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Ying-Tao Lin,1 Ying Chen,2 Tian-Xiu Liu,3 Fang Kuang,1 Ping Huang1 1Administration Office of Drug Clinical Trial, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, People’s Republic of China; 2Management Office of Science and Technology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, 350014, People’s Republic of China; 3Department of Thoracic Radiotherapy, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, 350014, People’s Republic of ChinaCorrespondence: Ping HuangAdministration Office of Drug Clinical Trial, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, People’s Republic of ChinaTel +86 13960908650Fax +86 0591 62752517Email 1967217973@qq.comPurpose: The aim of this study was to assess the cost-effectiveness of camrelizumab immunotherapy versus docetaxel or irinotecan chemotherapy as second-line therapy for advanced esophageal squamous cell carcinoma (ESCC), which was evaluated in the ESCORT trial.Materials and Methods: A partitioned survival model was developed to reflect the costs and effectiveness of the ESCORT trial. The clinical efficacy data, safety data, and health-related costs and utilities were derived from published data from clinical trials or health administration departments in China. Adverse event-related costs, drug administration, and other expenses were derived from a single center of Fujian Medical University Cancer Hospital in 2021. All survival analyses were performed with SPSS software. Overall survival was estimated with the Kaplan–Meier method, and progression-free survival was estimated with the life table method. Sensitivity analyses were conducted to assess the uncertainty of the model. Incremental cost, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) were calculated.Results: Camrelizumab therapy had 0.232 QALYs at an incremental cost of USD$9959.44 compared with the chemotherapy group with 0.158 QALYs at an incremental cost of USD$8601.67. The ICER was USD$18393.12/QALY. Probabilistic sensitivity analyses showed that when the willingness-to-pay threshold reached USD$31200/QALY, which is nearly three times the Chinese gross domestic product per capita, camrelizumab had an 80% possibility of being cost-effective versus docetaxel or irinotecan chemotherapy.Conclusion: Camrelizumab is a cost-effective option compared with docetaxel or irinotecan chemotherapy in patients with advanced ESCC as second-line therapy in China.Keywords: camrelizumab, chemotherapy, cost-effectiveness, esophageal squamous cell carcinoma

Microseismic monitoring technology has become an important technique to assess stability of rock mass in metal mines. Due to the special characteristics of underground metal mines in China, including the high tectonic stress, irregular shape and existence of ore body, and complex mining methods, the application of microseismic technology is more diverse in China compared to other countries, and is more challenging than in other underground structures such as tunnels, hydropower stations and coal mines. Apart from assessing rock mass stability and ground pressure hazards induced by mining process, blasting, water inrush and large scale goaf, microseismic technology is also used to monitor illegal mining, and track personnel location during rescue work. Moreover, microseismic data have been used to optimize mining parameters in some metal mines. The technology is increasingly used to investigate cracking mechanism in the design of rock mass supports. In this paper, the application, research development and related achievements of microseismic technology in underground metal mines in China are summarized. By considering underground mines from the perspective of informatization, automation and intelligentization, future studies should focus on intelligent microseismic data processing method, e.g., signal identification of microseismic and precise location algorithm, and on the research and development of microseismic equipment. In addition, integrated monitoring and collaborative analysis for rock mass response caused by mining disturbance will have good prospects for future development.

Aim This study investigated the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on renal outcomes in Asian patients with type 2 diabetes mellitus (T2DM). Materials and methods We searched Medline, EMBASE, and the Cochrane Library to identify randomized controlled trials published up to April 2020 that compared SGLT2 inhibitors with placebo or active comparator and reported any renal outcomes in Asian patients with T2DM. Random effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals (CIs). Results We included 14 studies, totaling 3792 patients, in the analysis. In the short term, SGLT2 inhibitors significantly slowed estimated glomerular filtration rate (eGFR) decline (MD: 0.80; 95% CI: 0.66 to 0.94; p p p p = 0.11). However, dapagliflozin does appear to reduce albuminuria (p = 0.005). Lastly, SGLT2 inhibitors increased the incidence of adverse events (AEs) related to renal function (OR: 1.90; 95% CI: 1.24 to 2.91; p = 0.003), but did not increase the incidence of renal impairment (OR: 0.85; 95% CI: 0.40 to 1.81; p = 0.68). Conclusion The use of SGLT2 inhibitors in Asian patients with T2DM can help delay the decline of eGFR and reduce Scr and UA. Although SGLT2 inhibitors have no overall advantage in reducing albuminuria, dapagliflozin does appear to reduce albuminuria, and while they may increase the occurrence of AEs related to renal function, they do not increase the incidence of renal impairment.

Background Geleophysic dysplasia (GD) presents the characterized clinical manifestations of acromelic dysplasia, including extremely short stature, short limbs, small hands and feet, stubby fingers and toes, joint stiffness and others. It is clinically distinct from the other acromelic dysplasia in terms of symptoms such as cardiac valvular abnormalities, progressive hepatomegaly and tracheal stenosis. Case summary We report on a Chinese 9-year-old girl with GD with the c.5243G>T (p.C1748F) mutation in FBN1 (fibrillin 1, OMIM 134797). She was born in Guangxi Zhuang Autonomous Region of China. The patient presented with typical clinical features of GD and recurrent respiratory tract infections over 6 years. Laboratory studies and chest computed tomography (CT) scan indicated bronchopneumonia. Her echocardiography revealed mild mitral valve thickening with regurgitation. Laryngopharyngeal CT and electronic bronchoscopy revealed severe glottic stenosis. Echocardiography examination displayed mild mitral valve thickening and regurgitation. Ophthalmic examination did not reveal myopia or lens dislocation. Treated with ceftriaxone sodium and methylprednisolone sodium succinate for injection as well as methylprednisolone orally, patient's symptoms had improved. Conclusion GD is a rare genetic condition that can cause life-threatening cardiovascular and respiratory problems. This study also found that the identified genotype of GD could be related to different clinical phenotypes.

BACKGROUND Endometrial stromal tumors originate from the endometrial stroma and account for < 2% of all uterine tumors. Uterine tumor resembling an ovarian sex cord tumor (UTROSCT) is a rare histological class of endometrial stromal and related tumors according to the latest World Health Organization classification of female genital tumors. Here, we report a case of UTROSCT in a 51-year-old woman. CASE SUMMARY A 51-year-old woman had irregular menses for 6 mo. The patient visited a local hospital for vaginal bleeding. Pelvic computed tomography (CT) showed a mass in the pelvic cavity. Five days later, she came to our hospital for further diagnosis. The results of contrast-enhanced CT and pelvic ultrasound at our hospital suggested a malignant pelvic tumor. She then underwent total removal of the uterus with bilateral salpingectomy. Postoperative histological examination showed that the tumor cells had abundant cytoplasm, ovoid and spindle-shaped nuclei, fine chromatin, a high nucleoplasm ratio, and a lamellar distribution. The findings were consistent with UTROSCT, and the results of immunohistochemical analysis supported that diagnosis. The tumor was International Federation of Gynecology and Obstetrics stage IB. No adjuvant therapy was administered after radical surgery. The patient was followed up for 58 mo, and no recurrence was found. CONCLUSION We report a case of UTROSCT with abnormal menstruation as a symptom, which is one of the most common symptoms. In patients with vaginal bleeding, ultrasonography can be used as a screening test because of its convenience, speed, and lack of radiation exposure. For patients with long-term tamoxifen use, routine monitoring of the endometrium is recommended. As UTROSCT may have low malignant potential, surgery remains the primary management strategy. Additionally, fertility preservation in patients of childbearing age is a vital consideration.

