Mesoporous polydopamine Targeting CDK4/6 Inhibitor toward Brilliant Synergistic Immunotherapy of Breast Cancer.

Immunotherapy utilizing anti-PD-L1 blockade has achieved dramatic success in clinical breast cancer management but is often hampered by the limited immune response. Increasing evidence shows that immunogenic cell death (ICD) recently arises as a promising strategy for enlarging tumor immunogenicity and eliciting systemic anti-tumor immunity effectively. However, developing simple but versatile, highly efficient but low-toxic, biosafe, and clinically available transformed ICD inducers remains a huge demand and is highly desirable. Herein, a multifunctional ICD inducer is purposefully developed A6-MPDA@PAL by integrating photothermal therapy (PTT) nanoplatforms mesoporous polydopamine (MPDA), CDK4/6 inhibitor palbociclib (PAL), and CD44-specific targeting A6 peptide in a simple way for augmenting the immune antitumor efficacy of anti-PD-L1 therapy. Remarkably, the light-inducible nanoplatforms exhibit multiple favorable therapeutic features ensuring a superior and biosafe PTT/chemotherapy efficacy. Together with stronger accumulative ICD induction, single administration of A6-MPDA@PAL can trigger robust systemic antitumor immunity and abscopal effect with the assistance of anti-PD-L1 blockade by fascinating the intratumoral infiltration of T lymphocytes and reversing the immunosuppressive tumor microenvironment simultaneously, therapy achieving brilliant synergistic immunotherapy with effective tumor ablation. This study presents a simple and smart ICD inducer opening up attractive clinical possibilities for reinforcing the anti-PD-L1 therapy against breast cancer.

Sirolimus plus prednisolone vs sirolimus monotherapy for kaposiform hemangioendothelioma: a randomized clinical trial.

The Kasabach-Merritt phenomenon (KMP) in kaposiform hemangioendothelioma (KHE) is characterized by life-threatening thrombocytopenia and consumptive coagulopathy. This study compared the efficacy and safety of sirolimus plus prednisolone vs sirolimus monotherapy as treatment strategies for KHE with KMP in the largest cohort to date. Participants were randomized to receive either sirolimus in combination with a short course of prednisolone or sirolimus monotherapy for at least 12 months. The primary outcome was defined as achievement of a durable platelet response (platelet count >100 × 109/L) at week 4. Participants completed efficacy assessments 2 years after the initial treatment. At week 4, a durable platelet response was achieved by 35 of 37 patients given sirolimus and prednisolone compared with 24 of 36 patients given sirolimus monotherapy (difference 27.9%; 95% confidence interval, 10.0-44.7). Compared with the sirolimus monotherapy group, the combination treatment group showed improvements in terms of measures of durable platelet responses at all points during the initial 3-week treatment period, median platelet counts during weeks 1 to 4, increased numbers of patients achieving fibrinogen stabilization at week 4, and objective lesion responses at month 12. Patients receiving combination therapy had fewer blood transfusions and a lower total incidence of disease sequelae than patients receiving sirolimus alone. The frequencies of total adverse events and grade 3-4 adverse events during treatment were similar in both groups. The responses seen in patients with KHE with KMP were profound and encouraging, suggesting that sirolimus plus prednisolone should be considered a valid treatment of KHE with KMP. This trial was registered at www.clinicaltrials.gov as #NCT03188068.

A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6.

Ykt6 is a soluble N-ethylmaleimide sensitive factor activating protein receptor (SNARE) critically involved in diverse vesicular fusion pathways. While most SNAREs rely on transmembrane domains for their activity, Ykt6 dynamically cycles between the cytosol and membrane-bound compartments where it is active. The mechanism that regulates these transitions and allows Ykt6 to achieve specificity toward vesicular pathways is unknown. Using a Parkinson's disease (PD) model, we found that Ykt6 is phosphorylated at an evolutionarily conserved site which is regulated by Ca2+ signaling. Through a multidisciplinary approach, we show that phosphorylation triggers a conformational change that allows Ykt6 to switch from a closed cytosolic to an open membrane-bound form. In the phosphorylated open form, the spectrum of protein interactions changes, leading to defects in both the secretory and autophagy pathways, enhancing toxicity in PD models. Our studies reveal a mechanism by which Ykt6 conformation and activity are regulated with potential implications for PD.

