Pembrolizumab versus ipilimumab for advanced melanoma: 10-year follow-up of the phase III KEYNOTE-006 study.

BACKGROUND: Pembrolizumab significantly improved overall survival (OS) versus ipilimumab for unresectable advanced melanoma in KEYNOTE-006 (NCT01866319); 10-year follow-up data are presented. PATIENTS AND METHODS: Patients with unresectable stage III or IV melanoma were randomly assigned (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 weeks or every 3 weeks for ≤2 years (pooled), or ipilimumab 3 mg/kg i.v. every 3 weeks for four cycles. After KEYNOTE-006, patients could transition to KEYNOTE-587 (NCT03486873) for long-term follow-up. Eligible patients could receive second-course pembrolizumab. The primary endpoint was OS; modified progression-free survival (PFS; censored at date last known alive), modified PFS on second-course pembrolizumab, and melanoma-specific survival were exploratory. RESULTS: Of 834 patients randomly assigned in KEYNOTE-006 (pembrolizumab, n = 556; ipilimumab, n = 278), 333 (39.9%) were eligible for KEYNOTE-587; 211/333 patients (25.3%) transitioned to KEYNOTE-587 (pembrolizumab, n = 159; ipilimumab, n = 52) and 122 (14.6%) did not. For patients who transitioned to KEYNOTE-587 (n = 211), median time from randomization in KEYNOTE-006 to data cut-off for KEYNOTE-587 (1 May 2024) was 123.7 months (range, 122.0-127.3 months). Median OS was 32.7 months [95% confidence interval (CI) 24.5-41.6 months] for pembrolizumab and 15.9 months (95% CI 13.3-22.0 months) for ipilimumab [hazard ratio (HR), 0.71 (95% CI 0.60-0.85)]; 10-year OS was 34.0% and 23.6%, respectively. Among patients who completed ≥94 weeks of pembrolizumab, median OS from week 94 was not reached (NR; 95% CI NR-NR); 8-year OS rate was 80.8%. Median modified PFS was 9.4 months (95% CI 6.7-11.6 months) for pembrolizumab and 3.8 months (2.9-4.3 months) for ipilimumab [HR, 0.64 (95% CI 0.54-0.75)]. Among patients who received second-course pembrolizumab, median modified PFS from start of second course was 51.8 months (95% CI 11.0 months-NR); 6-year modified PFS was 49.2%. Median melanoma-specific survival was 51.9 months (95% CI 30.0-114.7 months) for pembrolizumab and 17.2 months (13.9-25.9 months) for ipilimumab [HR, 0.66 (95% CI 0.55-0.81)]. CONCLUSIONS: These results confirm that pembrolizumab provides long-term survival benefits in advanced melanoma, supporting it as a standard of care in this setting.

MRI radiomics for predicting intracranial progression in non-small-cell lung cancer patients with brain metastases treated with epidermal growth factor receptor tyrosine kinase inhibitors.

AIM: To identify clinical and magnetic resonance imaging (MRI) radiomics predictors specialised for intracranial progression (IP) after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in non-small-cell lung cancer (NSCLC) patients with brain metastases (BMs). MATERIALS AND METHODS: Seventy EGFR-mutated NSCLC patients with a total of 212 BMs who received first-line EGFR-TKI therapy were enrolled. Radiomics features were extracted from the BM regions on the pretreatment contrast-enhanced T1-weighted images, and the radiomics score (rad-score) of each BM was established based on the selected features. Furthermore, the mean rad-score derived from the average rad-score of all included BMs in each patient was calculated. Univariate and multivariate logistic regression analyses were performed to identify potential predictors of IP. Prediction models based on different predictors and their combinations were constructed, and nomogram based on the optimal prediction model was evaluated. RESULTS: Thirty-three (47.1 %) patients developed IP, and the remaining 37 (52.9 %) patients were IP-free. EGFR-19del mutation (OR 0.19, 95 % CI 0.05-0.69), third-generation TKI treatment (OR 0.33, 95 % CI 0.16-0.67) and mean rad-score (OR 5.71, 95 % CI 1.65-19.68) were found to be independent predictive factors. Models based on these three predictors alone and in combination (combined model) achieved AUCs of 0.64, 0.64, 0.74, and 0.86 and 0.64, 0.64, 0.75, and 0.84 in the training and validation sets, respectively, and the combined model demonstrated optimal performance for predicting IP. CONCLUSIONS: The model integrating EGFR-19del mutation, third-generation TKI treatment and mean rad-score had good predictive value for IP after EGFR-TKI treatment in NSCLC patients with BM.

[Application of uniportal video-assisted thoracoscopic surgery in the treatment of tuberculous destroyed lung].