Background A novel and improved methodology is still required for the diagnosis of diabetic kidney disease (DKD). The aim of the present study was to identify novel biomarkers using extracellular vesicle (EV)-derived mRNA based on kidney tissue microarray data. Methods Candidate genes were identified by intersecting the differentially expressed genes (DEGs) and eGFR-correlated genes using the GEO datasets GSE30528 and GSE96804, followed by clinical parameter correlation and diagnostic efficacy assessment. Results Fifteen intersecting genes, including 8 positively correlated genes, B3GALT2, CDH10, MIR3916, NELL1, OCLM, PRKAR2B, TREM1 and USP46, and 7 negatively correlated genes, AEBP1, CDH6, HSD17B2, LUM, MS4A4A, PTN and RASSF9, were confirmed. The expression level assessment results revealed significantly increased levels of AEBP1 in DKD-derived EVs compared to those in T2DM and control EVs. Correlation analysis revealed that AEBP1 levels were positively correlated with Cr, 24-h urine protein and serum CYC and negatively correlated with eGFR and LDL, and good diagnostic efficacy for DKD was also found using AEBP1 levels to differentiate DKD patients from T2DM patients or controls. Conclusions Our results confirmed that the AEBP1 level from plasma EVs could differentiate DKD patients from T2DM patients and control subjects and was a good indication of the function of multiple critical clinical parameters. The AEBP1 level of EVs may serve as a novel and efficacious biomarker for DKD diagnosis.

Background Superficial CD34-positive fibroblastoma (SCPFT) is a newly discovered mesenchymal tumor characterized by high polymorphism, low mitotic rate, and diffuse CD34-positive reactions. Aim To further determine the clinicopathological features of SCPFT. Methods We retrospectively analyzed the clinicopathological data, immunohistochemistry results, and differential diagnoses of four patients with SCPFT and performed a literature review. Relevant fusion genes were also detected. Results The tumors were all located in the lower extremities and presented as slow-growing painless masses located in the dermis and subcutaneous tissue. Microscopically, the tumors were composed of spindle-shaped to epithelioid cells with scattered abnormal and pleomorphic nuclei on a fibrous or fibromyxoid background. Necrosis was not found in the tumor tissues, and mitotic figures were rare. Immunohistochemically, the tumor cells were strongly positive for vimentin and CD34, and CKpan showed focal positivity in two tumors. All four patients were followed (13-57 mo, mean 35 mo), and one patient experienced local recurrence. Conclusion SCPFT is a newly discovered borderline mesenchymal tumor that can locally recur or even metastasize. Familiarity with its clinicopathological features will help avoid confusion with skin mesenchymal tumors with similar features.

To assess transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a detention facility experiencing a coronavirus disease outbreak and evaluate testing strategies, we conducted a prospective cohort investigation in a facility in Louisiana, USA. We conducted SARS-CoV-2 testing for detained persons in 6 quarantined dormitories at various time points. Of 143 persons, 53 were positive at the initial test, and an additional 58 persons were positive at later time points (cumulative incidence 78%). In 1 dormitory, all 45 detained persons initially were negative; 18 days later, 40 (89%) were positive. Among persons who were SARS-CoV-2 positive, 47% (52/111) were asymptomatic at the time of specimen collection; 14 had replication-competent virus isolated. Serial SARS-CoV-2 testing might help interrupt transmission through medical isolation and quarantine. Testing in correctional and detention facilities will be most effective when initiated early in an outbreak, inclusive of all exposed persons, and paired with infection prevention and control.

To limit introduction of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), the United States restricted travel from China on February 2, 2020, and from Europe on March 13. To determine whether local transmission of SARS-CoV-2 could be detected, the New York City (NYC) Department of Health and Mental Hygiene (DOHMH) conducted deidentified sentinel surveillance at six NYC hospital emergency departments (EDs) during March 1-20. On March 8, while testing availability for SARS-CoV-2 was still limited, DOHMH announced sustained community transmission of SARS-CoV-2 (1). At this time, twenty-six NYC residents had confirmed COVID-19, and ED visits for influenza-like illness* increased, despite decreased influenza virus circulation.† The following week, on March 15, when only seven of the 56 (13%) patients with known exposure histories had exposure outside of NYC, the level of community SARS-CoV-2 transmission status was elevated from sustained community transmission to widespread community transmission (2). Through sentinel surveillance during March 1-20, DOHMH collected 544 specimens from patients with influenza-like symptoms (ILS)§ who had negative test results for influenza and, in some instances, other respiratory pathogens.¶ All 544 specimens were tested for SARS-CoV-2 at CDC; 36 (6.6%) tested positive. Using genetic sequencing, CDC determined that the sequences of most SARS-CoV-2-positive specimens resembled those circulating in Europe, suggesting probable introductions of SARS-CoV-2 from Europe, from other U.S. locations, and local introductions from within New York. These findings demonstrate that partnering with health care facilities and developing the systems needed for rapid implementation of sentinel surveillance, coupled with capacity for genetic sequencing before an outbreak, can help inform timely containment and mitigation strategies.

Heterostructure photocatalysts with a built-in electric field have become one of the most promising strategies to enhance photogenerated electron-hole pair separation. However, close contact between the two active components of heterogeneous photocatalysts remains a problem. Herein, the in-situ fabrication of an SnO2/SnS2 heterostructure photocatalyst was performed; the structure showed enhanced photocatalytic performance resulting from the tight-contact heterostructures. The results of photoelectrochemical measurements further verified that a tight-contact heterostructure improved the separation of photogenerated electron-hole pairs. The results of EIS Bode plots also demonstrated that such in-situ fabricated SnO2/SnS2 samples exhibited the longest carrier lifetime (41.6 μs) owing to the intimate interface of SnO2/SnS2 heterostructures.

Rheumatoid arthritis (RA) is a long-term inflammatory disease derived from an autoimmune disorder of the synovial membrane. Current therapeutic strategies for RA mainly aim to hamper the macrophages' proliferation and reduce the production of pro-inflammatory cytokines. Therefore, the accumulation of therapeutic agents targeted at the inflammatory site should be a crucial therapeutic strategy. Nowadays, the nanocarrier system incorporated with stimuli-responsive property is being intensively studied, showing the potentially tremendous value of specific therapy. Stimuli-responsive (i.e., pH, temperature, light, redox, and enzyme) polymeric nanomaterials, as an important component of nanoparticulate carriers, have been intensively developed for various diseases treatment. A survey of the literature suggests that the use of targeted nanocarriers to deliver therapeutic agents (nanotherapeutics) in the treatment of inflammatory arthritis remains largely unexplored. The lack of suitable stimuli-sensitive polymeric nanomaterials is one of the limitations. Herein, we provide an overview of drug delivery systems prepared from commonly used stimuli-sensitive polymeric nanomaterials and some inorganic agents that have potential in the treatment of RA. The current situation and challenges are also discussed to stimulate a novel thinking about the development of nanomedicine.