Rimegepant orally disintegrating tablet 75 mg for acute treatment of migraine in adults from China: a subgroup analysis of a double-blind, randomized, placebo-controlled, phase 3 clinical trial.

BACKGROUND: Rimegepant orally disintegrating tablet (ODT), an oral small-molecule calcitonin gene-related peptide receptor antagonist, is indicated for acute and preventive treatment of migraine in the United States and other countries. Previously, a large clinical trial assessed the efficacy and safety of rimegepant ODT 75 mg for the acute treatment of migraine in adults living in China or South Korea. A post hoc subgroup analysis of this trial was performed to evaluate the efficacy and safety of rimegepant for acute treatment of migraine in adults living in China. METHODS: Eligible participants were ≥ 18 years of age and had a ≥ 1-year history of migraine, with 2 to 8 attacks of moderate or severe pain intensity per month and < 15 headache days per month during the 3 months before screening. Participants self-administered rimegepant ODT 75 mg or matching placebo to treat a single migraine attack of moderate or severe pain intensity. The co-primary endpoints were pain freedom and freedom from the most bothersome symptom (MBS) at 2 h post-dose. Key secondary endpoints included pain relief at 2 h post-dose, ability to function normally at 2 h post-dose, use of rescue medication within 24 h post-dose, and sustained pain freedom from 2 to 24 h and 2 to 48 h post-dose. All p values were nominal. Safety was assessed via treatment-emergent adverse events (TEAEs), electrocardiograms, vital signs, and routine laboratory tests. RESULTS: Overall, 1075 participants (rimegepant, n = 538; placebo, n = 537) were included in the subgroup analysis. Rimegepant was more effective than placebo for the co-primary endpoints of pain freedom (18.2% vs. 10.6%, p = 0.0004) and freedom from the MBS (48.0% vs. 31.8%, p <  0.0001), as well as all key secondary endpoints. The incidence of TEAEs was comparable between the rimegepant (15.2%) and placebo (16.4%) groups. No signal of drug-induced liver injury was observed, and no study drug-related serious TEAEs were reported in the rimegepant group. CONCLUSIONS: A single dose of rimegepant 75 mg rimegepant was effective for the acute treatment of migraine in adults living in China, with safety and tolerability similar to placebo. TRIAL REGISTRATION: Clinicaltrials.gov NCT04574362 Date registered: 2020-10-05.

[Detection of pathogenic gene mutations in thirteen cases of congenital bilateral absence of vas deferens infertility patients].

OBJECTIVE: To detect the cystic fibrosis transmembrane transduction regulator (CFTR) gene mutations and congenital bilateral absence of vas deferens (CBAVD) susceptibility gene mutations in patients with CBAVD, and to explore their association with the risk of CBAVD. METHODS: Whole-exome sequencing and Sanger sequencing validation were conducted on the pathogenic genes CFTR, adhesion G protein-coupled receptor G2 (ADGRG2), sodium channel epithelial 1 subunit beta (SCNN1B), carbonic anhydrase 12 (CA12), and solute carrier family 9 member A3 (SLC9A3) in thirteen cases of isolated CBAVD patients. The polymorphic loci, intron and flanking sequences of CFTR gene were amplified by polymerase chain reaction (PCR) followed by Sanger sequencing. Bioinformatics methods were employed for conservative analysis and deleterious prediction of novel susceptibility gene mutations in CBAVD. Genetic analysis was performed on the pedigree of one out of thirteen patients with CBAVD to evaluate the risk of inheritance in offspring. RESULTS: Exome sequencing revealed CFTR gene exon mutations in only six of the thirteen CBAVD patients, with six missense mutations c.2684G>A(p.Ser895Asn), c.4056G>C(p.Gln1352His), c.2812G>(p.Val938Leu), c.3068T>G(p.Ile1023Arg), c.374T>C(p.Ile125Thr), c.1666A>G(p.Ile556Val)), and one nonsense mutation (c.1657C>T(p.Arg553Ter). Among these six patients, two also had the CFTR homozygous p.V470 site, additionally, mutations in CFTR gene exon regions were not detected in the remaining seven patients. Within the thirteen CBAVD patients, three carried the homozygous p.V470 polymorphic site, four carried the 5T allele, two carried the TG13 allele, and ten carried the c.-966T>G site. Four CBAVD patients simultaneously carried 2-3 of the aforementioned CFTR gene mutation sites. Susceptibility gene mutations in CBAVD among the thirteen patients included one ADGRG2 missense mutation c.2312A>G(p.Asn771Ser), two SLC9A3 missense mutations c.2395T>C(p.Cys799Arg), c.493G>A(p.Val165Ile), one SCNN1B missense mutation c.1514G>A(p.Arg505His), and one CA12 missense mutation c.1061C>T (p.Ala354Val). Notably, the SLC9A3 gene c.493G>A (p.Val165Ile) mutation site was first identified in CBAVD patients. The five mutations exhibited an extremely low population mutation frequency in the gnomAD database, classifying them as rare mutations. Predictions from Mutation Taster and Polyphen-2 software indicated that the harmfulness level of the SLC9A3 gene c.493G>A (p.Val165Ile) site and the SCNN1B gene c.1514G>A (p.Arg505His) site were disease causing and probably damaging. The genetic analysis of one pedigree revealed that the c.1657C>T (p.Arg553Ter) mutation in the proband was a de novo mutation, as neither the proband's father nor mother carried this mutation. The proband and his spouse conceived a daughter through assisted reproductive technology, and the daughter inherited the proband's pathogenic mutation c.1657C>T (p.Arg553Ter). CONCLUSION: CFTR gene mutations remain the leading cause of CBAVD in Chinese patients; however, the distribution and frequency of mutations differ from data reported in other domestic and international studies, highlighting the need to expand the CFTR mutation spectrum in Chinese CBAVD patients. The susceptibility genes ADGRG2, SLC9A3, SCNN1B, and CA12 may explain some cases of CBAVD without CFTR mutations. Given the lack of specific clinical manifestations in CBAVD patients, it is recommended that clinicians conduct further physical examinations and consider scrotal or transrectal ultrasound before making a defi-nitive diagnosis. It is advisable to employ CFTR gene mutation testing in preconception genetic screening to reduce the risk of CBAVD and cystic fibrosis in offspring.

