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Purpose: We investigated whether organoids can be generated from resected tumors of patients who received eight cycles of neoadjuvant FOLFIRINOX chemotherapy before surgery, and evaluated the sensitivity/resistance of these surviving cancer cells to cancer therapy. Experimental Design: We generated a library of 10 pancreatic ductal adenocarcinoma (PDAC) organoid lines: five each from treatment-naïve and FOLFIRINOX-treated patients. We first assessed the histologic, genetic, and transcriptional characteristics of the organoids and their matched primary PDAC tissue. Next, the organoids' response to treatment with single agents—5-FU, irinotecan, and oxaliplatin—of the FOLFIRINOX regimen as well as combined regimen was evaluated. Finally, global mRNA-seq analyses were performed to identify FOLFIRINOX resistance pathways. Results: All 10 patient-derived PDAC organoids recapitulate histologic, genetic, and transcriptional characteristics of their primary tumor tissue. Neoadjuvant FOLFIRINOX-treated organoids display resistance to FOLFIRINOX (5/5), irinotecan (5/5), and oxaliplatin (4/5) when compared with treatment-naïve organoids (FOLFIRINOX: 1/5, irinotecan: 2/5, oxaliplatin: 0/5). 5-Fluorouracil treatment responses between naïve and treated organoids were similar. Comparative global transcriptome analysis of treatment-naïve and FOLFIRINOX samples—in both organoids and corresponding matched tumor tissues—uncovered modulated pathways mainly involved in genomic instability, energy metabolism, and innate immune system. Conclusions: Resistance development in neoadjuvant FOLFIRINOX organoids, recapitulating their primary tumor resistance, suggests continuation of FOLFIRINOX therapy as an adjuvant treatment may not be advantageous for these patients. Gene-expression profiles of PDAC organoids identify targetable pathways involved in chemoresistance development upon neoadjuvant FOLFIRINOX treatment, thus opening up combination therapy possibilities.

Introduction As a homologue of the angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2) has been identified as the main receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion. We aimed to investigate the role of serum ACE in predicting the coronavirus disease 2019 (COVID-19) disease progression and the underlying mechanisms. Methods We retrospectively enrolled 120 patients with confirmed COVID-19 who underwent serum ACE detection on admission. The clinical characteristics and laboratory findings during hospitalization were evaluated dynamically to identify the potential risk factors for disease progression. Results ACE level was demonstrated as one of the independent risk factors. Patients with ACE level ≤ 33.5 U/L showed a higher cumulative virus RNA detection rate, elevated pro-inflammatory mediators levels, declined lymphocyte count, and decreased SARS-CoV-2-specific antibodies than those with ACE level > 33.5 U/L. Conclusion Lower serum ACE levels in relation to delayed virus elimination, hyperinflammatory condition, and impaired host antiviral immune responses contribute to disease progression of COVID-19.

Antimicrobial resistance (AMR) is a major public health challenge and spreads through humans, animals, and the environment. Many reports show that AMR genes (ARGs) or phenotypes can be transferred from food animals to humans. However, the level and correlation of AMR in different nodes of the poultry meat supply chain are still poorly understood. Herein, 225 Escherichia coli isolates were recovered from chilled chicken samples from markets (123) and chicken fecal samples from farms (102) in Zhejiang Province, China. The dominant sequence types (STs) were ST155 (8.89%), ST48 (7.56%), and ST10 (7.11%), which are common in chicken and fecal samples. Antimicrobial susceptibility testing (AST) analysis showed that the E. coli isolates from fecal samples and retail chickens were resistant to ampicillin (61.77% and 63.42%, respectively) and trimethoprim (56.87% and 52.85%). Moreover, 36.59% of the E. coli isolates from chilled chickens and 39.22% of the isolates from fecal samples were resistant to three or more antimicrobial agents. A total of 59 ARGs were identified in sequenced E. coli genomes, including the mcr-1 gene involved in colistin resistance. The E. coli from farms and markets could be clustered in the same branch according to core single nucleotide polymorphisms. In addition, toxin genes astA and hlyE were also predicted in 86.5% (32/37) and 13.5% (5/37) of the above genomes, respectively. Taken together, these findings demonstrated that E. coli isolates from markets and farms showed similar AMR patterns, suggesting that E. coli strains in markets may originate from farms.

Cholecystokinin-2 receptor (CCK2R) has been proven to be a specific biomarker for colorectal malignancies. Immunotoxins are a valuable class of immunotherapy agents consisting of a targeting element and a bacterial or plant toxin. Previous work demonstrated that targeting CCK2R is a good therapeutic strategy for the treatment of colorectal cancer (CRC). In the present study, we developed a new version of CCK2R-targeting immunotoxin GD9P using a targeted peptide, GD9, as the binding motif and a truncated Pseudomonas exotoxin A (PE38) as the cytokiller. BALB/c nude mice were treated with different doses of GD9P, and pharmacodynamics, pharmacokinetic, and toxicological data were obtained throughout this study. Compared to the parental immunotoxin rCCK8PE38, GD9P exhibited about 1.5-fold yield, higher fluorescence intensity, and increased antitumor activity against human CRC in vitro and in vivo. The IC50 values of GD9P in vitro ranged from 1.61 to 4.55 nM. Pharmacokinetic studies were conducted in mice with a T1/2 of 69.315 min. When tumor-bearing nude mice were treated with GD9P at doses ≥2 mg/kg for five doses, a rapid shrinkage in tumor volume and, in some cases, complete remission was observed. A preliminary safety evaluation demonstrated a good safety profile of GD9P as a Pseudomonas exotoxin A-based immunotherapy. The therapy in combination with oxaliplatin can increase the antitumor efficacy and reduce the toxic side effects caused by chemotherapy. In conclusion, the data support the use of GD9P as a promising immunotherapy targeting CCK2R-expressing colorectal malignancies.

In the optical imaging system, the dynamic modulation transfer function (DMTF) is affected by the wave aberration of optical system, the signal resolution and transfer characteristics of detector modules, and the image blur caused by the carrier motion, which has become one of the important parameters of the photoelectric imaging system. Based on the testing principle of dynamic and static modulation transfer function of photoelectric imaging system, a DMTF measuring device was developed, in which the focal length of optical collimation system was 10 000 mm, and the speed control range of moving target was 30 mm/s~5 000 mm/s, which met the DMTF test of photoelectric imaging system with long focal length. A series of experiments were carried out, and the results show that the repeatability of DMTF measurement is better than 0.01, and the uncertainty of measurement can reach to U= 0.05 (k=2).

We demonstrate a stable compact passively Q-switched laser generating 40 μJ, subnanosecond (< 1 ns) duration, 1064 nm pulses at a repetition rate of 10 kHz. With a composite Nd:YAG/Cr4+:YAG crystal in a simple and compact resonator end-pumped by intense 808 nm pulse, we effectively improve the stability of output laser pulses corresponding to the interpulse amplitude instability less 1% (rms) and the period jitter less 1 μs. These measured pulse-time characteristics agree with numerical simulations and the beam is close to the diffraction limit, with M2 < 1.2. The excellent optical properties and structure make this laser to be an attractive source for high-resolution 3D imaging radars or other widespread applications.

