BACKGROUND:For dislocation of acromioclavicular joint induced by coracoclavicular ligament fracture,single EndoButton Plate reconstruction and double EndoButton Plates reconstruction are common repair methods.Further study on the stress distribution and fracture risk of the two repair methods is of great significance. OBJECTIVE:To study the biomechanical properties of the coracoclavicular ligament,and compare the fixation effect,stress distribution and failure mode of single and double EndoButton Plates reconstruction. METHODS:(1)Finite element simulation analysis:Mimics,Wrap and SolidWorks were used to establish normal coracoclavicular ligament,single EndoButton Plate reconstruction and double EndoButton Plates reconstruction.Ansys software was used to analyze the stress and deformation of the scapula and clavicle of each model under vertical load.(2)Sample experiment:Fifteen intact scapular-clavicle specimens were randomly grouped into five groups,with three specimens in each group.In group A,the acromioclavicular ligament was severed and the coracoclavicular ligament remained intact.In group B,acromioclavicular ligaments and trapeoid ligaments were severed,leaving intact conical ligaments.In group C,acromioclavicular ligaments and conical ligaments were cut off,and the intact traprex ligaments were retained.In group D,acromioclavicular and coracoclavicular ligaments were severed,and coracoclavicular ligaments were repaired by single EndoButton Plate reconstruction.In group E,acromioclavicular and coracoclavicular ligaments were severed,and the coracoclavicular ligaments were repaired by double EndoButton Plates reconstruction.The mechanical experiment was carried out by a mechanical testing machine to analyze the biomechanical status,stress distribution and failure patterns of the scapular-clavicle and clavicle. RESULTS AND CONCLUSION:(1)Finite element simulation analysis:The average stress of coracoclavicular ligament attached specimens was the lowest,and the risk of coracoclavicular fracture was less than that of single and double EndoButton Plates reconstruction.The mean stress of the coracoid process was similar in single and double EndoButton Plates reconstruction,and the fracture risk was similar.(2)Sample experiment:In groups A,B,C,D and E,the stiffness of specimens was(26.4±3.5),(19.8±2.8),(21.3±3.2),(57.7±4.1),and(46.2±2.8)N/mm,respectively;the ultimate loads were(545.5±53.7),(360.1±42.1),(250.9±44.4),(643.5±39.1),and(511.9±31.7)N,respectively;global stiffness in groups D and E was higher than that in group A(P=0.000 06,0.000 3);ultimate load in group D was higher than that in group A(P<0.05);the ultimate load was not significantly different between the group E and group A(P>0.05).Ligament fracture was observed in groups A,B and C and coracoid process fracture was found in groups D and E.(3)These results suggest that from the biomechanical analysis,Single EndoButton Plate reconstruction and double EndoButton Plates reconstruction are effective treatment techniques for coracoclavicular ligament fracture in acromioclavicular joint dislocation,but increase the risk of fracture.The double EndoButton Plates reconstruction dispersed the stress of the steel plate and reduced the contact force between the steel plate and bone,but slightly reduced the ultimate bearing capacity.Single and double EndoButton Plates reconstruction should be selected according to the actual clinical situation.

Approximately 140 million people worldwide are homozygous carriers of APOE4 (ε4), a strong genetic risk factor for late onset familial and sporadic Alzheimer's disease (AD), 91% of whom will develop AD at earlier age than heterozygous carriers and noncarriers. Susceptibility to AD could be reduced by targeted editing of APOE4, but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies. Here, we first screened eight cytosine base editor variants at four injection stages (from 1- to 8-cell stage), and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate (up to 100%) with the lowest bystander effects. In particular, 80% of AD-susceptible ε4 allele copies were converted to the AD-neutral ε3 allele in human ε4-carrying embryos. Stringent control measures combined with targeted deep sequencing, whole genome sequencing, and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells. Furthermore, base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage. Finally, we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia. Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos, a potential approach for reducing human susceptibility to AD or other genetic diseases.
Humans ; Apolipoprotein E4/genetics* ; Cytosine ; Mutation ; Blastocyst ; Heterozygote ; Gene Editing ; CRISPR-Cas Systems