A capped Tudor domain within a core subunit of the Sin3L/Rpd3L histone deacetylase complex binds to nucleic acid G-quadruplexes.

Chromatin-modifying complexes containing histone deacetylase (HDAC) activities play critical roles in the regulation of gene transcription in eukaryotes. These complexes are thought to lack intrinsic DNA-binding activity, but according to a well-established paradigm, they are recruited via protein-protein interactions by gene-specific transcription factors and posttranslational histone modifications to their sites of action on the genome. The mammalian Sin3L/Rpd3L complex, comprising more than a dozen different polypeptides, is an ancient HDAC complex found in diverse eukaryotes. The subunits of this complex harbor conserved domains and motifs of unknown structure and function. Here, we show that Sds3, a constitutively-associated subunit critical for the proper functioning of the Sin3L/Rpd3L complex, harbors a type of Tudor domain that we designate the capped Tudor domain. Unlike canonical Tudor domains that bind modified histones, the Sds3 capped Tudor domain binds to nucleic acids that can form higher-order structures such as G-quadruplexes and shares similarities with the knotted Tudor domain of the Esa1 histone acetyltransferase that was previously shown to bind single-stranded RNA. Our findings expand the range of macromolecules capable of recruiting the Sin3L/Rpd3L complex and draw attention to potentially new biological roles for this HDAC complex.

Association Between CYP2B6 Polymorphisms and Efficacy of Clopidogrel in Minor Stroke or Transient Ischemic Attack.

