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Metasurfaces have developed rapidly with the extraordinary electromagnetic properties in electromagnetic wave control in recent years. However, the conventional metasurfaces design based on the Method of Moments (MOM), Finite Element Method (FEM) and Finite Integration Technique (FIT) are still time-consuming and demand significant computation. In this paper, we proposed a polynomial regression of standardized K-nearest neighbor algorithm (PS-KNN). The trained model shows an excellent prediction ability, the means square error (MSE) of the forward model is only 3.463 × 10−6. We further report a reverse model based on forwarding prediction, which automatically constructs and optimizes the meta-atom by standardizing the electromagnetic properties (amplitude, phase, etc.) of the metasurface as the input of characteristic parameters. The MSE of the reverse model is 1.589 × 10−3. Finally, we cascade the two models, and predicted successfully eight meta-atoms by the closed-loop network and arrange them into a focused array. The results demonstrate the algorithm model avoids extensive modeling operations and numerical calculation and over 300 times faster than traditional electromagnetic simulation software. It offers a novel effective methodology to accelerate the on-demand design of complex metasurfaces and optical structures.

C1q tumor necrosis factor (TNF)-related protein 9 (CTRP9) is a novel member of the C1q/TNF superfamily. According to our previous review, CTRP9 plays a vital role in the process of cardiovascular diseases, including regulating energy metabolism, modulating vasomotion, protecting endothelial cells, inhibiting platelet activation, inhibiting pathological vascular remodeling, stabilizing atherosclerotic plaques, and protecting the heart. We proposed that CTRP9 could play multiple positive and beneficial roles in vascular lesions in ischemic stroke (IS). Here, we aimed to study the relationship between serum CTRP9 and the etiology, severity, and prognosis of IS patients. A total of 302 patients with IS and 173 non-stroke controls were selected from the same hospital, and all patients with IS were followed up 12 months after stroke onset. Stroke etiology was classified according to the Trial of ORG 10172 in Acute Stroke Treatment classification. Symptomatic severity was determined using the National Institutes of Health Stroke Scale score. The lesion volume of acute cerebral ischemia was measured using magnetic resonance imaging (MRI). The unfavorable functional outcome was a combination of death or major disability 12 months after stroke onset. Receiver operating characteristic (ROC) curves and integrated discrimination improvement (IDI) and net reclassification improvement (NRI) statistics were applied in the statistical analysis. We found that serum CTRP9 levels and the ratios of CTRP9/total cholesterol (TC), CTRP9/triglyceride (TG), CTRP9/low-density lipoprotein cholesterol (LDL-C), and CTRP9/high-density lipoprotein cholesterol (HDL-C) were associated with the presence of IS. Moreover, the serum CTRP9 concentration was positively associated with the severity of IS. Incorporation of CTRP9/LDL-C levels into a fully adjusted model for IS-cardioembolic (CE) improved discrimination and calibration, and significantly improved reclassification. In addition, CTRP9 was a predictor of unfavorable functional outcomes. All the findings indicated that serum CTRP9 could be a promising blood-derived biomarker for the early evaluation and prognosis assessment of IS. Chinese Clinical Trial Registry, ChiCTR1800020330.

Objectives: FDA approval of PD-L1 IHC 22C3 pharmDx for use as an aid in identifying head and neck squamous cell carcinoma (HNSCC) patients for treatment with pembrolizumab was based on the results of rigorous analytical and clinical validation testing. Methods: For the HNSCC indication, the device was validated at Agilent Technologies on the performance of sensitivity and precision using the Combined Positive Score (CPS) ≥ 1 and CPS ≥ 20 cutoffs; external validation studies were performed at three external laboratories. CPS ≥ 1 and CPS ≥ 20 cutoffs were evaluated in KEYNOTE-048, a phase 3 clinical trial. Results: Analytical validation studies supporting the companion diagnostic indication (CPS ≥ 1) achieved point estimates of > 85% for negative, positive, and overall percent agreement. Clinical validation studies show that HNSCC patients treated with pembrolizumab as a single agent had an overall survival (OS) of 12.3 months at CPS ≥ 1 (95% CI, 10.8-14.9) compared with patients receiving cetuximab, platinum, and 5-fluorouracil (CPS ≥ 1 OS of 10.3 months (95% CI, 9.0-11.5)). Conclusion: Analytical and clinical validation studies demonstrate that PD-L1 IHC 22C3 pharmDx is a precise companion diagnostic assay, allowing for selection of eligible HNSCC patients for treatment with pembrolizumab.

PURPOSE: The sperm DNA fragmentation index (DFI) was quantitatively measured and its relationship with age, semen quality, and infertility conditions was investigated. METHODS: Semen routine test and sperm DFI were performed in 2760 infertile male and 2354 male whose spouse experienced at least one unexplained miscarriage to analyze the correlation between sperm DNA damage, semen routine parameters, and age. RESULTS: Sperm DFI was significantly lower from patients whose wife experienced unexplained miscarriage compared to infertility males (p = 0.000). An inverse correlation between sperm DFI and sperm progressive motility was observed (r(s) = − 0.465, p = 0.000) and sperm DFI was positively correlated with age (r(s) = 0.255, p = 0.000). However, the correlation between sperm DFI and sperm concentration, semen volume, total sperm count, and motile sperm count were not proved. CONCLUSIONS: Sperm DFI is an important indicator for evaluating the quality of semen. Sperm DNA integrity testing is preferentially recommended to those who have decreased sperm progressive motility, especially older men. An integrative analysis of sperm DFI, sperm progressive motility, age, and infertility conditions can provide a more comprehensive assessment of male fertility.

Background: Alport syndrome (AS) is a hereditary renal basement membrane disease that can lead to end-stage renal disease in young adults. It can be diagnosed by genetic analysis, being mostly caused by mutations in COL4A3, COL­4A4, and COL4A5. To date, there is no radical cure for this disease. Objectives: The aim of this study was to avoid the transmission of AS within an affected family by selecting healthy embryos for uterine transfer. The embryos were identified by preimplantation genetic testing for monogenic disorders (PGT-M). Methods: We used next-generation sequencing (NGS) to identify mutations in the proband and his parents. The results of NGS were confirmed by Sanger sequencing. Targeted NGS combined with targeted single-nucleotide polymorphism haplotyping was used for the in vitro identification of COL4A5 mutations in human embryos to prevent their intergenerational transmission. Results: The c.349_359delGGACCTCAAGG and c.360_361insTGC mutations in COL4A5 were identified in a family affected by X-linked AS. Whole-genome sequencing by NGS with targeted haplotyping was performed on biopsied trophectoderm cells. A healthy baby was born after transfer of a single freeze-thawed blastocyst. Conclusions: The use of targeted NGS for identifying diagnostic markers combined with targeted haplotyping is an easy and efficient PGT-M method for preventing intergenerational transmission of AS.

This paper presents a secure communication access authentication technology for power wireless private network. At the physical layer, the device is identified based on physical radio frequency fingerprint authentication, which improves the security of device access. At the same time, the idea of distributed authentication is used to reduce the device authentication pressure of the gateway on the core network side and improve the speed of access device authentication.

