[Erdheim-Chester disease initially discovered at extraskeletal locations: a clinicopathological analysis of four cases].

Objective: To investigate the clinicopathological features of Erdheim-Chester disease (ECD) initially diagnosed at extraskeletal locations. Methods: Clinical and pathological data of four cases of ECD diagnosed initially in extraskeletal locations were collected at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2013 to June 2023. BRAF V600E gene was detected by reverse transcription polymerase chain reaction (RT-PCR). Pertinent literatures were reviewed. Results: Four ECD patients included two males and two females ranging in ages from 2 years 11 months to 69 years. The lesions located in the lung (two cases), central nervous system (one case), and the testicle (one case) were collected in the study. One patient had occasional fever at night, one had nausea and vomiting, and two were asymptomatic. Radiologically, the two pulmonary ECD showed diffuse ground-glass nodules in both lungs, and the lesions in central nervous system and testicle both showed solid masses. Microscopically, there were infiltration of foamy histiocyte-like cells and multinucleated giant cells in a fibrotic background, accompanied by varying amounts of lymphocytes and plasma cells. The infiltration of tumor cells in pulmonary ECD was mainly seen in the subpleural area, interlobular septa, and perivascular and peribronchiolar areas. The fibrosis was more pronounced in the pleura and interlobular septa, and less pronounced in the alveolar septa. Immunohistochemical staining showed that all tumor cells expressed CD68, CD163 and Fô€ƒ¼a; one case showed S-100 expression; three cases were positive for BRAF V600E; all were negative for CD1α and Langerin. RT-PCR in all four cases showed BRAF V600E gene mutation. Conclusions: Extraskeletal ECD is often rare and occult, and could be easily misdiagnosed, requiring biopsy confirmation. The radiologic findings of pulmonary ECD is significantly different from other types of ECD, and the histopathological features of pronounced infiltration in the subpleura area, interlobular septa, perivascular and peribronchiolar areas can be helpful in the differential diagnosis from other pulmonary diseases. Detection of BRAF V600E gene mutation by RT-PCR and its expression by immunohistochemical staining are also helpful in the diagnosis.

[Advances of pathological diagnosis and molecular pathology of lung neuroendocrine neoplasms].

The pathological classification and diagnostic criteria for lung neuroendocrine neoplasms (NENs) in the 2021 World Health Organization (WHO) lung tumor classification are similar to the prior classifications. However, the advances on the molecular studies of lung NENs have shown that both small cell lung carcinoma and large cell neuroendocrine carcinoma are highly heterogeneous tumors with neuroendocrine characteristics and can be subclassified based on the features of genomics or transcriptomics, which are valuable in the diagnosis of lung NENs subtypes and patient treatment. In addition, it is necessary to interpret emerging concepts such as "lung neuroendocrine tumor G3" and "histological transformation" from pathological perspectives, as well as to know the novel neuroendocrine biomarkers such as INSM1 and POU2F3. This article summarized the diagnostic changes and the advances of molecular pathology of lung NENs based on the latest WHO classification and molecular research.

[Metformin use and risk of ischemic stroke in patients with type 2 diabetes: A cohort study].

OBJECTIVE: To explore the association between the use of metformin and the risk of ischemic stroke in patients with type 2 diabetes. METHODS: A prospective cohort study was designed from the Fangshan family cohort in Beijing. According to metformin use at baseline, 2 625 patients with type 2 diabetes in Fangshan, Beijing were divided into metformin group or non-metformin group and the incidence of ischemic stroke between the different groups during follow-up was estimated and compared by Cox proportional hazard regression model. The participants with metformin were first compared with all the parti-cipants who did not use metformin, and then were further compared with those who did not use hypoglycemic agents and those who used other hypoglycemic agents. RESULTS: The patients with type 2 diabetes were with an average age of (59.5±8.7) years, and 41.9% of them were male. The median follow-up time was 4.5 years. A total of 84 patients developed ischemic stroke during follow-up, with a crude incidence of 6.4 (95%CI: 5.0-7.7) per 1 000 person-years. Among all the participants, 1 149 (43.8%) took metformin, 1 476 (56.2%) were metformin non-users, including 593 (22.6%) used other hypoglycemic agents, and 883 (33.6%) did not use any hypoglycemic agents. Compared with metformin non-users, the Hazard ratio (HR) for ischemic stroke in metformin users was 0.58 (95%CI: 0.36-0.93; P = 0.024). Compared with other hypoglycemic agents, HR was 0.48 (95%CI: 0.28-0.84; P < 0.01); Compared with the group without hypoglycemic agents, HR was 0.65 (95%CI: 0.37-1.13; P=0.13). The association between metformin and ischemic stroke was statistically significant in the patients ≥ 60 years old compared with all the metformin non-users and those who used other hypoglycemic agents (HR: 0.48, 95%CI: 0.25-0.92; P < 0.05). Metformin use was associated with a lower incidence of ischemic stroke in the patients with good glycemic control (0.32, 95%CI: 0.13-0.77; P < 0.05). In the patients with poor glycemic control, and the association was not statistically significant (HR: 0.97, 95%CI: 0.53-1.79; P>0.05). There was an interaction between glycemic control and metformin use on incidence of ischemic stroke (Pinteraction < 0.05). The results of the sensitivity analysis were consistent with the results in the main analysis. CONCLUSION: Among patients with type 2 diabetic in rural areas of northern China, metformin use was associated with lower incidence of ischemic stroke, especially in patients older than 60 years. There was an interaction between glycemic control and metformin use in the incidence of ischemic stroke.