Background The effect of tumor size on account of long-term survival results in perihilar cholangiocarcinoma (PCCA) patients has remained a controversial debate. It is urgent necessary to identify the optimal cutoff value of tumor size in PCCA and integrate tumor size with other prognostic factors into a nomogram to improve the predictive accuracy of prognosis of patients with PCCA. Methods Three hundred sixty-three PCCA patients underwent surgical resection were extracted from the Surveillance, Epidemiology and End Results (SEER) database. X-tile program was used to identify the optimal cutoff value of tumor size. A nomogram including tumor size was established to predict 1-, 3- and 5-year cancer-specific survival (CSS) based on the independent risk factors chosen by Kaplan-Meier methods and multivariable cox regression models. The precision of the nomogram for predicting survival was validated internally and externally. Results PCCA patients underwent surgical resection were classified into 1–19 mm, 20–33 mm and ≥ 34 mm subgroups based on the optimal cutoff for tumor size in terms of CSS. And we noticed that more larger tumor size group had worse tumor grade, advanced T stage, more positive regional lymph nodes and more frequent vascular invasion. The nomogram according to the independent factors was well calibrated and displayed better discrimination power than 7th Tumor-Node-Metastasis (TNM) stage systems. Conclusions The results demonstrated that the larger tumor size of PCCA was, the worse survival would be. The proposed nomogram, which outperforms the conventional TNM staging system, showed relatively good performance and could be considered as convenient individualized predictive tool for prognosis of PCCA patients.

ObjectivePancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Thus far, most drugs have failed to significantly improve patient survival. N6-methyladenosine (m6A) plays an important role in the progression of PDAC, but its aberrant regulation driven by germline variants in human diseases remains unclear.DesignWe first performed an exome-wide association analysis in 518 PDAC patients with overall survival and replicated in an independent population containing 552 PDAC patients. Then, a series of biochemical experiments in vitro and in vivo were conducted to investigate potential mechanisms of the candidate variant and its target gene PIK3CB underlying the PDAC progression. Moreover, the PIK3CB-selective inhibitor KIN-193 was used to block PDAC tumour growth.ResultsWe identified a missense variant rs142933486 in PIK3CB that is significantly associated with the overall survival of PDAC by reducing the PIK3CB m6A level, which facilitated its mRNA and protein expression levels mediated by the m6A ‘writer’ complex (METTL13/METTL14/WTAP) and the m6A ‘reader’ YTHDF2. The upregulation of PIK3CB is widely found in PDAC tumour tissues and significantly correlated with the poor prognosis of PDAC, especially in PTEN-deficient patients. We further demonstrated that PIK3CB overexpression substantially enhanced the proliferation and migration abilities of PTEN-deficient PDAC cells and activated AKT signalling pathway. Remarkably, KIN-193, a PIK3CB-selective inhibitor, is shown to serve as an effective anticancer agent for blocking PTEN-deficient PDAC.ConclusionsThese findings demonstrate aberrant m6A homoeostasis as an oncogenic mechanism in PDAC and highlight the potential of PIK3CB as a therapeutic target for this disease.

The 3D printing technology with unique strategies for accurate fabrication of biomaterials in regenerative medicine has been widely applied in bone regeneration. However, the traditional 3D printing scaffolds are only stacked by solid struts without any hollow channel structures, which limits the new bone tissue formation. In this study, a special 3D scaffold with hollow channels and a micro-nano surface was prepared by a modified 3D printing strategy combined with the hydrothermal treatment approach. By regulating the reaction solution of hydrothermal treatment, the micro-nano structures formed on the surface of scaffolds can be successfully controlled. Moreover, the scaffolds have the ability to facilitate the attachment and proliferation of BMSCs after culturing for 1, 3, and 7 days in vitro. Interestingly, the in vivo results demonstrated that the hollow channels and the micro-nano surface present synergistic effects on bone regeneration. They both boost the new bone formation in femur defects in rabbits for 12 weeks after operation. The study demonstrates a 3D scaffold with special surface microstructures and hollow struts that can overcome the shortages of most traditional scaffolds and meanwhile improve the bioactivity of biomaterials for bone tissue engineering.

BackgroundInadequate number of lymph nodes examined was not uncommon. We aimed to assess the clinical role of inadequate number of lymph nodes examined in stage II colon cancer.MethodsThe cancer data used in our study were obtained from the SEER (Surveillance, Epidemiology and End Results) program. Using the chi-square test, all the variables obtained in our study were compared based on whether patients had enough (≥12) lymph nodes examined. Kaplan–Meier analysis was used for overall survival (OS) analysis, and log-rank test was applied to compare different N stages with the total number of lymph nodes examined. Multivariate analysis was carried out by creating a Cox proportional hazard model to assess the prognostic roles of different variables.ResultsIn total, 80,296 stage II/III colon cancer patients were recruited for our study. N0 stage with p < 0.001). Multivariate analyses indicated that OS of N0 stage with p = 0.018].ConclusionsN0 stage with less than eight lymph nodes examined in stage II colon cancer presented with no better OS compared to that of N1 stage. Stage II colon cancer with less than eight lymph nodes examined needed to be given greater emphasis in clinical practice.

Coronavirus disease-2019 (COVID‐19) has become a global pandemic. COVID-19 runs its course in two phases, the initial incubation phase and later clinical symptomatic phase. Patients in the initial incubation phase often have insidious clinical symptoms, but they are still highly contagious. At the later clinical symptomatic phase, the immune system is fully activated and the disease may enter the severe infection stage in this phase. Although many patients are known for their respiratory symptoms, they had neurological symptoms in their first 1–2 days of clinical symptomatic phase, and ischaemic stroke occurred 2 weeks after the onset of the clinical symptomatic phase. The key is to prevent a patient from progressing to this severe infection from mild infection. We are sharing our experience on prevention and management of COVID-19.

Malodor is becoming the main secondary pollution in the municipal sewage sludge-composting process. Ammonia and volatile sulfide compounds (VSCs) are the representative odorants that generated and emitted during the composting process. The emission characteristics of ammonia and VSCs were studied at different workshops in a full-scale municipal sludge-composting plant in North People's Republic of China. Results show that ammonia was the most dominant odorant of all the workshops and relative high concentrations of VSCs were detected at sludge stacking yard and composting workshop. The odor pattern of VSCs at the composting workshop and stacking yard were different. The odor pollution occurred mainly in the first 15 days of the composting process, in which the odor contribution of ammonia increased with time and the VSCs contributed largely in the first 5 days. The cumulative release concentration of VSCs from compost materials was in the order of DMDS (dimethyl disulfide) > DMS (dimethyl sulfide) > CS2 > MT (methyl mercaptan), and the total VSCs release concentration was in the range of 50–3200 μg·m−3. The production of ammonia correlated to the temperature and nitrogen content and state changes, however, the production of VSCs was more complicated due to the reaction and transformation of VSCs. Optimization of aerobic composting conditions and process parameters should be further studied to reduce the emission of odor gas from compost. Implications: Along with the widespread use of sludge aerobic composting in People's Republic of China, the malodor pollution during the composting treatment is becoming a serious environmental issue. The odor pollution occurred mainly in the first 15 days, and ammonia was the main odorant of all the workshops and need to be controlled. Relative high concentrations of VSCs were detected at sludge stacking yard and composting workshop, however, the odor impact of VSCs were different. The generation of VSCs is more complicated than ammonia due to the reaction and transformation of VSCs.