Objective The aim of this study was to validate the results of two Emanuel syndromes detected by non-invasive prenatal screening (NIPS) screening using invasive methods, providing clinical performance of NIPS on chromosome microduplication detection. Methods NIPS was performed to diagnose the Emanuel syndrome. Amniocentesis or cordocentesis was performed to confirm the positive screening result of Emanuel syndrome cases. Fetal sample was detected by karyotyping, fluorescence in situ hybridization (FISH), and single nucleotide polymorphism array (SNP Array). Parental karyotyping and FISH were also carried out. Results Two cases with chromosomal abnormalities of 11q23.3q25 and 22q11.1q11.21 were found by NIPS. Chromosomal karyotyping showed that the two fetuses each have a small supernumerary marker chromosome (sSMC), SNP Array further demonstrated double duplications approximately 18 Mb in 11q23.3q25 and 3 Mb in 22q11.1q11.21. FISH confirmed that the small supernumerary marker chromosome (sSMC) was ish der(22)t(11;22) (TUPLE1+, ARSA-). Ultrasound scan and MRI showed some structure malformations in two fetuses. The two mothers were found to be a balanced carrier: 46,XX, t(11;22)(q23.3;q11.2). Conclusion NIPS could effectively identify Emanuel syndrome, which may indicate risks of a parent being a balanced rearrangement carrier. The followed confirmation test for positive sample is necessary and ensures the accuracy of the diagnosis.

Study Objective To evaluate in vitro fertility (IVF) outcomes of proximal fallopian tube embolization by interventional radiology compared with laparoscopic salpingectomy before embryo transfer (ET) in patients with hydrosalpinx. Design A single-center, off-label, nonrandomized prospective study. Setting Academic university hospital. Patients One hundred and fifty-five patients with hydrosalpinx were identified on ultrasound or hysterosalpingography desiring IVF between April 2016 and December 2017. Interventions Radiologically guided tubal occlusion with embolization microcoils (RTO-EM) and laparoscopic salpingectomy. Measurements and Main Results Of 155 analyzed patients, 42 were treated with RTO-EM and 113 with laparoscopic salpingectomy. The subsequent IVF outcomes including implantation, clinical pregnancy, miscarriage, ectopic pregnancy, and ongoing pregnancy (fetal heartbeat on ultrasound beyond 10 weeks) were compared between the two groups. Implantation and clinical pregnancy per ET cycle in the RTO-EM group were similar to that of the salpingectomy group (26.7% vs. 30.2%, p = .511, and 39.0% vs. 45.3%, p = .400, respectively), with a similar miscarriage rate. There was no statistically significant difference in ectopic pregnancies between the two groups. Moreover, no difference was detected in ongoing pregnancy per cycle between the two groups (33.9% vs. 41.2%, p = .324). The ongoing-pregnancy rate per patient following RTO-EM was 47.6% (20 of 42) compared with 61.9% (70 of 113) following salpingectomy (p = .108; odds ratio: 0.56; 95% confidence interval, 0.27–1.14). Conclusion Pregnancy in the RTO-EM group was comparable to the salpingectomy group in patients with hydrosalpinx prior to ET treatment. Radiologically guided tubal occlusion with embolization microcoils may be an alternative to salpingectomy for patients with hydrosalpinx planning IVF-ET.

This article summarizes the highlights from the 7th China Bioanalysis Forum (CBF) Annual Conference in June 2019. The annual CBF conference provided a great platform for the Chinese bioanalytical community to discuss the current bioanalytical regulations, share challenges and experiences. With rapid growth of the pharma industry in China in the past decade and advancement in regulatory reform, the overall science and quality of regulated bioanalysis have now reached international standards. The CBF continues its efforts in promoting scientific excellence, quality and regulatory compliance in China and facilitating close collaboration with the international bioanalysis community.

Most cases of small cell lung cancer (SCLC) are diagnosed at an advanced stage. The objective of this study was to investigate patient characteristics, survival, chemotherapy treatments, and health care use after a diagnosis of advanced SCLC in subjects enrolled in a health system network. This was a retrospective cohort study of patients aged ≥ 18 years who either were diagnosed with stage III/IV SCLC or who progressed to advanced SCLC during the study period (2005–2015). Patients identified from the Indiana State Cancer Registry and the Indiana Network for Patient Care were followed from their advanced diagnosis index date until the earliest date of the last visit, death, or the end of the study period. Patient characteristics, survival, chemotherapy regimens, associated health care visits, and durations of treatment were reported. Time-to-event analyses were performed using the Kaplan-Meier method. A total of 498 patients with advanced SCLC were identified, of whom 429 were newly diagnosed with advanced disease and 69 progressed to advanced disease during the study period. Median survival from the index diagnosis date was 13.2 months. First-line (1L) chemotherapy was received by 464 (93.2%) patients, most commonly carboplatin/etoposide, received by 213 (45.9%) patients, followed by cisplatin/etoposide (20.7%). Ninety-five (20.5%) patients progressed to second-line (2L) chemotherapy, where topotecan monotherapy (20.0%) was the most common regimen, followed by carboplatin/etoposide (14.7%). Median survival was 10.1 months from 1L initiation and 7.7 months from 2L initiation. Patients in a regional health system network diagnosed with advanced SCLC were treated with chemotherapy regimens similar to those in earlier reports based on SEER-Medicare data. Survival of patients with advanced SCLC was poor, illustrating the lack of progress over several decades in the treatment of this lethal disease and highlighting the need for improved treatments.

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.

Objectives: The aim of this study was to investigate the efficacy of combination therapy of caspofungin and TMP/SMZ (trimethoprim/sulfamethoxazole) in moderate to severe pneumocystis jirovecii pneumonia (PJP) in patients without human immunodeficiency virus infection (HIV) and the relationship between therapeutic effect and plasma (1, 3) Beta-d-Glucan (BDG) levels. Methods: We retrospectively reviewed HIV-negative patients with PJP diagnosed in our department, who were treated with combination therapy of caspofungin and TMP/SMZ or monotherapy of TMP/SMZ during a six and a half year period. Results: A total of 126 moderate to severe PJP patients were enrolled in the study. In the multivariate analysis, low lymphocyte counts, high serum lactate dehydrogenase levels at the diagnosis of PJP and progression to shock were significant risk factors for death. In all patients, there was no significant difference in risk of death at 3 months. In the group of BDG ≥ 800 pg/m, patients receiving combination therapy was associated with a significantly decreased risk of death at 3 months, whereas in the group of BDG

We studied patients with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) associated with or without lymphoma and measured risk factors suggestive of an underlying lymphoma and follow-up outcomes.CLIPPERS patients associated with or without lymphoma were included into this study. Clinical presentations were documented, risk factors suggestive of an underlying lymphoma were tested, and prognostic differences in terms of death were compared.Ten patients had a diagnosis of CLIPPERS associated with lymphoma, with 6 B-cell non-Hodgkin lymphoma, 2 T-cell non-Hodgkin lymphoma and 2 Hodgkin lymphoma. Using multivariate logistic analysis, the following 3 independent risk factors were found to be related to a final diagnosis of lymphoma: hyperreflexia (HR 16.56; 95% CI 1.03-265.29; p = 0.032), elevated protein in CSF (HR 11.59; 95% CI 1.24-108.39; p = 0.047), and recurrences between 2 months and 1 year after treatment (HR 29.27; 95% CI 2.09-409.58; p = 0.012). The model calibration was satisfactory (p = 0.392 with the Hosmer-Lemeshow test), and the discrimination power was good (area under the receiver operating characteristic curve 0.921; p 0.001, 95% CI 0.826-1.000). Patients with CLIPPERS associated with lymphoma had higher mortality rate and lymphoma was a significant predictor of total mortality (HR 0.040; 95% CI 0.006-0.262; p = 0.001).Hyperreflexia, elevated protein in CSF and recurrences between 2 months and 1 year after treatment are risk factors suggesting an underlying lymphoma. Relapses during high-dose steroids maintenance therapy can be indicative of lymphoma, too. Patients having CLIPPERS associated with lymphoma have a worse prognosis than those without lymphoma.

