Circadian disruption is being increasingly recognized as a critical factor in the development and progression of Parkinson’s disease (PD). This review aims to provide an in-depth overview of the relationship between circadian disruption and PD by exploring the molecular, cellular, and behavioral aspects of this interaction. This review will include a comprehensive understanding of how the clock gene system and transcription–translation feedback loops function and how they are diminished in PD. The article also discusses the role of clock genes in the regulation of circadian rhythms, as well as the impact of clock gene dysregulation on mitochondrial function, oxidative stress, and neuroinflammation, including the microbiota-gut-brain axis, which have all been proposed as being crucial mechanisms in the pathophysiology of PD. Finally, this review highlights potential therapeutic strategies targeting the clock gene system and circadian rhythm for the treatment of PD.

Objective: To investigate the safety and efficacy of laparoscopic surgery in locally advanced gastric cancer patients with neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy. Methods: Between November 2020 and April 2021, patients with locally advanced gastric cancer who were admitted to the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology were prospectively enrolled in this study. Inclusion criteria were: (1) patients who signed the informed consent form voluntarily before participating in the study; (2) age ranging from 18 to 75 years; (3) patients staged preoperatively as cT3-4N+M0 by the TNM staging system; (4) Eastern Collaborative Oncology Group score of 0-1; (5) estimated survival of more than 6 months, with the possibility of performing R0 resection for curative purposes; (6) sufficient organ and bone marrow function within 7 days before enrollment; and (7) complete gastric D2 radical surgery. Exclusion criteria were: (1) history of anti-PD-1 or PD-L1 antibody therapy and chemotherapy; (2) treatment with corticosteroids or other immunosuppre- ssants within 14 days before enrollment; (3) active period of autoimmune disease or interstitial pneumonia; (4) history of other malignant tumors; (5) surgery performed within 28 days before enrollment; and (6) allergy to the drug ingredients of the study. Follow-up was conducted by outpatient and telephone methods. During preoperative SOX chemotherapy combined with PD-1 inhibitor immunotherapy, follow-up was conducted every 3 weeks to understand the occurrence of adverse reactions of the patients; follow-up was conducted once after 1 month of surgical treatment to understand the adverse reactions and survival of patients. Observation indicators were: (1) condition of enrolled patients; (2) reassessment after preoperative therapy and operation received (3) postoperative conditions and pathological results. Evaluation criteria were: (1) tumor staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system; (2) tumor regression grading (TRG) of pathological results were evaluated with reference to AJCC standards; (3) treatment-related adverse reactions were evaluated according to version 5.0 of the Common Terminology Criteria for Adverse Events; (4) tumor response was evaluated by CT before and after treatment with RECIST V1.1 criteria; and (5) Clavien-Dindo complication grading system was used for postoperative complications assessment. Results: A total of 30 eligible patients were included. There were 25 males and 5 females with a median age of 60.5 (35-74) years. The primary tumor was located in the gastroesophageal junction in 12 cases, in the upper stomach in 8, in the middle stomach in 7, and in the lower stomach in 3. The preoperative clinical stage of 30 cases was III. Twenty-one patients experienced adverse reactions during neoadjuvant chemotherapy combined with immunotherapy, including four cases of CTCAE grade 3-4 adverse reactions resulting in bone marrow suppression and thoracic aortic thrombosis. All cases of adverse reactions were alleviated or disappeared after active symptomatic treatment. Among the 30 patients who underwent surgery, the time from chemotherapy combined with immunotherapy to surgery was 28 (23-49) days. All 30 patients underwent laparoscopic radical gastrectomy, of which 20 patients underwent laparoscopic-assisted radical gastric cancer resection; 10 patients underwent total gastrectomy for gastric cancer, combined with splenectomy in 1 case and cholecystectomy in 1 case. The surgery time was (239.9±67.0) min, intraoperative blood loss was 84 (10-400) ml, and the length of the incision was 7 (3-12) cm. The degree of adenocarcinoma was poorly differentiated in 18 cases, moderately differentiated in 12 cases, nerve invasion in 11 cases, and vascular invasion in 6 cases. The number lymph nodes that underwent dissection was 30 (17-58). The first of gas passage, the first postoperative defecation time, the postoperative liquid diet time, and the postoperative hospitalization time of 30 patients was 3 (2-6) d, 3 (2-13) d, 5 (3-12) d, and 10 (7-27) d, respectively. Postoperative complications occurred in 23 of 30 patients, including 7 cases of complications of Clavien-Dindo grade IIIa or above. Six patients improved after treatment and were discharged from hospital, while 1 patient died 27 days after surgery due to granulocyte deficiency, anemia, bilateral lung infection, and respiratory distress syndrome. The remaining 29 patients had no surgery-related morbidity or mortality within 30 days of discharge. Postoperative pathological examination showed TRG grades 0, 1, 2, and 3 in 8, 9, 4, and 9 cases, respectively, and the number of postoperative pathological TNM stages 0, I, II, and III was 8, 7, 8, and 7 cases, respectively. The pCR rate was 25.0% (8/32). Conclusion: Laparoscopic surgery after neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy for locally advanced gastric cancer is safe and feasible, with satisfactory short-term efficacy. Early detection and timely treatment of related complications are important.
Male ; Female ; Humans ; Middle Aged ; Aged ; Adolescent ; Young Adult ; Adult ; Stomach Neoplasms/pathology* ; Neoadjuvant Therapy ; Immune Checkpoint Inhibitors ; Gastrectomy/methods* ; Esophagogastric Junction/pathology* ; Laparoscopy ; Immunotherapy ; Postoperative Complications ; Retrospective Studies ; Treatment Outcome