Purpose To develop and test a mission-oriented and multi-dimensional benchmarking method for a small scale university aiming for internationally first-class basic research. Design/methodology/approach An individualized evidence-based assessment scheme was employed to benchmark ShanghaiTech University against selected top research institutions, focusing on research impact and competitiveness at the institutional and disciplinary levels. Topic maps opposing ShanghaiTech and corresponding top institutions were produced for the main research disciplines of ShanghaiTech. This provides opportunities for further exploration of strengths and weakness. Findings This study establishes a preliminary framework for assessing the mission of the university. It further provides assessment principles, assessment questions, and indicators. Analytical methods and data sources were tested and proved to be applicable and efficient. Research limitations To better fit the selective research focuses of this university, its schema of research disciplines needs to be re-organized and benchmarking targets should include disciplinary top institutions and not necessarily those universities leading overall rankings. Current reliance on research articles and certain databases may neglect important research output types. Practical implications This study provides a working framework and practical methods for mission-oriented, individual, and multi-dimensional benchmarking that ShanghaiTech decided to use for periodical assessments. It also offers a working reference for other institutions to adapt. Further needs are identified so that ShanghaiTech can tackle them for future benchmarking. Originality/value This is an effort to develop a mission-oriented, individually designed, systematically structured, and multi-dimensional assessment methodology which differs from often used composite indices.

The SLC10A1 Ser267Phe (S267F) variant has been reported to severely inhibit hepatitis B virus (HBV) infection and taurocholate transport activity. This study aimed to clarify the effects of this variant on HBV infection and bile acid metabolism. SLC10A1 S267F was genotyped in 2907 HBV-exposed subjects (including HBV persistent carriers and spontaneously recovered subjects) and 1364 unexposed subjects (HBV marker-negative subjects), followed by replication I, comprising 914 exposed subjects and 1123 unexposed subjects, and replication II, comprising 355 children born to HBsAg-positive mothers (226 HBV-infected children and 129 controls). Intriguingly, SLC10A1 AA was observed only in the unexposed group, but not in the exposed group. The SLC10A1 A allele consistently decreased HBV infection risk compared with the G allele (OR = 0.76, 95% CI: 0.64-0.90 in combined samples). In addition, children with the SLC10A1 GA genotype had a reduced risk of perinatal transmission (OR = 0.31, 95% CI: 0.14-0.71). Moreover, unexposed subjects with the SLC10A1 AA genotype exhibited decreased serum total cholesterol and low-density lipoprotein cholesterol compared to those with the GG or GA genotypes (P = 2.975 × 10-4 and 0.004, respectively). The study highlighted the role of the SLC10A1 S267F variant in the loss of the ability to support HBV infection and taurocholate transport activity. Subjects with the AA genotype may escape from HBV infection and present decreased cholesterol levels as a consequence of impaired bile acid uptake.

Pancreatic cancer is one of the deadliest malignancies with few early detection tests or effective therapies. PI3K‐AKT signaling is recognized to modulate cancer progression. We previously identified that a genetic variant in PKN1 increased pancreatic cancer risk through the PKN1/FAK/PI3K/AKT pathway. In order to investigate the associations between genetic variations in that pathway and pancreatic cancer prognosis, we conducted a two‐stage survival analysis in a total of 547 Chinese pancreatic cancer patients. Consequently, a variant, rs13167294 A>C in PIK3R1, was significantly associated with poor survival in both stages and with hazard ratio being 1.32 (95% CI = 1.13‐1.56, P = 0.0007) in the combined analysis. Function annotation and prediction suggested that genetic variants in this locus might affect overall survival of pancreatic cancer patients by regulating PIK3R1 expression.

Treatment for osteochondral defects remains a great challenge. Although several clinical strategies have been developed for management of osteochondral defects, the reconstruction of both cartilage and subchondral bone has proved to be difficult due to their different physiological structures and functions. Considering the restriction of cartilage to self-healing and the different biological properties in osteochondral tissue, new therapy strategies are essential to be developed. This review will focus on the latest developments of bioactive scaffolds, which facilitate the osteogenic and chondrogenic differentiation for the regeneration of bone and cartilage. Besides, the topic will also review the basic anatomy, strategies and challenges for osteochondral reconstruction, the selection of cells, biochemical factors and bioactive materials, as well as the design and preparation of bioactive scaffolds. Specifically, we summarize the most recent developments of single-type bioactive scaffolds for simultaneously regenerating cartilage and subchondral bone. Moreover, the future outlook of bioactive scaffolds in osteochondral tissue engineering will be discussed. This review offers a comprehensive summary of the most recent trend in osteochondral defect reconstruction, paving the way for the bioactive scaffolds in clinical therapy. The translational potential of this article: This review summaries the latest developments of single-type bioactive scaffolds for regeneration of osteochondral defects. We also highlight a new possible translational direction for cartilage formation by harnessing bioactive ions and propose novel paradigms for subchondral bone regeneration in application of bioceramic scaffolds. Keywords: Bioactive scaffolds, Bioceramics, Cartilage repair, Osteochondral regeneration, Subchondral bone regeneration

Based on gas dynamics and computational fluid dynamics, the numerical simulation of the steady-state flow field of igniter working in the two conditions was conducted with FLUENT. The numerical simulation results were validated by experiments. Influences of ignition gas flow pipe on the igniter's working performance were analyzed on the basis of test validation. The analysis results show that the combustion chamber pressure has atmospheric pressure and that the igniter works with ignition gas flow pipe. The velocity of throat is lower than the speed of sound and the sonic position moves to the position of ignition gas flow pipe; the velocity, pressure and temperature of throat increase; but the flux, pressure and temperature of outlet decrease. Under the different conditions of combustion chamber pressure, the outlet velocity, pressure, temperature and flux have a stable section; but the flux decreases.

The hydrodynamics in the membrane module of a full-scale sMBR at 500 m3/d was simulated by computational fluid dynamics (CFD) in this study. Several key indexes, including membrane distance (d), aeration design, height of gas-liquid dispersion hm, and freeboard height hf and operational conditions, including SADp and liquid viscosity, were optimized through investigating their impacts on water velocity distribution and membrane shear stress. The CFD model was validated by comparing the simulated trace element RTD curves with experimental results. The optimal design and operational parameters for the full scale sMBR are as following: membrane distance d = 35 mm, air diffusers parallel located 75–100 mm under the bottom of the membrane module, the free board height hf adjusted to 400 mm, and the SADp recommended as 20 in the full-scale MBR studied.