BACKGROUND: CYP2B6 (cytochrome P450 subfamily IIB polypeptide 6), encoded by the CYP2B6 gene, is a critical enzyme involved in clopidogrel metabolism. However, the association between CYP2B6 polymorphisms and the efficacy of clopidogrel in minor stroke or transient ischemic attack for secondary stroke prevention remains unclear. METHODS: Based on CHANCE (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) randomized clinical trial of aspirin plus clopidogrel versus aspirin alone, we investigated the role of CYP2B6 polymorphisms and the efficacy of clopidogrel in patients with minor stroke or transient ischemic attack in China from October 2009 to July 2012. A total of 2853 patients were successfully genotyped for CYP2B6-516G>T, rs3745274 and CYP2B6-1456 T>C, rs2054675. The primary efficacy and safety outcomes were new stroke and any bleeding within 90 days. RESULTS: Among the 2853 patients, 32.8% were identified as the carriers of the CYP2B6-516 GT/TT or -1456 TC/CC genotype. The incidences of 90-day new stroke in aspirin plus clopidogrel and aspirin alone groups were 7.1% versus 11.3% among noncarriers, respectively; and 9.7% versus 12.2% among carriers, respectively. The efficacy of aspirin plus clopidogrel versus aspirin alone was not significantly different (P interaction=0.29) in noncarriers (adjusted hazard ratio, 0.61 [95% CI, 0.45-0.83]) compared to carriers (adjusted hazard ratio, 0.80 [95% CI, 0.54-1.18]). The incidence (n=51) of 90-day any bleeding in aspirin plus clopidogrel and aspirin alone groups were 2.2% (21 bleeds) versus 1.9% (18 bleeds) among noncarriers (adjusted hazard ratio, 1.11 [95% CI, 0.59-2.09]) and 1.9% (9 bleeds) versus 0.7% (3 bleeds) among carriers (adjusted hazard ratio, 3.23 [95% CI, 0.86-12.12]). Similar findings were observed during the 1-year follow-up. CONCLUSIONS: In this post hoc analysis of the CHANCE trial, we did not observe a significant difference in the efficacy of aspirin plus clopidogrel compared with aspirin in carriers versus noncarriers of CYP2B6-516 GT/TT or -1456 TC/CC genotype. Our results suggest that both carriers and noncarriers suffering from a minor stroke are likely to benefit from aspirin plus clopidogrel treatment over aspirin monotherapy for secondary prevention. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00979589.

Long-term outcomes of sirolimus treatment for kaposiform hemangioendothelioma: Continuing successes and ongoing challenges.

Treatment with sirolimus, an inhibitor of the mammalian target of rapamycin pathway, has improved the prognosis of patients with kaposiform hemangioendothelioma (KHE). However, the efficacy, durability and tolerability of long-term sirolimus treatment in patients with KHE have not been well elucidated. We performed efficacy and safety assessments based on more than 4.5 years of follow-up in patients receiving sirolimus therapy for KHE. One hundred sixty-seven patients were analyzed, including 102 (61.1%) patients with the Kasabach-Merritt phenomenon (KMP). Follow-up was conducted after a median of 56.0 months. A total of 154 (92.2%) patients had a durable response to sirolimus treatment. No difference in durable response was found between patients without KMP and patients with KMP (95.4% vs 90.2%; difference, 5.2%; 95% confidence interval [CI], -4.0% to 13.1%). Rebound growth occurred in 17.3% of patients upon sirolimus discontinuation. Early treatment discontinuation (odds ratio [OR]: 3.103; 95% CI: 1.529-6.299; P = .002) and mixed lesion type (OR: 2.271; 95% CI: 0.901-5.727; P = .047) were associated with tumor rebound growth. No KHE-related deaths occurred in this cohort. At the last follow-up, approximately 17.4% of patients had active disease and/or changes in body structures to a variable extent. Serious adverse events occurred most commonly during the first year of sirolimus therapy. Follow-up of almost 4.5 years demonstrated that the efficacy of sirolimus persisted over time and that long-term treatment with sirolimus was not associated with unacceptable cumulative toxicities. However, nonresponse, tumor relapse and long-term sequelae remained challenges despite intensified and prolonged sirolimus therapy.

The identification of PSEN1 p.Tyr159Ser mutation in a non-canonic early-onset Alzheimer's disease family.

More than 300 missense mutations in PSEN1 gene have been correlated to the early-onset Alzheimer's disease (EOAD), but given the high diversity of PS1 (the PSEN1 gene product) substrates and the involvement of PS1 in multiple biological functions, different mutants may represent different EOAD etiologies, and how each mutant contributes to the EOAD remains to be further investigated. Here we report the identification of a novel PSEN1 p.Tyr159Ser in a family with multiple EOAD cases. The mutant PS1 protein (PS1Y159S) was analyzed for its activity in producing amyloid-ß (Aß) and for the efficiency in maturation in vitro. We also screened other mutations and SNPs that may modify the effect of PSEN1 p.Tyr159Ser on AD pathogenesis. The blood samples of the family were collected for whole-exome gene sequencing and analysis. The identified mutant PS1 and several other PS1 mutants were co-expressed with the APP Swedish mutant to compare the effects on APP processing and PS1 maturation.1. The proband and her siblings over 50 years old showed typical AD or MCI symptoms. Exon sequencing identified the p.Tyr159Ser mutation in the PSEN1 gene. As not until the age of 78 did the proband's mother who carried this mutation displayed the symptoms of uncharacterized neuropsychiatry instead of AD, but all the mutation bearing lower generation developed AD or MCI after the age of 50, we also analyzed mutations/SNPs that are different between the mother and the lower generation. By in vitro assays, we found that the Y159S substitution strongly increased Aß42/Aß40 ratio and significantly affected PS1 maturation. The newly discovered PSEN1 p.Tyr159Ser is an AD-causing mutation, yet, the carriers are not obligated AD patients. Mutations/SNPs in other gene may modify the effects of this mutation, and the identification of these mutations/SNPs may facilitate the discovery of AD-preventing mechanisms and methods.