Aim To share the experience of local aspiration and instillation of methotrexate (MTX) to selective reduction of live interstitial pregnancy and to evaluate its clinical effect and the outcome of intrauterine pregnancy. Methods Twelve patients with heterotopic interstitial pregnancy were enrolled at Women's Hospital, Zhejiang University School of Medicine, from 2006 to 2017. All the pregnancies were derived from assisted reproductive technology (ART). The transvaginal aspiration to interstitial pregnancy sac and local instillation of MTX (range from 12.5 to 30 mg) were performed for the patients under ultrasound-guide. The prognosis and pregnancy outcomes were followed up. Results No severe side effects of medical treatment were observed in all patients. Three cases underwent subsequent laparotomy cornual resection, and no perioperative complications were found in these three patients. Twelve patients gave birth to 13 healthy infants without congenital anomalies. The average birth weight and gestational age was 2837 g (SD ± 605 g) and 36.8 weeks (SD ± 2.4 weeks). No growth anomalies and mental retardation were observed in live birth offspring. Conclusion The transvaginal ultrasound-guided aspiration and injection of MTX might be a feasible alternative treatment for heterotopic interstitial pregnancy when vital signs of patients are stable.

In this paper, the case of two adjacent frame structures is studied by establishing a mechanical model based on the transfer matrix method of multibody system (MS-TMM). The transfer matrices of the related elements and total transfer equation are deduced, combining with the Hertz-damp mode. The pounding process of two adjacent frame structures is calculated by compiling the relevant MATLAB program during severe ground motions. The results of the study indicate that the maximum error of the peak pounding forces and the peak displacements at the top of the frame structure obtained by the MS-TMM and ANSYS are 6.22% and 9.86%, respectively. Comparing the calculation time by ANSYS and MS-TMM, it shows that the computation efficiency increases obviously by using the MS-TMM. The pounding mainly occurs at the top of the short structure; meanwhile, multiple pounding at the same time may occur when the separation gap is small. The parametric investigation has led to the conclusion that the pounding force, the number of poundings, the moment of pounding, and the structural displacement are sensitive to the change of the seismic peak acceleration and the separation gap size.

Although most children conceived by assisted reproductive technology (ART) are healthy, there are concerns regarding the potential long-term health implications of ART. It has been reported that alterations in insulin-induced gene (INSIG), sterol regulatory element binding protein (SREBP), and SREBP cleavage-activating protein (SCAP) are involved in cardiometabolic changes. Thus, ART mouse models were established via in vitro fertilization (IVF), intracytoplasmic injection (ICSI), and in vitro oocyte maturation (IVM). A significantly higher systolic blood pressure was identified in the IVM aged female mice. In addition, abnormalities in the blood lipids and liver function were identified in the IVM- or ICSI-conceived elderly mice. Furthermore, ICSI or IVM significantly affected the hepatic expression and methylation of INSIG-SCAP-SREBP from a young to old age. Our animal data indicated that ICSI or IVM result in a higher risk of cholesterol metabolism dysfunction in older mice, which may be associated with long-term alterations of INSIG-SCAP-SREBP.

Image encryption is an efficient visual technology to protect private images. This paper develops an image encryption algorithm utilizing the principles of the Josephus problem and the filtering technology. The encryption algorithm follows the classical diffusion and confusion structure. The principle of Josephus problem is used to shuffle the image pixels to different positions to achieve the confusion property. Using a randomly generated filter, the filtering technology can spread slight changes of the original image to all pixels of the cipher image to obtain diffusion property. The simulation results show that the developed image encryption algorithm is able to encrypt different kinds of images into cipher images with uniform distribution. The security analysis demonstrates that it has an extremely sensitive secret key, can resist various security attacks, and has a better performance than several advanced image encryption algorithms.

Cross-Border E-Commerce has been given great priority in China’s economic development, which dramatically enhances international E-trade transactions of China. However, the development mode of comprehensive pilot areas for cross-border E-commerce is still in its early testing stage and thus remains unverified. Therefore, based on on-site observation and report data analysis about China comprehensive pilot areas for cross-border E-commerce in Henan province, this paper tends to find out the main factors that affect the development performance of manufacturing enterprises located within these areas. The influence is examined with regard to five aspects: transaction size, growth space, industrial penetration, supporting environment and platform aggregation. It concludes that the main problems include such as partial laws are not suitable for the actual, low government supervision efficiency, shortage of talents, unbalanced development of cities and counties, and unclear industries of export-oriented enterprises. Finally, a strategic planning framework is tentatively proposed for local SME’s of China aiming at the promotion of their commercial development via the new mode of comprehensive pilot areas.

Objectives We analysed the peripheral blood lymphocyte subsets of human immunodeficiency virus (HIV)-negative patients infected with pneumocystis pneumonia (PCP) to determine the relationships between the levels of different types of lymphocytes and the prognosis of patients. Methods We retrospectively reviewed HIV-negative patients with PCP diagnosed in our department. All the eligible patients underwent lymphocyte subset analysis on admission. Results A total of 88 HIV-negative PCP patients were enrolled in the study. In univariate analyses, low CD4+ T cell count, low CD8+ T cell count, and low natural killer cell (NK cell) count were associated with higher in-hospital mortality. CD8+ T cell count ≤300/μL was found to be an independent risk factor for poor prognosis in multivariate logistical regression analysis (p = 0.015, OR = 11.526, 95% CI = 1.597–83.158). Although low CD4+ T cell and NK cell counts were not independent risk factors, the mortality rates of PCP patients decreased as the CD4+ T cell and NK cell counts increased. Conclusion The immune process of Pneumocystis jirovecii infection is complex but important. We propose that lymphocyte subsets could give clinicians a better understanding of patient immune status, helping with the early identification of potentially lethal infections and treatment decision making, such as adjusting the immunosuppressive regimen and choosing an appropriate patient monitoring level.

Since the birth of narrowband Internet of Things (NB-IoT), the Internet of Things (IoT) industry has made a considerable progress in the application for smart cities, smart manufacturing, and healthcare. Therefore, the number of UEs is increasing exponentially, which brings considerable pressure to the efficient resource allocation for the bandwidth and power constrained NB-IoT networks. In view of the conventional algorithms that cannot dynamically adjust resource allocation, resulting in a low resource utilization and prone to resource fragmentation, this paper proposes a double deep Q-network (DDQN)-based NB-IoT dynamic resource allocation algorithm. It first builds an NB-IoT environment model based on the real environment. Then, the DDQN algorithm interacts with the NB-IoT environment model to learn and optimize resource allocation strategies until it converges to the optimum. Finally, the simulation results show that the DDQN-based NB-IoT dynamic resource allocation algorithm is better than the traditional algorithm in the resource utilization, average transmission rate, and UE average queuing time.

The use of bisphenol A (BPA) has been substantially limited since 2010 due to its toxicity to human health. A group of bisphenol analogues that are structurally similar to BPA have been developed as the alternatives and used widely. The reproductive toxicity of these emerging chemicals has caused substantial concerns in recent years. Whether bisphenol analogues affect miscarriage, especially unexplained recurrent miscarriage (URM), remains to be explored. We conducted a hospital-based, case-control study with 1180 URM cases and 571 controls in China from 2014 to 2016. Concentrations of six bisphenol analogues (BPA, BPAF, BPAP, BPB, BPP and BPS) were measured in the urine samples collected at median intervals of 7.6 months after last miscarriage (interquartile ranges: 4.8, 14.7 months). Multiple logistic regression, Bayesian kernel machine regression (BKMR) and quantile g-computation (q-gcomp) were used to assess the relationship of bisphenol analogues with URM risk. We observed significantly higher levels of all urinary bisphenols in the cases than the controls. After controlling for potential confounders, bisphenol analogues were significantly associated with increased odds of URM in varying degrees. A dose-response pattern was observed for the associations of BPAF, BPAP and BPB quartiles with URM. The mixed exposure of six bisphenol analogues was positively associated with the risk of URM (adjusted odds ratio (aOR) = 1.25; 1.11-1.42), which was mainly driven by BPAP (60.1%), BPAF (25.1%) and BPA (14.8%). After age stratification, the risks tended to be higher in women aged 30 years or older, compared to women30 years. Our large case-control study indicates that environmental exposure to bisphenol analogues is associated with an increased risk of URM. Older women may be more vulnerable to the insult.