FOXA1 is a pioneer transcription factor which has been established as a carcinogenic factor and can regulate the expression of downstream target genes in breast cancer. We hypothesized that genetic variants modulating FOXA1 expression might play a role in the risk of breast cancer. Physical interaction predicted by PreSTIGE analysis and CHIA-PET data integration with cis-expression quantitative trait loci (cis-eQTL) based SNP-FOXA1 analysis were used to identify potentially regulatory variants modulating the expression of FOXA1. Then, we utilized a case–control study consisting of 855 new diagnosed breast cancer cases and 920 controls in the Chinese population to identify breast cancer associated variants. Biological assays were conducted in breast cancer cell lines to illustrate the effects of associated variants on breast cancer risk. We identified that rs7160774 G > A variant was associated with lower risk of breast cancer (OR = 0.77, 95% confidence interval = 0.62–0.96, P = 0.022). Biological experiments indicated that rs7160774[A] allele down-regulated the expression of FOXA1 compared to the G allele by influencing transcription factor binding affinity, thus playing an important role in the development of breast cancer. Our study suggested that the regulatory variant rs7160774 was associated with risk of breast cancer by long-range modulating FOXA1 expression and provided critical insights into pinpoint causal genetic variants.

Helium bubbles, which are typical radiation microstructures observed in metals or alloys, are usually investigated using transmission electron microscopy (TEM). However, the investigation requires human inputs to locate and mark the bubbles in the acquired TEM images, rendering this task laborious and prone to error. In this paper, a machine learning method capable of automatically identifying and analyzing TEM images of helium bubbles is proposed, thereby improving the efficiency and reliability of the investigation. In the proposed technique, helium bubble clusters are first determined via the density-based spatial clustering of applications with noise algorithm after removing the background and noise pixels. For each helium bubble cluster, the number of helium bubbles is determined based on the cluster size depending on the specific image resolution. Finally, the helium bubble clusters are analyzed using a Gaussian mixture model, yielding the location and size information on the helium bubbles. In contrast to other approaches that require training using numerous annotated images to establish an accurate classifier, the parameters used in the established model are determined using a small number of TEM images. The results of the model formulated according to the proposed approach achieved a higher F1 score validated through some helium bubble images manually marked. Furthermore, the established model can identify bubble-like objects that humans cannot facilely identify. This computationally efficient method achieves object recognition for material structure identification that may be advantageous to scientific work.

Bisphenol A (BPA) may induce oxidative stress as well as the toxicity of colon cancer cells. We hypothesized that BPA exposure and interactions with genetic variants might be associated with colorectal cancer (CRC) risk, and the association might be partly mediated by oxidative stress. We measured urinary BPA and three oxidative stress markers [8-iso-prostaglandinF2α (8-isoPGF2α), 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)] in 275 new CRC cases and 538 healthy controls. A set of 25 genetic variations in 12 candidate DNA repair genes and 5 metabolic enzyme genes were genotyped by Sequenom MassARRAY approach. In multivariable logistic regression, significant positive associations of CRC risk with BPA, 8-OHdG and HNE-MA were observed. Additionally, 8-OHdG, HNE-MA and 8-isoPGF2α were significantly positively associated with BPA (P

Background Patients in the intensive care unit (ICU) often have serious infections, and anti-infection treatment is vital for these patients. Procalcitonin (PCT) is often used to identify bacterial infections and monitor the effectiveness of anti-infection treatments. This study aims to analyze the current research hotspots of the application of PCT in ICU patients, and to suggest future research directions. Methods The Science Citation Index Expanded (SCI-EXPANDED) database in the Web of Science Core Collection (WOSCC) was used as the data source to search literature from 1995 to February 6, 2021. The search strategy was subject term = procalcitonin AND Web of Science categories = Critical Care Medicine. Using CiteSpace software, literature on the application of PCT in ICU patients was analyzed. Results A total of 1,243 papers, including 665 (53.5%) original articles, 87 (7.0%) reviews, 93 (7.5%) letters, 297 (23.9%) conference abstracts, and 101 (8.1%) other articles, were analyzed. The citation frequency was 40,442, the h-index was 96, and the average number of citations per item was 32.54. Research was mainly from the United States, Germany, France, and Spain, amongst others. The research institutions were mainly Univ Basel Hosp, Univ Pittsburgh, and Univ Hosp Geneva. Authors including Schuetz P made more contributions. Critical Care Medicine, Intensive Care Medicine, and Critical Care were important journals in this field of research. The keywords with the highest frequency were PCT, sepsis, and infection, and the more central ones were PCT, inflammation, septic shock, and C-reactive protein. The keywords with the strongest citation bursts were PCT, cytokine, and serum. Conclusions Papers are mainly published in critical care medical journals. The countries, institutions, and authors that carry out research are relatively limited. The current hot spots are still inflammation, infection, and shock, especially the management and prognosis prediction of critically ill patients.

Currently, the controversy regarding the expression profile and function of BUB1B in different malignancies still exist. In this project, we aimed to explore the role and molecular mechanism of BUB1B in the progression of extrahepatic cholangiocarcinoma (ECC). The expression levels of BUB1B in human ECC were evaluated by immunohistochemistry, western blot, and real-time PCR. The role and mechanism of BUB1B in CCA cell proliferation and invasion were investigated in both in vitro and in vivo functional studies. To indicate the clinical significance, a tissue microarray was performed on 113 ECC patients, followed by univariate and multivariate analyses. The expression of BUB1B was increased in both human CCA tissues and CCA cells. Results from loss-of-function and gain-of-function experiments suggested that the inhibition of BUB1B decreased the proliferation and invasiveness of CCA cells in vitro and in vivo, while overexpression of BUB1B achieved the opposite effect. Furthermore, the activation of c-Jun N-terminal kinase-c-Jun (JNK)-c-Jun pathway was regulated by BUB1B. BUB1B regulated the proliferation and invasiveness of CAA cells in a JNK-c-Jun-dependent manner. Clinically, ECC patients with BUB1B high expression had worse overall survival and recurrence-free survival than those with BUB1B low expression. Multivariate analysis identified that BUB1B was an independent predictor for postoperative recurrence and overall survival of ECC patients. In conclusion, BUB1B promoted ECC progression via JNK/c-Jun pathways. These findings suggested that BUB1B could be a potential therapeutic target and a biomarker for predicting prognosis for ECC patients.

Background Human epidermal stem cells (hESCs) play an important role in re-epithelialization and thereby in facilitating wound healing, while an effective way to activate hESCs remains to be explored. Calcium silicate (CS) is a form of bioceramic that can alter cell behavior and promote tissue regeneration. Here, we have observed the effect of CS on hESCs and investigated its possible mechanism. Methods Using a mouse full-thickness skin excision model, we explored the therapeutic effect of CS on wound healing and re-epithelialization. In vitro, hESCs were cultured with diluted CS ion extracts (CSIEs), and the proliferation, migration ability and stemness of hESCs were evaluated. The effects of CS on the epidermal growth factor (EGF), epidermal growth factor receptor (EGFR) and extracellular signal-related kinase (ERK) signaling pathway were also explored. Results In vivo, CS accelerated wound healing and re-epithelialization. Immunohistochemistry demonstrated that CS upregulated cytokeratin 19 and integrin β1 expression, indicating that CS improved hESCs stemness. In vitro studies confirmed that CS improved the biological function of hESCs. And the possible mechanism could be due to the activation of the EGF/EGFR/ERK signaling pathway. Conclusion CS can promote re-epithelialization and improve the biological functions of hESCs via activating the EGF/EGFR/ERK signaling pathway.

