Ziziphi Spinosae Semen (ZSS), a traditional Chinese medicine, is used in clinics for the treatment ofinsomnia in China and other Asian countries. Herein, we described for the first time a comparative pharmacokinetics study of the six major compounds of ZSS in normal control (NC) and para-chlor-ophenylalanine (PCPA)-induced insomnia model (IM) rats that were orally administered the aqueous extract of ZSS. An ultra-high-performance liquid chromatography coupled with quadrupole orbitrap mass (UHPLC-Q-Orbitrap-MS) method was developed and validated for the simultaneous determination of coclaurine, magnoflorine, spinosin, 6'''-feruloylspinosin, jujuboside A (JuA), and jujuboside B (JuB) in ZSS in rat plasma. The established approach was successfully applied to a comparative pharmacokinetic study. The systemic exposures of spinosin and 6'''-feruloylspinosin were decreased in the IM group compared to the NC group, while plasma clearance (CL) was significantly increased. The Tmax values of JuA and JuB in IM rats were significantly lower than those in NC rats. The T1/2 of JuA in the IM group was significantly accelerated. The pharmacokinetic parameters of coclaurine and magnoflorine were not evidently affected between the two groups. These results indicate that the pathological state of insomnia altered the plasma pharmacokinetics of spinosin, 6'''-feruloylspinosin, JuA, and JuB in the ZSS aqueous extract, providing an experimental basis for the role of ZSS in insomnia treatment. The comparative pharmacokinetics-based UHPLC-Q-Orbitrap-MS using full-scan mode can therefore provide a reliable and suitable means for the screening of potentially effective substances applied as quality markers of ZSS.

BACKGROUND/AIMS: Anti-reflux barrier dysfunction is one of the primary mechanisms in gastroesophageal reflux disease (GERD) pathogenesis. The esophagogastric junction contractile integral (EGJ-CI) is a new metric adopted to evaluate the EGJ contractility, which implies the anti-reflux barrier function. The aim of the current study was to validate this new metric in patients with GERD and its correlation with the esophageal acid exposure, as well as the efficacy of proton pump inhibitor treatment. METHODS: Ninety-eight patients with GERD and 21 healthy controls were included in the study. Upper endoscopy, high-resolution manometry (HRM) and 24-hour multichannel intraluminal impedance-pH monitoring were performed in all patients. Three respiration cycles were chosen at the initial HRM resting frame and the value computed with distal contractile integral tool was then divided by the duration of the cycles to yield EGJ-CI. All the patients were treated with esomeprazole 20 mg twice-daily for 8 weeks. RESULTS: EGJ-CI was lower in the patients with GERD than that of the controls (P < 0.05). For patients with GERD, EGJ-CI was lower in those with hiatal hernia (P < 0.05). The new metric correlated with esophageal acid exposure in the supine position (P < 0.05), and it also negatively correlated to the total reflux episodes (P < 0.05). There was no significant difference on EGJ-CI between patients with and without response to the esomeprazole treatment (P = 0.627). CONCLUSIONS: EGJ-CI reflected the dysfunction of the anti-reflux barrier in patients with GERD, but it had little impact on the esomeprazole response.
Endoscopy ; Esomeprazole ; Esophagogastric Junction* ; Gastroesophageal Reflux* ; Hernia ; Hernia, Hiatal ; Humans ; Manometry ; Proton Pump Inhibitors ; Proton Pumps ; Respiration ; Supine Position