[The timing of pericardial drainage catheter removal and restart of the anticoagulation in patients suffered from perioperative pericardial tamponade during atrial fibrillation catheter ablation and uninterrupted dabigatran: Experiences from 20 cases].

Objective: To investigate the timing of pericardial drainage catheter removal and restart of the anticoagulation in patients with atrial fibrillation (AF) suffered from perioperative pericardial tamponade during atrial fibrillation catheter ablation and uninterrupted dabigatran. Methods: A total of 20 patients with pericardial tamponade, who underwent AF catheter ablation with uninterrupted dabigatran in Beijing Anzhen Hospital from January 2019 to August 2021, were included in this retrospective analysis. The clinical characteristics of enrolled patients, information of catheter ablation procedures, pericardial tamponade management, perioperative complications, the timing of pericardial drainage catheter removal and restart of anticoagulation were analyzed. Results: All patients underwent pericardiocentesis and pericardial effusion drainage was successful in all patients. The average drainage volume was (427.8±527.4) ml. Seven cases were treated with idarucizumab, of which 1 patient received surgical repair. The average timing of pericardial drainage catheter removal and restart of anticoagulation in 19 patients without surgical repair was (1.4±0.7) and (0.8±0.4) days, respectively. No new bleeding, embolism and death were reported during hospitalization and within 30 days following hospital discharge. Time of removal of pericardial drainage catheter, restart of anticoagulation and hospital stay were similar between patients treated with idarucizumab or not. Conclusion: It is safe and reasonable to remove pericardial drainage catheter and restart anticoagulation as soon as possible during catheter ablation of atrial fibrillation with uninterrupted dabigatran independent of the idarucizumab use or not in case of confirmed hemostasis.

[Analysis of dyslipidemia management status in atrial fibrillation patients with very high and high risk of atherosclerotic cardiovascular disease].

Objective: To analyze the status of statins use and low-density lipoprotein cholesterol (LDL-C) management in patients with atrial fibrillation (AF) and very high/high risk of atherosclerotic cardiovascular disease (ASCVD) from Chinese Atrial Fibrillation Registry (CAFR). Methods: A total of 9 119 patients with AF were recruited in CAFR between January 1, 2015 to December 31, 2018, patients at very high and high risk of ASCVD were included in this study. Demographics, medical history, cardiovascular risk factors, and laboratory test results were collected. In patients with very high-risk, a threshold of 1.8 mmol/L was used as LDL-C management target and in patients with high risk, a threshold of 2.6 mmol/L was used as LDL-C management target. Statins use and LDL-C compliance rate were analyzed, multiple regression analysis was performed to explore the influencing factors of statins use. Results: 3 833 patients were selected (1 912 (21.0%) in very high risk of ASCVD group and 1 921 (21.1%) in high risk of ASCVD group). The proportion of patients with very high and high risk of ASCVD taking statins was 60.2% (1 151/1 912) and 38.6% (741/1 921), respectively. Attainment rate of LDL-C management target in patients with very high and high risk were 26.7% (511/1 912) and 36.4% (700/1 921), respectively. Conclusion: The proportion of statins use and attainment rate of LDL-C management target are low in AF patients with very high and high risk of ASCVD in this cohort. The comprehensive management in AF patients should be further strengthened, especially the primary prevention of cardiovascular disease in AF patients with very high and high risk of ASCVD.

[Current use of oral anticoagulation therapy and influencing factors among coronary artery disease patients with nonvalvular atrial fibrillation in China].