A strontium-containing hydrogel protects hearts against myocardial ischemia/reperfusion injury., Timely restoration of blood supply following myocardial infarction is critical to save the infarcted myocardium, while reperfusion would cause additional damage. Strontium ions have been shown to promote angiogenesis, but it is unknown whether they can save the damaged myocardium. We report that myocardial ischemia/reperfusion (I/R)–induced functional deterioration and scar formation were notably attenuated by injection of strontium ion–containing composite hydrogels into murine infarcted myocardium at 20 minutes of reperfusion following 60 minutes of ischemia. These beneficial effects were accompanied by reduced cardiomyocyte apoptosis and increased angiogenesis. The effects of strontium ions were further confirmed by the enhanced viability of cardiomyocytes and stimulated angiogenesis in vitro. These findings are the first to reveal the cardioprotective effects of strontium ions against I/R injury, which may provide a new therapeutic approach to ischemic heart disease at a lower cost, with higher stability, and with potentially greater safety.

Molecular variation of different geographic populations and cholangiocarcinoma (CCA) subtypes indicate CCA’s potential genomic heterogeneity and novel genomic features. We analyzed exome-sequencing data of 87 perihialr cholangiocarcinoma (pCCA) and 261 intrahepatic cholangiocarcinoma (iCCA) from 3 Asian centers (including 43 pCCAs and 24 iCCAs from our center). Patients with iCCA presented higher tumor mutation burden and copy number alteration burden (CNAB) than pCCA patients, and CNAB indicated a poorer pCCA prognosis. In our newly identified 12 significantly mutated genes and 5 focal CNA regions, post-transcriptional modification-related novel driver genes METTL14 and RBM10 are prone to occur in pCCA. We demonstrated the tumor-suppressing functional role of METTL14, a major RNA N6-adenosine methyltransferase (m6A), and its loss-of-function mutation R298H may function through m6A modification on new driver gene MACF1. Our results may be valuable for better understanding of post-transcriptional modification effects CCA development, and similarities and differences between pCCA and iCCA.

The increasing vulnerabilities in Android kernel make it an attractive target to the attackers. Most kernel-targeted attacks are initiated through system calls. For security purpose, Google has introduced a Linux kernel security mechanism named “seccomp” since Android O to constrain the system calls accessible to the Android apps. Unfortunately, existing Android seccomp mechanism provides a fairly coarse-grained restriction by enforcing a unified seccomp policy containing more than 250 system calls for Android apps, which greatly reduces the effectiveness of seccomp. Also, it lacks an approach to profile the unnecessary system calls for a given Android app. In this paper we present a two-level control scheme named SASAK, which can shrink the attack surface of Android kernel by strictly constraining the system calls available to the Android apps with seccomp mechanism. First, instead of leveraging a unified seccomp policy for all Android apps, SASAK introduces an architecture- dedicated system call constraining by enforcing two separate and refined seccomp policies for the 32-bit Android apps and 64-bit Android apps, respectively. Second, we provide a tool to profile the necessary system calls for a given Android app and enforce an app-dedicated seccomp policy to further reduce the allowed system calls for the apps selected by the users. The app-dedicated control could dynamically change the seccomp policy for an app according to its actual needs. We implement a prototype of SASAK and the experiment results show that the architecture-dedicated constraining reduces 39.6% system calls for the 64-bit apps and 42.5% system calls for the 32-bit apps. 33% of the removed system calls for the 64-bit apps are vulnerable, and the number for the 32-bit apps is 18.8%. The app-dedicated restriction reduces about 66.9% and 62.5% system calls on average for the 64-bit apps and 32-bit apps, respectively. In addition, SASAK introduces negligible performance overhead.

Objective: This study was intended to investigate the relationship between COVID-19 disease and ovarian function in reproductive-aged women.Methods: Female COVID-19 patients of reproductive age were recruited between January 28 and March 8, 2020 from Tongji Hospital in Wuhan. Their baseline and clinical characteristics, as well as menstrual conditions, were recorded. Differentials in ovarian reserve markers and sex hormones (including anti-Müllerian hormone [AMH], follicle-stimulating hormone [FSH], the ratio of FSH to luteinizing hormone [LH], estradiol [E2], progesterone [P], testosterone [T], and prolactin [PRL] were compared to those of healthy women who were randomly selected and individually matched for age, region, and menstrual status. Uni- and multi-variable hierarchical linear regression analyses were performed to identify risk factors associated with ovarian function in COVID-19 women.Results: Seventy eight patients agreed to be tested for serum hormone, of whom 17 (21.79%) were diagnosed as the severe group and 39 (50%) were in the basal level group. Menstrual status (P = 0.55), menstrual volumes (P = 0.066), phase of menstrual cycle (P = 0.58), and dysmenorrhea history (P = 0.12) were similar without significant differences between non-severe and severe COVID-19 women. Significant lower serum AMH level/proportion (0.19/0.28 vs. 1.12 ng/ml, P = 0.003/0.027; AMH ≤ 1.1 ng/ml: 75/70.4 vs. 49.7%, P = 0.009/0.004), higher serum T (0.38/0.39 vs. 0.22 ng/ml, P < 0.001/0.001) and PRL (25.43/24.10 vs. 12.12 ng/ml, P < 0.001/0.001) levels were observed in basal level and the all-COVID-19 group compared with healthy age-matched control. When adjusted for age, menstrual status and parity variations in multivariate hierarchical linear regression analysis, COVID-19 disease was significantly associated with serum AMH (β = −0.191; 95% CI: −1.177–0.327; P = 0.001), T (β = 0.411; 95% CI: 11.154–22.709; P < 0.001), and PRL (β = 0.497; 95% CI: 10.787–20.266; P < 0.001), suggesting an independent risk factor for ovarian function, which accounted for 3.2% of the decline in AMH, 14.3% of the increase in T, and 20.7% of the increase in PRL.Conclusion: Ovarian injury, including declined ovarian reserve and reproductive endocrine disorder, can be observed in women with COVID-19. More attention should be paid to their ovarian function under this pandemic, especially regarding reproductive-aged women.Clinical Trial Number: ChiCTR2000030015.