Background: and Purpose The optimal management of patients with acute basilar artery occlusion (BAO) is uncertain. We aimed to evaluate the safety and efficacy of endovascular thrombectomy (EVT) compared to medical management (MM) for acute BAO through a meta-analysis of randomized controlled trials (RCTs). Methods: We performed a systematic review and meta-analysis of RCTs of patients with acute BAO. We analyzed the pooled effect of EVT compared to MM on the primary outcome (modified Rankin Scale [mRS] of 0–3 at 3 months), secondary outcome (mRS 0–2 at 3 months), symptomatic intracranial hemorrhage (sICH), and 3-month mortality rates. For each study, effect sizes were computed as odds ratios (ORs) with random effects and Mantel-Haenszel weighting. Results: Four RCTs met inclusion criteria including 988 patients. There were higher odds of mRS of 0-3 at 90 days in the EVT versus MM group (45.1% vs. 29.1%, OR 1.99, 95% confidence interval [CI] 1.04–3.80; P=0.04). Patients receiving EVT had a higher sICH compared to MM (5.4% vs. 0.8%, OR 7.89, 95% CI 4.10–15.19; P<0.01). Mortality was lower in the EVT group (35.5% vs. 45.1%, OR 0.64, 95% CI 0.42–0.99; P=0.05). In an analysis of two trials with BAO patients and National Institutes of Health Stroke Scale (NIHSS) <10, there was no difference in 90-day outcomes between EVT versus MM. Conclusion In this systematic review and meta-analysis, EVT was associated with favorable outcome and decreased mortality in patients with BAO up to 24 hours from stroke symptoms compared to MM. The treatment effect in BAO patients with NIHSS <10 was less certain. Further studies are of interest to evaluate the efficacy of EVT in basilar occlusion patients with milder symptoms.

Background: and Purpose Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year. Methods: We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020). Results: There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths. Conclusions During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT.

Varicoceles adversely impact semen quality and sperm DNA fragmentation, which typically improve with surgical repair. Some men with varicoceles have ipsilateral testicular atrophy due to damage from the varicocele. This study assessed semen quality and the sperm DNA fragmentation index (DFI) response to varicocele repair in men with ipsilateral testicular atrophy (TA) versus men with no testicular atrophy (NTA). Semen parameter values and DFI in both groups were compared preoperatively and postoperatively. The Mann-Whitney U test and the Wilcoxon signed-rank test were used where appropriate. There were 20 men in the TA group and 121 men in the NTA group with no difference in age, varicocele grade, or preoperative semen parameter values between the two groups. The NTA group had a higher preoperative DFI than the TA group. Both groups showed improvement in semen quality postoperatively, only the TA group showed a significant improvement in DFI, whereas the NTA group showed significant improvements in several parameter values and DFI. The change from preoperative to postoperative parameter values when comparing the two groups revealed a difference in total sperm motile count and DFI, with a larger mean improvement in the NTA group than in the TA group. Both TA and NTA groups showed improved semen quality and DFI after varicocele repair, but the NTA group had more improvement than the TA group. However, only total motile count (TMC) and DFI had a significantly greater mean change in preoperative to postoperative response in the NTA group than in the TA group.

Faculty ; Female ; Humans ; Kidney ; Lipids ; Male ; Physical Fitness ; Universities

Animals ; Benzo(a)pyrene/toxicity* ; Cytokines ; Dibutyl Phthalate/toxicity* ; Female ; Liver ; Male ; NF-kappa B ; Rats ; Rats, Sprague-Dawley