Objective: To examine the efficacy of uniportal video-assisted thoracoscopic surgery in the treatment of tuberculous destroyed lung. Methods: This is a retrospective case series study. The clinical data of 33 patients with tuberculous destroyed lung who had received uniportal video-assisted thoracoscopic pulmonary resection from June 2020 to May 2022 in Department of Surgery, Wuhan Pulmonary Hospital were retrospectively analyzed. There were 13 males and 20 females, aged (47.5±16.2) years (range: 19 to 68 years). The course of the disease was from 15 days to 8 years. All 33 cases had pleural adhesions, including 30 cases with total pleural adhesions and atresia. There were 21 cases of calcification of the thoracic lymph node, 17 cases of aspergillus infection, 4 cases of drug-resistant tuberculosis. The surgical incision was located at the midline of the fifth intercostal axilla, length 4 to 5 cm. The principle of separating pleural adhesions was easy first and difficult later, and then appropriate procedures were selected to resect the diseased lung based on the exploration situation. There were 12 cases that underwent superior lobectomy, 11 cases that underwent superior lobectomy and dorsal segmentectomy, 3 cases that underwent inferior lobectomy, 3 cases that underwent pneumonectomy, 2 cases that underwent middle and inferior lobectomy, and 1 case that underwent superior lobectomy, dorsal segmentectomy and basal segment wedgectomy. The surgical techniques, perioperative evaluation and treatment, management of complications, and the outcome were summarized. Results: Six cases were converted to thoracoscope assisted small incision or thoracotomy. For 27 cases who successfully underwent uniportal VATS, the operation time was (238.7±76.8) minutes (range: 60 to 420 minutes), the intraoperative bleeding was (400.4±315.9) ml (range: 50 to 1 200 ml). The duration of postoperative drainage was (12.7±8.3) days (range: 3 to 42 days). The postoperative hospital stay was (15.2±7.9) days (range: 6 to 43 days). Persistent postoperative pulmonary leakage occurred in 12 cases. There were 2 cases of active thoracic bleeding, one of which was cured with conservative treatment. The other case underwent secondary operation. One case of bronchopleural fistula was cured after continuous thoracic drainage to control infection and implantation of one-way bronchial valve through a fiberoptic bronchoscope. Conclusion: For selected patients with tuberculous destroyed lung, choosing the reasonable surgical procedures and techniques, the uniportal VATS could reduce surgical trauma.

[Diagnostic value of rapid exchange test in patients with peritoneal dialysis catheter dysfunction].

A total of 36 patients with suspected peritoneal dialysis (PD) catheter dysfunction in the First Hospital of China Medical University from June 2020 to August 2022 were included, and five patients with normal PD catheter were also included as the control group. There were 22 males and 19 females, and aged (45±21) years. The volume of rapid-phase drainage in the control and dysfunction groups was (2 086±65) and (1 181±637) ml, and the total drainage time was (15.2±1.3) and (38.3±14.9) min, respectively. The volume of rapid-phase drainage in the dysfunction group was reduced and the total drainage time was longer than that in the control group (both P<0.05). Compared with group with PD catheter migration, the duration of new bag instillation was prolonged, the drainage volume in the rapid-phase was reduced, the total drainage duration was prolonged, and the ultrafiltration volume was decreased in the group with PD catheter obstruction (all P<0.05). The rapid exchange test can provide an early preliminary diagnosis of PD catheter dysfunction and identify the type of catheter dysfunction.

[Construction and analysis of functional network of hemi-brain in patients with brain tumors before and after anesthesia based on resting-state functional magnetic resonance imaging].

Objective: To construct and analyze the functional network changes of hemi-brain in patients with brain tumor before and after anesthesia by using resting state functional magnetic resonance imaging (rs-fMRI). Methods: A total of 18 right-handed patients were prospectively included (6 males and 12 females). The patients underwent glioma resection in Peking University International Hospital from December 2018 to December 2021, and age ranged from 20 to 65 (45.1±13.6) years, with American Society of Anesthesiologists (ASA) grade of Ⅰ-Ⅱ. MRI scans were performed while the patient was awake and at the depth of surgical anesthesia. The functional network of healthy lateral brain was constructed and analyzed by means of graph theory, and its global and local topological properties were calculated. Global topology attributes included global efficiency (Eg), local efficiency (Eloc), clustering parameters (Cp), length parameter of shortest path (Lp), and small world (SW). Topology attributes of nodes included node degree (ND), node efficiency (NE) and between centrality (BC). The global and nodal topological properties of the hemi-brain network were compared between patients with different hemispherical space occupying under wakefulness and anesthesia. Results: At the awake state, Eloc and Cp in the global topological attributes of hemi-brain network were 0.259±0.007 and 0.197±0.010, respectively, and decreased to 0.242±0.013 and 0.177±0.021, respectively after anesthesia, with statistically significant differences (all P<0.01). The topological attributes of the nodes in hemi-side brain showed that ND, NE and BC were increased in the default mode network-related brain regions, while NE and BC were decreased in the limbic system and subcortical structures. Eloc and Cp were 0.258±0.008 and 0.198±0.008 respectively in the patients with left hemisphere space occupying, and decreased to 0.241±0.011 and 0.177±0.015 respectively after anesthesia, with statistically significant differences (all P<0.01). However, only Eloc decreased in patients with right hemisphere space occupying after anesthesia, and Eloc was 0.260±0.006 and 0.243±0.016 respectively when awake and after anesthesia, with statistically significant differences (P<0.05). The topological attributes of nodes in patients with space occupying in different cerebral hemispheres showed bidirectional changes after anesthesia, and patients with space occupying in the left cerebral hemisphere were more likely to be widely affected after anesthesia. The effects of anesthetic drugs may show hemispheric laterality. If the tumor was in the dominant hemisphere, the compensatory function of the dominant side was more likely to be damaged. Conclusions: During anesthesia-induced loss of consciousness in patients with brain tumors, both the ability to integrate information and the functional connections between local regions are weakened, and some brain regions have functional connection reorganization. The changes of brain network after anesthesia are bidirectional regulation.