Diastolic dysfunction is condition of a stiff ventricle and a function of aging. It causes significant cardiovascular mortality and morbidity, and in fact, three million Americans are currently suffering from this condition. To date, all the pharmacological clinical trials have been negative. The lack of success in attenuating/ameliorating diastolic dysfunction stems from lack of duplication of myriads of clinical manifestation in pre-clinical settings. Here we report, a novel genetically engineered mice which may represents a preclinical model of human diastolic dysfunction to some extent. Topoisomerase 2 beta (Top2b) is an important enzyme in transcriptional activation of some inducible genes through transient double-stranded DNA breakage events around promoter regions. We created a conditional, tissue-specific, inducible Top2b knockout mice in the heart. Serendipitously, echocardiographic parameters and more invasive analysis of left ventricular function with pressure–volume loops show features of diastolic dysfunction. This was also confirmed histologically. At the cellular level, the Top2b knockdown showed morphological changes and molecular signaling akin to human diastolic dysfunction. Reverse phase protein analysis showed activation of p53 and inhibition of, Akt, as the possible mediators of diastolic dysfunction. Finally, activation of p53 and inhibition of Akt were confirmed in myocardial biopsy samples obtained from human diastolic dysfunctional hearts. Thus, we report for the first time, a Top2b downregulated preclinical mice model for diastolic dysfunction which demonstrates that Akt and p53 are the possible mediators of the pathology, hence representing novel and viable targets for future therapeutic interventions in diastolic dysfunction.

Objectives: This study aimed to evaluate and update incidence trends of soft-tissue sarcoma (STS) and to develop a nomogram to predict cancer-specific survival (CSS) in patients diagnosed with primary STS of the liver. Methods: Patients with hepatic STS were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Joinpoint regression analyses were performed to assess the incidence trends of STS. A nomogram was developed based on the independent risk factors chosen by Cox regression models. The calibration curve, area under the receiver operating characteristic curve (AUC), C‐index, and decision curve analysis (DCA) were used to assess the predictive performance of the nomogram. Results: The incidence of STS increased between 1994 and 2012. There was a sudden decline in the incidence of STS from 2013. The incidence of STS was different in distinct races and genders. The nomogram for predicting the CSS of hepatic STS according to the independent factors was well calibrated and it displayed optimal discrimination power. Conclusion: This study highlights that age, sex, tumor size, quality of surgery, and histologic subtypes may contribute to the prognosis of hepatic STS, and STS may be etiologically distinct and should be considered separately in different races and genders.

The impact of tumor size on account of the long-term survival results in gallbladder cancer (GBC) patients has been controversial. It is urgent necessary to identify the optimal cut-off value of tumor size in resected GBC, and we attempted to integrate tumor size with other prognostic factors into a prognostic nomogram to predict the cancer-specific survival (CSS) of GBC patients. 1639 patients with resected GBC were extracted from the Surveillance, Epidemiology and End Results (SEER) database. X-tile program was used to identify the optimal cut-off value of tumor size. A nomogram including tumor size was established to predict 1-, 3- and 5-year CSS based on the independent risk factors chosen by univariate and multivariable cox analyses. The precision of the nomogram for predicting survival was validated with Harrell’s concordance index (C-index), calibration curves, and receiver operating characteristic curve (ROC) internally and externally. Patients with GBC were classified into 1–13 mm, 14–63 mm and 64 mm subgroup based on the optimal cut-off for tumor size in terms of CSS. The nomogram according to the independent factors was well calibrated and displayed better discrimination power than 7th tumor–node–metastasis (TNM) stage systems. The results demonstrated that increased tumor size is closely associated with the worse CSS. Our novel nomogram, which outperforms the conventional TNM staging system, showed satisfactory accuracy and clinically practicality for predicting the outcome of resected GBC patients.

Background: Epirubicin combined with docetaxel is the cornerstone of neoadjuvant chemotherapy (NAC) for breast cancer. The efficacy of NAC for luminal A breast cancer patients is very limited, and single nucleotide polymorphism is one of the most important factors that influences the efficacy. Our study is aimed to explore genetic markers for the efficacy of epirubicin combined with docetaxel for NAC in patients with luminal A breast cancer. Methods: A total of 421 patients with two stages of luminal A breast cancer were enrolled in this study from 2 centers. Among them 231 patients were included in the discovery cohort and 190 patients are in the replication cohort. All patients received epirubicin 75 mg/m2 and docetaxel 75 mg/m2 on day 1, in a 21-day cycle, a cycle for 2-6 cycles. Before treatment, 2 ml of peripheral blood was collected from each patient to isolate genomic DNA. Fourteen functional variants potentially regulating epirubicin/docetaxel response genes were prioritized by CellMiner and bioinformatics approaches. Moreover, biological assays were performed to determine the effect of genetic variations on response to chemotherapy. Results: The patients carrying rs6484711 variant A allele suffered a poor response to epirubicin and docetaxel for NAC (OR = 0.37, 95% CI: 0.18-0.74, P = 0.005) in combined stage. Moreover, expression quantitative trait loci (eQTL) analyses and luciferase reporter assays revealed that rs6484711 A allele significantly increased the expression of ABTB2. Subsequent biological assays illustrated that upregulation of ABTB2 significantly reduced the apoptosis rate of breast cancer cells and enhanced the chemo-resistance to epirubicin. Conclusions: Our study demonstrated rs6484711 polymorphism regulating ABTB2 expression might predict efficacy to epirubicin based NAC in luminal A breast cancer patients. These results provided valuable information about potential role of genetic variations in individualized chemotherapy.

Background Recent studies have indicated that females with coronavirus disease 2019 (COVID-19) have a lower morbidity, severe case rate, and mortality and better outcome than those of male individuals. However, the reasons remained to be addressed. Methods To find the factors that potentially protect females from COVID-19, we recruited all confirmed patients hospitalized at 3 branches of Tongji Hospital (N = 1902), and analyzed the correlation between menstrual status (n = 509, including 68 from Mobile Cabin Hospital), female hormones (n = 78), and cytokines related to immunity and inflammation (n = 263), and the severity/clinical outcomes in female patients, Nonmenopausal females with COVID-19 had milder severity, better outcome, and shorter hospital stays than menopausal patients. E2 might be a potential protective factor against COVID-19, partly through its regulation of cytokines, which significantly correlated with severity of infection.

Background and purposeCOVID-19 is an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Apart from respiratory complications, acute cerebrovascular disease (CVD) has been observed in some patients with COVID-19. Therefore, we described the clinical characteristics, laboratory features, treatment and outcomes of CVD complicating SARS-CoV-2 infection.Materials and methodsDemographic and clinical characteristics, laboratory findings, treatments and clinical outcomes were collected and analysed. Clinical characteristics and laboratory findings of patients with COVID-19 with or without new-onset CVD were compared.ResultsOf 219 patients with COVID-19, 10 (4.6%) developed acute ischaemic stroke and 1 (0.5%) had intracerebral haemorrhage. COVID-19 with new onset of CVD were significantly older (75.7±10.8 years vs 52.1±15.3 years, pConclusionAcute CVD is not uncommon in COVID-19. Our findings suggest that older patients with risk factors are more likely to develop CVD. The development of CVD is an important negative prognostic factor which requires further study to identify optimal management strategy to combat the COVID-19 outbreak.