Objective To investigate the middle-term clinical and radiological outcomes of self-locking and zero-profile cages for the treatment of multi-segmental cervical spondylosis in elderly patients through anterior decompression and fusion approach.Methods A total of 39 old patients with multi-segmental cervical spondylosis who received anterior cervical decompression and internal fixation with self-locking and zero-profile cages from January 2013 to January 2015 were retrospectively analyzed.The operation time,intraoperative bleeding volume and post-operational complications were recorded.The functions of cervical spine before and 1-month,1-year,the last follow-up after treatment were evaluated by using the neck pain visual analogue scale(VAS) score,the Japanese orthopedic association (JOA)score and neck disability index (NDI)score.The subjective satisfaction at the final follow-up was evaluated by using Odom's criteria.The whole cervical spine curvature,the range of motion of cervical spine,the height of fused segment,Cobb angle of fused segment,C2～C7 line of force at sagittal view,Cage sedimentation rate and fusion rate before and 1-month and 1-year and the last follow-up after treatment were evaluated by using X-ray and CT and compared between the two groups.Results All patients were followed up,and the mean follow-up time was(35.0±5.3)months(24-48 months).The average operation time was(110.0±21.3)min(85-180 min).The average intraoperative bleeding volum was (50.3 ± 10.6)ml (20-150 ml).There were significant differences in JOA and NDI scores before versus at 1-month,1-year and the final follow-up after treatment(F=9.93 and 28.21,P=0.001 and 0.001).The VAS score of neck pain was lower at 1-month,1-year follow-up than at pre-treatment(P＜0.05),while there were no significant differences in VAS score before treatment versus at the final treatment(P＞0.05).The fineness rate by the Odom criteria was 84.6 ％ (33/39 cases)at the final follow-up.The whole cervical spine curvature,the height of fused segment,the Cobb angle of fused segment and C2-C7 line of force at sagittal view were significantly improved at 1-month,1-year and the final follow-up versus pre-treatment(P＜0.05).The improvements in whole cervical spine curvature and the height of fused segment were lost in some degree with the time extension of follow-up,and the degree of improvements losing was higher at the final follow-up than at 1-year follow-up.At last follow up and in all of patients,the rate of segment fusion were 87.2 ％ (102/117 cases) and Cage sedimentation rate was still 21.4 ％ (25/117 cases).Conclusions Self-locking and zero-profile cages can shorten the operation time,reduce the incidence of postoperative dysphagia,and have good clinical efficacy and fusion rate.But the improvements in cervical spine curvature and the height of fused segement are gradually lost,and the cage has a subsidence in some degree in the middle-term follow-up.Thus,a comprehensive consideration is still needed when choosing self-locking and zero-profile cages for clinical application.

Objective: Studies on duration of untreated psychosis are common in patients with schizophrenia, but few studies have investigated the relationship between duration of untreated illness (DUI) and suicide, especially in patients with chronic schizophrenia. Therefore, we intended to investigate the relationship between DUI and suicide and clinical correlates in patients with chronic schizophrenia. Methods: A total of 1,555 Chinese patients with chronic schizophrenia were enrolled in this study. DUI was measured in years, reflecting the prolonged untreated periods observed in this population. Clinical correlates were assessed, including symptoms, cognitive functioning, and body mass index. Suicidal ideation and attempts were also examined. Statistical analyses, including multivariate models, were employed to investigate the associations between DUI and clinical correlates while controlling for potential confounders. Results: The study revealed a significant proportion (23.3%) of patients with chronic schizophrenia in China received their first treatment after a 4-year delay, with the longest untreated duration reaching 39 years. Patients with longer DUI exhibited more severe negative symptoms, lower immediate memory scores, a higher likelihood of being overweight, and surprisingly, a reduced likelihood of suicidal ideation and attempts. Each additional year of untreated illness was associated with a 3% decrease in the risk of suicidal ideation and attempts. Conclusion The findings underscore the prevalence of extended untreated periods in Chinese patients with chronic schizophrenia and highlight the impact of DUI on negative symptoms, cognitive function, and body weight. Intriguingly, a longer DUI was associated with a lower risk of suicidal ideation and attempts.