The anterior pituitary gland drives highly conserved physiologic processes in mammalian species. These hormonally controlled processes are central to somatic growth, pubertal transformation, fertility, lactation, and metabolism. Current cellular models of mammalian anteiror pituitary, largely built on candidate gene based immuno-histochemical and mRNA analyses, suggest that each of the seven hormones synthesized by the pituitary is produced by a specific and exclusive cell lineage. However, emerging evidence suggests more complex relationship between hormone specificity and cell plasticity. Here we have applied massively parallel single-cell RNA sequencing (scRNA-seq), in conjunction with complementary imaging-based single-cell analyses of mRNAs and proteins, to systematically map both cell-type diversity and functional state heterogeneity in adult male and female mouse pituitaries at single-cell resolution and in the context of major physiologic demands. These quantitative single-cell analyses reveal sex-specific cell-type composition under normal pituitary homeostasis, identify an array of cells associated with complex complements of hormone-enrichment, and undercover non-hormone producing interstitial and supporting cell-types. Interestingly, we also identified a Pou1f1-expressing cell population that is characterized by a unique multi-hormone gene expression profile. In response to two well-defined physiologic stresses, dynamic shifts in cellular diversity and transcriptome profiles were observed for major hormone producing and the putative multi-hormone cells. These studies reveal unanticipated cellular complexity and plasticity in adult pituitary, and provide a rich resource for further validating and expanding our molecular understanding of pituitary gene expression programs and hormone production.

Objective: To describe the genetic structure of populations in different areas of China, and explore the effects of different strategies to control the confounding factors of the genetic structure in cohort studies. Methods: By using the genome-wide association study (GWAS) on data of 4 500 samples from 10 areas of the China Kadoorie Biobank (CKB), we performed principal components analysis to extract the first and second principal components of the samples for the component two-dimensional diagram generation, and then compared them with the source of sample area to analyze the characteristics of genetic structure of the samples from different areas of China. Based on the CKB cohort data, a simulation data set with cluster sample characteristics such as genetic structure differences and extensive kinship was generated; and the effects of different analysis strategies including traditional analysis scheme and mixed linear model on the inflation factor (λ) were evaluated. Results: There were significant genetic structure differences in different areas of China. Distribution of the principal components of the population genetic structure was basically consistent with the geographical distribution of the project area. The first principal component corresponds to the latitude of different areas, and the second principal component corresponds to the longitude of different areas. The generated simulation data showed high false positive rate (λ=1.16), even if the principal components of the genetic structure was adjusted or the area specific subgroup analysis was performed, λ could not be effectively controlled (λ>1.05); while, by using a mixed linear model adjusting for the kinship matrix, λ was effectively controlled regardless of whether the genetic structure principal component was further adjusted (λ=0.99). Conclusions: There were large differences in genetic structure among populations in different areas of China. In molecular epidemiology studies, bias caused by population genetic structure needs to be carefully treated. For large cohort data with complex genetic structure and extensive kinship, it is necessary to use a mixed linear model for association analysis.
China ; Genetic Structures ; Genome-Wide Association Study ; Humans ; Linear Models ; Principal Component Analysis

Objective: From the economic point of view, this study was to systematically assess the status quo on lung cancer screening in the world and to provide reference for further research and implementation of the programs, in China. Methods: PubMed, EMbase, The Cochrane Library,CNKI and Wanfang Data were searched to gather papers on studies related to economic evaluation regarding lung cancer screening worldwide, from the inception of studies to June 30(th), 2018. Basic characteristics, methods and main results were extracted. Quality of studies was assessed. Cost were converted to Chinese Yuan under the exchange rates from the World Bank. The ratio of incremental cost-effectiveness ratio (ICER) to local GDP per capita were calculated. Results: A total of 23 studies (only 1 randomized controlled trial) were included and the overall quality was accepted. 22 studies were from the developed countries. Nearly half of the studies (11 studies) took 55 years old as the starting age of the screening program. Smoking history was widely applied for the selection of criteria on target populations (18). Low-dose computed tomography (LDCT) was involved in every study used to evaluate the economic effectiveness. Annual (17) and once-life time (7) screening were more common frequencies. 22 studies reported ICERs for LDCT screening, compared to no screening, of which 17 were less than 3 times local GDP per capita, and were considered as cost-effectiveness, according to the WHO's recommendation. 15 and 7 studies reported ICERs for annual and once-life time screening, of which 12 and 7 studies were in favor the results of their cost-effectiveness, respectively. Additionally, the cost-effectiveness of once-lifetime screening was likely to be superior to the annual screening. Differences of cost-effectiveness among the subgroups, by starting age or by the smoking history, might exist. Conclusions: Based on the studies, evidence from the developed countries demonstrated that LDCT screening programs on lung cancer, implemented among populations selected by age and smoking history, generally appeared more cost-effective. Combined with the local situation of health resource, the findings could provide direction for less developed regions/countries lacking of local evidence. Low frequency of LDCT screening for lung cancer could be adopted when budget was limited. Data on starting ages, smoking history and other important components related to the strategy of screening programs, needs to be precisely evaluated under the situation of local population.
China ; Cost-Benefit Analysis ; Early Detection of Cancer/methods* ; Humans ; Lung Neoplasms/prevention & control* ; Middle Aged ; Quality-Adjusted Life Years ; Randomized Controlled Trials as Topic