The photoelectrocatalytic (PEC) technique has attracted much attention to getting clear energy and environmental purification. Simultaneous reactions of solar energy generation could be used to app...

The etiologic agent of an outbreak of pneumonia in Wuhan, China, was identified as severe acute respiratory syndrome coronavirus 2 in January 2020. A patient in the United States was given a diagnosis of infection with this virus by the state of Washington and the US Centers for Disease Control and Prevention on January 20, 2020. We isolated virus from nasopharyngeal and oropharyngeal specimens from this patient and characterized the viral sequence, replication properties, and cell culture tropism. We found that the virus replicates to high titer in Vero-CCL81 cells and Vero E6 cells in the absence of trypsin. We also deposited the virus into 2 virus repositories, making it broadly available to the public health and research communities. We hope that open access to this reagent will expedite development of medical countermeasures.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can spread rapidly within skilled nursing facilities. After identification of a case of Covid-19 in a skilled nursing facility, we assessed transmission and evaluated the adequacy of symptom-based screening to identify infections in residents. Methods We conducted two serial point-prevalence surveys, 1 week apart, in which assenting residents of the facility underwent nasopharyngeal and oropharyngeal testing for SARS-CoV-2, including real-time reverse-transcriptase polymerase chain reaction (rRT-PCR), viral culture, and sequencing. Symptoms that had been present during the preceding 14 days were recorded. Asymptomatic residents who tested positive were reassessed 7 days later. Residents with SARS-CoV-2 infection were categorized as symptomatic with typical symptoms (fever, cough, or shortness of breath), symptomatic with only atypical symptoms, presymptomatic, or asymptomatic. Results Twenty-three days after the first positive test result in a resident at this skilled nursing facility, 57 of 89 residents (64%) tested positive for SARS-CoV-2. Among 76 residents who participated in point-prevalence surveys, 48 (63%) tested positive. Of these 48 residents, 27 (56%) were asymptomatic at the time of testing; 24 subsequently developed symptoms (median time to onset, 4 days). Samples from these 24 presymptomatic residents had a median rRT-PCR cycle threshold value of 23.1, and viable virus was recovered from 17 residents. As of April 3, of the 57 residents with SARS-CoV-2 infection, 11 had been hospitalized (3 in the intensive care unit) and 15 had died (mortality, 26%). Of the 34 residents whose specimens were sequenced, 27 (79%) had sequences that fit into two clusters with a difference of one nucleotide. Conclusions Rapid and widespread transmission of SARS-CoV-2 was demonstrated in this skilled nursing facility. More than half of residents with positive test results were asymptomatic at the time of testing and most likely contributed to transmission. Infection-control strategies focused solely on symptomatic residents were not sufficient to prevent transmission after SARS-CoV-2 introduction into this facility.

With the continuing demand for the minimization of electrochemical energy storage devices, the volumetric performance has become equally important as the gravimetric metrics for rechargeable batter...

Background A history of abdominal biliary tract surgery has been identified as a relative contraindication for laparoscopic common bile duct exploration (LCBDE), and there are very few reports about laparoscopic procedures in patients with a history of abdominal biliary tract surgery. Methods We retrospectively reviewed the clinical outcomes of 227 consecutive patients with previous abdominal biliary tract operations at our institution between December 2013 and June 2019. A total of 110 consecutive patients underwent LCBDE, and 117 consecutive patients underwent open common bile duct exploration (OCBDE). Patient demographics and perioperative variables were compared between the two groups. Results The LCBDE group performed significantly better than the OCBDE group with respect to estimated blood loss [30 (5–700) vs. 50 (10–1800) ml; p = 0.041], remnant common bile duct (CBD) stones (17 vs. 28%; p = 0.050), postoperative hospital stay [7 (3–78) vs. 8.5 (4.5–74) days; p = 0.041], and time to oral intake [2.5 (1–7) vs. 3 (2–24) days; p = 0.015]. There were no significant differences in the operation time [170 (60–480) vs. 180 (41–330) minutes; p = 0.067]. A total of 19 patients (17%) in the LCBDE group were converted to open surgery. According to Clavien’s classification of complications, the LCBDE group had significantly fewer postoperative complications than the OCBDE group (40 vs. 57; p = 0.045). There was no mortality in either group. Multiple previous operations (≥ 2 times), a history of open surgery, and previous biliary tract surgery (including bile duct or gallbladder + bile duct other than cholecystectomy alone) were risk factors for postoperative adhesion (p = 0.000, p = 0.000, and p = 0.000, respectively). Conclusion LCBDE is ultimately the least invasive, safest, and the most effective treatment option for patients with previous abdominal biliary tract operations and is especially suitable for those with a history of cholecystectomy, few previous operations (

A novel constellation shaped 11-QAM signaling scheme based on geometric shaping (GS) and probabilistic shaping (PS) is proposed in this paper. The 11-QAM signals are obtained by Huffman coding with an optimized 11-QAM constellation structure. Then the non-uniform 11-QAM signals are generated by bit-interleaved coded modulation (BICM), which can get a better performance of bit error ratio (BER) and approach the Shannon limit. An experiment of the proposed 11-QAM constellation is carried out to transmit data over 25-km standard single-mode fiber (SSMF) in the polarization division multiplexed coherent optical communication system. Results show that when the data rate reaches 33Gbps, the proposed GS/PS 11-QAM scheme respectively outperforms the traditional uniformly distributed star 8-QAM and the traditional PS 9-QAM by 2.9dB and 1.2dB in OSNR.

In order to achieve higher data rate, higher spectral efficiency and greater transmission distance, the scheme of trellis coded modulation with three dimension 9QAM mapping based on a novel probabilistic shaping (PS) method is proposed in this paper. The bit error rate performance of three dimension 9QAM–TCM is investigated by simulation and compared with three dimension 8QAM–TCM scheme. Research results show that the Eb/N0 of the proposed three dimension 9QAM–TCM scheme is 1.2 dB smaller than that of three dimension 8QAM–TCM at the bit error rate of 10−4.

Myelodysplastic syndromes (MDSs) refractory or relapsed after hypomethylating agents (HMAs) remain a therapeutic challenge. The CHG regimen has been demonstrated to be effective in initially treating higher risk MDS. The current study evaluated the efficacy and toxicity of the CHG regimen in patients who were resistant to decitabine. Patients with higher risk MDS relapsed or refractory to decitabine were enrolled in this study. Each patient received the CHG regimen (cytarabine (25 mg/day, days 1–14) and homoharringtonine (1 mg/day, days 1–14) intravenously with G-CSF (300 μg/day) subcutaneously from day 0 until neutrophil count recovery to 2.0 × 109 cells/L). Next gene sequencing with a 31-gene panel was carried out in patients. Thirty-three patients were enrolled, including 12 relapsed and 21 refractory cases. The overall response rate (ORR) was 39.4% (13 of 33), with 9 (27.3%) achieving complete remission (CR), 2 having marrow CR (mCR), and 2 achieving partial remission (PR). The CR rate was higher in patients harboring fewer gene mutations (0–1) (55.6%) than in those with more gene mutations (> 1) (12.5%) (p = 0.021). The median overall survival (OS) of the 33 patients was 7.0 months. Patients who achieved a response had significantly longer survival times than were found in those without a response (21.0 M vs. 4.0 M, p

Adaptive forwarding routing algorithm is proposed in order to solve the problem that the traditional routing algorithm is insensitive to the dynamic change of satellite network state. This algorithm mainly uses the real-time perception of local network state, to realize load balancing. The simulation results show that it achieves shorter end-to-end delay and lower packet loss rate.

