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The sonographic appearance of benign and malignant breast nodules overlaps to some extent, and we aimed to assess the performance of the Gail model as an adjunctive tool to ultrasound (US) Breast Imaging Reporting and Data System (BI-RADS) for predicting the malignancy of nodules.From 2018 to 2019, 2607 patients were prospectively enrolled by 35 health care facilities. An individual breast cancer risk was assessed by the Gail model. Based on B-mode US, color Doppler, and elastography, all nodules were evaluated according to the fifth edition of BI-RADS, and these nodules were all confirmed later by pathology.We demonstrated that the Gail model, age, tumor size, tumor shape, growth orientation, margin, contour, acoustic shadowing, microcalcification, presence of duct ectasia, presence of architectural distortion, color Doppler flow, BI-RADS, and elastography score were significantly related to breast cancer (all p0.001). The sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and area under the curve (AUC) for combining the Gail model with the BI-RADS category were 95.6%, 91.3%, 85.0%, 97.6%, 92.8%, and 0.98, respectively. Combining the Gail model with the BI-RADS showed better diagnostic efficiency than the BI-RADS and Gail model alone (AUC 0.98 vs 0.80, p0.001; AUC 0.98 vs 0.55, p0.001) and demonstrated a higher specificity than the BI-RADS (91.3% vs 59.4%, p0.001).The Gail model could be used to differentiate malignant and benign breast lesions. Combined with the BI-RADS category, the Gail model was adjunctive to US for predicting breast lesions for malignancy. For the diagnosis of malignancy, more attention should be paid to high-risk patients with breast lesions.

BackgroundPrescription drug use has soared in the USA within the last two decades. Prescription drugs can impair motor skills essential for the safe operation of a motor vehicle, and therefore can affect traffic safety. As one of the epicentres of the opioid epidemic, Florida has been struck by high opioid misuse and overdose rates, and has concurrently suffered major threats to traffic disruptions safety caused by driving under the influence of drugs. To prevent prescription opioid misuse in Florida, Prescription Drug Monitoring Programs (PDMPs) were implemented in September 2011.ObjectiveTo examine the impact of Florida’s implementation of a mandatory PDMP on drug-related MVCs occurring on public roads.MethodsWe employed a difference-in-differences approach to estimate the difference in prescription drug-related fatal crashes in Florida associated with its 2011 PDMP implementation relative to those in Georgia, which did not use PDMPs during the same period (2009–2013). The analyses were conducted in 2020.ResultsIn Florida, there was a significant decline in drug-related vehicle crashes during the 22 months post-PDMP. PDMP implementation was associated with approximately two (−2.21; 95% CI −4.04 to –0.37; pConclusionsThe implementation of PDMPs in Florida provided important benefits for traffic safety, reducing the rates of prescription opioid-related vehicle crashes.

BACKGROUND Bezoars are conglomerates of indigestible foreign material that can be found in the gastrointestinal tract. Gastric ulcer, gastrointestinal perforation, and intestinal obstruction are the main complications. Acute pancreatitis secondary to bezoar is rare. Here, we present a rare case of a migratory gastric bezoar complicated by acute pancreatitis and small bowel obstruction after dissolution therapy. CASE SUMMARY A-65-year-old woman underwent gastroscopy because of epigastric pain, which revealed a huge bezoar and a gastric ulcer 10 d prior. The patient was discharged with a prescription of drinking 1 L Coca-Cola daily for 6 d, without repeat gastroscopy. However, she suddenly developed epigastric pain, nausea and vomiting for 3 d. Abdominal computed tomography (CT) revealed mild inflammation of the pancreas. Magnetic resonance cholangiopancreatography showed no abnormalities in the pancreatic duct or common bile duct. The nasogastric tube still showed drainage of more than 1.6 L of dark fluid each day after symptomatic treatment. Abdominal CT re-examination suggested intestinal obstruction. Esophagogastroduodenoscopy revealed a huge yellowish hard mass in the jejunal lumen, and we used the basket and net to fragment the bezoar. She was discharged with a good outcome. CONCLUSION Endoscopic therapy is the first choice for gastric bezoars. When mechanical disintegration cannot be achieved, timing of repeat endoscopy is important during Coca-Cola dissolution therapy.

Aurora kinases are a family of serine/threonine kinases, and promote mitotic spindle assembly by regulating centrosome duplication and separation. Aurora kinases are overexpressed in a variety of...

The population decline in the common hippopotamus (Hippopotamus amphibius) has necessitated the preservation of their genetic resources for species conservation and research. Of all actions, cryopreservation of fibroblast cell cultures derived from animal biopsy is considered a simple but efficient means. Nevertheless, preserving viable cell cultures of the common hippopotamus has not been achieved to our knowledge. To this end, we detailed a method to establish fibroblast cell cultures from a female common hippopotamus fetus in this study. By combining the classic tissue explant direct culture and enzymatic digestion methods, we isolated a great number of cells with typical fibroblastic morphology and high viability. Characterization of the fibroblast cultures was carried out using different techniques. In short, neither bacteria/fungi nor mycoplasma was detectable in the cell cultures throughout the study. The population doubling time was 23.9 h according to the growth curve. Karyotyping based on Giemsa staining showed that cultured cells were diploid with 36 chromosomes in all, one pair of which was sex chromosomes. Mitochondrial cytochrome C oxidase subunit I gene sequence of the cultured cells was 99.26% identical with the Hippopotamus amphibius complete mitochondrial DNA sequence registered in GenBank, confirming the cells were derived from a common hippopotamus. Flow cytometry and immunofluorescence staining results revealed that the detected cells were positive for fibroblast markers, S100A4 and Vimentin. In conclusion, we isolated and characterized a new fibroblast cell culture from a common hippopotamus skin sample and the cryopreserved cells could be useful genetic materials for the future research.