Aim: We evaluated the relationship between clinical and genomic characteristics and tumor mutational burden (TMB) in small cell lung cancer. Materials & methods: In a retrospective analysis of small cell lung cancer patients aged ≥18, we assessed treatment patterns and survival in relation to TMB; the association of clinical and genomic characteristics with TMB was determined by multivariate regression. High TMB (TMB-H) was defined as ≥10 mutations/megabase. Results: Among 186 patients, treatment patterns and overall survival were similar for TMB-H and non-TMB-H patients. TMB was determined for 179 patients, 41.9% of whom were TMB-H. Short variants of LRP1B, FAT3, MLL3, MED12 and NOTCH3 were significantly associated with TMB-H (p ≤ 0.01). Conclusion: Neither treatment patterns nor survival differed by TMB status.

Background Treatment with the anti–PD-1 antibody pembrolizumab has improved clinical outcomes in multiple previously treated advanced solid tumors. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity as monotherapy in patients with previously treated advanced ovarian, breast, pancreatic, and prostate cancers with BRCA1/BRCA2 mutations (BRCAm). Activity was also seen in patients with previously treated advanced solid tumors with other homologous recombination repair mutation (HRRm) and in those with ovarian cancer with homologous recombination repair deficiency (HRD) phenotype. PARP inhibitors have been found to increase interferon signaling and tumor infiltrating lymphocytes, enhancing tumor susceptibility to immune checkpoint blockade. Antitumor activity of PD-(L)1 plus PARP inhibition was found to be higher than expected with either agent alone in patients with recurrent ovarian cancer regardless of BRCAm or HRD status and in patients with BRCAm breast cancer. KEYLYNK-007 (NCT04123366) evaluates the antitumor activity and safety of olaparib in combination with pembrolizumab in patients with previously treated advanced solid tumors with HRRm and/or HRD. Methods This phase 2, nonrandomized, multicenter, open-label study will enroll approximately 300 patients aged ≥18 years with histologically/cytologically confirmed, previously treated, advanced solid tumors with HRRm and/or HRD per Lynparza HRR-HRD assay (Foundation Medicine, Inc., Cambridge, MA, USA), with an ECOG PS of 0-1. Patients will be grouped by biomarker status: subgroup 1: BRCAm; subgroup 2: HRRm without BRCAm; and subgroup 3: HRD positive without HRRm (loss of heterozygosity score ≥16 per Lynparza HRR-HRD assay). Patients will receive olaparib 300 mg twice daily + pembrolizumab 200 mg intravenously Q3W (35 cycles) until PD, unacceptable AEs, intercurrent illness, investigator decision, withdrawal of consent, or pregnancy. Tumor imaging assessment by blinded independent central review (BICR) per RECIST v1.1 or Prostate Cancer Working Group (PCWG)–modified RECIST v1.1 for prostate cancer will occur Q9W for 12 months, then Q12W until PD, start of new anticancer treatment, withdrawal of consent, pregnancy, or death. AEs will be monitored throughout the study and for 30 days after final dose (90 days for serious AEs). The primary endpoint is ORR (RECIST v1.1 or PCWG–modified RECIST version 1.1 by BICR). Secondary endpoints include duration of response (DOR) and PFS (RECIST v1.1 or PCWG–modified RECIST v1.1 by BICR), OS, and safety. Point estimate and exact Clopper-Pearson CI for ORR, and Kaplan-Meier estimates for DOR, PFS, and OS will be calculated. A total of 89 sites are currently enrolling in 20 countries. Results N/A Conclusions N/A Trial Registration ClinicalTrials. gov identifier, NCT04123366 Ethics Approval An independent institutional review board or ethics committee approved the protocol at each study site, and the trial is being conducted in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki.

Previously, it has been shown that stable nanobubbles (∼150 nm) free in an alkaline α-cyclodextrin (α-CD) solution can be removed by repeated filtration and regenerated by air injection. Recently, we found that the existence of nanobubbles can induce attraction between a spherical latex particle (radius ∼3.2 μm) and a flat hydrophilic surface. Using total internal reflection microscopy (TIRM), we are able to directly measure such a weak interaction (down to ∼0.1 μN m−1 within a range up to 200 nm). The weak attraction disappears as soon as the nanobubbles are removed. Our results suggest that the origin of such weak attraction comes from the exclusion or depletion of the charged nanobubbles from the gap between the particle and surface; namely, an imbalance between the osmotic pressures inside and outside the gap.

Perfluoroalkyl substances (PFAS) are known to be endocrine-disrupting compounds, but are nevertheless widely used in consumer and industrial products and have been detected globally in human and wildlife. Data from animal and epidemiological studies suggest that PFAS may affect human fertility. This led us to consider whether maternal or paternal plasma PFAS had effects on in vitro fertilization (IVF) outcomes. The study population consisted of 96 couples who underwent IVF treatment in 2017 due to tubal factor infertility. The concentrations of 10 PFAS in blood samples from both male and female partners were measured. Poisson regression with log link was performed to evaluate the association between the tertiles of PFAS concentrations and numbers of retrieved oocytes, mature oocytes, two-pronuclei (2 PN) zygotes, and good-quality embryos, while multiple linear regression models were used to investigate the correlation between plasma PFAS and semen parameters. Multivariable logistic regression was used to evaluate the association between the tertiles of PFAS concentrations and clinical outcomes. It was found that maternal plasma concentrations of perfluorooctanoic acid (PFOA) were negatively associated with the numbers of retrieved oocytes (ptrend = 0.023), mature oocytes (ptrend = 0.015), 2 PN zygotes (ptrend = 0.014), and good-quality embryos (ptrend = 0.012). Higher paternal plasma PFOA concentrations were found to be significantly associated with reduced numbers of 2 PN zygotes (ptrend = 0.047). None of the maternal or paternal PFAS were significantly associated with the probability of implantation, clinical pregnancy, or live birth. To our knowledge, the present study is the first to assess the association between parental exposure to PFAS and IVF outcomes. Our results suggest the potential reproductive effects of PFAS on both men and women, and that exposure to PFAS may negatively affect IVF outcomes. Future studies, particularly with large sample size cohorts, are needed to confirm these findings.

In view of the frequent access problem of massive terminal equipment in the power wireless private network, it is necessary to develop more efficient access authentication mechanism and technology. This paper designs a new privacy-enhanced group authentication protocol for wireless networks based on the end-to-end identity authentication framework of massive power wireless private networks in groups. Compared with the traditional end-to-end authentication method, this protocol enhances the privacy protection function. At the same time. the protocol can meet the real-time requirements of group communication scenarios, and can also better meet the business requirements of power wireless private network.

LTE power wireless private network communication systems are widely adopted by the State Grid of China. In this paper, two improved security schemes for LTE power wireless private network communication system are proposed. Firstly, the security isolation scheme of wireless side network in LTE power wireless private network communication system is proposed. By setting two PLMNs in the power wireless communication system messages broadcast on the base station side, which corresponding to the production control area and management information area respectively, the two areas are identified to form a logical isolation. Secondly, by adding and assigning an access level to terminals of different services in the LTE power wireless private network communication system, the power service terminal realizes the access control of the network system, so as to achieve the access guarantee of some services under special conditions. These two improved schemes will be useful for the future in FDD system.