[Analysis of prognosis and associated factors in multiple recurrent epithelial ovarian cancer with three times or more cytoreductive surgeries].

Objective: To explore the prognosis of epithelial ovarian cancer patients with multiple recurrences (≥2 times) who underwent three times or more cytoreductive surgeries, and to analyze the factors associated with prognosis. Methods: The clinicopathological data and follow-up data of 23 patients with ovarian cancer admitted to the Obstetrics and Gynecology Hospital of Fudan University from January 1, 2015 to January 30, 2022 with three times or more cytoreductive surgeries were collected. The degree of surgical resection, site of recurrence and metastasis, postoperative complications, and prognosis were retrospectively analyzed. The univariate Cox proportional hazards model was performed to identify the variables associated with survival. Results: (1) The median age of 23 patients with multiple recurrent ovarian cancer was 48 years old (44-55 years). Among them, 18 cases underwent tertiary cytoreductive surgery (TCS), 2 cases underwent quaternary cytoreductive surgery, 2 cases underwent quinary cytoreductive surgery, and 1 case underwent senary cytoreductive surgery. Among the 23 patients with multiple recurrent ovarian cancer, 21 cases (91%, 21/23) had serous carcinoma, 16 cases (70%, 16/23) had advanced stage (stage Ⅲ-Ⅳ), and 19 cases (83%, 19/23) had high differentiation. (2) Based on the premise that satisfactory cytoreduction was achieved by primary debulking surgery (PDS) and no visible residual disease (R0) was achieved by secondary cytoreductive surgery (SCS), the maximum diameter of the recurrent tumors was up to 10.0 cm and 62% (20/32) of patients with multiple metastatic sites. The R0 rate for three times or more cytoreductive surgeries (32 times in total) reached 88% (28/32), with a postoperative complication rate of 47% (15/32), and only 3% (1/32) for grade Ⅲ or above. During a median follow-up time of 31.1 months (20.6-43.9 months) after TCS, 20 patients (87%, 20/23) recurred after TCS, and 8 patients (35%, 8/23) eventually died of ovarian cancer. Among them, the three-year postoperative survival rate of 22 patients with R0 was 57.6%, and the patient with residual lesions ≥1 cm died at 9.2 months after TCS. (3) In univariate analysis, ages, the time interval between PDS and SCS >32 months, the interval between SCS and TCS >16 months, and no metastatic peritoneal carcinoma were associated with longer progression free survival after TCS (all P<0.05); while treatment-free interval (TFI) >10 months after SCS, the interval between SCS and TCS >16 months, no ascites and platinum-sensitive status were associated with disease-specific survival after TCS (all P<0.05). Conclusions: It is feasible to perform three times or more cytoreductive surgeries in patients with multiple recurrent ovarian cancer who are expected to achieve R0 and have manageable complications. However, the pros and cons of surgery need to be carefully evaluated for the patients whose ascites are massive and whose previous cytoreduction does not achieve R0. A prolonged TFI and previously longer surgical interval might get potential survival benefits.

[Chest hemorrhage after left total pulmonary resection for secondary rifampin-resistant tuberculosis:a case report].

The patient had received five courses of anti-tuberculosis treatment for recurrent tuberculosis. The drug sensitivity test results of the first three courses showed drug-sensitive pulmonary tuberculosis, and the fourth diagnosis was rifampin-resistant tuberculosis (RR-TB), complicated by chronic obstructive pulmonary disease, type Ⅱ respiratory failure, pulmonary heart disease, and heart failure (grade Ⅲ). The patient stopped taking the anti-tuberculosis drugs on his own in the eighth month of receiving the resistant treatment. After admission, the symptoms improved temporarily after receiving oxygen therapy, anti-infection, and anti-tuberculosis treatment. Because of hemoptysis, the patient underwent arterial embolization by catheterization, but a large amount of hemoptysis occurred shortly thereafter. Emergency left total lung resection and gauze packing for hemostasis were performed. After surgery, the patient's vital signs were maintained with mechanical ventilation and vasopressors. Forty-eight hours after surgery, the gauze was removed, and the patient underwent tracheotomy, enteral nutrition, and anti-tuberculosis treatment. After discharge, the patient underwent rehabilitative exercise and anti-resistant tuberculosis therapy. The patient's condition remained stable for more than six months of follow-up.

[Analysis of time for diagnosis of nontuberculous mycobacterial lung disease and its associated factors in a tuberculosis-designated hospital in Shanghai].