Angiosarcoma (AS) is a rare disease with a dismal prognosis. The treatment landscape and prognostic factors for advanced AS, including locally advanced, unresectable, and metastatic disease remain elusive. The Asian Sarcoma Consortium is an international collaborative effort to understand the sarcoma treatment landscape in Asia. We undertook a retrospective chart review of AS patients seen in 8 sarcoma academic centers across Asia. Patients with complete clinical, treatment, and follow‐up data were enrolled. Overall, 276 advanced AS patients were included into this study; 84 (30%) of the patients had metachronous metastatic AS. The median age was 67 y; primary sites of AS was cutaneous in 55% and visceral in 45% of patients. In total, 143 (52%) patients received at least 1 line of systemic chemotherapy. The most common first‐line chemotherapy regimen used was paclitaxel (47.6%) followed by liposomal doxorubicin (19.6%). The median overall survival (OS) was 7.8 mo. Significant prognostic factors for OS included age > 65 (hazard ratio (HR) 1.54, P = .006), male gender (HR 1.39, P = .02), and a cutaneous primary AS site (HR 0.63, P = .004). The median progression‐free survival (PFS) for first‐line chemotherapy was 3.4 mo. PFS for single vs combination or paclitaxel vs liposomal doxorubicin chemotherapy regimens were comparable. This study provides an insight into the treatment patterns and prognostic factors of advanced AS patients in Asia. Prognosis of advanced AS remains poor. Data from this study serve as a benchmark for future clinical study design., With a total of 276 advanced angiosarcoma patients, we provided the complete clinicopathological demographics, treatment patterns, and prognostic outcomes of advanced angiosarcoma in Asia.

To examine the longitudinal associations of sleep duration and sleep quality with coronary heart disease (CHD) risk among individuals aged ≥ 20 years. A systematic review and meta-analysis of observational cohort studies were performed to evaluate the association between sleep quality and duration, and the risk of CHD. We searched three databases including PUBMED, the Cochrane Library and EMBASE, selected relevant studies and used the classical and Net-work models to establish the hazard ratio (HRs) of the results. Data extracted from 11 studies including 769,452 participants and 14,769 patients with CHD events were reviewed. In the classical meta-analysis, night sleep duration of 8 h showed an increased risk of CHD (HR = 1.13, and 1.13, respectively) compared with reference sleep (7–8 h). However, the net-work model stratified sleep quality into good and poor subgroups, and there was no change in CHD risk in each subgroup despite different sleep hours. Furthermore, individuals with poor-quality sleep were at a greater risk of CHD than those with good-quality sleep (HR = 1.4, 1.3, and 1.4 for 8 h, respectively). Moreover, individuals with reference time sleep but that of poor quality were associated with an increased risk of CHD compared with good sleepers having short/long sleep duration (HR = 1.3 and 1.2, respectively). Poor-quality sleep was associated with great morbidity and mortality of CHD, independent of sleep duration. Sleep quality rather than sleep duration might be crucial for increased CHD risk, suggesting the potential importance of poor-quality sleep as a possible CHD risk factor.

Overproduction of pro-inflammatory cytokines in the aged, which is called inflammaging, leads to the deterioration of periodontitis. Toll-like receptor 4 (TLR4) plays a role in the regulation of cellular senescence, and its expression increases with age. However, there has been limited research into the molecular mechanisms underlying the onset of periodontal inflammaging, and the interplay between TLR4 and inflammaging. In the present study, wild-type and TLR4 gene knockout mice were used to investigate the activation of the TLR4 pathway in mouse periodontitis and the expression of the nucleotide-binding and oligomerization domain-like receptor 3 (NLRP3) inflammasome, an upstream immune checkpoint during the development of inflammaging. Activation of TLR4 in a mouse model of periodontitis enhanced the expression of a senescence-associated secretory phenotype (SASP), which boosted the inflammaging process. Conversely, TLR4 activation downregulated the expression of B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and promoted the priming of NLRP3 inflammasome, both of which are regulators of SASP. Treating gingival fibroblasts with Bmi-1 inhibitor PTC209, it was demonstrated that TLR4 activated the NLRP3 pathway and the inflammaging process by suppressing Bmi-1. In addition, there was a significant reduction in the expression of Bmi-1 expression in the gingiva of patients with periodontitis compared with healthy controls. In conclusion, the present study demonstrated that TLR4 acted by inhibiting Bmi-1 to enhance the NLRP3 pathway and SASP factors. This cascade of reactions may contribute to the senescence of the periodontium.

Summary Background Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma. Methods In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0–2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov , NCT02601950 , and is ongoing. Findings Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7–26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8–19·0), median duration of response was not reached (95% CI 9·2–not estimable). 16 (26% [95% CI 16–39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9–7·4). Median progression-free survival was 5·5 months (95% CI 3·4–5·9), and median overall survival was 19·0 months (11·0–not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths. Interpretation Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway ( NCT04204941 ). Funding Epizyme.