Importance The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, is serious and has the potential to become an epidemic worldwide. Several studies have described typical clinical manifestations including fever, cough, diarrhea, and fatigue. However, to our knowledge, it has not been reported that patients with COVID-19 had any neurologic manifestations. Objective To study the neurologic manifestations of patients with COVID-19. Design, Setting, and Participants This is a retrospective, observational case series. Data were collected from January 16, 2020, to February 19, 2020, at 3 designated special care centers for COVID-19 (Main District, West Branch, and Tumor Center) of the Union Hospital of Huazhong University of Science and Technology in Wuhan, China. The study included 214 consecutive hospitalized patients with laboratory-confirmed diagnosis of severe acute respiratory syndrome coronavirus 2 infection. Main Outcomes and Measures Clinical data were extracted from electronic medical records, and data of all neurologic symptoms were checked by 2 trained neurologists. Neurologic manifestations fell into 3 categories: central nervous system manifestations (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure), peripheral nervous system manifestations (taste impairment, smell impairment, vision impairment, and nerve pain), and skeletal muscular injury manifestations. Results Of 214 patients (mean [SD] age, 52.7 [15.5] years; 87 men [40.7%]) with COVID-19, 126 patients (58.9%) had nonsevere infection and 88 patients (41.1%) had severe infection according to their respiratory status. Overall, 78 patients (36.4%) had neurologic manifestations. Compared with patients with nonsevere infection, patients with severe infection were older, had more underlying disorders, especially hypertension, and showed fewer typical symptoms of COVID-19, such as fever and cough. Patients with more severe infection had neurologic manifestations, such as acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]), impaired consciousness (13 [14.8%] vs 3 [2.4%]), and skeletal muscle injury (17 [19.3%] vs 6 [4.8%]). Conclusions and Relevance Patients with COVID-19 commonly have neurologic manifestations. During the epidemic period of COVID-19, when seeing patients with neurologic manifestations, clinicians should suspect severe acute respiratory syndrome coronavirus 2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent further transmission.

Summary The efficient transmission of severe acute respiratory syndrome-2 coronavirus (SARS-CoV-2) from patients to health care workers or family members has been a worrisome and prominent feature of the ongoing outbreak. On the basis of clinical practice and in-vitro studies, we postulated that post-exposure prophylaxis (PEP) using Arbidol is associated with decreased infection among individuals exposed to confirmed cases of COVID-19 infection. We conducted a retrospective cohort study on family members and health care workers who were exposed to patients confirmed to have SARS-CoV-2 infection by real-time RT-PCR and chest computed tomography (CT) from January 1 to January 16, 2020. The last follow-up date was Feb. 26, 2020. The emergence of fever and/or respiratory symptoms after exposure to the primary case was collected. The correlations between post-exposure prophylaxis and infection in household contacts and health care workers were respectively analyzed. A total of 66 members in 27 families and 124 health care workers had evidence of close exposure to patients with confirmed COVID-19. The Cox regression based on the data of the family members and health care workers with Arbidol or not showed that Arbidol PEP was a protective factor against the development of COVID-19 (HR 0.025, 95% CI 0.003–0.209, P=0.0006 for family members and HR 0.056, 95% CI 0.005–0.662, P=0.0221 for health care workers). Our findings suggest Arbidol could reduce the infection risk of the novel coronavirus in hospital and family settings. This treatment should be promoted for PEP use and should be the subject of further investigation.

COVID-19 has become a global pandemic. The rapid outbreak has overwhelmed healthcare system and exhausted medical resources. There is a concern that many patients with other diseases cannot be promptly treated. Stroke is the leading cause of death and disability worldwide. In the context of COVID-19 epidemic, stroke remains to be a medical emergency. Ultraearly intravenous thrombolysis for patients with acute ischaemic stroke (AIS) is highly time-sensitive.1 How to balance the benefit of timely and efficacious care of the stroke patients to the risk of SARS-CoV-2 infection of healthcare professionals is the most challenging issue. Recently, there have been reports on the decreasing the Reporting of Observational Studies in Epide of cases of patients with stroke presented to the hospitals during the pandemic.2 On the other hand, stroke is not uncommon among patients with COVID-19.3 Here, we report intravenous thrombolytic therapy for patients with AIS at four stroke centres in the epicentre of Wuhan, Hubei during the epidemic, and compare the treatment provided during the same period in 2019. ### Study design This is a retrospective analysis of two groups of patients with AIS received intravenous tissue plasminogen activator (tPA) during 1 January to 30 Marchh of 2019 and 2020 in four hospitals (Wuhan Union Hospital,Wuhan Puren Hospitol, Wuhan People’s Hospital of Dongxihu District, People’s Hospital of Three Gorges University in Yichang adjacent to Wuhan). All four hospitals continuously received emergency cases during COVID-19 epidemic. The deadline for follow-up was 30 April 2020. ### Participants All patients with AIS enrolled must meet the following criteria: (1) treated with intravenous tPA (0.9 mg/kg), (2) received either a CT or MRI of brain before/after intravenous tPA. All patients with AIS treated with intravenous tPA had real-time reverse-transcription PCR analysis (RT-PCR) from the throat swab specimens and a chest CT scan during hospitalisation and follow-up …

ImportanceHow to explain the better prognosis of female coronavirus disease 2019 (COVID-19) patients than that of males?ObjectiveTo determine the correlation between menstruation status/sex hormones and prognosis of COVID-19, and to identify potential protective factors for female patients.Design, Setting, and ParticipantsA cross-sectional study of COVID-19 patients who were hospitalized at Tongji and Mobile Cabin Hospitals from Jan 28, 2020 to March 8, 2020.ExposuresConfirmed SARS-CoV-2 infection.Main Outcomes and MeasuresSex differences in severity and composite endpoints (admission to intensive care unit (ICU), use of mechanical ventilation, or death) of COVID-19 patients were compared. The correlation analysis and cox/logistic regression modeling of menstruation status/sex hormones and prognosis were conducted. Correlation between cytokines related to immunity and inflammation and disease severity or estradiol (E2) was revealed.ResultsChi square test indicated significant differences in distribution of composite endpoints (pp=0.029). E2 showed protective effect against disease severity (HR= 0.335, 95%CI = (0.105-1.070), p= 0.046). In the Mann-Whitney U test, the higher levels of IL6 and IL8 were found in severe group (p= 0.040, 0.033). The higher levels of IL2R, IL6, IL8 and IL10 were also observed in patients with composite end points (p). E2 levels were negatively correlated with IL2R, IL6, IL8 and TNFα in luteal phase (Pearson Correlation=−0.592, −0.558, −0.545, −0.623; p=0.033, 0.048, 0.054, 0.023) and with C3 in follicular phase (Pearson Correlation=-0.651; p=0.030).Conclusions and RelevanceMenopause is an independent risk factor for COVID-19. E2 and AMH are negatively correlated with COVID-19’s severity probably due to their regulation of cytokines related to immunity and inflammation.Key PointsQuestionAny differences in the outcomes between hospitalized female and male COVID-19 patients? If so, why?FindingsFemale patients display better prognosis than male patients. Non-menopausal women have shorter length of hospital stays, and AMH and E2 are negatively correlated with COVID-19’s severity. There is a negative correlation between E2 and the levels of IL6, IL8, IL2R and TNF-α, which are significantly correlated with disease severity or composite endpoint.MeaningNon-menopause and female sex hormones, especially E2 and AMH, are potential protective factors for females COVID-19 patients. E2 supplements could be potentially used for COVID-19 patients.