Increased systemic immune-inflammation index predicts hemorrhagic transformation in anterior circulation acute ischemic stroke due to large-artery atherosclerotic.

BACKGROUND AND PURPOSE: Inflammation and immune response play an important role in hemorrhage transformation after acute ischemic stroke. According to previous studies, systemic immune-inflammation index is associated with severity of stroke. We aimed to evaluate the association between systemic immune-inflammation index and hemorrhage transformation in anterior circulation acute ischemic stroke due to large-artery atherosclerosis. METHODS: This was a retrospective analysis of patients with anterior circulation acute ischemic stroke due to large-artery atherosclerosis. The laboratory data were collected within 24 h after admission. Hemorrhage transformation was defined on follow-up magnetic resonance imaging or Computed Tomography. The univariate analysis and multivariate logistic regression were performed to assess the association of systemic immune-inflammation index with hemorrhage transformation. Then the relationship between systemic immune-inflammation index and hemorrhage transformation in different stroke subtypes was further studied. RESULTS: We included 310 Chinese anterior circulation acute ischemic stroke patients due to large-artery atherosclerosis (mean age 65 ± 11.4 years; 72.6% male). Hemorrhage transformation occurred in 41 patients (13.2%). After multivariate regression analyses, systemic immune-inflammation index (odds ratio [OR] 1.109, 95% Confidence Interval [CI] 1.054-1.167, p＜0.001) was independently associated with hemorrhage transformation. Systemic immune-inflammation index was found to be significantly related to hemorrhagic transformation in artery-to-artery embolization (OR 1.111, 95% CI 1.029-1.210, p＜0.001) and in-situ thrombosis (OR 1.059, 95% CI 1.011-1.194, p = 0.045). CONCLUSIONS: Higher systemic immune-inflammation index is associated with greater risk of hemorrhagic transformation in patients with anterior circulation acute ischemic stroke due to large-artery atherosclerosis, especially in artery-to-artery embolization and in-situ thrombosis.

IMU/UWB Fusion Method Using a Complementary Filter and a Kalman Filter for Hybrid Upper Limb Motion Estimation.

Motion capture systems have enormously benefited the research into human-computer interaction in the aerospace field. Given the high cost and susceptibility to lighting conditions of optical motion capture systems, as well as considering the drift in IMU sensors, this paper utilizes a fusion approach with low-cost wearable sensors for hybrid upper limb motion tracking. We propose a novel algorithm that combines the fourth-order Runge-Kutta (RK4) Madgwick complementary orientation filter and the Kalman filter for motion estimation through the data fusion of an inertial measurement unit (IMU) and an ultrawideband (UWB). The Madgwick RK4 orientation filter is used to compensate gyroscope drift through the optimal fusion of a magnetic, angular rate, and gravity (MARG) system, without requiring knowledge of noise distribution for implementation. Then, considering the error distribution provided by the UWB system, we employ a Kalman filter to estimate and fuse the UWB measurements to further reduce the drift error. Adopting the cube distribution of four anchors, the drift-free position obtained by the UWB localization Kalman filter is used to fuse the position calculated by IMU. The proposed algorithm has been tested by various movements and has demonstrated an average decrease in the RMSE of 1.2 cm from the IMU method to IMU/UWB fusion method. The experimental results represent the high feasibility and stability of our proposed algorithm for accurately tracking the movements of human upper limbs.

Performance Enhancement of INS and UWB Fusion Positioning Method Based on Two-Level Error Model.