Both stromal tumor-infiltrating lymphocytes (sTILs) and programmed death-ligand 1 (PD-L1) affect responses to immunotherapy; however, the extent of sTIL and PD-L1 expression within various metaplastic components in metaplastic breast carcinoma (MBC), which are critical for the characterization of immune microenvironments, remains unreported. We profiled sTIL infiltration and PD-L1 expression in different metaplastic components of specimens from 82 MBC patients. The overall positivity for high or intermediate (H/I) sTIL, immune cell-PD-L1 (IcPD-L1), and tumor cell-PD-L1 (TcPD-L1) was 34.1%, 47.6%, and 17.1%, respectively, but differences specific to MBC subtypes and each metaplastic component existed. Squamous cell carcinoma exhibited the highest positivity rates of sTIL(H/I) (50.0%) and IcPD-L1 (66.7%), while matrix-producing carcinoma had the lowest respective rates (14.3% and 28.6%). The positivity rates of sTIL(H/I) and IcPD-L1 were the highest in squamous component (Sq) and the lowest in chondroid component (Ch). All cases that had discordant sTIL categories between carcinoma of no special type (NST) and metaplastic components showed sTIL(H/I) positivity higher in Sq, but lower in spindled component (Sp) and Ch. While there was no pattern of higher IcPD-L1-positivity in Sp, six of the seven cases that were TcPD-L1-discordant between NST and Sp were TcPD-L1-positive in Sp, suggesting a trend for higher TcPD-L1 in Sp. The diagnostic predictability of total tumor IcPD-L1 positivity based on IcPD-L1 positivity in Sq and Ch was 95.2% and 33.3%, respectively. Multivariate analysis showed that sTIL(H/I) positivity, but not PD-L1 positivity, correlated with better survival. Our data implicate distinct immune microenvironments in different metaplastic components in MBC, which may have immunopathologic, diagnostic, and therapeutic significance.

To evaluate the value of renal diffusion kurtosis imaging (DKI) in the diagnosis of early diabetic nephropathy (DN) in a rat model. Forty male Zucker diabetic fatty rats that spontaneously developed type 2 diabetes mellitus (DM) and 20 age-matched nondiabetic lean Zucker rats were included. Renal DKI scans and histological examinations were performed on the rats in batches at the end of the 4th, 8th, 12th, 16th, and 20th week after DM model was built. Based on renal histopathological appearance, included animals were divided into three groups: a nondiabetic control group, a DM group without DN, and an early DN group. Mean kurtosis (MK) and mean diffusivity (MD) values of renal cortex and medulla were analyzed statistically. MK values of renal cortex and medulla tended to increase from the control group to the early DN group, respectively, while MD values tended to decrease. The cutoff MD and MK values of renal cortex and medulla showed different values in discriminating early DN from controls. Among them, cutoff MK value of medulla of 0.62 was the best parameter (sensitivity, 93.9%; specificity, 96.4%; and area under the curve, 0.95). For discriminate early DN from DM without DN and DM without DN from controls, cutoff MK value of renal cortex or medulla achieved an area under the curve of 0.76–0.85. MR DKI may be valuable for the noninvasive detection of early DN, and MK value might serve as a more sensitive biomarker of early DN than MD value. • In this article, diffusion kurtosis imaging (DKI) was used to detect the changes in the kidneys due to early diabetic nephropathy (DN). • MR DKI may be valuable for the noninvasive detection of early DN. • The mean kurtosis values of renal cortex and medulla might serve as a more sensitive biomarker of early DN than the mean diffusivity values.

Introduction The Affordable Care Act of 2010 expanded Medicaid to low-income adults at or below 138% of the Federal Poverty Level (FPL). The aim of this study was to examine if expanding Medicaid to adults had an impact on preventive health care utilization of children from low-income families (focusing on families with annual incomes 0%-99% and 100%-199% of the FPL). Methods This study used data from the 2016 and 2017 National Survey of Children's Health and a quasi-experimental difference-in-differences method. The dependent variable was the number of preventive care visits in the past year and the primary independent variable was the Medicaid expansion status of the state. Louisiana expanded Medicaid in 2016 (treatment group) and neighboring nonexpansion states of Texas and Mississippi constituted the control group. Differences in dependent variable were calculated between survey years 2016 and 2017. Results In Louisiana, the change in the predicted probability of at least 1 preventive care visit among children of ages 0-17 years, from 0% to 99% FPL families, was higher by 26 percentage points after Medicaid was expanded (2017 vs. 2016), as compared with the change in the predicted probability (2017 vs. 2016) of at least 1 preventive care visit among children of ages 0-17 years, from 0% to 99% FPL families in the nonexpansion states, Texas and Mississippi. Conclusions Children in poverty residing in a Medicaid expansion state, Louisiana, had increased likelihood of having an annual preventive care visit after expansion of Medicaid eligibility under the Affordable Care Act, as compared with children in nonexpansion states. Thus, this study showed that the implications of the public health insurance expansion for adults were not limited to adult health outcomes, but extended to children's health care utilization.