Objective: To investigate current use of oral anticoagulant (OAC) therapy and influencing factors among coronary artery disease (CAD) patients with nonvalvular atrial fibrillation (NVAF) in China. Methods: Results of this study derived from "China Atrial Fibrillation Registry Study", the study prospectively enrolled atrial fibrillation (AF) patients from 31 hospitals, and patients with valvular AF or treated with catheter ablation were excluded. Baseline data such as age, sex and type of atrial fibrillation were collected, and drug history, history of concomitant diseases, laboratory results and echocardiography results were recorded. CHA2DS2-VASc score and HAS-BLED score were calculated. The patients were followed up at the 3rd and 6th months after enrollment and every 6 months thereafter. Patients were divided according to whether they had coronary artery disease and whether they took OAC. Results: 11 067 NVAF patients fulfilling guideline criteria for OAC treatment were included in this study, including 1 837 patients with CAD. 95.4% of NVAF patients with CAD had CHA2DS2-VASc score≥2, and 59.7% of patients had HAS-BLED≥3, which was significantly higher than NVAF patients without CAD (P<0.001). Only 34.6% of NVAF patients with CAD were treated with OAC at enrollment. The proportion of HAS-BLED≥3 in the OAC group was significantly lower than in the no-OAC group (36.7% vs. 71.8%, P<0.001). After adjustment with multivariable logistic regression analysis, thromboembolism(OR=2.48,95%CI 1.50-4.10,P<0.001), left atrial diameter≥40 mm(OR=1.89,95%CI 1.23-2.91,P=0.004), stain use (OR=1.83,95%CI 1.01-3.03, P=0.020) and ß blocker use (OR=1.74,95%CI 1.13-2.68,P=0.012)were influence factors of OAC treatment. However, the influence factors of no-OAC use were female(OR=0.54,95%CI 0.34-0.86,P=0.001), HAS-BLED≥3 (OR=0.33,95%CI 0.19-0.57,P<0.001), and antiplatelet drug(OR=0.04,95%CI 0.03-0.07,P<0.001). Conclusion: The rate of OAC treatment in NVAF patients with CAD is still low and needs to be further improved. The training and assessment of medical personnel should be strengthened to improve the utilization rate of OAC in these patients.

[Investigation and analysis of late reporting and under-reporting of occupational diseases from 2018 to 2020 in China].

Objective: To understand the late reporting and the under-reporting of occupational disease from 2018 to 2020 in China and analyze the causes, so as to provide scientific evidence for improving the quality of occupational disease reports in China, timely acquiring the incidence of occupational disease, and assessing the occupational hazards. Methods: From May to December 2021, A total of 320 occupational disease diagnostic institutions were selected for investigation. The original documents of occupational disease diagnosis cases from 2018 to 2020 were compared with the online reported cases, and late reported and under-reported cases of occupational disease were analyzed. Results: A total of 32207 diagnosed cases from 2018 to 2020 were investigated, including 28934 confirmed cases and 3273 cases without occupational disease. The overall late reported rate and under-reported rate of confirmed cases were 20.2% and 2.1%, respectively. There were significant differences in the rate of late reporting and under-reporting of occupational diseases in different regions and different types of diagnostic institutions (P<0.001). The southwest region had the highest rates of late reporting and under-reporting, 61.6% and 7.9% respectively. The late reported rate of all kinds of occupational diseases was about 15.0%, and the under-reported rate was from 1.5.0% to 5.0%. Conclusion: At present, the phenomenon of late reporting and under-reporting occupational diseases is still obvious. It is necessary to strengthen the inspection of occupational disease reporting, improve the quality of occupational disease reporting, and provide scientific basis for the formulation of occupational disease prevention and control policies.

[Interaction between ischemic stroke risk loci identified by genome-wide association studies and sleep habits].

OBJECTIVE: To explore the relationship between sleep habits (sleep duration, sleep efficiency, sleep onset timing) and ischemic stroke, and whether there is an interaction between sleep habits and ischemic stroke susceptibility gene loci. METHODS: A questionnaire survey, physical examination, blood biochemical testing and genotyping were conducted among rural residents in Beijing, and the gene loci of ischemic stroke suggested by previous genome-wide association studies (GWAS) were screened. Multivariable generalized linear model was used to analyze the correlation between sleep habits, sleep-gene interaction and ischemic stroke. RESULTS: A total of 4 648 subjects with an average age of (58.5±8.7) years were enrolled, including 1 316 patients with ischemic stroke. Compared with non-stroke patients, stroke patients with sleep duration ≥9 hours, sleep efficiency < 80%, and sleep onset timing earlier than 22:00 accounted for a higher proportion (P < 0.05). There was no significant association between sleep duration and risk of ischemic stroke (OR=1.04, 95%CI: 0.99-1.10, P=0.085). Sleep efficiency was inversely associated with the risk of ischemic stroke (OR=0.18, 95%CI: 0.06-0.53, P=0.002). The risk of ischemic stroke in the subjects with sleep efficiency < 80% was 1.47-fold (95%CI: 1.03-2.10, P=0.033) of that in the subjects with sleep efficiency ≥80%. Falling asleep earlier than 22:00 was associated with 1.26 times greater risk of stroke than falling asleep between 22:00 and 22:59 (95%CI: 1.04-1.52, P=0.017). Multifactorial adjustment model showed that rs579459 on ABO gene had an interaction with sleep time (P for interaction =0.040). When there were two T alleles for rs579459 on the ABO gene, those who fell asleep before 22:00 had 1.56 times (95%CI: 1.20-2.04, P=0.001) the risk of stroke compared with those who fell asleep between 22:00 and 22:59, and there was no significant difference when the number of pathogenic alleles was 0 or 1. In the model adjusted only for gender, age and family structure, sleep duration and the number of T allele rs2634074 on PITX2 gene had an interaction with ischemic stroke (P for interaction=0.033). CONCLUSION: Decreased sleep efficiency is associated with increased risk of ischemic stroke, and falling asleep earlier than 22:00 is associated with higher risk of ischemic stroke. Sleep onset timing interacted with rs579459 in ABO gene and the risk of ischemic stroke. Sleep duration and PITX2 rs2634074 may have a potential interaction with ischemic stroke risk.