In 2016, a national one million general population cohort project was set up in China for the first time in "Precision Medicine Research" Key Project, National Key Research and Development Program of China, which consists of general population cohorts in seven areas in China. As one of the seven major areas in China, northeastern China has unique climate and specific dietary patterns, and population aging is serious in this area. And the burden of chronic and non-communicable diseases ranks tops in China. Therefore, it is of great significance to establish a large general population cohort in northeastern China to explore the area specific exposure factors related to pathogenesis and prognosis of chronic and non-communicable diseases, develop new prevention strategies to reduce the burden of the diseases and improve the population health in northeastern China. In July 2018, the general population cohort study in northeastern China was launched, the study includes questionnaire survey, health examination and blood, urine and stool sample collection and detection in recruited participants. By now, the cohort has covered all age groups, and the baseline data of 115 414 persons have been collected. This paper summarizes the design and practice of the general population cohort study in northeastern China to provide reference for related research in China.

Objective:To compare the hemostatic effects and patient comfort of different compression methods for hemostasis after transradial coronary intervention.Methods:A total of 160 patients who received transradial coronary intervention in The Affiliated Hospital of Hangzhou Normal University from October 2018 to February 2020 were included in this study. In group A ( n = 80), patients underwent spiral compression at the puncture point (release for 1 turn at 2 hours after surgery, rotation for 1 circle after 1 hour, and full decompression). In group B ( n = 80), patients underwent spiral compression at the puncture point (release for 1 turn at 2 hours after surgery, rotation for 1 circle after 2 hours, and full decompression). Percutaneous arterial oxygen saturation value in the affected limb, heart rate, and Visual Analog Scale score at different times after surgery, pain and comfort score at 2 and 12 hours post-surgery were compared between the two groups. Results:Percutaneous arterial oxygen saturation value at 4 and 12 hours post-surgery in group A was (96.6 ± 0.7)% and (97.8 ± 0.5)%, respectively, which was significantly higher than that in group B [(96.2 ± 0.6)%, (97.6 ± 0.7)%, t = 3.88, 2.08, both P < 0.05]. There were no significant differences in total score and subscale score of the General Comfort Questionnaire at 2 hours post-surgery between groups A and B (both P < 0.05). At 12 hours post-surgery, scores of psychological and physical subscales and total score of the General Comfort Questionnaire in group A were (23.64 ± 3.02) points, (12.64 ± 2.05) points, (68.25 ± 6.04) points, which were significantly higher than those in group B [(22.20 ± 2.96) points, (11.38 ± 2.47) points, (64.42 ± 6.71) points, t = 3.05, 3.51, 3.79, all P < 0.05]. At 2 hours post-surgery, there was no significant difference in Numerical Rating Scale score between groups A and B ( P > 0.05). At 4 and 12 hours post-surgery, Numerical Rating Scale score in group A was (2.51 ± 0.58) points and (1.75 ± 0.76) points, respectively, which was significantly lower than that in group B [(2.95 ± 0.63) points, (2.31 ± 0.71) points, t = -4.59, -4.82, both P < 0.05). The incidence of complications was significantly lower in group A than in group B (8.75% vs. 20.00%, χ2 = 4.11, P < 0.05). Conclusion:Compression for hemostasis is highly effective by releasing for 1 turn at 2 hours after transradial coronary intervention, rotating for 1 circle after 1 hour, and full compression because it can greatly mitigate pain, ensure the oxygen supply to the affected limbs, and improve patient comfort.

Objective To investigate the relationship between the treatment of EGFR-TKI icotinib and the prognosis of advanced lung adenocarcinoma patients with EGFR mutation. Methods Patients with advanced lung adenocarcinoma who had EGFR19 and 21 gene mutations and were treated with EGFR-TKI icotinib were enrolled. The relationships of clinical features, EGFR gene mutation subtypes, and different sites with patients'prognosis were analyzed. Results A total of 101 patients with advanced lung adenocarcinoma were included in this study, including 58 cases (57.4%) of EGFR gene exon 19 deletion mutation (EGFR Del19) and 43 cases (42.6%) of EGFR gene exon 21 point mutation (EGFR L858R). The objective response rate was 63.4%. The mPFS and mOS were 13 months and 27 months, respectively. In addition, the mPFS and mOS of EGFR Del19 and EGFR19 mutation 746-750 were higher than those of EGFR L858R and other EGFR mutations, respectively. Meanwhile, multivariate analysis showed that the number of metastatic sites and pleural metastasis were independent influencing factors of patients'OS (P=0.027; P=0.041). The mOS of patients with the number of metastatic sites ≤3 and without pleural metastasis were 29 and 27 months, respectively. Conclusion There is no significant difference found in overall survival of advanced lung adenocarcinoma patients treated with icotinib among different EGFR mutation subtypes and sites. Herein, the overall survival time is longer in patients with less than three metastatic sites and without pleural metastasis.