Objective To investigate changes in CT manifestations and results of reverse transcription polymerase chain reaction (RT-PCR) testing between afferent and second-generation coronavirus disease 2019 (COVID-19) outside the original city (Wuhan) until recovery Methods We collected 26 consecutive COVID-19 patients undergoing initial and follow-up CT scans together with RT-PCR until recovery from 2 hospitals outside the original city Seventeen patients with afferent infection and 9 with second-generation infection were assigned to Group A and B, respectively By observing CT manifestations, we scored COVID-19, and statistically analyzed numbers of patients with changes in CT scores and RT-PCR results between stages Results The total score of COVID-19 on initial CT manifestations was higher in Group A than in Group B (P < 0 05) COVID-19 progressed more frequently from stage 1 to 2, and relieved from stage 3 to 4 in Group A (P < 0 05) The similar trend in Group A could not be found in Group B Results of RT-PCR in most of patients in Group A turned negative at stage 4 while those in Group B turned negative at stage 3 (P < 0 05) Conclusion Changes in CT manifestation and RT-PCR result can be different between afferent and second-generation COVID-19 until recovery

The extreme complexity of mammalian brains requires a comprehensive deconstruction of neuroanatomical structures. Scientists normally use a brain stereotactic atlas to determine the locations of neurons and neuronal circuits. However, different brain images are normally not naturally aligned even when they are imaged with the same setup, let alone under the differing resolutions and dataset sizes used in mesoscopic imaging. As a result, it is difficult to achieve high-throughput automatic registration without manual intervention. Here, we propose a deep learning-based registration method called DeepMapi to predict a deformation field used to register mesoscopic optical images to an atlas. We use a self-feedback strategy to address the problem of imbalanced training sets (sampling at a fixed step size in nonuniform brains of structures and deformations) and use a dual-hierarchical network to capture the large and small deformations. By comparing DeepMapi with other registration methods, we demonstrate its superiority over a set of ground truth images, including both optical and MRI images. DeepMapi achieves fully automatic registration of mesoscopic micro-optical images, even macroscopic MRI datasets, in minutes, with an accuracy comparable to those of manual annotations by anatomists. Electronic supplementary material The online version of this article (10.1007/s12021-020-09483-7) contains supplementary material, which is available to authorized users.

Health Information Exchange (HIE) exhibits remarkable benefits for patient care such as improving healthcare quality and expediting coordinated care. The Office of the National Coordinator (ONC) for Health Information Technology is seeking patient-centric HIE designs that shift data ownership from providers to patients. There are multiple barriers to patient-centric HIE in the current system, such as security and privacy concerns, data inconsistency, timely access to the right records across multiple healthcare facilities. After investigating the current workflow of HIE, this paper provides a feasible solution to these challenges by utilizing the unique features of blockchain, a distributed ledger technology which is considered "unhackable". Utilizing the smart contract feature, which is a programmable self-executing protocol running on a blockchain, we developed a blockchain model to protect data security and patients' privacy, ensure data provenance, and provide patients full control of their health records. By personalizing data segmentation and an "allowed list" for clinicians to access their data, this design achieves patient-centric HIE. We conducted a large-scale simulation of this patient-centric HIE process and quantitatively evaluated the model's feasibility, stability, security, and robustness.

OBJECTIVES Cardiovascular dysautonomia can be present at early, late and even prodromal stages of Parkinson's disease. This study aimed to describe the characteristics of 24-h ambulatory blood pressure (BP) monitoring and investigate the frequency of cardiovascular dysautonomia in Parkinson's disease without an abnormal BP history. METHODS Parkinson's disease patients without history of abnormal BP were consecutively enrolled from three Chinese centres, on whom office BP measurement, neurological evaluations and 24-h ambulatory BP monitoring were performed. RESULTS Totally, 101 Parkinson's disease patients (42.6% women) with an average age of 66.6 ± 8.2 years were included in our cohort, and data analysis revealed that 26 (25.74%) patients suffered from orthostatic hypotension, among whom 18 (69.23%) were symptomatic. Patients with orthostatic hypotension compared with those without had significantly higher nocturnal SBP level, and more severe nonmotor symptoms, autonomic dysfunction and cognitive impairment. Further, 54 out of 101 (53.47%) individuals had a reverse dipping pattern in SBP and/or DBP. Reverse dippers had more cases of orthostatic hypotension (P

Objective To discuss the high resolution computed tomography (HRCT) manifestations of coronavirus disease 2019 (COVID-19) patients among different clinical types on initial and follow-up CT. Methods Seven COVID-19 patients admitted to the Affiliated Hospital of North Sichuan Medical Collage were enrolled. All patients underwent initial and follow-up chest HRCT. The main CT features and semi-quantitative score which represent disease severity among different clinical types were evaluated. Result On initial CT, the main abnormalities observed in common and severe cases respectively were pure ground glass opacities (GGOs) and patchy consolidation surrounded by GGOs. Critical cases had multiple consolidation surrounded by wide range of GGOs distributed in the whole lung fields. The scope and density score in common (4.5 and 5), severe (9.5 and 9.5) and critical (19 and 12) cases were increased by gradient. On follow-up CT, common and severe types manifested as decreasing density of lesion, absorbed consolidation and GGOs. Critical cases showed progression of the disease. The extent and progression scores in common and severe patients were significantly decreased, while the range score of patients with critical disease reached the highest points, accompanied with an increase in the density score. Conclusion CT scanning can accurately assess the severity of COVID-19, and help to monitor disease transformation during follow-up among different clinical conditions.

Introduction Metastatic breast cancer (MBC) with leptomeningeal metastases (LM) has dismal survival. We aim to determine if modern systemic therapy, especially the bevacizumab, cisplatin, and etoposide (BEEP) regimen, is beneficial to MBC LM patients. Methods We excerpted data from a prospectively collected cytopathology database for MBC patients who were diagnosed with LM by positive cerebrospinal fluid cytology. The primary outcome was OS from cytologically confirmed LM until death. Univariate and multivariate analyses were performed to elucidate prognostic factors. Results We identified 34 patients with cytologically confirmed LM. Treatments after LM diagnosis included: intrathecal methotrexate (82.4%), systemic chemotherapy (68%; BEEP n = 19, others n = 4), and whole brain radiotherapy (n = 5, 14.7%). Three of seven HER2-positive patients (43%) also received intrathecal trastuzumab. OS was improved in 2014–2016 compared with 2011–2013 (13.57 vs 3.20 months, p = 0.004), when 12/17 (71%) versus 7/17 (41%) patients received BEEP, respectively. In the multivariate model including all treatments, BEEP (HR 0.24, p = 0.003) and intrathecal trastuzumab (HR 0.22, p = 0.035), but not intrathecal methotrexate (HR 0.86, p = 0.78), remained significant prognostic factors. Conclusions MBC with LM is treatable—systemic BEEP are efficacious and may improve survival.