In GNSS-denied environments, especially when losing measurement sensor data, inertial navigation system (INS) accuracy is critical to the precise positioning of vehicles, and an accurate INS error compensation model is the most effective way to improve INS accuracy. To this end, a two-level error model is proposed, which comprehensively utilizes the mechanism error model and propagation error model. Based on this model, the INS and ultra-wideband (UWB) fusion positioning method is derived relying on the extended Kalman filter (EKF) method. To further improve accuracy, the data prefiltering algorithm of the wavelet shrinkage method based on Stein's unbiased risk estimate-Shrink (SURE-Shrink) threshold is summarized for raw inertial measurement unit (IMU) data. The experimental results show that by employing the SURE-Shrink wavelet denoising method, positioning accuracy is improved by 76.6%; by applying the two-level error model, the accuracy is further improved by 84.3%. More importantly, at the point when the vehicle motion state changes, adopting the two-level error model can provide higher computational stability and less fluctuation in trajectory curves.

Constrained ESKF for UAV Positioning in Indoor Corridor Environment Based on IMU and WiFi.

The indoor autonomous navigation of unmanned aerial vehicles (UAVs) is the current research hotspot. Unlike the outdoor broad environment, the indoor environment is unknown and complicated. Global Navigation Satellite System (GNSS) signals are easily blocked and reflected because of complex indoor spatial features, which make it impossible to achieve positioning and navigation indoors relying on GNSS. This article proposes a set of indoor corridor environment positioning methods based on the integration of WiFi and IMU. The zone partition-based Weighted K Nearest Neighbors (WKNN) algorithm is used to achieve higher WiFi-based positioning accuracy. On the basis of the Error-State Kalman Filter (ESKF) algorithm, WiFi-based and IMU-based methods are fused together and realize higher positioning accuracy. The probability-based optimization method is used for further accuracy improvement. After data fusion, the positioning accuracy increased by 51.09% compared to the IMU-based algorithm and by 66.16% compared to the WiFi-based algorithm. After optimization, the positioning accuracy increased by 20.9% compared to the ESKF-based data fusion algorithm. All of the above results prove that methods based on WiFi and IMU (low-cost sensors) are very capable of obtaining high indoor positioning accuracy.

Identification of close relationship between large-scale circulation patterns and ozone-precursor sensitivity in the Pearl River Delta, China.

To curb the continuous deterioration of ozone (O3) pollution in China, identifying the O3-precursor sensitivity (OPS) and its driving factors is a prerequisite for formulating effective O3 pollution control measures. Traditional OPS identification methods have limitations in terms of spatiotemporal representation and timeliness; therefore, they are not appropriate for making OPS forecasts for O3 contingency control. OPS is not only influenced by local precursor emissions but is also closely related to meteorological conditions governed by large-scale circulation (LSC). In this study, a localized three-dimensional numerical modeling system was used to investigate the relationship between LSC and OPS in the Pearl River Delta (PRD) of China during September 2017, a month with continuous O3 pollution. Our results highlighted that there was a close relationship between LSC and OPS over the PRD, and the four dominant LSC patterns corresponded well to the NOx-limited, NOx-limited, VOC-limited, and transitional regimes, respectively. The clear linkage between LSC and OPS was mainly driven by the spatial heterogeneity of NOx and VOC emissions within and beyond the PRD along the prevailing winds under different LSC patterns. A conceptual model was developed to highlight the intrinsic causality between the LSC and OPS. Because current technology can accurately forecast LSC 48-72 h in advance, the LSC-based OPS forecast method provided us with a novel approach to guide contingency control and management measures to reduce peak O3 at a regional scale.

Analysis of the therapeutic effect of transanal endoscopic microsurgery on large rectal adenoma.

Purpose: Rectal adenoma, a pre-cancerous lesion, is one of the indications for transanal endoscopic microsurgery (TEM). TEM has its unique advantages in the treatment of rectal adenomas. However, there are few reports on the therapeutic effects of large rectal adenoma (LRA). The objective of this study was to investigate the value of TEM in the treatment of LRA. Materials and Methods: We collected data from patients who underwent surgery at our center from 2007 to 2017. The postoperative pathology of all patients was rectal adenoma and the diameter of the adenoma was 3 cm or greater. Moreover, all patients underwent TEM. We followed up to observe the incidence of no wound healing, rectal stenosis and recurrence rate of rectal adenoma. The risk factors of adenoma recurrence and wound healing were analysed using single- and multiple-factor analysis. Results: The clinicopathological data of 85 patients with LRA were collected through a pre-set table. During the follow-up period, eight patients were lost to follow-up, and three (3.90%) patients developed rectal stenosis. After 2 years of post-operative follow-up, 20 (25.97%) patients had recurrence and 57 (74.03%) patients had no recurrence. Multivariate analysis showed that positive margin was an independent risk factor for recurrence of adenoma. Conclusions: TEM is feasible in the treatment of large rectal tumours in Centers of Expertise with the technique.