BACKGROUNDInformation is limited on messenger RNA (mRNA) BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccine effectiveness (VE) in preventing SARS-CoV-2 infection or attenuating disease when administered in real-world conditions.METHODSProspective cohorts of 3,975 healthcare personnel, first responders, and other essential and frontline workers completed weekly SARS-CoV-2 testing during December 14 2020—April 10 2021. Self-collected mid-turbinate nasal swabs were tested by qualitative and quantitative reverse-transcription–polymerase-chain-reaction (RT-PCR). VE was calculated as 100%×(1−hazard ratio); adjusted VE was calculated using vaccination propensity weights and adjustments for site, occupation, and local virus circulation.RESULTSSARS-CoV-2 was detected in 204 (5.1%) participants; 16 were partially (≥14 days post-dose-1 to 13 days after dose-2) or fully (≥14 days post-dose-2) vaccinated, and 156 were unvaccinated; 32 with indeterminate status (CONCLUSIONSAuthorized mRNA vaccines were highly effective among working-age adults in preventing SARS-CoV-2 infections when administered in real-world conditions and attenuated viral RNA load, febrile symptoms, and illness duration among those with breakthrough infection despite vaccination.

Background: Postmenopausal women often suffer from chronic pain, memory decline and mood depression. The mechanisms underlying the neuronal disorders are not fully understood and effective treatment is still lacking.Methods: Oral administration of magnesium-L-threonate was tested to treat the neuronal disorders in ovariectomized and aging mice. The pain hypersensitivity, memory function and depression were measured with a set of behavioral tests. Western blots and immunochemistry were used to assess molecular changes.Results: Chronic oral administration of magnesium-L-threonate substantially prevented or reversed the chronic pain, and memory/emotional deficits in both ovariectomized and aging female mice. We found that phospho-p65, an active form of nuclear factor-kappaB, tumor necrosis factor-alpha and interleukin-1beta were significantly upregulated in the neurons of dorsal root ganglion, spinal dorsal horn and hippocampus in ovariectomized and aging mice. The microglia and astrocytes were activated in spinal dorsal horn and hippocampus. The peptidergic C-fibers in dorsal horn were increased, which are associated with potentiation of C-fiber-mediated synaptic transmission in the model mice. In parallel with neuroinflammation and synaptic potentiation, free Mg2+ levels in plasma, cerebrospinal fluid and dorsal root ganglion neurons were significantly reduced. Oral magnesium-L-threonate normalized the neuroinflammation, synaptic potentiation and Mg2+ deficiency, but did not affect the estrogen decline in ovariectomized and aging mice. Furthermore, in cultured dorsal root ganglion neurons estrogen elevated intracellular Mg2+, and depressed the upregulation of phospho-p65, tumor necrosis factor-alpha and interleukin-1beta exclusively in the presence of extracellular Mg2+.Conclusions: Estrogen decline in menopause causes neuroinflammation by reducing intracellular Mg2+ in neurons, leading to chronic pain, memory/emotional deficits. Thus, supplement Mg2+ by oral magnesium-L-threonate may be a novel approach for treating menopause-related neuronal disorders.

Massive data traffic demand for satellite networks has been increased with the emergence of global broadband services. Due to limited onboard processing capacity and imbalanced distribution of global traffic, severe link congestion may occur in hot spots, deteriorating the performance of the whole network. A link cost modification applied in load balancing algorithm based on artificial bee colony is proposed for routing and wavelength assignment problem to distribute traffic in advance. Moreover, congestion avoidance based on wavelength utilization is designed for unexpected congestion to minimize the adverse impact of congestion on network performance. Experiment results show that the method we proposed realizes high performance in communication success rate and average transmission delay and also achieves the maximum utilization of wavelength utilization under the condition of low blocking rate and the equalization of traffic load.

PURPOSE To investigate the potential value of inflow-based vascular-space-occupancy (iVASO) MR imaging in differentiating metastatic from inflammatory lymph nodes (LNs). METHODS Ten female New Zealand rabbits with 2.5-3.0 kg body weight were studied. VX2 cells and egg yolk emulsion were inoculated into left and right thighs, respectively, to induce ten metastatic and ten inflammatory popliteal LNs. Conventional MRI and iVASO were performed 2 h prior to, and 10, 20 days after inoculation (D0, D10, D20). The short-axis diameter (S), short- to long-axis diameter ratio (SLR), and arteriolar blood volume (BVa) at each time point and their longitudinal changes of each model were recorded and compared. At D20, all rabbits were sacrificed to perform histological evaluation after the MR scan. RESULTS The mean values of S, SLR and BVa showed no significant difference between the two groups at D0 (P = 0.987, P = 0.778, P = 0.975). The BVa of the metastatic group was greater than that of the inflammatory at both D10 and D20 (P

Effective electricity consumption forecasting is extremely significant for enterprises' electricity planning which can provide data support for production decision, thus improving the level of enterprises' clean production. In recent years, recurrent neural network (RNN) and its variants have led to extensive research for time series forecasting. However, the performance and selection of these models in enterprise electricity forecasting have not been reported. With this study, we attempted to back some of these solutions with experimental results. This paper focused on a comparison for daily enterprise electricity consumption forecasting using different RNN models, i.e, standard RNN, long short-term memory-based RNN (LSTM), and gated recurrent unit-based RNN (GRU). To test their regression performance, three Chinese enterprises with different scales of electricity consumption are investigated. The comparison results show that the LSTM and the GRU models are slightly better than that of the RNN in terms of normalized root-mean-square error, mean absolute percentage error and threshold statistic. Moreover, the GRU model with the simplest structure is significantly different from the RNN, but not from LSTM in terms of Friedman testing. Hence the GRU model can be regarded as the first candidate for the enterprise electricity consumption forecasting in the future work. National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [71801044]; Humanities and Social Science Foundation of Ministry of Education of ChinaMinistry of Education, China [17YJC630003]; Natural Science Foundation of ChongqingNatural Science Foundation of Chongqing [cstc2018jcyjAX0436]; Project of China Scholarship Council [201908500020]; Open Grant of Chongqing Technology and Business University [KFJJ2018106, 1756012] info:eu-repo/semantics/publishedVersion