With the maturity of wireless communication technology, the ubiquitous power Internet of things (PIoT) has also been developed rapidly in recent years. Due to the wide variety of power services, different services have different requirements for communication networks. Therefore, the feasibility of network slicing technology in the PIoT needs to be considered. In this paper, we first introduce the key technologies of network slicing. Then, we analyze the power services and its requirements on wireless communication. And finally, we study the combination point of network slicing technology and different services of smart grid.

Multimodal sentiment analysis utilizes multiple heterogeneous modalities for sentiment classification. The recent multimodal fusion schemes customize LSTMs to discover intra-modal dynamics and design sophisticated attention mechanisms to discover the inter-modal dynamics from multimodal sequences. Although powerful, these schemes completely rely on attention mechanisms which is problematic due to two major drawbacks 1) deceptive attention masks, and 2) training dynamics. Nevertheless, strenuous efforts are required to optimize hyperparameters of these consolidate architectures, in particular their custom-designed LSTMs constrained by attention schemes. In this research, we first propose a common network to discover both intra-modal and inter-modal dynamics by utilizing basic LSTMs and tensor based convolution networks. We then propose unique networks to encapsulate temporal-granularity among the modalities which is essential while extracting information within asynchronous sequences. We then integrate these two kinds of information via a fusion layer and call our novel multimodal fusion scheme as Deep-HOSeq (Deep network with higher order Common and Unique Sequence information). The proposed Deep-HOSeq efficiently discovers all-important information from multimodal sequences and the effectiveness of utilizing both types of information is empirically demonstrated on CMU-MOSEI and CMU-MOSI benchmark datasets. The source code of our proposed Deep-HOSeq is and available at https://github.com/sverma88/Deep-HOSeq--ICDM-2020., Comment: Accepted at ICDM 2020

Image encryption is a straightforward strategy to protect digital images by transforming images into unrecognized ones. The chaos theory is a widely used technology for image encryption as it has many significant properties such as ergodicity and initial state sensitivity. When chaotic systems are used in image encryption, their chaos performance highly determines the security level. This paper presents a two-dimensional (2D) Logistic-Sine-coupling map (LSCM). Performance estimations demonstrate that it has better ergodicity, more complex behavior and larger chaotic range than several newly developed 2D chaotic maps. Utilizing the proposed 2D-LSCM, we further propose a 2D-LSCM-based image encryption algorithm (LSCM-IEA), which adopts the classical confusion-diffusion structure. A permutation algorithm is designed to permutate image pixels to different rows and columns while a diffusion algorithm is developed to spread few changes of plain-image to the whole encrypted result. We compare the efficiency of LSCM-IEA with several advanced algorithms and the results show that it has higher encryption efficiency. To show the superiority of LSCM-IEA, we also analyze the security of LSCM-IEA in terms of key security, ability of defending differential attack, local Shannon entropy and contrast analysis. The analysis results demonstrate that LSCM-IEA has better security performance than several existing algorithms.

The lightweight optimal design of bolted flange joint system without gaskets is still a challenging problem, mainly owing to two issues: the relatively large number of mutually dependent geometric design parameters and the complicated role played by the contact details between members. With these two issues properly addressed, this article aims for devising a concise formulation for lightweight optimal design of bolted joint systems without gaskets. After a systematic examination of the correlations between design parameters, the total number of free design variables is reduced to three: member thickness, bolt spacing, and bolt specification, respectively. Besides, a finite element analysis that can resolve more contact details between members is conducted, and the influencing factors on the pressure distribution at the member surface are thus identified, with a criterion for the system sealing failure incorporated. Based on the findings in this work, a novel design scheme for the joint system is proposed, and good agreement between our predictions and results obtained by a full three-dimensional finite element analysis is shown. The proposed approach can be used to optimize the design parameters of bolted joint systems considering sealing performance without heavy finite element computation and can find applications in many relevant engineering fields.

Objectives: Pembrolizumab (pembro) showed durable antitumor activity and manageable safety in patients (pts) with advanced cervical cancer in an earlier interim analysis of KEYNOTE-158 (NCT02628067). Based on those results, the US FDA granted accelerated approval of pembro for pts with advanced, PD-L1-positive cervical cancer that progressed on or after chemotherapy. We present an updated analysis of pts included in the cervical cancer cohort of KEYNOTE-158 based on 17 months of additional follow-up. Methods: KEYNOTE-158 is a phase 2 basket study investigating the antitumor activity of pembro across several cancer types. Key eligibility criteria for the cervical cancer cohort included histologically or cytologically confirmed disease, progression on or intolerance to ≥1 line of standard therapy, an ECOG PS of 0 or 1, and provision of a tumor sample for biomarker analysis. Pts received pembro 200 mg once every 3 weeks for 2 years or until progression, intolerable toxicity, or physician or patient decision. Tumor imaging was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. PD-L1 positivity, defined as a combined positive score (CPS) ≥1, was evaluated retrospectively by immunohistochemistry. The primary endpoint was the objective response rate (ORR) assessed per RECIST v1.1 by independent central radiology review. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 98 pts were treated. Median age was 46 (range, 24 to 75) years, 65.3% had ECOG PS 1, and 94.9% had stage M1 disease. A total of 83.7% of enrolled pts had PD-L1–positive tumors. As of the June 27, 2019 data cutoff, the median follow-up duration, defined as first dose of study medication to data cutoff, was 36.9 (range, 34.3 to 41.0) months. In the updated analysis, 2 partial responses (PR) converted to complete responses (CR) and 2 additional PR occurred for a total of 5 CR and 9 PR; ORR was 14.3% (95% CI, 8.0% to 22.8%). A total of16 pts had stable disease (SD), and the disease control rate (CR+PR+SD) was 30.6%. All 14 responses were in pts with PD-L1–positive tumors, resulting in an ORR of 17.1% (95% CI, 9.7% to 27.0%) in the PD-L1–positive cohort (N=82) and 0.0% (95% CI, 0.0% to 21.8%) in the PD-L1–negative cohort. A total of 7 of 14 responses were ongoing after ≥24 months of follow-up. Median DOR had not been reached (range, 3.7+ to 35.2+). Median (95% CI) PFS and OS were 2.1 (2.1 to 2.2) months and 9.3 (7.6 to 11.7) months, respectively. Treatment-related adverse events (AEs) occurred in 65.3% of pts, and the most common were hypothyroidism (11.2%), fatigue (11.2%), and decreased appetite (9.2%). 12.2% of pts had treatment-related grade 3-4 AEs; there were no grade 5 AEs. Conclusions: With 17 months of additional follow-up, pembro continues to show durable antitumor activity and manageable safety in pts with advanced cervical cancer, similar to the previous report.