[Incidence and risk factors of ischemic stroke in patients with type 2 diabetes among urban workers in Beijing, China].

OBJECTIVE: To explore the incidence of ischemic stroke after the onset of type 2 diabetes, and further analyze the risk factors, so as to provide a basis for further research. METHODS: The data were obtained from the database of the Beijing Urban Employee Basic Medical Insurance Database. The study used a prospective design to describe the incidence of ischemic stroke in patients with type 2 diabetes. In our study, these patients were followed up for seven years. Multivariate Logistic regression models were used to analyze the risk factors of ischemic stroke in patients with type 2 diabetes. RESULTS: A total of 185 813 newly diagnosed type 2 diabetes patients were enrolled, with an average age of (58.5±13.2) years, and 49.0% of them were males. A total of 10 393 patients with newly diagnosed ischemic stroke occurred in 7 years, with a cumulative incidence of 5.6% and an incidence density of 8.1/1 000 person-years. Ischemic stroke occurred in all age groups in patients with type 2 diabetes. The cumulative incidence was 1.5% (95%CI: 1.3%-1.6%) in group ≤44 years old, 3.6% (95%CI: 3.4%-3.7%) in group 45-54 years old, 5.4% (95%CI: 5.2%-5.5%) in group 55-64 years old, and 9.2% (95%CI: 9.0%-9.4%) in group ≥65 years old, and the cumulative incidence increased with age (P < 0.05). Cumulative incidence rate of the males (6.8%, 95%CI: 6.7%-7.0%) was higher than the females (4.4%, 95%CI: 4.3%-4.6%). Among the patients < 80 years old, the cumulative incidence rate of the males was higher than that of the females in all the age groups. In the patients ≥80 years of age, the cumulative incidence was higher in the females (9.2%) than in the males (7.9%). Further analysis revealed that complications, such as coronary heart disease (OR=3.18, 95%CI: 2.72-3.72), heart failure (OR=1.53, 95%CI: 1.32-1.79) and kidney failure (OR=1.45, 95%CI: 1.20-1.75) were associated with ischemic stroke in the patients with type 2 diabetes. CONCLUSION: The incidence level of ischemic stroke in patients with type 2 diabetes is high. It is necessary to strengthen the management of risk factors in elderly patients, screen the complications of type 2 diabetes as early as possible, and take active preventive and control measures.

[Application of ureteral access sheath in the operation of middle and lower ureteral calculi in patients with massive benign prostatic hyperplasia].

Objective: To examine the effectiveness and safety of application of the ureteral access sheath in the treatment of middle or lower ureteral calculi in patients with large-volume benign prostatic hyperplasia above grade Ⅲ, which is expected to avoid the simultaneous or staged treatment of benign prostatic hyperplasia via eliminate the difficult angle and resistance of ureteroscopy caused by severe prostatic hyperplasia. Methods: From April 2018 to December 2020, the clinical data of 27 patients with massive benign prostatic hyperplasia above grade Ⅲ and middle and lower ureteral calculi treated with indwelling ureteral access sheath plus ureteroscopy holmium laser lithotripsy at Department of Urology, Zhejiang Quhua Hospital were retrospectively analyzed and followed up. All the patients were male, aged (69.7±12.8) years (range: 55 to 87 years). Prostate volume measured by transrectal ultrasound was (94.8±16.2) cm3 (range: 85 to 186 cm3). The ureteral access sheath was indwelled in advance, and then the semirigid ureteroscopy was introduced through the working channel of the sheath. Holmium laser lithotripsy was performed, and intraoperative and postoperative complications were recorded. Urinary abdominal plain X-ray or CT urography were performed at 1-and 2-month postopaerative to evaluate the residual stones and clinical efficacy. Results: The ureteral access sheath was placed and holmium laser lithotripsy under a semirigid ureteroscopy was performed successfully in all the 27 patients. In 2 patients, a second session of auxiliary procedure was required due to the large load of preoperative stones and residual stones after surgery, among whom 1 patient received extracorporeal shock wave lithotripsy and 1 patient underwent extracorporeal shock wave lithotripsy plus ureteroscopic lithotripsy. The stone free rate at 1-and 2-month postoperative were 92.6% (25/27) and 100% (27/27), respectively. There were no severe complications such as ureteral avulsion and perforation, perirenal hematoma, septic shock, severe hematuria, urinary retention, iatrogenic ureteral stricture occurred during and after the surgery. The ureteral calculus was wrapped by polyps heavily in 1 patient, he was diagnosed as ureteral stenosis 1 month postoperative, receiving laparoscopic resection of ureteral stricture plus anastomosis 3 months postoperative. Conclusions: In the operations of middle and lower ureteral calculi in patients with large-volume prostatic hyperplasia above grade Ⅲ, the ureteral access sheath can be placed first to effectively eliminate the difficult angle and resistance of ureteroscopy caused by severe prostatic hyperplasia, and then semirigid ureteroscopic lithotripsy can be safely performed. It could avoid the treatment of benign prostatic hyperplasia at the same time or by stages.