Background Clindamycin is a lincosamide antibiotic used to treat staphylococcal and streptococcal infections. Reports of clinical Streptococcus agalactiae isolates with the rare lincosamide resistance/macrolide susceptibility (LR/MS) phenotype are increasing worldwide. In this study, we characterised three clinical S. agalactiae strains with the unusual L phenotype from China. Methods Three clinical S. agalactiae strains, Sag3, Sag27 and Sag4104, with the L phenotype were identified from 186 isolates collected from 2016 to 2018 in Shanghai, China. The MICs of clindamycin, erythromycin, tetracycline, levofloxacin, and penicillin were determined using Etest. PCR for the lnu(B) gene was conducted. Whole genome sequencing and sequence analysis were carried out to investigate the genetic context of lnu(B). Efforts to transfer lincomycin resistance by conjugation and to identify the circular form by inverse PCR were made. Results Sag3, Sag27, and Sag4104 were susceptible to erythromycin (MIC ≤0.25 mg/L) but resistant to clindamycin (MIC ≥1 mg/L). lnu(B) was found to be responsible for the L phenotype. lnu(B) in Sag3 and Sag27 were chromosomally located in an aadE-spw-lsa(E)-lnu(B) resistance gene cluster adjacent to an upstream 7-kb tet(L)-cat resistance gene cluster. Two resistance gene clusters were flanked by the IS6-like element, IS1216. Sag4104 only contained partial genes of aadE-spw-lsa(E)-lnu(B) resistance gene cluster and was also flanked by IS1216. Conclusion These results established the presence of the L phenotype associated with lnu(B) in clinical S. agalactiae isolates in China. The lnu(B)-containing multi-resistance gene cluster possibly acts as a composite transposon flanked by IS1216 and as a vehicle for the dissemination of multidrug resistance among S. agalactiae.

Fiber supercapacitor (FSC) is a promising power source for wearable/stretchable electronics and high capacitive performance of FSCs is highly desirable for practice flexible applications. Here, we report a composite of manganese dioxide (MnO2) and activated carbon fibers (ACFs) with high MnO2 mass loading and microporous structure (abbreviated as MnO2@ACF), which is used as a fiber electrode to produce a FSC with a high capacitive performance and a good flexibility. The MnO2@ACF composite electrode in FSCs delivers an ultrahigh specific capacitance of 410 mF/cm2 at 0.1 mA/cm2, corresponding to a high energy density of 36 µWh/cm2 and high power density of 726 µW/cm2. Such high capacitive performance and simple fabrication method indicates that the MnO2@ACF composite is a very promising electrode material for flexible fiber supercapacitors.

For lithium-ion capacitors (LICs), the electrode mass balancing and the electrode potential tuning are two techniques that have been widely used to maximize the gravimetric specific capacity and voltage to achieve a maximum gravimetric energy density. However, it is also great important to consider the volumetric performances of energy storage devices for the compact and portable applications. Herein, for achieving high-volumetric-performance LICs, we propose an electrode thickness matching strategy, which is to minimize the thickness of thick cathodes as close to the one of thin anodes as possible via increasing the gravimetric specific capacity and density of cathode materials. It is demonstrated that introducing a highly dense but porous activated carbon/graphene (AC/G) composite rather than the low-density traditional activated carbon as the cathode material, the volumetric energy density of the assembled AC/G//graphite LIC can be increased by 62% to reach a maximum of 98 Wh L-1, which represents one of the highest records for the contemporary LICs. We believe that the thickness matching should be a universal strategy for achieving high volumetric performances and can be applicable to other electrochemical energy storage devices.

The flexible photonic generation of millimeter-wave (mm-wave) vector signal adopting frequency multiplication enabled by two paralleled phase modulators and pre-coded radio frequency (RF) signals based on dynamic pre-coding algorithm is proposed and demonstrated. One driving signal has the original phase information and a phase deviation for dispersion compensation while the other signal has an opposite phase information and the same compensation phase. The amplitude depends on that of the regular vector symbol and the ratio of driving voltage to half-wave voltage of the phase modulator (PM). Two RF signals modulate the identical light waves from one laser via phase modulators respectively. The light waves are then transmitted over a fiber link after the selection of proper orders of harmonics by the wavelength selective switch (WSS). At the receiver, the optical signal is applied directly to a photodetector (PD) to generate the mm-wave vector signal at the desired frequency. The simulation of proposed scheme with radio over fiber (RoF) link transmission has been build. The result shows that the error vector magnitude (EVM) of generated 60 GHz, 100 GHz, and 140 GHz 16 quadrature-amplitude-modulation (QAM) signals of 1 Gb/s is no more than 20% after 80 km fiber transmission when the power into PD is no less than −10 dBm under ideal condition.

Vanadium dioxide is one kind of desirable infrared modulator for sensors because of its remarkable temperature-responsive infrared modulation ability via autogeneic metal–insulator transition. Howe...

The fault diagnosis of the gearbox is a complex and important work. In this paper, a multilayer gated recurrent unit (MGRU) method is proposed for spur gear fault diagnosis, that is, three-layer gated recurrent unit (GRU). The vibration signals are firstly monitored on the test bench, and then extracted in both time domain and time-frequency domain. Finally, MGRU is used to learn representation and classification. The MGRU can improve the representation of information and identify the features of fault types more precisely with the increasing number of layers. The proposed method was tested by two spur gears with 10 state modes. To evaluate the method's classification accuracy, four methods were utilized for comparison, i.e., the GRU, long short-term memory (LSTM), multilayer LSTM (MLSTM), and support vector machine (SVM), respectively. In addition, the separability and robustness analysis are also discussed for the proposed MGRU performance. All of the results exhibited that the proposed MGRU approach is effective for spur gear fault diagnosis.

ObjectiveTo investigate a Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak event involving multiple healthcare facilities in Riyadh, Saudi Arabia; to characterize transmission; and to explore infection control implications.DesignOutbreak investigation.SettingCases presented in 4 healthcare facilities in Riyadh, Saudi Arabia: a tertiary-care hospital, a specialty pulmonary hospital, an outpatient clinic, and an outpatient dialysis unit.MethodsContact tracing and testing were performed following reports of cases at 2 hospitals. Laboratory results were confirmed by real-time reverse transcription polymerase chain reaction (rRT-PCR) and/or genome sequencing. We assessed exposures and determined seropositivity among available healthcare personnel (HCP) cases and HCP contacts of cases.ResultsIn total, 48 cases were identified, involving patients, HCP, and family members across 2 hospitals, an outpatient clinic, and a dialysis clinic. At each hospital, transmission was linked to a unique index case. Moreover, 4 cases were associated with superspreading events (any interaction where a case patient transmitted to ≥5 subsequent case patients). All 4 of these patients were severely ill, were initially not recognized as MERS-CoV cases, and subsequently died. Genomic sequences clustered separately, suggesting 2 distinct outbreaks. Overall, 4 (24%) of 17 HCP cases and 3 (3%) of 114 HCP contacts of cases were seropositive.ConclusionsWe describe 2 distinct healthcare-associated outbreaks, each initiated by a unique index case and characterized by multiple superspreading events. Delays in recognition and in subsequent implementation of control measures contributed to secondary transmission. Prompt contact tracing, repeated testing, HCP furloughing, and implementation of recommended transmission-based precautions for suspected cases ultimately halted transmission.

