longitude, which is an indicator of the fission process. Finally, MDL28170, administered 1 h after burn injury, preserved mitochondrial function and heart performance, and increased the survival rate. Overall, these results provided the first evidence that mitochondrial recruitment of calpain confers heart dysfunction after severe burn injury, which involves aberrant mitochondrial dynamics., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)