[Combined resection of thoracic and abdominal organ clusters: a series of 50 cases].

Objective: To examine the technique and effect of combined thoracic and abdominal organ clusters resection. Methods: From February 2019 to August 2021, totally 50 cases of combined thoracoabdominal organ cluster resection were completed at Transplant Medical Center, the Second Affiliated Hospital of Guangxi Medical University from donation after brain death donors. There were 47 males and 3 females, aging (34.8±12.3) years (range: 5 to 55 years). The length of hospital stay(M(IQR)) was 4(4) days (range: 2 to 43 days), the length of tube time was 4(2) days (range: 1 to 43 days). Through the midsternal incision and the abdominal grand cross incision, the cold perfusion was performing simultaneously when the perfusion lines of each target organ was established respectively. The combined resection was performed with the diaphragm as the boundary and the organ cluster as the unit. The heart and lung were separated on site and sent to the transplant hospital, and the abdominal organ cluster was directly preserved and returned to our hospital for further separation and repair. Results: Totaly 21 hearts, 47 pairs of lungs, 49 livers, 47 pairs of kidneys and 11 pancreas were harvested by this surgical treatment. The resection time was (32.6±6.5) minutes (range: 19 to 50 minutes), with no hot ischemia time. There was no accidental injury that affected organ quality and function. Heart transplantation was performed in 17 cases, combined heart-kidney transplantation in 2 cases, double lung transplantation in 43 cases, single lung transplantation in 6 cases, liver transplantation in 41 cases, combined liver-pancreas-duodenal cluster transplantation in 1 case, combined liver-kidney transplantation in 3 cases, combined pancreas-kidney transplantation in 9 cases, and kidney transplantation in 74 cases. Conclusion: Simultaneous perfusion and combined resection of thoracic and abdominal organ clusters for donation after brain death donors are feasible and effective.

[The association of high-sensitivity C-reactive protein with new-onset hypertension in different age groups].

Objective: To investigate the association between high sensitivity C-reactive protein (hsCRP) level and new-onset hypertension in different age groups. Methods: This was a prospective cohort study involving non-hypertensive population in Kailuan Group community who participated in health examination between 2006 and 2007.Follow-up was conducted every 2 years, and the time of new onset of hypertension was used as the endpoint of follow-up. The endtime of follow-up for patients without hypertension was the time of death or the last follow-up (December 31, 2017).According to the baseline hsCRP level, the participants were divided into low-risk group (hsCRP<1.0 mg/L), medium-risk group (hsCRP ≥1.0 and ≤3.0 mg/L), and high-risk group (hsCRP>3.0 mg/L), and further stratified by age. Kaplan-Meier method was used to calculate the cumulative incidence of hypertension in each group. Multivariate Cox regression model was used to analyze the association between hsCRP level and new-onset hypertension. Results: A total of 51 179 participants were included in this study, including 38 606 males (75.43%) with an average age of (48.1±12.2) years. The baseline hsCRP was 0.64 (0.25, 1.60) mg/L. The baseline hsCRP was 0.30 (0.16, 0.59), 1.57 (1.20, 2.10), 5.17 (3.80, 7.10) mg/L respectively in low-, medium- and high-risk groups. During the follow-up of (8.1±2.2) years, a total of 9 523 (18.60%) patients developed hypertension, and the cumulative incidence rates of low-, medium- and high-risk groups were 17.41%, 20.48% and 20.73%, respectively. The cumulative incidence of hypertension in low-, medium- and high-risk groups of<45, 45-54, 55-64, ≥65 years old were 13.53%, 15.82%, 16.76%; 19.27%, 22.84%, 21.62%; 21.55%, 24.19%, 24.88%;20.20%, 22.35%, 19.11%, respectively. Except for people aged ≥65 years, there were significant differences in the cumulative incidence of hypertension in low-, medium- and high-risk groups (all P<0.05).Multivariate Cox regression analysis showed that the risk of new-onset hypertension in the high risk group was 1.11 times higher than that in the low risk group (HR=1.11, 95%CI 1.05-1.18). The risk of new-onset hypertension in the high-risk group was 1.22 times (HR=1.22, 95%CI 1.08-1.38), 1.14 times (HR=1.14, 95%CI 1.04-1.26), 1.16 times (HR=1.16, 95%CI 1.04-1.30), and 1.02 times (HR=1.02, 95%CI 0.86-1.20) of the low-risk group, in the<45, 45-54, 55-64, and ≥65 years old groups, respectively. Conclusion: Higher hsCRP level is a risk factor for new-onset hypertension, and the risk of developing hypertension caused by elevated hsCRP is age-dependent.