A prospective multicenter study of sirolimus for complicated vascular anomalies.

OBJECTIVE: Complicated vascular anomalies (VAs) can be intractable and uncontrollable using conventional treatment and can result in lethal outcomes. We undertook a prospective, multicenter phase II trial to evaluate the efficacy and safety of sirolimus in pediatric patients with complicated VAs. METHODS: Eligible patients were required to be aged 0 to 14 years and to have a complicated VA. The patients were treated with daily oral sirolimus for 12 months. The primary endpoint was the response, which was measured using sequential volumetric magnetic resonance imaging. The secondary endpoints were the disease severity score and quality of life. RESULTS: Of 126 patients enrolled on an intention-to-treat basis, 98 (77.8%) had had an objective response to sirolimus, with a ≥20% decrease in lesion volume. Compared with those with arteriovenous malformations, the response rates were higher (>80%) for patients with common lymphatic malformations, venous malformations, kaposiform hemangioendothelioma, and combined malformations with a prominent venous and/or lymphatic component (P < .05). Improvements in the disease severity score and quality of life were obtained in 83.3% and 79.4% of patients, respectively. The most common adverse event was mucositis in 47 patients. More serious adverse events included reversible grade 4 pneumonitis in 3 patients and grade 4 upper respiratory infection in 1 patient. All these adverse events were considered at least possibly related to the treatment. CONCLUSIONS: Sirolimus is an apparently effective option for pediatric patients with various types of complicated VAs. Close monitoring of possible adverse events is required. The results from the present trial are the basis for future prospective studies using new therapeutic approaches.

Association of change in air quality with hospital admission for acute exacerbation of chronic obstructive pulmonary disease in Guangdong, China: A province-wide ecological study.

AIMS: To assess possible effect of air quality improvements, we investigated the temporal change in hospital admissions for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) associated with pollutant concentrations. METHODS: We collected daily concentrations of particulate matter (i.e., PM2.5, PM10 and PMcoarse), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3), and admissions for AECOPD for 21 cities in Guangdong from 2013 to 2017. We examined the association of air pollution with AECOPD admissions using two-stage time-series analysis, and estimated the annual attributable fractions, numbers, and direct hospitalization costs of AECOPD admissions with principal component analysis. RESULTS: From 2013-2017, mean daily concentrations of SO2, PM10 and PM2.5 declined by nearly 40%, 30%, and 26% respectively. As the average daily 8 h O3 concentration increased considerably, the number of days exceeding WHO target (i.e.,100 µg/m³) increased from 103 in 2015-152 in 2017. For each interquartile range increase in pollutant concentration, the relative risks of AECOPD admission at lag 0-3 were 1.093 (95% CI 1.06-1.13) for PM2.5, 1.092 (95% CI 1.08-1.11) for O3, and 1.092 (95% CI 1.05-1.14) for SO2. Attributable fractions of AECOPD admission advanced by air pollution declined from 9.5% in 2013 to 4.9% in 2016, then increased to 6.0% in 2017. A similar declining trend was observed for direct AECOPD hospitalization costs. CONCLUSION: Declined attributable hospital admissions for AECOPD may be associated with the reduction in concentrations of PM2.5, PM10 and SO2 in Guangdong, while O3 has emerged as an important risk factor. Summarizes the main finding of the work： Reduction in PM may result in declined attributable hospitalizations for AECOPD, while O3 has emerged as an important risk factor following an intervention.

Low-power-consumption polymer Mach-Zehnder interferometer thermo-optic switch at 532 nm based on a triangular waveguide.