Objective: To investigate the pathogenic characteristics, bacteriological diagnosis time and its associated factors among patients with nontuberculous mycobacterial (NTM) lung disease in a large tuberculosis-designated hospital in Shanghai from 2020 to 2021, in order to improve diagnosis efficiency and formulate precision treatment. Methods: On the basis of the Tuberculosis Database in Shanghai Pulmonary Hospital, NTM patients diagnosed by the Department of Tuberculosis between January 2020 and December 2021 were screened. Demographic, clinical and bacterial information were retrospectively collected. Chi-square test, paired-sample nonparametric test and logistic regression model were used to analyze the factors associated with the diagnosis time of NTM lung disease. Results: A total of 294 patients with bacteriologically confirmed NTM lung disease were included in this study, 147 males and 147 females with a median age of 61(46, 69) years. Of them, 227 (77.2%) patients had comorbidity of bronchiectasis. Species identification results showed that Mycobacterium Avium-Intracellulare Complex was the main pathogen of NTM lung disease (56.1%), followed by Mycobacterium kansasii (19.0%) and Mycobacterium abscessus (15.3%). Species such as Mycobacterium xenopi and Mycobacterium malmoense were rarely identified, accounting for a total proportion of only 3.1%. Positive culture rates for sputum, bronchoalveolar lavage fluid and puncture fluid were 87.4%, 80.3% and 61.5%, respectively. Paired-sample analysis showed that the positive rate of sputum culture was significantly higher than that of smear microscopy (87.1% vs. 48.4%, P<0.01), while no statistical difference was observed between sputum and bronchoalveolar lavage fluid on positive culture rate (78.7% vs. 77.3%, P>0.05). Patients with cough or expectoration were observed with 4.04-fold (95%CI 1.80-9.05) or 2.95-fold (95%CI 1.34-6.52) higher probability of positive sputum culture, compared to those without. Regarding bronchoalveolar lavage fluid, female or patients with bronchiectasis had a 2.82-fold (95%CI 1.16-6.88) or 2.38-fold (95%CI 1.01-5.63) higher probability to achieve a positive culture. The median time to diagnosis of NTM lung disease was 32 (interquartile range: 26-42) days. The results of multivariable analysis showed that patients with symptom of expectoration (aOR=0.48, 95%CI 0.29-0.80) needed a shorter diagnosis time in comparison with patients without expectoration. With Mycobacterium Avium-Intracellulare Complex as a reference, lung disease caused by Mycobacterium abscessus needed shorter diagnosis time (aOR=0.43, 95%CI 0.21-0.88), whereas those caused by rare NTM species were observed to require a longer diagnosis time (aOR=8.31, 95%CI 1.01-68.6). Conclusion: The main pathogen causing NTM lung disease in Shanghai was Mycobacterium Avium-Intracellulare Complex. Sex, clinical symptoms and bronchiectasis had an impact on the positive rate of mycobacterial culture. The majority of patients in study hospital were timely diagnosed. Clinical symptoms and NTM species were associated with the bacteriological diagnosis time of NTM lung disease.

[Effect of sugammadex on postoperative nausea and vomiting after surgery for intracranial aneurysm].

Objective: To investigate the effect of sugammadex on postoperative nausea and vomiting(PONV) after intracranial aneurysm surgery. Methods: Data from intracranial aneurysms patients who met the inclusion and exclusion criteria and underwent interventional surgery in the Department of Neurosurgery, Peking University International Hospital from January 2020 to March 2021 were prospectively included. According to the random number table method, the patients were divided by 1∶1 into the neostigmine+atropine group (group N) and the sugammadex group (group S). Use an acceleration muscle relaxation monitor for muscle relaxation monitoring, and administer neostigmine+atropine and sugammadex to block residual muscle relaxation drugs after surgery. The incidence rates of PONV and severity, the appearance of anesthesia, and the correlation between PONV and postoperative complications were recorded in both groups during five periods after surgery: 0-0.5 hours (T1),>0.5-2.0 hours(T2),>2.0-6.0 hours (T3),>6.0-12.0 hours (T4) and >12.0-24.0 hours (T5). Group comparisons of quantitative data were performed by the independent sample t-test, and categorical data was performed by the χ2 or rank sum test. Results: A total of 66 patients were included in the study, including 37 males and 29 female, aged (59.3±15.4) years (range: 18 to 77 years). The incidence rates of PONV of 33 patients in group S at different time periods of T1, T2, T3, T4, and T5 after surgery were respectively 27.3%(9/33),30.3%(10/33),12.1%(4/33),3.0%(1/33),0(0/33),and the incidence rates of PONV of 33 patients in the group N at different time periods of T1, T2, T3, T4 and T5 after surgery were respectively 36.4%(12/33),36.4%(12/33),33.3%(11/33),6.1%(2/33) and 0(0/33).The incidence of PONV was lower in the group S only in the T3 period after reversal than in the group N (χ2=4.227, P=0.040).However, there was no statistically significant difference in the incidence of PONV between the two groups of patients in other periods (all P>0.05). The recovery time for spontaneous breathing in patients in group S was (7.7±1.4) minutes, the extubation time was (12.4±5.3) minutes, and the safe exit time for anesthesia recovery was (12.3±3.4) minutes; the N groups were (13.9±2.0) minutes, (18.2±6.0) minutes, and (18.6±5.2) minutes, respectively; three time periods in group S were shorter than those in group N, and the differences were statistically significant (all P<0.05). The results regarding the occurrence of complications in patients with different levels of PONV at different time intervals after surgery in the two groups were as follows: in the T3 time period of group N, a significant difference was observed only in the occurrence of postoperative complications among patients with different levels of PONV (χ2=24.786, P<0.01). However, in the T4 time period, significant differences were found in the occurrence of postoperative complications among both the same level and different level PONV patients (χ2=15.435, 15.435, both P<0.01). Significant differences were also observed in the occurrence of postoperative complications among the same level and different level PONV patients in both the T3 and T4 time periods of group S (all P<0.01). Conclusion: Sugammadex can be used to reverse muscle relaxation in patients undergoing intracranial aneurysm intervention surgery,and it does not have a significant impact on the incidence of PONV, it can also optimize the quality of anesthesia recovery and reduce the incidence of complications after intracranial aneurysm embolization surgery.