The novel AKT inhibitor afuresertib suppresses human Merkel cell carcinoma MKL-1 cell growth.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine neoplasm of the skin, which has an exceedingly poor prognosis. The AKT/mammalian target of rapamycin (mTOR) signalling pathway, which plays a pivotal role in the modulation of protein synthesis and cell survival, has been shown to be extremely important for Merkel cell carcinogenesis. In the current study, we found that AKT has important regulatory functions in MCC cells and that inhibition of AKT with the novel ATP-competitive AKT inhibitor, afuresertib, has widespread effects on proliferative pathways. In particular, we found that treatment of MCC cells with afuresertib led to deactivation of mTOR and glycogen synthase kinase 3 pathway proteins while increasing activation of proapoptotic pathways through the upregulation of p16 expression and phosphomodulation of the B-cell lymphoma-2-associated death promoter. Overall, afuresertib treatment led to significant and robust inhibition of MCC cell proliferation, thus raising intriguing questions regarding the potential efficacy of AKT inhibition for the future clinical management of MCC.

[The impact of digoxin on the long-term outcomes in patients with coronary artery disease and atrial fibrillation].

Objective: To investigate the long-term safety of digoxin in patients with coronary artery disease (CAD) and atrial fibrillation (AF). Methods: This was a prospective study, in which 25 512 AF patients were enrolled from China Atrial Fibrillation Registry Study. After exclusion of patients receiving ablation therapy at the enrollment, 1 810 CAD patients [age: (71.5±9.3)years] with AF were included. The subjects were grouped into the digoxin group and non-digoxin group, and were followed up for a period of 80 months. Long-term outcomes were compared between the groups and an adjusted Cox regression analysis was applied to evaluate the risk of digoxin on the long-term outcomes. The primary endpoint was all-cause mortality. Results: The patients were followed up for a median period of 3.05 years. After multivariable adjustment, the Cox regression analysis showed that digoxin significantly increased the risk of all-cause mortality (HR=1.28, 95%CI 1.01-1.61, P=0.038), cardiovascular mortality (HR=1.48,95%CI 1.10-2.00,P=0.010), cardiovascular hospitalization (HR=1.67,95%CI 1.35-2.07,P=0.008) and the composite endpoints (HR=2.02,95%CI 1.71-2.38,P<0.001). In the subgroup of patients with heart failure (HF), digoxin was not associated with the risk of all-cause mortality, but was still associated with the increased risk of cardiovascular mortality (HR=1.44,95%CI 1.05-1.98,P=0.025), cardiovascular hospitalization (HR=1.44,95%CI 1.09-1.90,P=0.010) and the composite endpoints (HR=1.37, 95%CI 1.01-1.70, P=0.004). However, in the subgroup of patients without HF, digoxin was only associated with all-cause mortality (HR=2.56,95%CI 1.44-4.54,P=0.001). Conclusion: Digoxin significantly increased the risk of all-cause mortality in CAD patients with AF, especially in patients without HF.

[Clinical analysis of left atrial appendage occlusion for stroke prevention in elderly patients with atrial fibrillation].

To evaluate the efficacy and safety of left atrial appendage occlusion (LAAO) in patients with atrial fibrillation (AF) over 75 years. A total of 82 patients with AF who underwent LAAO successfully in Beijing Anzhen Hospital from March 2014 to March 2019 were divided into two groups according to age: the elderly group (aged>75 years) and the young group (aged ≤75 years). Risk of perioperative complications and incidence of ischemic stroke and major bleeding during follow-up were retrospectively analyzed. The results showed that there were no significant differences in procedure-related ischemic stroke(0 vs.1.6%,P=0.768) and major bleeding (0 vs.1.6%,P=0.768) during perioperative period between the two groups. No complications as death or pericardial tamponade occurred in the two group. During a (25.9±15.9) months period of followed up, ischemic stroke event rate was 3.6/100 person-years in the elderly group and 4.9/100 person-years in the young group, respectively. Major bleeding event rate was 2.5/100 person-years in the elderly group and 0/100 person-years in the young group, respectively. Compared with the expected ones, the relative risk reduction (RRR) of stroke in the elderly group was more profound than that in the young group (32.0% vs. 25.0%), while the risk of major bleeding in the young group was significantly lower than that in the elderly group (RRR 100% vs. 56.9%). Therefore, LAAO might be suitable for stroke prevention in the elderly AF patients.