Objective:s To evaluate the impacts of prior surgical scores(PSS) on the clinical efficacy and perioperative safety of cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) for pseudomyxoma peritonei(PMP).Methods:From the comprehensive PMP database, we collect the cases treated for the first time by CRS+ HIPEC, to form this study cohort. The clinicopathological features, PSS, CRS+ HIPEC details, overall survival(OS), and serious adverse events(SAEs) are systematically analyzed, to study the correlations between PSS and OS or SAEs.Results:335 PMP cases received standardized CRS+ HIPEC in this study. The median OS is 58.2 months for PSS-0 patients, 63.7 months for PSS-1, and 55.4 months for PSS-2/3, with no statistically significant differences in OS among the different PSS groups(χ 2=0.499, P=0.779). Subgroup analysis by pathologic types also found no statistically significant differences among the different PSS groups. Moreover, no significantly statistical differences are observed in overall SAEs(χ 2=0.625, P=0.722), CRS-related SAEs(χ 2=0.267, P=0.901), and non-CRS-related SAEs(χ 2=0.677, P=0.715), among the different PSS groups. Conclusions:PSS does not pose significant impacts on the efficacy and safety of CRS+ HIPEC for PMP patients at experienced treatment center.

Objective To establish the patient derived xenograft ( PDX) model of pseudomyxoma peritonei (PMP), and identify the key characteristics of tumor biology of this model, in order to provide a reliable model for studying the pathological mechanisms and new therapeutic strategies of PMP. Methods PMP tumor tissue was obtained from surgery and cut into pieces after washing. Then tumor pieces were implanted subcutaneously in BAL B／c?nu mice for 6 stable passages. In the 7th passage, tumor tissue was implanted orthotopically into abdomen. Subcutaneous tumor and orthotopic tumor were then homogenized to make tumor cell suspension, implanted into abdomen of 10 BAL B／c?nu mice through midline laparotomy, 100 μl for each. The key experimental parameters including body weight changes in the observation period, experimental peritoneal cancer index (ePCI) score at the autopsy, histopathological and immunohistochemical characteristics, and gene expression profiles by high?throughput whole?genome exon sequencing were detected and recorded. Results The successful rate of established orthotopic PDX model of human PMP was 100%(10／10). The animals showed smooth body weight increases after tumor inoculation until day 27, then the body weight began to decrease steadily. Widespread tumor dissemination of PMP tumor through the whole abdomen was found by autopsy, including the diaphragm, liver, spleen, stomach, kidney, parietal peritoneum, bowel and mesenterium. Gelatinous ascites was also observed in abdominopelvic cavity.The ePCI score ranged from 5 to 9, with a 8 of median ePCI. Histopathological studies showed peritoneal mucinous carcinomatosis accompanied with signet ring cells ( PMCA?S ), obvious tumor cell atypia and parenchymal invasion. Immunohistochemistry showed the expressions of MUC1, MUC2, MUC5AC, CEA, CA199, CK20, CDX?2 and Ki?67 were positive, MUC6, CK7 and p53 were negative. Whole?exome sequencing identified that the most significant genetic alteration is the exon10 missense mutation c.1621A＞C of KIT gene, the mutation abundance was 89.7%. Conclusion PDX model of PMCA?S is successfully established, which displays the characters of high?degree malignancy, high proliferation and strong aggressiveness.