[Association between clinical phenotypes of hypertrophic cardiomyopathy and Ca2+ gene variation gene variation].

Objective: To observe the association between clinical phenotypes of hypertrophic cardiomyopathy (HCM) patients and a rare calcium channel and regulatory gene variation (Ca2+ gene variation) and to compare clinical phenotypes of HCM patients with Ca2+ gene variation, a single sarcomere gene variation and without gene variation and to explore the influence of rare Ca2+ gene variation on the clinical phenotypes of HCM. Methods: Eight hundred forty-two non-related adult HCM patients diagnosed for the first time in Xijing Hospital from 2013 to 2019 were enrolled in this study. All patients underwent exon analyses of 96 hereditary cardiac disease-related genes. Patients with diabetes mellitus, coronary artery disease, post alcohol septal ablation or septal myectomy, and patients who carried sarcomere gene variation of uncertain significance or carried>1 sarcomere gene variation or carried>1 Ca2+ gene variation, with HCM pseudophenotype or carrier of ion channel gene variations other than Ca2+ based on the genetic test results were excluded. Patients were divided into gene negative group (no sarcomere or Ca2+ gene variants), sarcomere gene variation group (only 1 sarcomere gene variant) and Ca2+ gene variant group (only 1 Ca2+ gene variant). Baseline data, echocardiography and electrocardiogram data were collected for analysis. Results: A total of 346 patients were enrolled, including 170 patients without gene variation (gene negative group), 154 patients with a single sarcomere gene variation (sarcomere gene variation group) and 22 patients with a single rare Ca2+ gene variation (Ca2+ gene variation group). Compared with gene negative group, patients in Ca2+ gene variation group had higher blood pressure and higher percentage of family history of HCM and sudden cardiac death (P<0.05); echocardiographic results showed that patients in Ca2+ gene variation group had thicker ventricular septum ((23.5±5.8) mm vs. (22.3±5.7) mm, P<0.05); electrocardiographic results showed that patients in Ca2+ gene variation group had prolonged QT interval ((416.6±23.1) ms vs. (400.6±47.2) ms, P<0.05) and higher RV5+SV1 ((4.51±2.26) mv vs. (3.50±1.65) mv, P<0.05). Compared with sarcomere gene variation group, patients in Ca2+ gene variation group had later onset age and higher blood pressure (P<0.05); echocardiographic results showed that there was no significant difference in ventricular septal thickness between two groups; patients in Ca2+ gene variation group had lower percentage of left ventricular outflow tract pressure gradient>30 mmHg (1 mmHg=0.133 kPa, 22.8% vs. 48.1%, P<0.05) and the lower early diastolic peak velocity of the mitral valve inflow/early diastolic peak velocity of the mitral valve annulus (E/e') ratio ((13.0±2.5) vs. (15.9±4.2), P<0.05); patients in Ca2+ gene variation group had prolonged QT interval ((416.6±23.1) ms vs. (399.0±43.0) ms, P<0.05) and lower percentage of ST segment depression (9.1% vs. 40.3%, P<0.05). Conclusion: Compared with gene negative group, the clinical phenotype of HCM is more severe in patients with rare Ca2+ gene variation; compared with patients with sarcomere gene variation, the clinical phenotype of HCM is milder in patients with rare Ca2+ gene variation.

[Features of the state of health, including physical development, of adolescent girls living in the middle and high mountains of the Kyrgyz Republic].

Adolescent girls aged 15-18 are in an active process of growth and development, as evidenced by the dynamics of changes in height and weight indicators. Low values of average growth indicators were determined among girls in Batken, on average 2 cm less than the average indicators of girls in Bishkek, however, the statistical analysis performed did not confirm the reliability of these differences. In 84.3% of the surveyed adolescent girls living in Naryn, iron deficiency anemia was detected. Kidney and urinary tract diseases (31.4%) took the first place in the structure of diseases among girls in Batken. Diffuse enlargement of the thyroid gland was found in 13% of women living in highlands. Inflammatory diseases of the genitourinary system are two or more times more common among girls in the middle and high mountains than in Bishkek: vulvitis in 8.7-11.4% of cases against 4.1% of cases, urogenital diseases in 6.5-17.4 versus 3.9 respectively. This indicates the need to introduce specific preventive programs for girls living in the middle and high mountains.