Objectives: Advanced vulvar carcinoma typically affects the elderly and treatment options are limited. Moderate antitumor activity of pembrolizumab (ORR, 6%) was noted in a small population of patients (pts) with PD-L1-positive vulvar cancer in the phase 1b KEYNOTE-028 study. KEYNOTE-158 ( ClinicalTrials.gov , NCT02628067) is a larger, nonrandomized, multicohort, open-label, phase 2 study that evaluates pembrolizumab in pts with previously treated advanced cancers irrespective of tumor PD-L1 expression. We report results for pts in the vulvar carcinoma cohort receiving pembrolizumab monotherapy. Methods: Enrolled pts were aged ≥18 y with histologically/cytologically documented advanced vulvar squamous cell carcinoma with prior treatment failure; measurable disease per RECIST v1.1; ECOG performance status ≤1; and tumor samples available for biomarker analysis, including PD-L1. PD-L1 positivity was defined as combined positive score ≥1 with expression evaluated using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA, USA). Pts received pembrolizumab 200 mg Q3W until disease progression, unacceptable toxicity, or completion of 35 treatment cycles. Tumor imaging was performed every 9 weeks for 1 y and every 12 weeks thereafter. Response was assessed per RECIST v1.1 by independent central radiologic review. The primary endpoint was ORR. Secondary endpoints included duration of response (DOR), PFS, OS, and safety. Results: A total of 101 pts were enrolled. As of October 5, 2020, median time from start of treatment to data cutoff was 36.0 (range, 15.4–55.2) months. Median age was 64.0 (range, 31–87) y; 9 (8.9%) pts had no prior therapy, 57 (56.4%) had 1, 23 (22.8%) had 2, and 11 (10.9%) had 3 or more lines of prior therapy. Tumors were PD-L1–positive in 84 pts (83.2%), PD-L1–negative in 7 pts (6.9%), and non-evaluable/not assessed in 10 pts (9.9%). Overall, ORR was 10.9% (95% CI, 5.6–18.7); 1 pt had a CR and 10 pts had PR. Among pts with PD-L1–positive tumors, 8 of 84 (9.5%; 95% CI, 4.2–17.9) had CR or PR; among pts with PD-L1–negative tumors, 2 of 7 (28.6%; 95% CI, 3.7–71.0) had CR or PR. Among pts with a response, median DOR was 20.4 months (range, 2.1+ to 28.0). Among all enrolled pts (n=101), median PFS was 2.1 months (95% CI, 2.0–2.1) and median OS was 6.2 months (95% CI, 4.9–9.4 months). Treatment-related AEs occurred in 51 pts (50.5%), including 12 pts (11.9%) who had grade 3–5 events (no event occurred in >1 pt). There were 2 deaths (2.0%) considered related to treatment (hepatitis, n=1; fulminant hepatitis, n=1). Neither pt had comorbidities or pre-existing liver disease to contribute to these events; no other contributing factors were identified. A total of 5 pts (5.0%) discontinued because of treatment-related AEs. Immune-mediated AEs occurred in 18 pts (17.8%). Conclusions: Pembrolizumab monotherapy was associated with durable responses in a subset of pts with vulvar carcinoma (ORR, 10.9%; median DOR, 20.4 months). Responses occurred in both PD-L1-positive and PD-L1-negative pts.

Background: Poly-ADP-ribose polymerase (PARP) inhibition plus PD-(L)1 blockade has shown encouraging antitumor activity in patients (pts) with recurrent ovarian or breast cancer with BRCAm and in pts with recurrent ovarian cancer regardless of BRCAm or HRD status. We present initial results of the ongoing KEYLYNK-007 (NCT04123366) study of antitumor activity and safety of olaparib + pembrolizumab in pts with previously treated, advanced, HRRm and/or HRD positive solid tumors. Methods: This phase 2, nonrandomized, multicenter, open-label study enrolled adult pts with histologically/cytologically confirmed, previously treated, advanced solid tumors with centrally-confirmed HRRm and/or HRD positive per Lynparza HRR-HRD assay, and ECOG PS of 0−1, and without prior PARP or PD-(L)1 inhibitor therapy or progression on or ≤4 wks after platinum therapy. Pts received olaparib 300 mg BID and pembrolizumab 200 mg Q3W for 35 cycles or until PD, unacceptable AEs, intercurrent illness, or investigator decision. The primary endpoint was ORR. Results: As of 25 Sep 2020, 168 pts were enrolled (BRCAm, n = 40; HRRm without BRCAm, n = 64; HRD positive without HRRm, n = 64). Median (range) time from first dose to data cutoff was 4.5 (0.1−8.4), 4.5 (0.1−7.5), and 5.3 (0.3−7.9) mo, respectively. Efficacy outcomes in pts with ≥4 mo follow-up are shown in the Table. Grade 3−4 treatment-related AEs occurred in 60 pts (35.7%); 4 pts (2.4%) discontinued treatment due to treatment-related AE; there were no grade 5 treatment-related AEs. Common (≥15%) treatment-related AEs were nausea (39.3%), anemia (30.4%), and fatigue (15.5%), comparable with monotherapy. Conclusions: Olaparib + pembrolizumab showed promising antitumor activity with manageable safety in pts with a range of advanced HRRm and/or HRD positive solid tumors, especially BRCAm. Enrollment is ongoing. Table. Efficacy OutcomesOlaparib Plus PembrolizumabEfficacy Outcomesa, bBRCAmc (n = 21)HRRmd Without BRCAmc (n = 32)HRD Positivee Without HRRmd (n = 47)HRRmd (n = 53)HRD Positivee (n = 76)ORR,f-h (95% CI)28.6 (11.3 to 52.2)6.3 (0.8 to 20.8)19.1 (9.1 to 33.3)15.1 (6.8 to 27.6)21.1 (12.5 to 31.9)- Tumor types with confirmed responsesCervical, endometrial, prostate, duodenalOvarian and neuroendocrineiOvarian (3), breast, peritoneum, NSCLC, cervicalCervical, endometrial, prostate, duodenal, ovarian, neuroendocrineCervical (2), endometrial, prostate, duodenal, ovarian (4), breast, peritoneum, NSCLC- Tumor types with unconfirmed responsesNSCLC, neuroendocrineNoneNSCLC (2)NSCLC, neuroendocrineNSCLC (3), neuroendocrineDOR,f,j median (range), moNR (0.0+ to 2.6+)4.2 (4.1+ to 4.2)NR (0.0+ to 4.2+)4.2(0.0+ to 4.2)NR (0.0+ to 4.2+)PFS,j median (95% CI), moNR (2.3 to NR)3.3 (2.0 to 4.6)4.1 (2.2 to NR)3.9(2.2 to 6.1)4.1(2.3 to NR)Estimated PFS rate at 3 mo,j %66.250.058.456.059.5NR, not reached.“+” indicates no PD by the time of last disease assessment.aTumor imaging assessed by blinded independent central review per RECIST version 1.1 or Prostate Cancer Working Group-modified RECIST version 1.1bIn pts enrolled ≥4 mo before the data cutoff date (25 September 2020).cDeleterious or suspected deleterious mutations in the BRCA1 and/or BRCA2 genes from the tumor tissue-based Lynparza HRR-HRD assay.dDeleterious or suspected deleterious mutations in at least 1 of 15 prespecified HRR genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L) from the tumor tissue-based Lynparza HRR-HRD assay.eDeleterious or suspected deleterious mutation in BRCA1 or BRCA2, or loss of heterozygosity score ≥16 from the tumor tissue-based Lynparza HRR-HRD assay.fIncludes confirmed and unconfirmed responses.gORR (95% CI) in pts with confirmed responses (primary endpoint): BRCAm, 19.0% (5.4%-41.9%); HRRm without BRCAm, 6.3% (0.8%-20.8%); HRD positive without HRRm, 14.9% (6.2%-28.3%); HRRm, 11.3% (4.3%-23.0%); HRD positive, 15.8% (8.4%-26.0%).hNumber of patients with responses: BRCAm, 4 confirmed + 2 unconfirmed; HRRm without BRCAm, 2 confirmed; HRD positive without HRRm, 7 confirmed + 2 unconfirmed; HRRm, 6 confirmed + 2 unconfirmed; HRD positive, 12 confirmed + 4 unconfirmed.iBoth pts had ATM mutation.jFrom Kaplan-Meier method for censored data. Citation Format: Michele Maio, Ronnie Shapira-Frommer, Timothy A. Yap, Tudor Ciuleanu, Henry Gomez, Andrew Hill, Iwona Lugowska, Ozgur Ozyilkan, Karina Vera, Seock-Ah Im, Anna Kryzhanivska, Serhii Lysenko, Michael Schenker, Salomon M. Stemmer, Sanatan Saraf, Razvan Cristescu, PhD, Fan Jin, Alexander Gozman, Miguel Quintela-Fandino. Olaparib plus pembrolizumab in patients with previously treated advanced solid tumors with homologous recombination repair mutation (HRRm) and/or homologous recombination deficiency (HRD): Initial results of the phase 2 KEYLYNK-007 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT178.