Objectives: To assess the performance of elastography (ES) and ultrasound (US) in predicting the malignancy of breast lesions and to compare their combined diagnostic value with that of magnetic resonance imaging (MRI). Materials and Methods: The study prospectively enrolled 242 female patients with dense breasts treated in 35 heath care facilities in China between November 2018 and October 2019. Based on conventional US and elastography, radiologists classified the degree of suspicion of breast lesions according to the US Breast Imaging Reporting and Data System (BI-RADS) criteria. The diagnostic value was compared between US BI-RADS and MRI BI-RADS, with pathological results used as the reference standard. Results: The results demonstrated that irregular tumor shape, a nonparallel growth orientation, indistinct margins, angular contours, microcalcifications, color Doppler flow and ES score on US imaging were significantly related to breast cancer in dense breasts (P=0.001; P=0.001; P=0.008; P

The measurement of the right and wrong results of cognitive tasks has important applications in many commercial and educational areas such as the drivers’ training system, the simulation training and online learning system. This Letter aims to distinguish the heartbeat pattern of cognitively wrong responses to that of cognitively right responses based on the electrocardiogram (ECG) through 36 subjects with different professional backgrounds. The experimental design methods were double-digit and five-digit addition/subtraction, which were blindly selected by subjects from a black box. Through the R–R interval (RRI) series obtained from the ECG data, some linear, nonlinear and moment features were extracted to evaluate the cognitive task results by using pattern recognition methods. The binary classification of RRI datasets indicated that autonomic nerve patterns of the right and wrong cognitive heartbeat responses were distinguishable.

Summary: Understanding the mechanisms of activity-dependent gene transcription underlying adaptive behaviors is challenging at neuronal-subtype resolution. Using cell-type specific molecular analysis in agouti-related peptide (AgRP) neurons, we reveal that the profound hunger-induced transcriptional changes greatly depend on plant homeodomain finger protein 6 (PHF6), a transcriptional repressor enriched in AgRP neurons. Loss of PHF6 in the satiated mice results in a hunger-state-shifting transcriptional profile, while hunger fails to further induce a rapid and robust activity-dependent gene transcription in PHF6-deficient AgRP neurons. We reveal that PHF6 binds to the promoters of a subset of immediate-early genes (IEGs) and that this chromatin binding is dynamically regulated by hunger state. Depletion of PHF6 decreases hunger-driven feeding motivation and makes the mice resistant to body weight gain under repetitive fasting-refeeding conditions. Our work identifies a neuronal subtype-specific transcriptional repressor that modulates transcriptional profiles in different nutritional states and enables adaptive eating behavior. : Gan et al. show that PHF6 is a transcriptional repressor enriched in AgRP neurons and regulates immediate-early gene (IEG) expression. Depletion of PHF6 in AgRP neurons decreases hunger-driven feeding motivation and makes the mice resistant to body weight gain under repetitive fasting/refeeding conditions. Keywords: PHF6, hunger-driven feeding behavior, AgRP neuron, activity-dependent gene transcription, immediate-early genes, IEGs, Börjeson-Forssman-Lehmann syndrome, BFLS

Pangolins are among the most critically endangered animals due to heavy poaching and worldwide trafficking. However, their demographic histories and the genomic consequences of their recent population declines remain unknown. We generated high-quality de novo reference genomes for critically endangered Malayan (Manis javanica, MJ) and Chinese (M. pentadactyla, MP) pangolins and re-sequencing population genomic data from 74 MJs and 23 MPs. We recovered the population identities of illegally traded pangolins and previously unrecognized genetic populations that should be protected as evolutionarily distinct conservation units. Demographic reconstruction suggested environmental changes have resulted in a population size fluctuation of pangolins. Additionally, recent population size declines due to human activities have resulted in an increase in inbreeding and genetic load. Deleterious mutations were enriched in genes related to cancer/diseases and cholesterol homeostasis, which may have increased their susceptibility to diseases and decreased their survival potential to adapt to environmental changes and high-cholesterol diets. This comprehensive study provides not only high-quality pangolin reference genomes, but also valuable information concerning the driving factors of long-term population size fluctuations and the genomic impact of recent population size declines due to human activities, which is essential for pangolin conservation management and global action planning.