Observation of Non-Markovian Spin Dynamics in a Jaynes-Cummings-Hubbard Model Using a Trapped-Ion Quantum Simulator.

The Jaynes-Cummings-Hubbard (JCH) model is a fundamental many-body model for light-matter interaction. As a leading platform for quantum simulation, the trapped ion system has realized the JCH model for two to three ions. Here, we report the quantum simulation of the JCH model using up to 32 ions. We verify the simulation results even for large ion numbers by engineering low excitations and thus low effective dimensions; then we extend to 32 excitations for an effective dimension of 2^{77}, which is difficult for classical computers. By regarding the phonon modes as baths, we explore Markovian or non-Markovian spin dynamics in different parameter regimes of the JCH model, similar to quantum emitters in a structured photonic environment. We further examine the dependence of the non-Markovian dynamics on the effective Hilbert space dimension. Our Letter demonstrates the trapped ion system as a powerful quantum simulator for many-body physics and open quantum systems.

Experimental Realization of the Rabi-Hubbard Model with Trapped Ions.

Quantum simulation provides important tools in studying strongly correlated many-body systems with controllable parameters. As a hybrid of two fundamental models in quantum optics and in condensed matter physics, the Rabi-Hubbard model demonstrates rich physics through the competition between local spin-boson interactions and long-range boson hopping. Here, we report an experimental realization of the Rabi-Hubbard model using up to 16 trapped ions and present a controlled study of its equilibrium properties and quantum dynamics. We observe the ground-state quantum phase transition by slowly quenching the coupling strength, and measure the quantum dynamical evolution in various parameter regimes. With the magnetization and the spin-spin correlation as probes, we verify the prediction of the model Hamiltonian by comparing theoretical results in small system sizes with experimental observations. For larger-size systems of 16 ions and 16 phonon modes, the effective Hilbert space dimension exceeds 2^{57}, whose dynamics is intractable for classical supercomputers.

Quantum Simulation of the Two-Dimensional Weyl Equation in a Magnetic Field.

Quantum simulation of 1D relativistic quantum mechanics has been achieved in well-controlled systems like trapped ions, but properties like spin dynamics and response to external magnetic fields that appear only in higher dimensions remain unexplored. Here we simulate the dynamics of a 2D Weyl particle. We show the linear dispersion relation of the free particle and the discrete Landau levels in a magnetic field, and we explicitly measure the spatial and spin dynamics from which the conservation of helicity and properties of antiparticles can be verified. Our work extends the application of an ion trap quantum simulator in particle physics with the additional spatial and spin degrees of freedom.

Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study.

OBJECTIVE: Pembrolizumab demonstrated a clinically meaningful objective response rate in patients with previously treated, advanced MSI-H/dMMR endometrial cancer in the multicohort phase 2 KEYNOTE-158 study (ClinicalTrials.gov, NCT02628067). We present health-related quality of life (HRQoL) results for these patients. METHODS: This analysis included patients from cohorts D (endometrial cancer with any MSI status) and K (any MSI-H/dMMR solid tumor except colorectal) who had previously treated, advanced MSI-H/dMMR endometrial cancer. Patients received pembrolizumab 200 mg Q3W for 35 cycles. EORTC QLQ-C30 and EQ-5D-3L questionnaires were administered at baseline, at regular intervals during treatment, and 30 days after treatment discontinuation. Pre-specified exploratory analyses included changes from baseline to week 9 in QLQ-C30 global health status (GHS)/QoL and EQ-5D-3L visual analog scale (VAS) score for all patients and by best overall response. RESULTS: 84 of 90 enrolled patients completed ≥1 HRQoL questionnaire and were included in the analysis. QLQ-C30 and EQ-5D-3L compliance rates were 90% and 94%, respectively, at baseline, and 92% and 93% at week 9. Mean (95% CI) QLQ-C30 GHS/QoL scores improved from baseline to week 9 by 6.08 (0.71-11.46) points in the overall population, with greater improvement in patients who achieved complete or partial response (11.67 [5.33-18.00]-point increase). Mean (95% CI) EQ-5D-3L VAS scores improved by 6.00 (2.25-9.75) points in the overall population and 9.11 (5.24-12.98) points in patients with CR/PR. CONCLUSIONS: Pembrolizumab maintained or improved HRQoL in patients with previously treated, advanced MSI-H/dMMR endometrial cancer, further supporting efficacy and safety results from KEYNOTE-158 and pembrolizumab use in this setting.

[Application of multiple post labeling delay time arterial spin labeling imaging in the quantitative blood flow analysis of brain subregions in healthy adults].