ObjectiveTo evaluate and analyze the characteristics of lower limb muscle activity and plantar pressure in females with the in-toeing gait using International Classification of Functioning, Disability and Health (ICF) and biomechanical methods. MethodsA total of 60 young females were recruited from September 2021 to May 2022, out of whom 30 females with in-toeing gait were as experimental group, and 30 females with normal gait were as control group. The motor function of lower extremities was coded by ICF, and the surface EMG signals and plantar pressure characteristics of lower limbs (rectus femoris, biceps femoris, gastrocnemius and tibialis anterior) were measured by wireless surface EMG tester and insole plantar pressure system. ResultsThe integral electromyography (iEMG) and muscle contribution rate of tibialis anterior were higher (|t| > 2.000, P < 0.05), and the iEMG and muscle contribution rate of rectus femoris were lower (|t| > 2.233, P < 0.05) in the experimental group than in the control group. The contact area of the 2nd to the 5th metatarsal bone, heel lateral and total foot areas (t > 2.879, P < 0.01), the peak force of the 1st metatarsal bone, mid foot and heel lateral areas (t > 2.720, P < 0.01), the peak pressure of the 1st to the 5th metatarsal bone and heel lateral areas (t > 2.079, P < 0.05), and the impulse of the 1st and the 4th metatarsal bone, and heel lateral areas (t > 2.310, P < 0.05) were significantly higher, while the impulse of heel medial area was lower (t = -3.024, P = 0.002) in the experimental group than in the control group. ConclusionIn the process of natural walking, the muscle activity of the in-toeing gait in young female is dominated by tibialis anterior and rectus femoris, the contact area of heel lateral area is larger, the peak pressure, pressure, and impulse are higher, and the impulse of heel medial area is lower.

ObjectiveTo explore the exposure-lag-response relationship between temperature and risk of varicella incidence，and to provide a scientific evidence for early warning and precise prevention and control of varicella epidemic. MethodsDaily varicella cases and daily meteorological data were collected in Minhang District， Shanghai from 2010 to 2022. A distributed lag nonlinear model was used to determine the exposure-lag-response relationship between temperature and risk of varicella incidence. Furthermore， effect of temperature on the incidence risk was determined across different age groups. ResultsIn 2010‒2022， the total number of notified varicella cases was 26 207 in Minhang District， with the highest incidence in the group aged 3‒14 years （50.35%）. The seasonal pattern of daily varicella cases showed a double peak. The large peak was found in November and December， followed by a smaller peak in May and June. Moreover， the distributed lag nonlinear model showed a unimodal curve in the relationship between temperature and varicella incidence. The RR value reached its maximum peak of 1.90 （95%CI： 1.25‒2.87） at 7 ℃. A reverse U-shape was found in the lag-response curves between temperature and varicella incidence. Furthermore， the effect of temperature on the varicella incidence showed a unimodal pattern in the varicella cases aged 3‒14 years. The RR value reached its peak at 11 ℃ （RR=2.89， 95%CI： 1.33‒6.24）. In contrast， the effect of temperature on the varicella incidence in the cases aged 15 years and above showed a unimodal pattern， with RR value reaching the peak at 5 ℃ （RR=2.14， 95%CI： 1.33‒3.44）. ConclusionThe unimodal curve is found in the relationship between temperature and varicella incidence. Low temperature is associated with increased risk of varicella incidence. Children aged 3‒14 years are more susceptible to the effect of temperature on the varicella incidence.

Monoclonal antibodies (mAbs) are widely used in many fields due to their high specificity and ability to recognize a broad range of antigens. IL-17A can induce a rapid inflammatory response both alone and synergistically with other proinflammatory cytokines. Accumulating evidence suggests that therapeutic intervention of IL-17A signaling offers an attractive treatment option for autoimmune diseases and cancer. Here, we present a combinatorial approach for optimizing the affinity and thermostability of a novel anti-hIL-17A antibody. From a large naïve phage-displayed library, we isolated the anti-IL-17A mAb 7H9 that can neutralize the effects of recombinant human IL-17A. However, the modest neutralization potency and poor thermostability limit its therapeutic applications. affinity optimization was then used to generate 8D3 by using yeast-displayed random mutagenesis libraries. This resulted in four key amino acid changes and provided an approximately 15-fold potency increase in a cell-based neutralization assay. Complementarity-determining regions (CDRs) of 8D3 were further grafted onto the stable framework of the huFv 4D5 to improve thermostability. The resulting hybrid antibody 9NT/S has superior stabilization and affinities beyond its original antibody. Human fibrosarcoma cell-based assays and analyses in mice indicated that the anti-IL-17A antibody 9NT/S efficiently inhibited the secretion of IL-17A-induced proinflammatory cytokines. Therefore, this lead anti-IL-17A mAb might be used as a potential best-in-class candidate for treating IL-17A related diseases.