Endometriosis is one of the main causes for female infertility. Previous studies suggested that perfluoroalkyl substances (PFASs), a group of ubiquitous environmental chemicals with properties of endocrine disruption and reproductive toxicity, were risk factors for endometriosis but there lacks direct evidence on the possible role of PFASs in endometriosis-related infertility. To fill this gap, we examined the association between PFASs and endometriosis-related infertility among Chinese reproductive-age women in a case-control study, which comprised 157 surgically confirmed endometriosis cases and 178 controls seeking infertility treatment because of male reproductive dysfunction in 2014 and 2015. Blood specimens were collected at the enrollment and analyzed for ten PFASs. Logistic regression was utilized to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) for individual PFAS compound. Plasma concentrations of perfluorobutane sulfonic acid (PFBS) were associated with an increased risk of endometriosis-related infertility (second vs. lowest tertile: OR = 3.74, 95% CI: 2.04, 6.84; highest vs. lowest tertile: OR = 3.04, 95% CI: 1.65, 5.57). This association remained consistent when we restricted to subjects with no previous pregnancy (second vs. lowest tertile: OR = 2.91, 95% CI: 1.28, 6.61; highest vs. lowest tertile: OR = 3.41, 95% CI: 1.52, 7.65) or to subjects without other gynecologic pathology (second vs. lowest tertile: OR = 4.65, 95% CI: 2.21, 9.82; highest vs. lowest tertile: OR = 3.36, 95% CI: 1.58, 7.15). Plasma concentrations of perfluoroheptanoic acid (PFHpA), perfluorohexane sulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) were inversely associated with endometriosis-related infertility, but the associations were attenuated in the sensitivity analyses. Our preliminary evidence suggests that exposure to PFBS may increase the risk of female infertility due to endometriosis. Future prospective studies are necessary to confirm these findings. Keywords: Perfluoroalkyl substances, Perfluorobutane sulfonic acid, Endometriosis, Female infertility, Risk factor

In the present paper, a theoretical model for leakage analysis of bolted flange joints without gaskets, which can take the surface roughness into consideration, is proposed based on percolation theory. In this model, Persson’s rough contact theory is employed to predict the height of the critical constriction along the percolating path. Based on this model, a criterion of maximum allowable bolt spacing is also suggested to guarantee a low leakage rate. The reasonable agreement between the theoretical predictions and detailed three-dimensional finite element analysis results verifies the validity and usefulness of the proposed theoretical model.

Esophageal cancer is one of the most fatal diseases worldwide mainly because of its rapid progression and poor prognosis. Although the incidence of esophageal adenocarcinoma has markedly risen in North America and Europe in the past several decades, esophageal squamous cell carcinoma is still the predominant subtype of esophageal cancer, especially in China. It accounts for more than 90% of all esophageal squamous cell carcinoma cases in China. Geographical differentiation is one of the most distinctive characteristics of esophageal cancer. The progression, risk factors, and prognosis of these two subtypes of esophageal cancer differ. This study reviews the epidemiology, etiology, and prevention of esophageal squamous cell carcinoma in China, thereby providing systematic references for policy-makers who will decide on issues of esophageal cancer prevention and control.

Background Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disorder in the central nervous system (CNS) with distinct clinical, radiological, and pathological characteristics. The pathophysiology of CLIPPERS still remains unclear. Because a few cases about lymphoma mimicking the manifestations of CLIPPERS were reported and the prognosis of lymphoma is much worse, early identification of lymphoma is very important. Case presentation A 31-year-old woman was admitted with 3 months’ history of diplopia, dizziness, gait ataxia, and right facial numbness. The diagnosis of CLIPPERS was established based on the finding of punctate enhancing lesions in the cerebellum, thalamus, pons, medulla, and midbrain region in magnetic resonance imaging (MRI), together with the favorable clinical and radiological responses to corticosteroids. However, she was diagnosed as peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) by the pulmonary nodular and the skin biopsy almost 10 years later, and she got complete remission within 1 year after chemotherapy. Conclusion We report the first case of CLIPPERS developing PTCL-NOS. This case proposes that when brain biopsy was difficult to achieve, biopsies in extra-cerebral lesions under the assisting examination of positron emission tomography-computed tomography (PET-CT) can be helpful in further identification.

Aim: To compare the efficiency of karyotyping, chromosomal micro-array (CMA) and Non-invasive prenatal testing (NIPT) for diagnosing fetal chromosomal anomalies in middle and last trimesters. Design: Diagnostic test. Set: Prenatal Diagnosis Center of Taizhou City. Study Population: The pregnant women gone through amniocenteses for prenatal genetic diagnoses during the middle and late trimesters were recruited. Methods: Amniotic fluid cells were cultured for fetal karyotyping, and CMA test, and NIPT was carried out. Statistics: The diagnostic efficiency of NIPT for detecting imbalanced anomalies was compared with karyotyping and CMA. Results: Totally 69 imbalanced copy number variants (CNVs) were confirmed by CMA, 37 of them were confirmed by NIPT and 35 were found by karyotyping. The sensitivities of NIPT and karyotyping for diagnosing aneuploidy were 96.3% and 100% respectively. Only one mosaic sexual chromosome monosomy was missing diagnosed by NIPT. Whereas for detecting pathogenic deletions and duplications sized from 5-20M, the sensitivity of NIPT and karyotyping were 70% and 30%. Conclusions: The efficient of NIPT was similar to the karyotyping for detecting chromosome imbalance in 2nd and 3rd trimester. The ClinicalTrials.gov ID of this study is NCT03201666.

Background The noninvasive prenatal testing (NIPT) has been successfully used in the clinical screening of fetal trisomy 13, 18, and 21 in the last few years and researches on detecting sub‐chromosomal copy number variations (CNVs) and monogenic diseases are also in progress. To date, multiple tests are needed in order to complete a full set of fetus disorder screening, which is costly and time consuming. Therefore, an integrated 3‐in‐1 NIPT approach will be in great demand by routine clinical practice in the near future. Methods We designed a target capture sequencing panel with an associate bioinformatics pipeline to create a novel multi‐functional NIPT method and we evaluated its performance by testing 22 clinical samples containing aneuploidy, CNV, and single‐gene disorder. Chromosomal aneuploidy and CNV were detected based on the Z‐value approach, whereas single‐gene disorder was identified by using the “pseudo‐tetraploid” model to estimate the best‐suited genotype for each locus. Results The performance of this newly constructed 3‐in‐1 system was promising. We achieved a 100% detection rate for chromosomal aneuploidies (7/7), a 100% diagnosis rate for fetus CNVs larger than 20 Mb (3/3), and an 86.4% accuracy for single‐gene disorder screening (19/22). Conclusion For the first time, we showed that it is possible to use just a single NIPT test to detect three distinct types of fetus disorder and laid a foundation for developing a cheaper, faster, and multi‐functional NIPT method in the future.

Optimizers in electromagnetic (EM) simulation software are facing challenges in optimization efficiency, supported optimization types and optimization results usability. Aiming to fill these gaps, a new antenna design exploration scheme is proposed, called Antenna Rapid Optimization Platform (AROP). The scheme adopts ANSOFT HFSS and MATLAB co-simulation method and provides a friendly graphical interface based on the antenna optimization process. State-of-the-art intelligent optimization algorithms and surrogate model methods are embedded, addressing efficient multi-objective antenna optimization problems and generating Pareto optimal solution sets. Design results show that the surrogate models assisted by evolutionary algorithms built into AROP can largely improve optimization capacity for high-performance antenna synthesis and deal with complex antenna designs with high-dimensional parameter space.