The forecast of electricity consumption plays an essential role in marketing management. In this study, a random forest (RF) model coupled with ensemble empirical mode decomposition (EEMD) named EEMD-RF is presented for forecasting the daily electricity consumption of general enterprises. The candidate data is first decomposed into several intrinsic mode functions (IMFs) by the EEMD. Through fast Fourier transformation, the features in each IMF are extracted in the time-frequency domain, then simulated and predicted by the RF model. Finally, the results of each IMF are integrated into the overall trend of the daily electricity consumption for those enterprises. The proposed method was applied to two enterprises located in the Jiangsu High-Tech Zone, and the period of collected data was from January 1, 2015 to May 3, 2016. To show the applicability and superiority of the EEMD-RF approach, two basic models (a back-propagation neural network (BPNN) and least squares support vector regression (LSSVM) and five model experiments (EEMD-BPNN, EEMD-LSSVM, RF, BPNN and LSSVM) were selected for comparison. Among these approaches, the proposed model exhibited the best forecast performance in terms of mean absolute error, mean absolute percentage error, and root-mean-square error.

This study assessed the environmental impacts of a composite polyvinylidene fluoride (PVDF) membrane (incorporating nanomaterials) and compared with neat PVDF membrane on algal membrane photoreactor (A-MPR) system's overall sustainability. The life cycle assessment (LCA) was carried out using Simapro 8.4.0 with cradle-to-gate approach, including raw materials, equipment, transportation and electricity consumption using ReCiPe 1.13 (H) and IPCC 2013 GWP 100a methodology. From the LCA analysis, silver/graphene oxide - polyvinylidene fluoride (Ag/GO-PVDF) membrane fabrication showed higher environmental impact than the neat PVDF membrane fabrication due to the addition of Ag/GO nanohybrids into the polymer. However, the A-MPR system using the Ag/GO-PVDF membrane exhibited better environmental footprint due to the improved performance of the modified membrane in producing higher volume of permeate as the output. Therefore, the A-MPR system using Ag/GO-PVDF membrane had outweighed the additional environmental impact of the Ag/GO-PVDF membrane fabrication process. Energy demand was identified as the main environmental hotspot in the LCA analysis. Subsequently, sensitivity analysis was performed to find out the effect of various energy mix for electricity generation towards the environment. The analysis revealed that the energy source for electricity generation had significant influence on the overall sustainability of the A-MPR system. The use of grid with 100% renewable energy (hydropower and geothermal) and solar photovoltaic might be able to mitigate 94.8% and 97.5% of CO2 emission, respectively.

Acute statin treatment has been reported to be critical in protecting the cardiac cells against ischemia/reperfusion injury by activating PI3K/Akt signal pathway. In vitro rat myocardial ischemia/reperfusion model, chronic statin treatment led to upregulation of phosphatase and tensin homolog (PTEN). This has been potentially indicated the correlation in PTEN and protective effect of statin on myocardium. In this current study, we evaluated the role of sodium orthovanadate a nonspecific inhibitor to PTEN and its correlation with atorvastatin on protecting myocardium against ischemia/reperfusion injury. We found a long-term statin treatment could increase the PTEN level, and this process was counteracted in the presence of sodium orthovanadate. However, the phosphotyrosine level was not affected by this statin. Besides, this process was mediated by Akt signaling since phosphorylated Akt level was altered by statin and sodium orthovanadate treatment. In a conclusion, this study showed a potential mechanism underlying PTEN-induced attenuation in long-term statin's therapeutic effect, which provided the new insight into the synergic role of PTEN and atorvastatin in protecting cardiac cells against ischemia/reperfusion injury.

Background: Unfractionated heparin (UFH), despite its limitations, has been used as the primary anticoagulant alternative during the percutaneous coronary intervention (PCI). Some studies indicated that intravenous enoxaparin could be an effective and safe option. Our team used enoxaparin alone at one time according to the guidelines (Class IIA) and found a little catheter thrombosis during PCI. We recommend a new anticoagulation strategy using enoxaparin in combination with UFH. Enoxaparin has a more predictable anticoagulant response with no need of repeatedly monitoring anticoagulation during PCI. This retrospective study aimed to evaluate the efficacy and safety of using enoxaparin in combination with UFH in PCI patients with complex coronary artery disease. Methods: Between January 2015 and April 2017, 600 PCI patients who received intravenous UFH at an initial dose of 3000 U plus intravenous enoxaparin at a dose of 0.75 mg/kg (observation group) and 600 PCI patients who received UFH at a dose of 100 U/kg (control group) were consecutively included in this retrospective study. The endpoints were postoperative 48-h thrombolysis in myocardial infarction (TIMI) bleeding and transfusion and 30-day and 1-year major adverse cardio-cerebrovascular events (MACCE). Results: Baseline clinical, angiographic, and procedural characteristics were similar between groups, except there was less stent implantation per patient in the observation group (2.13 vs. 2.25 in the control group, P = 0.002). TIMI bleeding (3.3% vs. 4.7%) showed no significant difference between the observation group and control group. During the 30-day follow-up, the rate of MACCE was 0.9% in the observation group and 1.5% in the control group. There was no significant difference in the rates of MACCE, death, myocardial infarction, target vessel revascularization, cerebrovascular event, and angina within 30 days and 1 year after PCI between groups as well as in the subgroup analysis of transfemoral approach. Conclusions: UFH with sequential enoxaparin has similar anticoagulant effect and safety as UFH in PCI of complex coronary artery disease. Key words: Complex Coronary Heart Disease; Enoxaparin; Percutaneous Coronary Intervention; Unfractionated Heparin

Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly contagious respiratory virus causing severe morbidity in pigs worldwide. Control strategies for PRRSV often rely on detecting PRRSV, culling or isolating sick pigs, disinfecting pig barns, vaccination, and monitoring for virus spread. Given the high economic impact of PRRSV on pig farms, there is a great need for rapid and reliable PRRSV detection assays. We compared the performance of 2 commercial reverse-transcription real-time PCR (RT-rtPCR) assays, the VetMAX PRRSV NA and EU reagents (ABI assay) and the PRRSV general RT-rtPCR kit (Anheal assay), for the molecular detection of PRRSV in sera collected from pigs in China. Between June and September 2015, sera were collected from 219 healthy and 104 suspected PRRSV-infected pigs on 4 farms in China. Employing blinding, the 2 assays were run by 2 laboratories (Guangzhou Animal Health Inspection Institute [GAHII] and Sun Yat-sen University [SYSU] laboratories) and compared. Although both assays detected PRRSV with 100% specificity at both laboratories, the sensitivity (95% vs. 78% at GAHII; 94% vs. 72% at SYSU Laboratory) and the reproducibility (kappa value 0.933 vs. 0.931) were slightly better for the ABI assay compared to the Anheal assay.