SummaryBackgroundAs of March 2, 2020, SARS-CoV-2 has infected more than 80174 people and caused 2915 deaths in China. This virus rapidly spreads to 56 countries worldwide. Thus, in order to effectively block its transmission, it is urgent to uncover all the possible transmission routes of SARS-CoV-2.MethodsFrom January 28 to February 18, 2020, 35 female patients diagnosed with COVID-19 in Tongji Hospital were included in this descriptive study. The gynecologic history, clinical characteristics, laboratory findings and chest computed tomography (CT) of all patients were recorded in detail. To examine whether there is sexual transmission through vaginal from female to her partner, we employed real-time polymerase chain reaction testing (RT-PCR) to detect SARS-CoV-2 in vaginal environment (including vaginal discharge, cervical or vaginal residual exfoliated cells) and anal swab samples, and inquired recent sexual behaviors from the patients.FindingsThe age range of the 35 patients with COVID-19 was 37-88 years. Over 50% patients infected with SARS-CoV-2 had chronic diseases. We tested the vaginal environment and anal swabs from the 35 female patients with COVID-19 and found that only an anal swab sample from one patient was positive for SARS-CoV-2. All the samples from vaginal environment were negative for SARS-CoV-2. The infection rate of the patients’ sexual partner was 42·9%. Additionally, two female patients admitted having sex with their partners during a possible infection incubation period, while one patient’s partner was uninfected and the other patient’s partner was diagnosed with COVID-19 (after the diagnosis of the female patient).ConclusionNo positive RT-PCR result was found in the vaginal environment perhaps due to the lack of ACE2 expression, which is the receptor of SARS-CoV-2, in the vagina and cervix tissues (human protein atlas). The results from this study show no evidence of transmission of SARS-CoV-2 through vaginal sex from female to her partner. However, the risk of infection of non vaginal sex and other intimate contacts during vaginal sex should not be ignored.FundingThis work was financially supported by the Clinical Research Pilot Project of Tongji hospital, Huazhong University of Science and Technology (No. 2019CR205).

OBJECTIVETo study the neurological manifestations of patients with coronavirus disease 2019 (COVID-19).DESIGNRetrospective case seriesSETTINGThree designated COVID-19 care hospitals of the Union Hospital of Huazhong University of Science and Technology in Wuhan, China.PARTICIPANTSTwo hundred fourteen hospitalized patients with laboratory confirmed diagnosis of severe acute respiratory syndrome from coronavirus 2 (SARS-CoV-2) infection. Data were collected from 16 January 2020 to 19 February 2020.MAIN OUTCOME MEASURESClinical data were extracted from electronic medical records and reviewed by a trained team of physicians. Neurological symptoms fall into three categories: central nervous system (CNS) symptoms or diseases (headache, dizziness, impaired consciousness, ataxia, acute cerebrovascular disease, and epilepsy), peripheral nervous system (PNS) symptoms (hypogeusia, hyposmia, hypopsia, and neuralgia), and skeletal muscular symptoms. Data of all neurological symptoms were checked by two trained neurologists.RESULTSOf 214 patients studied, 88 (41.1%) were severe and 126 (58.9%) were non-severe patients. Compared with non-severe patients, severe patients were older (58.7 ± 15.0 years vs 48.9 ± 14.7 years), had more underlying disorders (42 [47.7%] vs 41 [32.5%]), especially hypertension (32 [36.4%] vs 19 [15.1%]), and showed less typical symptoms such as fever (40 [45.5%] vs 92 [73%]) and cough (30 [34.1%] vs 77 [61.1%]). Seventy-eight (36.4%) patients had neurologic manifestations. More severe patients were likely to have neurologic symptoms (40 [45.5%] vs 38 [30.2%]), such as acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]), impaired consciousness (13 [14.8%] vs 3 [2.4%]) and skeletal muscle injury (17 [19.3%] vs 6 [4.8%]).CONCLUSIONCompared with non-severe patients with COVID-19, severe patients commonly had neurologic symptoms manifested as acute cerebrovascular diseases, consciousness impairment and skeletal muscle symptoms.

The immune system is essential for tissue repair and regeneration. Regardless of innate or adaptive immune responses, immunosuppressive strategies such as macrophage polarization and regulatory T (Treg) cells induction can be utilized to modulate the immune system to stimulate tissue repair and regeneration. Biomaterials provide an ideal platform which can serve as scaffolds to support damaged tissues and function as carriers to deliver immunosuppressive factors such as cytokines, drugs, microRNA, growth factors and stem cells. Herein, we present an overview of the immunosuppressive modulation by biomaterials in tissue regeneration and highlight the mechanisms of macrophage polarization and Treg cells induction. Overall, we propose that future biomaterials for regenerative strategies will not only involve more interactions between biomaterials and the immune system, but also require more knowledge about mechanisms of immune suppression, which will further enhance the clinical application of biomaterials.

Bisphenol A (BPA), a common endocrine disrupter, can be activated by cytochrome P450 (CYP) metabolizing enzymes and might influence the development of breast cancer (BC). We hypothesized that BPA could interact with CYP genes, synergistically contributing to the BC risk.Urinary BPA was measured in a total of 302 newly diagnosed BC patients and 302 healthy controls by ultra-high performance liquid chromatography-high resolution mass spectrometry. A set of seven CYP gene polymorphisms was genotyped by using the Sequenom MassARRAY system. A multivariate logistic regression model was used to assess the associations of BPA and BPA-SNP interaction with BC risk.BC patients had a higher urinary BPA concentration than healthy individuals (P 0.001). Each 1-unit increase in log-transformed urinary BPA was associated with a 54 % increased BC risk [95 % confidence interval (CI), 1.34-1.77, P 0.001]. Individuals with the CYP19A1 rs1902580 GA + AA genotype showed a significantly higher BC risk than those with the GG genotype (OR = 1.45, 95 % CI, 1.01-2.09, P 0.05). A significant BPA-CYP17A1 rs743572 interaction was found to be associated with a higher risk of BC (PThe positive association of BPA exposure with BC risk might be modified by CYP17A1 rs743572, providing evidence for the interaction effect of environment-genes on the etiology of BC.

Research on restoration of degraded areas is a popular topic in landscape ecology and restoration ecology. Finding proper methods to determine the restoration priorities for coal mining subsidence areas has great significance in improving urban ecosystem services and human well-beings in coal resources cities. Based on analysis of the existing research of ecological restoration priorities and green infrastructure (GI as short) theory, this paper proposes an integrated approach that combines habitat quality evaluation module in InVEST model (an integrated ecosystem services assessment tool based on ArcGIS), biodiversity service equivalent and landscape connectivity index to determine the restoration priorities. Using the Chinese coal resource city of Xuzhou as an example, the results of the integrated approach indicated that restoration priority values of coal mining subsidence areas in Xuzhou could be categorized into 5 grades, with high restoration priorities (Priority Class 5 and Class 4) generally located in the Jiawang district, the western Pangzhuang east district, the eastern and southern parts of the Dongzhuang west district and the northern Dahuangshan district. These regions are strongly recommended for integration into urban green infrastructure and for preferential restoration.