2565 Background: Approval of pembrolizumab for the treatment of unresectable or metastatic MSI-H/dMMR solid tumors that have progressed on prior therapy was supported by data from KEYNOTE-158 (NCT02628067). At the data cutoff of Dec 6, 2018, the ORR was 34.3% among 233 patients (pts) with MSI-H/dMMR solid tumors enrolled in all cohorts of KEYNOTE-158, 77.6% had duration of response (DOR) ≥24 mo, median PFS was 4.1 mo, and median OS was 23.5 mo. We present results from 351 pts enrolled in KEYNOTE-158 cohort K at the data cutoff of Oct 5, 2020. Methods: Cohort K of this phase 2, open-label study enrolled adults with any previously treated advanced noncolorectal MSI-H solid tumor, measurable disease per RECIST v1.1, and ECOG PS of 0–1. MSI-H/dMMR status was assessed locally from a tumor tissue sample and defined as ≥1 of 4 MMR proteins absent by immunohistochemistry or as ≥2 allelic loci size shifts of 5 microsatellite markers by PCR. Pts received pembrolizumab 200 mg Q3W for up to 35 cycles or until PD, unacceptable toxicity, investigator decision, or withdrawal of consent. The primary endpoint was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints were DOR and PFS per RECIST v1.1 by BICR, OS, and safety. Efficacy was assessed in all pts who received ≥1 dose of treatment with ≥6 mo follow-up; safety was assessed in all treated pts. Results: 351 pts were enrolled in KEYNOTE-158 cohort K across multiple tumor types, including endometrial (22.5%), gastric (14.5%), small intestine (7.4%), ovarian (7.1%), cholangiocarcinoma (6.3%), and pancreatic (6.3%). 41.0% had 1 prior line of therapy; 55.6% had ≥2 prior lines. Median time from first dose to database cutoff (Oct 5, 2020) was 37.5 (range, 0.2–55.6) mo; 16.0% were continuing treatment. The ORR among the 321 eligble pts was 30.8% (CR, 27; PR, 72); median DOR was 47.5 mo (Table). Treatment-related AEs occurred in 64.7% of pts (grade 3–5, 12.0%), led to discontinuation in 6.6%, and led to death in 3 pts (myocarditis, pneumonia, and Guillain-Barre syndrome). Immune-mediated AEs and infusion reactions occurred in 20.2% of pts (grade 3–4, 4.3%) and led to death in 2 pts with no other contributing factors (myocarditis [AE start, day 26; death, day 33] and Guillain-Barre syndrome [AE start, day 22; death, day 41]). Conclusions: Pembrolizumab demonstrated a high ORR (30.8%), durable clinical benefit, and a manageable safety profile in this heavily pretreated advanced MSI-H/dMMR noncolorectal pan-tumor population. Clinical trial information: NCT02628067. [Table: see text]

Background Traditional Chinese medicine (TCM) is an integral part of mainstream medicine in China, with theories and practices that are completely different from modern medicine. TCM should not be ignored or confused with modern medicine in the analysis of the Chinese health care system, including the analysis of mobile health (mHealth) apps. To date, differences between TCM apps and modern medicine apps have not be systematically investigated. Objective The aim of this study was to systematically compare the quality of apps for TCM and modern medicine in China. Methods In December 2020, we searched iOS (iTunes) and Android (Tencent, Oppo, and Huawei app stores) platforms for all mHealth apps and then categorized them as TCM or modern medicine apps if they were included in the final analysis. The included apps were downloaded on smartphones and assessed by 2 reviewers on the following 4 aspects: (1) data in the app stores, including user ratings, download counts, cost, target users, and year of last update; (2) functionality; (3) quality of the app content as determined by the Mobile App Rating Scale (MARS); and (4) analysis of the app privacy and security. Results In total, 658 apps were analyzed, including 261 TCM medicine apps and 397 modern medicine apps. The average download count of modern medicine apps (approximately 5 million) was more than 10 times that of TCM apps (approximately 400,000). Regarding functionalities, 64.7% (257/397) of modern medicine apps provided telemedicine (74/261, 28.4% in TCM apps), 62.7% (249/397) provided registration (70/261, 26.8% in TCM apps), and 45.6% (181/397) provided communication (38/261, 14.6% in TCM apps). A larger proportion of TCM apps provided prescription and medication management (144/261, 55.2% in TCM apps versus 168/397, 42.3% in modern medicine apps). The majority of modern medicine apps (329/397, 82.9%) combined ≥3 functionalities compared with one-third of TCM apps (93/261, 34.6%). We then selected 81 top apps for quality and safety assessment (41 TCM apps and 40 modern medicine apps). Of these, the mean overall MARS score of TCM apps (2.7, SD 0.5) was significantly lower than modern medicine apps (3.6, SD 0.4). Almost all modern medicine apps (38/40, 95%) addressed privacy and security by providing a privacy policy and describing how to protect personal data, but less than half of the TCM apps (18/41, 44%) described this information (P Conclusions The different functionalities reflect the distinct innate characteristics of these two medical systems. Although great progress has been made and the Chinese mHealth market size is large, there still exist many opportunities for future development, especially for TCM.

321 Background: Second-line treatment options for patients with biliary tract cancers (BTC) are limited. Lenvatinib, an anti-angiogenic multikinase inhibitor, in combination with the programmed death-1 immune checkpoint inhibitor pembrolizumab, has demonstrated promising antitumor activity with a manageable safety profile in patients with select advanced solid tumors. LEAP-005 (NCT03797326) is evaluating the efficacy and safety of lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors; here we present results from the BTC cohort of LEAP-005. Methods: In this nonrandomized, open-label, phase II study, eligible patients were aged ≥18 years with histologically or cytologically documented advanced (metastatic and/or unresectable) BTC with disease progression after 1 prior line of therapy, measurable disease per RECIST v1.1, ECOG PS of 0‒1, and tissue sample evaluable for PD-L1 expression. Patients received lenvatinib 20 mg once daily plus pembrolizumab 200 mg Q3W for up to 35 cycles (approximately 2 years) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 years in patients experiencing clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints were the disease control rate (DCR; comprising CR, PR, and SD), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 weeks, then Q12W to week 102, and Q24W thereafter. Results: 31 patients were enrolled in the BTC cohort (ECOG PS 1, 55%; 84% ex-US). As of April 10, 2020, median time from first dose to data cutoff (DCO) was 9.5 months (range, 3.1‒11.9), with 16 patients on treatment at DCO. There were 3 (10%) PRs and 18 (58%) SDs. ORR was 10% (95% CI, 2‒26), and DCR was 68% (95% CI, 49‒83). Median DOR was 5.3 months (range, 2.1+ to 6.2). Median PFS was 6.1 months (95% CI, 2.1‒6.4). Median OS was 8.6 months (95% CI, 5.6 to NR). Treatment-related AEs occurred in 30 patients (97%), including 15 (48%) who had grade 3‒4 AEs; there were no treatment-related deaths. 2 (6%) discontinued treatment due to treatment-related AEs (myocarditis, pyrexia; n = 1 each). The most frequent treatment-related AEs were hypertension (42%), dysphonia (39%), diarrhea (32%), fatigue (32%), and nausea (32%). 14 patients (45%) had immune-mediated AEs and 1 patient (3%) had an infusion-related reaction. Conclusions: Lenvatinib plus pembrolizumab demonstrated encouraging efficacy and manageable toxicity in patients with advanced BTC who had received 1 line of prior therapy. Based on these data, enrollment in the BTC cohort has been expanded to 100 patients. Clinical trial information: NCT03797326.