Background The coronavirus disease 2019 (COVID-19) pandemic continues to produce substantial morbidity and mortality. To understand the reasons for the wide-spectrum complications and severe outcomes of COVID-19, we aimed to identify cellular targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and replication in various tissues. Methods We evaluated RNA extracted from formalin-fixed, paraffin-embedded autopsy tissues from 64 case patients (age range, 1 month to 84 years; 21 COVID-19 confirmed, 43 suspected COVID-19) by SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR). For cellular localization of SARS-CoV-2 RNA and viral characterization, we performed in situ hybridization (ISH), subgenomic RNA RT-PCR, and whole-genome sequencing. Results SARS-CoV-2 was identified by RT-PCR in 32 case patients (21 COVID-19 confirmed, 11 suspected). ISH was positive in 20 and subgenomic RNA RT-PCR was positive in 17 of 32 RT-PCR–positive case patients. SARS-CoV-2 RNA was localized by ISH in hyaline membranes, pneumocytes, and macrophages of lungs; epithelial cells of airways; and endothelial cells and vessel walls of brain stem, leptomeninges, lung, heart, liver, kidney, and pancreas. The D614G variant was detected in 9 RT-PCR–positive case patients. Conclusions We identified cellular targets of SARS-CoV-2 tropism and replication in the lungs and airways and demonstrated its direct infection in vascular endothelium. This work provides important insights into COVID-19 pathogenesis and mechanisms of severe outcomes., By analyzing tissues from patients with fatal COVID-19, using in situ hybridization and RT-PCR, we identified cellular targets of SARS-CoV-2 tropism and replication in the lungs, airways, and vascular endothelium. These findings provide important insights into COVID-19 pathogenesis and severe outcomes.

Temporomandibular disorders (TMD) are a group of diseases in the oral and maxillofacial region that can manifest as acute or chronic persistent pain, affecting millions of people worldwide. Although hundreds of studies have explored mechanisms and treatments underlying TMD, multiple pathogenic factors and diverse clinical manifestations make it still poorly managed. Appropriate animal models are helpful to study the pathogenesis of TMD and explore effective treatment measures. At present, due to the high cost of obtaining large animals, rodents and rabbits are often used to prepare TMD animal models. Over the past decade, various animal models have been intensively developed to understand neurobiological and molecular mechanisms of TMD, and seek effective treatments. Although these models cannot carry out all clinical features, they are valuable in revealing the mechanisms of TMD and creating curative access. Currently, there are multitudinous animal models of TMD research. They can be constructed in different means and summarized into four ways according to the various causes and symptoms, including chemical induction (intra-articular injection of ovalbumin, collagenase, formalin, vascular endothelial growth factor, intramuscular injection of complete Freund’s adjuvant, etc.), mechanical stress stimulation (passive mouth opening, change of chewing load), surgical operation (partial disc resection, joint disc perforation) and psychological stress induction. Here, we summarize and discuss different approaches of animal models for determining neurophysiological and mechanical mechanisms of TMD and assess their advantages and limitations, respectively.

A six-year old boy presented with mycoplasmal pneumonia combined with recurrent pneumothorax. The patient had been treated with azithromycin and methylprednisolone for mycoplasmal pneumonia after admission, however his condition deteriorated. We increased the dosage of methylprednisolone and changed to erythromycin from azithromycin, his condition improved progressively. He presented pneumothorax twice during recovery phase. He was put on thoracic closed drainage and was cured. Pneumothorax is rare complication of mycoplasmal pneumonia. Here we reported the case to raise awareness of this condition.

Depression is a common mental disorder affecting approximately 17 % of the world population. Current therapeutic options are suboptimal due to a lower efficacy and high rates of side effects. Traditional Chinese medicine such as Radix Polygalae has been applied to depressed patients with encouraging outcomes. The main ingredient extracted from Radix Polygalae is onjisaponin B. The aim of this study was to investigate the therapeutic effects of onjisaponin B in experimental depression in mice. 30 male C57/Bl6 mice aged between 6 and 8 w old (25-30 g upon arrival) were purchased from Animal Centre of Shanghai Branch, Chinese Academy of Sciences (Shanghai, China) in this study and inducted to depression mice model. Tail suspension test, forced swimming test, measurement of monoamines and monoamine oxidase methods were used to detect the function of onjisaponin B in depression mice model. Our data showed that in depression mice model, onjisaponin B attenuates the severity of experimental depression. Onjisaponin B inhibits activity of monoamine oxidase A and increases the abundance of 5-hydroxytryptamine and noradrenaline in the brain. These preclinical results indicated the application of onjisaponin B in depressed mice and provided a new potential treatment strategy for patients with clinical depression.

To improve the convergence speed of routing and wavelength assignment (RWA) algorithm of satellite network, the Fast Convergence RWA based on Ant Colony Algorithm (ACO-FC RWA) is proposed. The results show the better network performance.

In order to improve the resilience of the satellite network and increase the communication success rate when the node fails, an intelligent backup multi-path ant colony routing algorithm (IMB-ACR) is proposed. In this algorithm, the parameter of betweenness centrality is used to evaluate the importance of satellite nodes, and use it to determine whether to calculate a backup routes, which means the backup routes will be calculated if and only if there are key nodes in the original routes. This is what distinguishes IMB-ACR from traditional multipath routing algorithms, as a consequence of the distinguishing feature, we can improve the anti-destructive and resilient ability of satellite network while reduce time overhead. The simulation results show that, compared with the KACR algorithm, the communication success rate of the IMB-ACR algorithm increases by 3%; when the number of failed nodes climbs to 4, IMB-ACR is twice as resilient as K-ACR which based on resilient slope; In addition, the time cost of the IMB-ACR algorithm is 0.3028s, which is lower than that of the K-ACR algorithm. Thus it can be seen that IMB-ACR algorithm still performs well in terms of communication success rate and resilient recovery ability under the condition of low time overhead.

There is a growing need for efficient bandwidth allocation in broadband satellite communication system. Firstly, a cross-layer bandwidth framework is constructed by considering information exchange between application layer, medium access control (MAC) layer and physical layer. Then, in order to allocate bandwidth resources, a utility function is established with modified factor by optimized bee colony algorithm. In the bee colony optimization-based cross layer dynamic bandwidth allocation algorithm (BO-CL-DBA), important channel factors including modulation order, coding efficiency, transmission rate and quality of service (QoS) priority for different users are considered and analyzed. Furthermore, a simulation model is developed to evaluate performance such as utility value, user satisfaction and throughput. The result demonstrates high allocation efficiency which meets multi QoS requirements.