[Clinical characteristics of 170 cases of macrodactyly].

OBJECTIVE: To analyze the clinical characteristics of 170 cases of macrodactyly. METHODS: Medical records of 170 macrodactyly patients at Beijing Jishuitan Hospital between March 2006 and October 2019, including demographic characteristics, clinical presentations, anatomical distributions, X-rays, pathological findings, and treatments, were reviewed. PIK3CA mutation analyses of 12 patients were also reviewed. RESULTS: Disease incidence was similar across sex and geographical regions. Multiple-digit involvement was 3.9 times more frequent than single-digit involvement. In upper deformit: ies, the index finger, middle finger and thumb were mostly involved, and the second and third toes were the most affected on the foot. Two digits were affected more often than three digits, with the affected multiple digits were adjacent most time. The cases of progressive macrodactyly, in which the affected digits grew at a faster rate than the unaffected digits, were found more than static type. Most of progressive macrodactyly were noticed at birth. In terms of nerve involvement, affected fingers mostly occurred in the median nerve innervation area (79.4%) accompanied by median nerve and brunches enlargement and fat infiltration, i.e., nerve territory oriented; affected toes mostly occurred in the medial plantar nerve innervation area (89.1%), marked with overgrowth of adipose tissue with a lesser degree of neural overgrowth, i.e., lipomatous. Only 17 cases had comorbid of syndactyly. The metacarpal bones were involved only in progressive type of macrodactyly. Ten of the 12 cases subjected to PIK3CA mutation analysis were positive. Among all tested specimens, PIK3CA mutation levels ranged from 7% to 27%. In terms of tissue sources in which a mutation was found, adipose tissue had the highest mutation detection rate, followed by nerve and skin. All the DNA samples of blood from the 12 PIK3CA mutation-positive patients were negative. CONCLUSION: Macrodactyly fingers mostly occurred in the median nerve innervation area accompanied by median nerve and brunches enlargement and fat infiltration. The index and middle fingers were mostly involved. Macrodactyly toes mostly occurred in the medial plantar nerve innervation area, marked with overgrowth of adipose tissue with a lesser degree of neural overgrowth. The second and third toes were the most affected on the foot. A high proportion (83%) of isolated macrodactyly patients carry activating PIK3CA mutations. Adipose, nerve, and skin tissues provide the highest PIK3CA mutation detection yield among all types of tissue studied.

[Prevalence and risk factors of osteoarthritis in patients with type 2 diabetes in Beijing, China from 2015 to 2017].

OBJECTIVE: To explore the prevalence and related factors of osteoarthritis in patients with type 2 diabetes mellitus, and provided a scientific basis for the prevention of the comorbidity. METHODS: The data were obtained from the database of all designated medical institutions in Beijing from 2015 to 2017. Data of the adult patients with type 2 diabetes mellitus were collected for descriptive analysis, and a Logistic regression model was used to explore the related factors of osteoarthritis in the patients with type 2 diabetes mellitus. RESULTS: A total of 1 046 264 diagnosed type 2 diabetes mellitus adult patients were included in our study, with an average age of 63.07 years, and 50.78% were males. Among the patients with type 2 diabetes mellitus, there were 341 561 cases with osteoarthritis, and the prevalence of osteoarthritis was 32.65%. The prevalence of females (38.05%) was higher than that of males (27.41%), and the difference was statistically significant (P < 0.05). Osteoarthritis occurred in all age groups among the patients with type 2 diabetes mellitus, with the highest prevalence of osteoarthritis in the age group of 65-69 years (36.76%), and the lowest prevalence in the age group ≤44 years (14.3%). Before the age of 70, the prevalence increased with age. Further analysis of related factors for osteoarthritis in the patients with type 2 diabetes mellitus showed that female (OR=1.62, 95%CI: 1.61-1.63), age (OR=1.01, 95%CI: 1.01-1.01), had other comorbidities (OR=1.19, 95%CI: 1.18-1.21), used hypoglycemic drugs (OR=0.79, 95%CI: 0.78-0.80), having the cardiovascular disease (OR=1.13, 95%CI: 1.11-1.15), having cerebrovascular disease (OR=1.25, 95%CI: 1.23-1.28), and having nephropathy (OR=1.61, 95%CI: 1.51-1.71) were associated with the osteoarthritis in the type 2 diabetic mellitus patients. CONCLUSION: Our study revealed that the prevalence of osteoarthritis in patients with type 2 diabetes mellitus is high in Beijing area. Health education and disease monitoring should be strengthened in middle-aged and elderly patients. Screening for comorbidities should be carried out as soon as possible, with the focus on menopausal women.