Background Basal leaf removal is widely practiced to increase grape cluster sunlight exposure that controls berry rot and improves quality. Studies on its influence on volatile compounds in grape berries have been performed mostly in Mediterranean or marine climate regions. It is uncertain whether similar efficiency can be achieved when grape berries are grown under continental climate. This study aimed to dissect the variation in volatile compound production and transcriptome in sunlight-exposed grape berries in a dry-hot climate region and to propose the key genes related to the variation. Results Four cluster sunlight exposure strategies, including basal leaf removal at pepper-corn size stage, leaf removal at véraison (LR-V), leaf moving at véraison (LM-V), and half-leaf removal at véraison, were implemented at the north foot of the Mt. Tianshan region of northwestern China. Various cluster exposure treatments resulted in a decline in the concentrations of norisoprenoids and monoterpenes in ripening grape berries. Both β-carotene and lutein, the substrates of norisoprenoid biosynthesis, were reduced by cluster sunlight exposure. K-means cluster analysis showed that some genes involved in biosynthesis such as VviTPS55, VviTPS60, VviTPS66, VviCCD4a and VviCCD4b exhibited lower expression levels in exposed berries at least at one of the tested stages. Two C6-derived esters with fruity attributes, ethyl hexanoate and hexyl acetate, were reduced markedly. In contrast, main C6 alcohol compound levels were elevated in the LR-V- and LM-V-treated grape berries, which corresponded to the up-regulated expression of VviLOXA, VviLOXO and VviADH1 in the oxylipin pathway. Most of the differentially expressed genes in the exposed and control berries were enriched to the “stress response” processes, and this transcriptome difference was accumulated as the berries matured. Besides, LR-V treatment stimulated a significant up-regulation in photosynthesis-related genes in the grape berries, which did not happen with LM-V treatment. Conclusions Cluster sunlight exposure in dry-hot climate viticulture resulted in different volatile-targeted transcriptomic and metabolic responses from those obtained in the temperate Mediterranean or marine climate region. Therefore, a modified canopy management should be adopted to improve the aroma of grape berries.

Purpose The role of chemotherapy (CT) and radiotherapy (RT) for management of extraskeletal osteosarcoma (ESOS) remains controversial. We examined disease outcomes for ESOS patients and investigated the association between CT/RT with recurrence and survival. Patients and methods Retrospective review at 25 international sarcoma centers identified patients ≥18 years old treated for ESOS from 1971 to 2016. Patient/tumour characteristics, treatment, local/systemic recurrence, and survival data were collected. Kaplan–Meier survival and Cox proportional-hazards regression and cumulative incidence competing risks analysis were performed. Results 370 patients with localized ESOS treated definitively with surgery presented with mainly deep tumours (n = 294, 80%). 122 patients underwent surgical resection alone, 96 (26%) also received CT, 70 (19%) RT and 82 (22%) both adjuvants. Five-year survival for patients with localized ESOS was 56% (95% CI 51%–62%). Almost half of patients (n = 173, 47%) developed recurrence: local 9% (35/370), distant 28% (102/370) or both 10% (36/370). Considering death as a competing event, there was no significant difference in cumulative incidence of local or systemic recurrence between patients who received CT, RT, both or neither (local p = 0.50, systemic p = 0.69). Multiple regression Cox analysis showed a significant association between RT and decreased local recurrence (HR 0.46 [95% CI 0.26–0.80], p = 0.01). Conclusion Although the use of RT significantly decreased local recurrences, CT did not decrease the risk of systemic recurrence, and neither CT, nor RT nor both were associated with improved survival in patients with localized ESOS. Our results do not support the use of CT; however, adjuvant RT demonstrates benefit in patients with locally resectable ESOS.

We studied the protection of degraded Porphyra yezoensis polysaccharide (PYP) on human proximal tubular epithelial cells (HK-2) from cytotoxicity of nano-calcium oxalate monohydrate (COM) crystal, and the regulation of adhesion and endocytosis of the COM crystal. Four degraded fractions, namely, PYP1, PYP2, PYP3, and PYP4, were successfully obtained, with molecular weights (Mws) of 576.2, 49.5, 12.6, and 4.02 kDa, respectively. PYP protection reduced the crystal toxicity, prevented the destruction of cell morphology and cytoskeleton, inhibited the production of reactive oxygen species and the decline of lysosomal integrity, and reduced the expression of osteopontin and transmembrane protein (CD44). PYPi inhibited the adhesion and endocytosis of HK-2 cells by nano-COM. Endocytic COM crystals were accumulated in the lysosomes. With decreasing molecular weight, the ability of PYP to reduce cell damage and inhibit cell adhesion and endocytosis increased. PYP4, which has the smallest molecular weight, weaker intramolecular hydrogen bonds and more reducing groups, showed the best biological activity. PYPi can reduce the oxidative damage of the crystal to the cell, inhibit the adhesion and endocytosis of the crystal, and reduce the risk of kidney stone formation. Therefore, PYP, especially PYP4, has potential for use as a green drug to inhibit the formation and recurrence of calcium oxalate stones.

SARS-CoV-2 infection is mediated by the interaction of the spike glycoprotein trimer via its receptor-binding domain (RBD) with the host's cellular receptor. Vaccines seek to block this interaction by eliciting neutralizing antibodies, most of which are directed toward the RBD. Many protein subunit vaccines require powerful adjuvants to generate a potent antibody response. Here, we report on the use of a SARS-CoV-2 dimeric recombinant RBD combined with Neisseria meningitidis outer membrane vesicles (OMVs), adsorbed on alum, as a promising COVID-19 vaccine candidate. This formulation induces a potent and neutralizing immune response in laboratory animals, which is higher than that of the dimeric RBD alone adsorbed on alum. Sera of people vaccinated with this vaccine candidate, named Soberana01, show a high inhibition level of the RBD-ACE2 interaction using RBD mutants corresponding to SARS-CoV-2 variants of concern and wild-type expressed using the phage display technology. To our knowledge, this is the first time that the immunostimulation effect of N. meningitidis OMVs is evaluated in vaccine candidates against SARS-CoV-2.