During pregnancy, various physiological changes occur that can alter the pharmacokinetics of antiepileptic drugs, such as lamotrigine (LTG). Anticipating the change in LTG dose required to achieve a pre-pregnancy target concentration is challenging. This study aimed to develop a refined population pharmacokinetic (PopPK) model of LTG in pregnant women with epilepsy (WWE) to identify factors explaining the variability in pharmacokinetics and to establish a model-informed individualized dosing regimen. On that basis, a coarsened model containing only clinical variables was also developed to examine its predictive performance compared to the refined model. In total, 322 concentration-time points from 51 pregnant WWE treated with LTG were employed to establish a refined PopPK model that included endogenous estrogen profiles, variants of candidate genes encoding LTG-metabolizing enzymes and -transporter proteins, and other clinical variables and a coarsened model that included only clinical variables, respectively. Data from an additional 11 patients were used for external validation of these two models. A nonlinear mixed-effect modeling approach was used for PopPK analysis of LTG. The standard goodness-of-fit method, bootstrap, normalized prediction distribution errors and external evaluation were adopted to estimate the stability and predictive performance of the candidate models. Akaike information criterion (AIC) was used to compare the goodness of fit between these two models. A lower AIC indicates a better fit of the data and the preferred model. Recommended dosing regimens for pregnant WWE were selected using Monte Carlo simulation based on the established optimal model. In the refined PopPK model, the population mean of apparent LTG clearance (CL/F) in pregnant WWE was estimated to be 2.82 L/h, with an inter-individual variability of 23.6%. PopPK analysis indicated that changes in estrogen profile during pregnancy were the predominant reason for the significant variations in LTG-CL/F. Up to the 3rd trimester, the concentration accumulation effect of E2 increased LTG-CL/F by 5.109 L/h from baseline levels. Contrary to effect of E2, E3 as the main circulating estrogen in pregnancy with a peak value of 34.41 ng/mL is 1000-fold higher than that in non-pregnancy reduced LTG-CL/F by 1.413 L/h. In addition, the UGT2B7 rs4356975 C > T and ABCB1 rs1128503 A > G variants may contribute to a better understanding of the inter-individual variability in LTG-CL/F. LTG-CL/F was 1.66-fold higher in UGT2B7 rs4356975 CT or TT genotype carriers than in CC genotype carriers. In contrast, ABCB1 rs1128503 GG genotype carriers had only 71.9% of the LTG-CL/F of AA or AG genotype carriers. In the coarsened PopPK model, the gestational age was a promising predictor of changes in LTG-CL/F. When comparing these two models, the refined PopPK model was favored over the coarsened PopPK model (AIC = −30.899 vs. −20.017). Monte Carlo simulation based on optimal PopPK model revealed that the LTG dosage administered to carriers of the UGT2B7 rs4356975 CT or TT genotype required a 33–50% increase to reach the pre-pregnancy target concentration, and carriers of the ABCB1 rs1128503 GG genotype required a 33–66% lower dose of LTG than carriers of the ABCB1 rs1128503 AA or AG genotype. Changes in estrogen profile during pregnancy was a better predictor of variations in LTG-CL/F than gestational age. The developed model based on estrogen profile and pharmacogenetics can serve as a foundation for further optimization of dosing regimens of LTG in pregnant WWE.

Background and objectives To investigate the effect and the underlying mechanism of exosomes secreted by human umbilical cord mesenchymal stem cells (hUCMSCs) on diffuse alveolar hemorrhage (DAH) in murine lupus. Methods and results Exosomes were extracted from cultured hUCMSCs by ultracentrifugation. The expressions of exosome markers (Alix, CD63 and TSG101) were measured for identification of hUCMSC-derived exosomes (hUCMSC-exosomes). The alveolar hemorrhage of DAH mice was revealed by H&E staining. The primary alveolar macrophages were isolated from bronchoalveolar lavage fluid (BALF) of DAH mice. The expressions of M1 macrophage markers (iNOS, IL-6, TNF-α and IL-1β) and M2 macrophage markers (Arg1, IL-10, TGF-β and chi3l3) were detected. Flow cytometry measured the ratio of M1/M2 macrophages. ELISA measured the secretion of pro-inflammatory cytokines (IL-6 and TNF-α) and anti-inflammatory cytokines (IL-10 and TGF-β). DAH mice had hemorrhage and small-vessel vasculitis in the lung, with neutrophil and monocyte infiltration observed around the capillary and small artery. Furthermore, increases of IL-6 and TNF-α, and decreases of IL-10 and TGF-β were detected in the BALF of DAH mice. M1 makers were overexpressed in alveolar macrophages of DAH mice while M2 makers were lowly expressed. DAH mice had a higher proportion of M1 macrophages than M2 macrophages. After hUCMSC-exosome or methylprednisolone treatment in DAH mice, the alveolar injuries and inflammatory responses were attenuated, and the proportion of M2 macrophages was increased. Conclusions hUCMSC-exosomes attenuate DAH-induced inflammatory responses and alveolar hemorrhage by regulating macrophage polarization.

Background Neutrophilic asthma (NA) was a subtype of asthma. Soluble advanced glycosylation receptor (sRAGE) was considered to be associated with the neutrophilic airway. However, the role of sRAGE in NA still limited. Methods A NA mouse model was established and the levels of sRAGE in the bronchoalveolar lavage fluid (BALF) were measured by ELISA. Hematoxylin-eosin (HE) and Masson trichrome staining were used to identifying airway remodeling. Adeno-associated virus 9 (AAV9) overexpressed sRAGE and inhibitors for HMGB1, RAGE, and PI3K were used to intervene NA mouse model via tail-vein injection and intraperitoneally injection. Expressions of airway remodeling, EMT, and signaling markers were detected using qRT-PCR or western blotting. The levels of IL-17 and IL-6 in BALF were measured by ELISA. HMGB1 was applied to induce EMT of human bronchial epithelial cells (16HBE), then E-cadherin and vimentin expressions were examined after sRAGE, RAGE inhibitor, and PI3K inhibitor administration. Results sRAGE levels were significantly reduced in BALF and the airway remodeling was observed in the NA mouse model. AAV9-sRAGE significantly inhibited the neutrophilic airway inflammation, airway remodeling, and the expression of IL-17, IL-6, TGF-β1, RAGE, PI3K, and EMT markers -E-cadherin and vimentin in vivo. HMGB1 inhibitor, RAGE inhibitor, and PI3K inhibitor upregulated E-cadherin level. Moreover, HMGB1 promoted the EMT process via RAGE/PI3K in 16HBE cells and sRAGE reversed HMGB1- induced EMT in vitro. Conclusion sRAGE levels decrease in the mouse model with NA. sRAGE treatment attenuates neutrophilic airway inflammation, airway remodeling, and EMT. This suggests sRAGE may yield benefits in the treatment of NA.

BackgroundThe Diamond Princess cruise ship was the site of a large outbreak of coronavirus disease 2019 (COVID-19). Of 437 Americans and their travel companions on the ship, 114 (26%) tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).MethodsWe interviewed 229 American passengers and crew after disembarkation following a ship-based quarantine to identify risk factors for infection and characterize transmission onboard the ship.ResultsThe attack rate for passengers in single-person cabins or without infected cabinmates was 18% (58/329), compared with 63% (27/43) for those sharing a cabin with an asymptomatic infected cabinmate, and 81% (25/31) for those with a symptomatic infected cabinmate. Whole genome sequences from specimens from passengers who shared cabins clustered together. Of 66 SARS-CoV-2-positive American travelers with complete symptom information, 14 (21%) were asymptomatic while on the ship. Among SARS-CoV-2-positive Americans, 10 (9%) required intensive care, of whom 7 were ≥70 years.ConclusionsOur findings highlight the high risk of SARS-CoV-2 transmission on cruise ships. High rates of SARS-CoV-2 positivity in cabinmates of individuals with asymptomatic infections suggest that triage by symptom status in shared quarters is insufficient to halt transmission. A high rate of intensive care unit admission among older individuals complicates the prospect of future cruise travel during the pandemic, given typical cruise passenger demographics. The magnitude and severe outcomes of this outbreak were major factors contributing to the Centers for Disease Control and Prevention’s decision to halt cruise ship travel in US waters in March 2020.