Objective: To explore the normal ranges of perfusion parameters between cerebral hemisphere, cerebellar hemisphere and brain anatomical subregions (56 pairs) in different gender and age groups with multiple post labeling delay time (Multi-PLD) arterial spin labeling (ASL) imaging. Methods: From November 2020 to December 2020, 42 healthy adult volunteers (Male 25, Female 17) were recruited to perform 7 PLD ASL imaging, including 21 young adults (15 males and 6 females, aged 23-35 years) and 21 seniors (10 males and 11 females, aged 36-74 years). The data was processed offline by Cereflow software to obtain arterial arrival time (ATT) and corrected cerebral blood flow (CBF) and cerebral blood volume (CBV) perfusion parameters. SimpleITK standardization function was used to standardize the calculated perfusion image according to the anatomical automatic labeling (AAL) template. Therefore, CBF, ATT, CBV perfusion values of brain subregions were obtained. Paired samples t test, Wilcoxon rank sum test, independent samples t test and Mann-Whitney U test were used to compare the differences of perfusion parameters in the cerebral hemisphere, the cerebellar hemisphere, brain subregions depending on side, gender and age. Pearson correlation analysis was used to compare the correlations of perfusion parameters with age. Results: CBF in 62.5% (35/56) subregions and CBV in 44.6% (25/56) subregions were higher in right side than those in left side. ATT in most brain anatomical subregions (16/56) were higher in left side. The CBF [(35.30±8.31) vs. (34.34±7.53) ml·100g-1·min-1, P=0.021], CBV [(0.47±0.11) vs. (0.45±0.09) ml/100g, P<0.001], ATT [(1.30±0.10) vs. (1.24±0.11) s, P<0.001] in left cerebellar hemisphere were higher than that of right side. The CBF (28/56) of cerebral hemisphere, cerebellar hemisphere and brain subregions was higher in females than that in males, while ATT in 83.9% (47/56) subregions was lower than that in males (all P<0.05). CBV in female subjects was higher only in 5 brain regions (superior occipital gyrus, middle occipital gyrus, inferior occipital gyrus, superior parietal gyrus and cerebelum_7b) (all P<0.05). In young subjects, CBF in 44.6% (25/56) subregions and CBV in 33.9% (19/56) subregions were higher than those in the senior group (all P<0.05). The ATT in most subregions in young group were lower than those in senior group, but the difference was statistically significant only in rectus gyrus (P=0.026) and paracentral lobule (P=0.006). The CBF (r=-0.430, P=0.005) and CBV (r=-0.327, P=0.035) of cerebral hemisphere were negatively correlated with age. The CBF (24/25, r range:-0.497 --0.343, all P<0.05) and CBV (16/19, r range:-0.474 --0.322, all P<0.05) in most subregions were negatively correlated with age, while ATT was positively correlated (gyrus rectus: r=0.311, P=0.045; paracentral lobule: r=0.392, P=0.010). Conclusions: Multi-PLD ASL imaging could be applied for quantitative analysis of brain perfusion. The perfusion parameters of anatomical subregions are different depending on side, gender, and age.

[Laterally extended endopelvic resection for advanced or recurrent gynecological malignancies: clinicopathological analysis].

To explore the feasibility and safety of laterally extended endopelvic resection (LEER) for advanced and recurrent gynecological malignancies with pelvic sidewall involvement and to evaluate this therapeutic potential of this novel salvage treatment. The clinicopathological data of 5 patients with gynecological malignancies who received laparoscopic LEER treatment in Obstetrics and Gynecology Hospital of Fudan University from January 2019 to September 2021 were retrospectively analyzed, including 3 cases of recurrent cervical cancer, 1 case of primary advanced endometrial cancer and 1 case of pelvic aggressive angiomyxoma. Among them, four patients achieved complete resection (R0) with a negative resection margin; the other patient with recurrent cervical cancer did not complete surgery because of the extreme risk of continuing surgery. The median operation time was 345 (225-482) minutes and the median blood loss was approximately 300 (200-600) ml. Complications occurred in three patients, including lymphocysts, urinary tract infections, and deep venous thrombosis of the lower extremities. Within a median follow-up time of 283 (128-715) days, 4 patients survived tumor-free, and 1 patient died. The high rate of complete resection (R0) and the encouraging oncological outcomes suggest that LEER may be an alternative treatment option for patients with advanced and recurrent gynecological malignancies involving the pelvic sidewall.

Experimental Realization of Multi-ion Sympathetic Cooling on a Trapped Ion Crystal.

Trapped ions are one of the leading platforms in quantum information science. For quantum computing with large circuit depth and quantum simulation with long evolution time, it is of crucial importance to cool large ion crystals at runtime without affecting the internal states of the computational qubits, thus the necessity of sympathetic cooling. Here, we report multi-ion sympathetic cooling on a long ion chain using a narrow cooling beam focused on two adjacent ions, and optimize the choice of the cooling ions according to the collective oscillation modes of the chain. We show that, by cooling a small fraction of ions, cooling effects close to the global Doppler cooling limit can be achieved. This experiment therefore demonstrates an important enabling step for quantum information processing with large ion crystals.