We designed and fabricated a Mach-Zehnder interferometer (MZI) thermo-optic switch with an inverted triangular waveguide. The inverted triangular waveguide achieves a fundamental mode in a large waveguide dimension, which can reduce the coupling loss and increase the extinction ratio. The triangular waveguide-based switch was simulated and presented higher heating efficiency and lower power consumption than that of the traditional rectangular waveguide-based switch. Compared with the traditional rectangular waveguide-based device, the power consumption of the proposed device is reduced by 60%. Spacing photobleaching was introduced to fabricate the inverted triangular waveguide and adjust the refractive index to minimize the mode number. The insertion loss of the typical fabricated device with a 2 cm length is about 7.8 dB. The device shows an extinction ratio of ∼8.1dB at 532 nm with a very low power consumption of 2.2 mW, and the switching rise time and fall time are 110 and 130 µs, respectively. The proposed single-mode waveguide and low-power-consumption optical switch have great potential applications in visible optical communication fields such as wavelength division multiplexing and mode-division multiplexing.

Association of diurnal temperature range with daily hospitalization for exacerbation of chronic respiratory diseases in 21 cities, China.

BACKGROUND: The association between diurnal temperature range (DTR) and hospitalization for exacerbation of chronic respiratory diseases (CRD) was rarely reported. OBJECTIVES: To examine the association between DTR and daily hospital admissions for exacerbation of CRD and find out the potential effect of modifications on this association. METHOD: Data on daily hospitalization for exacerbation of chronic obstructive pulmonary disease (COPD), asthma and bronchiectasis and meteorology measures from 2013 through 2017 were obtained from 21 cities in South China. After controlling the effects of daily mean temperature, relative humidity (RH), particulate matter < 2.5 µm diameter (PM2.5) and other confounding factors, a standard generalized additive model (GAM) with a quasi-Poisson distribution was performed to evaluate the relationships between DTR and daily hospital admissions of CRD in a two-stage strategy. Subgroup analysis was performed to find potential modifications, including seasonality and population characteristics. RESULT: Elevated risk of hospitalization for exacerbation of CRD (RR = 1.09 [95%CI: 1.08 to 1.11]) was associated with the increase in DTR (the 75th percentile versus the 25th percentile of DTR at lag0-6). The effects of DTR on hospital admissions for CRD were strong at low DTR in the hot season and high DTR in the cold season. The RR (the 75th percentile versus the 25th percentile of DTR at lag0-6) of hospitalization was 1.11 (95%CI: 1.08 to 1.12) for exacerbations of COPD and 1.09 (95%CI: 1.05 to 1.13) for asthma. The adverse effect of DTR on hospitalization for bronchiectasis was only observed in female patients (RR = 1.06 [95%CI: 1.03 to 1.10]). CONCLUSION: Our study provided additional evidence for the association between DTR and daily hospitalization for exacerbation of CRD, and these associations are especially stronger in COPD patients and in the cold season than the hot season. Preventive measures to reduce the adverse impacts of DTR were needed for CRD patients.

Acute cerebral infarction with adenomyosis in a patient with fever: a case report.

BACKGROUND: It is reported that acute cerebral infarction with adenomyosis is associated with elevated D-Dimer, elevated CA125, anemia and menstruation. However, previous reports did not notice infection known as fever, which may be a potential risk factor for developing acute cerebral infarction with adenomyosis. CASE PRESENTATION: We describe a 34-year-old woman who presented headache and fever (38 °C) for 4 days and left limb weakness for 1 day during her menstrual phase. Laboratory test data showed: Hemoglobin (HGB) (112 g/L, normal: 120-150 g/L), Carcinoembryonic antigen 125 (CA125) (937.70 U/ml, normal: 0-35 U/ml), D-Dimer (27.4 mg/L, normal: 0-1.5 mg/L). Magnetic resonance imaging (MRI) indicated acute cerebral infarction in right basal ganglia and subcortical region of right frontotemporal lobe. Further, brain computed tomography angiography (CTA) showed that the M1 segment of right middle cerebral artery was strictured and the distal branches of right middle cerebral artery were significantly less than those on the opposite side. No obvious abnormality was found in cranial magnetic resonance venogram (MRV). She had a 5-year history of adenomyosis. No tumors were found by whole body positron emission tomography-computed tomography (PET-CT). We treated this patient by using anti-infective therapy for 1 week and using anticoagulant therapy with low molecular weight heparin for 2 weeks. Subsequently, the anticoagulant therapy was discontinued and replaced by antiplatelet therapy with clopidogrel. We followed up this patient for 4 months, and no recurrence of cerebral infarction was found. CONCLUSIONS: Acute cerebral infarction with adenomyosis may be related to elevated D-Dimer, elevated CA125, anemia and menstruation. Our report suggests that infection may be a potential risk factor for developing acute cerebral infarction with adenomyosis.