[Genotyping analysis of norovirus infectious diarrhea clusters in Songjiang district, Shanghai from 2017 to 2019].

Objective: We aimed to analyze the the genotyping of norovirus infectious diarrhea epidemic in Songjiang district, Shanghai, and explored the experience in handling the epidemic to provide a scientific basis for formulating prevention and treatment strategies. Methods: The epidemiological data and related samples of 69 outbreaks of infectious diarrhea caused by norovirus was collected from 2017 to 2019 in Songjiang district, Shanghai. Sequencing and type identification were performed by the method of gene sequencing for the junction region of Norovirus ORF1 and ORF2. Results: From 2017 to 2019, 69 outbreaks of norovirus infections diarrhea were reported in Songjiang district, Shanghai. A total of 1 767 samples were tested, including 619 case samples (positive rate 19.9%), 343 practitioner samples (positive rate 1.1%), 505 environmental samples (positive rate 0.5%) and 300 food samples (not detected). 141 sequences were obtained, and the genotype analysis showed that the genotype that mainly caused infectious diarrhea in 2017 and 2018 was GII.P16-GII.2 (50.98%, 26/51). In 2019, the genotypes that mainly caused infectious diarrhea were GII.P16-GII.2 (13.73%, 7/51) and GII.Pe-GII.4 (9.80%, 5/51). Conclusion: The main genotype of the 69 outbreaks of nororirus infectious diarrhea epidemic in Songjiang district, Shanghai from 2017 to 2019 was GII.P16-GII.2, which showed obvious peaks in spring, autumn and winter. There were more infections in kindergartens and schools. The surveillance of norovirus infection should be strengthened.

[Current researches and prospects of human induced pluripotent stem cells and gene editing technology of CRISPR/Cas9 in inherited ocular diseases].

Human induced pluripotent stem cells have the ability to differentiate into specific cell types or tissues of the eye in humans and have application prospects in retinal cell transplantation, corneal transplantation, and lens regeneration. Gene editing technology of clustered regularly interspaced short palindromic repeats/crispr-associated protein-9 nuclease (CRISPR/Cas9) can introduce causative mutations of inherited ocular diseases into human induced pluripotent stem cells effectively. Then they can be further differentiated into specific somatic cells maintaining a genetic disease background, which can mimic the occurrence of inherited ocular diseases in vitro. The cell model may help scientists study the mechanism of human disease development, establish an in vitro screening platform to find therapeutic drugs, and correct genetic mutations in the human genome for cell therapy. The combination of stem cells and gene editing technology is revolutionizing the regenerative medicine in ophthalmology and gene therapy of inherited ocular diseases. This review summarizes the current application of human induced pluripotent stem cells and its combination with gene editing technology in the study of inherited ocular diseases. (Chin J Ophthalmol, 2021, 57: 712-716).

[Safety and effectiveness of left atrial appendage occlusion in patients with atrial fibrillation and end-stage renal disease undergoing long-term hemodialysis].

Objective: To evaluate the safety and effectiveness of left atrial appendage occlusion (LAAO) in patients with atrial fibrillation and end-stage renal disease undergoing long-term hemodialysis. Methods: Six patients with AF and end-stage renal disease(ESRD)on long term hemodialysis who underwent LAAO from March 2017 to March 2021 in Beijing Anzhen Hospital were enrolled. Baseline characteristics such as age, sex, types of arrhythmia, stroke and bleeding score, and continuous dialysis time were collected. Four patients underwent LAAO, two patients underwent the combined procedure of catheter ablation and LAAO. Perioperative treatment and serious complications were recorded. Transesophageal echocardiography was repeated at 45 days and 60 days after the procedure. Telephone follow-up was conducted at 3, 6 and 12 months after the procedure, and every 6 months thereafter. Thromboembolism and major bleeding events and survival were evaluated. Results: The average age was (66.7±17.0) years old, and 5 were male (5/6). There were 4 patients with paroxysmal AF (4/6), and 2 patients with persistent AF (2/6). The mean CHA2DS2-VASc score was (4.8±1.5), and the HAS-BLED score was (3.5±1.4). The duration of hemodialysis was 2.6 (1.1, 8.3) years. Successfully Watchman implantation was achieved in all patients. There were no severe perioperative complications, and no device related thrombosis or leaks were observed by transesophageal echocardiography. During a mean of 22.0 (12.0, 32.0) months follow-up, there was no thromboembolism or major bleeding events. A total of 2 patients died, one from sudden cardiac death, and another one from heart failure. Conclusions: LAAO may be a safe and effective therapeutic option for prevention of thromboembolism in patients with atrial fibrillation and end-stage renal disease undergoing long-term hemodialysis, further studies with larger patient cohort are needed to confirm our results.