[The role and mechanism of NORAD in proliferation and apoptosis of mouse mesangial cells induced by high glucose].

Objective: To uncover the role and mechanism of non-coding RNA-activated by DNA damage (NORAD) in proliferation and apoptosis of mouse mesangial cells induced by high glucose. Methods: SV40-MES-13 cells were divided into high glucose group and low glucose group according to the concentration of glucose in the culture medium. After 24 hours of treatment, SV40-MES-13 cells were transfected with si-NORAD and si-Toll-like receptor (TLR4), and real-time fluorescence quantitative PCR (qRT-PCR) was used to detect the expression of NORAD and TLR4. NORAD, TLR4 overexpression plasmids and small interfering RNA were transfected into SV40-MES-13 cells respectively. Cell counting kit (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay and flow cytometry were performed to determine the results of cell proliferation and apoptosis. Luciferase activity and their mRNA levels were detected after cotransfection of pGL3-NORAD WT and miR-520h mimics or pGL3-TLR4 WT and miR-520h mimics. After cotransfection of si-NORAD and miR-520h inhibitors, TLR4 overexpression plasmids and miR-520h mimics, and cotransfection of si-TLR4 and miR-520h inhibitors, the levels of NORAD, miR-520h and TLR4, as well as cell proliferation were detected to verify the regulatory relationship among them. Results: NORAD and TLR4 were upregulated in SV40-MES-13 cells in high glucose group (1.65±0.08 vs 1.00±0.06, P=0.003; 1.96±0.09 vs 1.01±0.07, P=0.001). Overexpression of NORAD and TLR4 promoted the proliferative ability (1.34±0.04 vs 0.85±0.04, P=0.001; 1.33±0.02 vs 0.82±0.03, P<0.001) and inhibited the apoptosis in SV40-MES-13 cells (0.45±0.03 vs 0.94±0.06, P=0.001; 0.51±0.05 vs 0.99±0.03, P=0.001). The dual-luciferase reporter gene assay showed that miR-520h was confirmed to bind to NORAD and TLR4. The expression of NORAD and miR-520h affected each other, and miR-520h mimics reduced the expression of TLR4. The expression of TLR4 in cotransfected NORAD small interference RNA and miR-520h inhibitor was higher than that in NORAD small interference RNA alone (0.74±0.03 vs 0.55±0.03, P=0.014). Cotransfection of miR-520h mimics and TLR4 overexpression plasmids increased cell proliferation compared with miR-520h mimics alone (0.73±0.01 vs 0.61±0.02, P=0.007). Cotransfection of miR-520h inhibitors and TLR4 small interference RNA reduced cell proliferation compared with miR-520h inhibitors alone (1.31±0.04 vs 1.55±0.04, P=0.013). Conclusions: The regulatory loop NORAD/miR-520h/TLR4 promotes the proliferative ability and inhibits apoptosis in glomerular mesangial cells induced by high glucose.

[The value of intraoperative monitoring of cerebral oxygen saturation on postoperative cognitive function in elderly patients undergoing cardiac surgery].

Objective: To investigate the effect of cerebral oxygen saturation (rSO2) on postoperative cognitive dysfunction (POCD) in elderly patients undergoing cardiac anesthesia. Methods: Retrospective analysis was performed on 113 elderly patients (age 65-89) underwent cardiac surgery in Peking University International Hospital from June 2017 to December 2019, 67 male and 46 female patients were included. All operations were performed under general anesthesia, cardiopulmonary bypass, rSO2 and other relevant monitoring. Statistical analysis of the elderly patients with complications, cardiac surgery history, time of CPB, baseline value of rSO2 (rSO2 baseline), lowest intraoperative value of rSO2 (rSO2 min), time of operation, length of stay in CCU, length of hospital stay; Preoperative and postoperative NSE values; number of postoperative POCD and postoperative deaths were recorded. All data were obtained from the medical records system and anesthesia information system of Peking University International Hospital and risk factors related to POCD were analyzed by Logistic regression. Results: POCD occurred in 19 patients (16.8%), and also, intraoperative rSO2 decreased by more than 30% over the baseline. The variance of rSO2 (rSO2 baseline-rSO2 min) in POCD group and non-POCD group was (18.0±2.7) and (6.6±2.3), the variance of NSE (NSE after surgery-NSE before surgery) was (31.3±9.7) and (9.5±3.0) µg/L, respectively. The differences were statistically significant (t=18.35, 17.70, all P<0.05). rSO2 variability was positively correlated with NSE variability (r=0.697, P<0.05). Logistic regression analysis showed that the variation degree of rSO2 [OR(95%CI)was 0.374(0.059-1.895)]、 patients combined with diabetes mellitus [OR(95%CI)was 0.493 (0.041-1.812), history of stroke [OR(95%CI)was 0.325 (0.084-0.917)] and atrial fibrillation [OR(95%CI)was 0.176 (0.091-0.943)] were the risk factors for POCD. Conclusion: POCD can be predicted by monitoring the decline range of rSO2 intraoperatively. rSO2 is recommended as a routine monitoring item for elderly patients undergoing cardiac surgery.