Objective: To establish the patient derived xenograft (PDX) model of pseudomyxoma peritonei (PMP), and identify the key characteristics of tumor biology of this model, in order to provide a reliable model for studying the pathological mechanisms and new therapeutic strategies of PMP. Methods: PMP tumor tissue was obtained from surgery and cut into pieces after washing. Then tumor pieces were implanted subcutaneously in BAL B/c-nu mice for 6 stable passages. In the 7th passage, tumor tissue was implanted orthotopically into abdomen. Subcutaneous tumor and orthotopic tumor were then homogenized to make tumor cell suspension, implanted into abdomen of 10 BAL B/c-nu mice through midline laparotomy, 100 μl for each. The key experimental parameters including body weight changes in the observation period, experimental peritoneal cancer index (ePCI) score at the autopsy, histopathological and immunohistochemical characteristics, and gene expression profiles by high-throughput whole-genome exon sequencing were detected and recorded. Results: The successful rate of established orthotopic PDX model of human PMP was 100% (10/10). The animals showed smooth body weight increases after tumor inoculation until day 27, then the body weight began to decrease steadily. Widespread tumor dissemination of PMP tumor through the whole abdomen was found by autopsy, including the diaphragm, liver, spleen, stomach, kidney, parietal peritoneum, bowel and mesenterium. Gelatinous ascites was also observed in abdominopelvic cavity. The ePCI score ranged from 5 to 9, with a 8 of median ePCI. Histopathological studies showed peritoneal mucinous carcinomatosis accompanied with signet ring cells (PMCA-S), obvious tumor cell atypia and parenchymal invasion.Immunohistochemistry showed the expressions of MUC1, MUC2, MUC5AC, CEA, CA199, CK20, CDX-2 and Ki-67 were positive, MUC6, CK7 and p53 were negative. Whole-exome sequencing identified that the most significant genetic alteration is the exon10 missense mutation c. 1621A>C of KIT gene, the mutation abundance was 89.7%. Conclusion PDX model of PMCA-S is successfully established, which displays the characters of high-degree malignancy, high proliferation and strong aggressiveness.

From November 2014 to July 2017,637 patients with acute coronary syndrome (ACS) were included in the analysis,among whom there were 48 cases with prior ischemic stroke (7.5％).The risk factors,history,severity of coronary artery disease,medication status,and incidence of adverse cardiovascular and cerebrovascular events (cardiac death,re-infarction,heart failure,stroke) were analyzed.Compare with patients without prior ischemic stroke (control group) patients with prior ischemic stroke (study group) had lower rates in administration of beta blockers [50.00％(24/28) vs.69.78％(411/589),x2=8.02,P＜0.05]and interventional therapy[56.67％(17/30) vs.81.86％(334/408),x2=11.15,P＜0.05].However,there were no significant differences in medication of dual antiplatelet,statins and angiotensin converting enzyme inhibitors or angiotensin receptor blocker between two groups (P＞0.05);and there was no significant difference in major adverse cardiovascular events between two groups (P＞0.05).In the future,more studies are needed for clinical management of this group of patients.

Objective To establish the patient derived xenograft ( PDX) model of pseudomyxoma peritonei (PMP), and identify the key characteristics of tumor biology of this model, in order to provide a reliable model for studying the pathological mechanisms and new therapeutic strategies of PMP. Methods PMP tumor tissue was obtained from surgery and cut into pieces after washing. Then tumor pieces were implanted subcutaneously in BAL B／c?nu mice for 6 stable passages. In the 7th passage, tumor tissue was implanted orthotopically into abdomen. Subcutaneous tumor and orthotopic tumor were then homogenized to make tumor cell suspension, implanted into abdomen of 10 BAL B／c?nu mice through midline laparotomy, 100 μl for each. The key experimental parameters including body weight changes in the observation period, experimental peritoneal cancer index (ePCI) score at the autopsy, histopathological and immunohistochemical characteristics, and gene expression profiles by high?throughput whole?genome exon sequencing were detected and recorded. Results The successful rate of established orthotopic PDX model of human PMP was 100%(10／10). The animals showed smooth body weight increases after tumor inoculation until day 27, then the body weight began to decrease steadily. Widespread tumor dissemination of PMP tumor through the whole abdomen was found by autopsy, including the diaphragm, liver, spleen, stomach, kidney, parietal peritoneum, bowel and mesenterium. Gelatinous ascites was also observed in abdominopelvic cavity.The ePCI score ranged from 5 to 9, with a 8 of median ePCI. Histopathological studies showed peritoneal mucinous carcinomatosis accompanied with signet ring cells ( PMCA?S ), obvious tumor cell atypia and parenchymal invasion. Immunohistochemistry showed the expressions of MUC1, MUC2, MUC5AC, CEA, CA199, CK20, CDX?2 and Ki?67 were positive, MUC6, CK7 and p53 were negative. Whole?exome sequencing identified that the most significant genetic alteration is the exon10 missense mutation c.1621A＞C of KIT gene, the mutation abundance was 89.7%. Conclusion PDX model of PMCA?S is successfully established, which displays the characters of high?degree malignancy, high proliferation and strong aggressiveness.