Rationale and Objectives To assess the characteristics of pancreatic perfusion in normal pancreas and acute pancreatitis (AP) by using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). Method and Materials Eighty-One AP patients and 26 normal subjects underwent DCE-MRI. The Omitk-Tool was used to analyze perfusion parameters such as Ktrans, Vp, and AUC. The parameters of pancreas between AP and control groups were compared. In AP patients, the parameters were compared between edematous and necrotizing pancreatitis and among different grades of AP as determined by MR severity index (MRSI) and the 2012 Revised Atlanta Classification of AP. Results The Ktrans, Vp, and AUC values of AP were lower than those of the control group (p = 0.007, 0.000, and 0.025). According to MRSI, the Ktrans and AUC values were significantly different between mild and moderate (p = 0.000, 0.000) and between mild and severe (p = 0.008, 0.016) AP but not between moderate and severe AP (p = 0.218, 0.217). Based on the 2012 Revised Atlanta Classification, the Ktrans values were significantly different between mild and moderately severe (p = 0.000) and between mild and severe (p = 0.005) AP, but not between moderately severe and severe AP (p = 0.619). The Ktrans values were significantly different between edematous and necrotizing pancreatitis (p = 0.03). Conclusion The application of DCE-MRI to evaluate pancreatic perfusion contributes to the diagnosis of AP and its severity grade. Pancreatic perfusion is lower in AP patients than in patients with a normal pancreas, and pancreatic perfusion tends to decrease as the severity of AP increases.

Objectives: Public health accreditation is a 7-step process that starts with a period of preapplication during which a health department assesses its readiness for accreditation. However, no tools with established reliability and validity that quantitatively measure a local health department’s (LHD’s) capacity for accreditation are available to complete this initial step. We developed and validated a survey to measure accreditation capacity for LHDs. Methods: From January through April 2015, we administered a cross-sectional electronic survey instrument with 15 questions that tapped into domains of capacity for public health accreditation. We analyzed and grouped responses by using a confirmatory maximum likelihood factor analysis with oblique rotations. We assessed reliability by using Cronbach α, and we assessed validity by comparing responses with previously established instruments. We administered the survey to 174 LHD directors in Colorado, Kansas, and Nebraska, 153 (88%) of whom responded. Results: The factor analysis produced a 3-factor model of accreditation capacity, suggesting that accreditation capacity depends on 3 distinct latent constructs: support for accreditation, preparation, and planning and approach. The model had good scale reliability (average Cronbach α = 0.7) and validity (average factor correlation = 0.43). Conclusions: The survey developed and scored in this analysis can be used by LHDs to inform the feasibility of initiating the time-intensive and costly process of accreditation.

Purpose Sentinel lymph node biopsy (SLNB) is the standard management for clinically node-negative cutaneous melanoma patients. This study aimed to evaluate the role of SLNB in Taiwanese melanoma patients and in particular, patients with acral lentiginous melanoma (ALM). Patients and methods We retrospectively analyzed the clinicopathological characteristics and survival outcomes of the patients who underwent primary surgery followed by either SLNB or nodal observation at the Linkou Chang Gung Memorial Hospital from January 2000 to December 2011. Results Among the total of 209 patients, 127 underwent SLNB and 51 underwent nodal observation only after primary surgery. There were no significant differences in clinicopathological features between the two groups except that patients who underwent SLNB were older and had a higher rate of ALM than those under nodal observation. The median follow-up time was 43.5 months until July 2013. The patients who underwent SLNB had significantly better disease-free survival (DFS) (57.1 vs 18.7 months, p 2 mm, or ulceration. Conclusion SLNB was associated with favorable outcomes in patients with clinically node-negative cutaneous melanoma, particularly in Taiwanese patients with ALM, Breslow thickness ≤2 mm, and nonulcerated melanoma.

Controlling the global COVID-19 pandemic depends, among other measures, on developing preventive vaccines at an unprecedented pace. Vaccines approved for use and those in development intend to use neutralizing antibodies to block viral sites binding to the host’s cellular receptors. Virus infection is mediated by the spike glycoprotein trimer on the virion surface via its receptor binding domain (RBD). Antibody response to this domain is an important outcome of the immunization and correlates well with viral neutralization. Here we show that macromolecular constructs with recombinant RBD conjugated to tetanus toxoid induce a potent immune response in laboratory animals. Some advantages of the immunization with the viral antigen coupled to tetanus toxoid have become evident such as predominant IgG immune response due to affinity maturation and long-term specific B-memory cells. This paper demonstrates that subunit conjugate vaccines can be an alternative for COVID-19, paving the way for other viral conjugate vaccines based on the use of small viral proteins involved in the infection process.

With the COVID-19 vaccination widely implemented in most countries, propelled by the need to revive the tourism economy, there is a growing prospect for relieving the social distancing regulation and reopening borders in tourism-oriented countries and regions. This need incentivizes stakeholders to develop border control strategies that fully evaluate health risks if mandatory quarantines are lifted. In this study, we have employed a computational approach to investigate the contact tracing integrated policy in different border-reopening scenarios in Hong Kong, China. Explicitly, by reconstructing the COVID-19 transmission from historical data, specific scenarios with joint effects of digital contact tracing and other concurrent measures (i.e., controlling arrival population and community nonpharmacological interventions) are applied to forecast the future development of the pandemic. Built on a modified SEIR epidemic model with a 30% vaccination coverage, the results suggest that scenarios with digital contact tracing and quick isolation intervention can reduce the infectious population by 92.11% compared to those without contact tracing. By further restricting the inbound population with a 10,000 daily quota and applying moderate-to-strong community nonpharmacological interventions (NPIs), the average daily confirmed cases in the forecast period of 60 days can be well controlled at around 9 per day (95% CI: 7–12). Two main policy recommendations are drawn from the study. First, digital contact tracing would be an effective countermeasure for reducing local virus spread, especially when it is applied along with a moderate level of vaccination coverage. Second, implementing a daily quota on inbound travelers and restrictive community NPIs would further keep the local infection under control. This study offers scientific evidence and prospective guidance for developing and instituting plans to lift mandatory border control policies in preparing for the global economic recovery.

Background: Platelet endothelial aggregation receptor-1 (PEAR1) rs12041331 has been reported to affect agonist-stimulated platelet aggregation, but it remains unclear whether this variant plays a role in recurrent stroke. Here we assess the clinical relevance of PEAR1 rs12041331 in acute minor ischemic stroke (AMIS) and transient ischemic attack (TIA) Chinese patients treated with dual antiplatelet therapy (DAPT).Methods: We recruited 273 consecutive minor stroke and TIA patients, and Cox proportional hazard regression was used to model the relationship between PEAR1 rs12041331 and thrombotic and bleeding events.Results: Genotyping for PEAR1 rs12041331 showed 49 (18.0%) AA homozygotes, 129 (47.3%) GA heterozygotes, and 95 (34.7%) GG homozygotes. No association was observed between PEAR1 rs12041331 genotype and stroke or composite clinical vascular event rates (ischemic stroke, hemorrhagic stroke, TIA, myocardial infarction, or vascular death) or bleeding events regardless if individuals carried one or two copies of the A allele. Our results suggested that rs12041331 genetic polymorphism was not an important contributor to clinical events in AMIS and TIA patients in the setting of secondary prevention.Conclusions: Our data do provide robust evidence that genetic variation in PEAR1 rs12041331 do not contribute to atherothrombotic or bleeding risk in minor stroke and TIA patients treated with DAPT.

Type 1 diabetes mellitus (T1D) results from the destruction of insulin-producing β cells in the islet of the pancreas by lymphocytes. Non-obese diabetic (NOD) mouse is an animal model frequently used for this disease. It has been considered that T1D is a T cell-mediated autoimmune disease. Both CD4+ and CD8+ T cells are highly responsible for the destruction of β cells within the pancreatic islets of Langerhans. Previous studies have revealed that regulatory T (Treg) cells play a critical role in the homeostasis of the immune system as well as immune tolerance to autoantigens, thereby preventing autoimmunity. Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Previous reports have demonstrated that VPA treatment decreases the incidence and severity of collagen-induced arthritis and experimental autoimmune neuritis by increasing the population of Treg cells in these mouse disease models. Given the effect of VPA in the induction of Treg cells’ population, we evaluated the therapeutic potential and the protective mechanism of VPA treatment in the suppression of graft autoimmune rejection and immune recurrence in syngeneic or allogenic islet transplantation mouse models. In our study, we found that the treatment of VPA increased the expression of forkhead box P3 (FOXP3), which is a critical transcription factor that controls Treg cells’ development and function. Our data revealed that 400 mg/kg VPA treatment in recipients effectively prolonged the survival of syngeneic and allogenic islet grafts. The percentage of Treg cells in splenocytes increased in VPA-treated recipients. We also proved that adoptive transfer of VPA-induced Tregs to the transplanted recipients effectively prolonged the survival of islet grafts. The results of this study provide evidence of the therapeutic potential and the underlying mechanism of VPA treatment in syngeneic islet transplantation for T1D. It also provides experimental evidence for cell therapy by adoptive transferring of in vitro VPA-induced Tregs for the suppression of autoimmune recurrence.

BACKGROUND: Although early follow-up after discharge from an index admission (IA) has been postulated to reduce 30-day readmission, some researchers have questioned its efficacy, which may depend upon the likelihood of readmission at a given time and the health conditions contributing to readmissions. OBJECTIVE: To investigate the relationship between post-discharge services utilization of different types and at different timepoints and unplanned 30-day readmission, length of stay (LOS), and inpatient costs. DESIGN, SETTING, AND PARTICIPANTS: The study sample included 583,199 all-cause IAs among 2014 Medicare fee-for-service beneficiaries that met IA inclusion criteria. MAIN MEASURES: The outcomes were probability of 30-day readmission, average readmission LOS per IA discharge, and average readmission inpatient cost per IA discharge. The primary independent variables were 7 post-discharge health services (institutional outpatient, primary care physician, specialist, non-physician provider, emergency department (ED), home health care, skilled nursing facility) utilized within 7 days, 14 days, and 30 days of IA discharge. To examine the association with post-discharge services utilization, we employed multivariable logistic regressions for 30-day readmissions and two-part models for LOS and inpatient costs. KEY RESULTS: Among all IA discharges, the probability of unplanned 30-day readmission was 0.1176, the average readmission LOS per discharge was 0.67 days, and the average inpatient cost per discharge was $5648. Institutional outpatient, home health care, and primary care physician visits at all timepoints were associated with decreased readmission and resource utilization. Conversely, 7-day and 14-day specialist visits were positively associated with all three outcomes, while 30-day visits were negatively associated. ED visits were strongly associated with increases in all three outcomes at all timepoints. CONCLUSION: Post-discharge services of different types and at different timepoints have varying impacts on 30-day readmission, LOS, and costs. These impacts should be considered when coordinating post-discharge follow-up, and their drivers should be further explored to reduce readmission throughout the health care system. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-06708-6.

Ewing sarcoma and peripheral primitive neuroectodermal tumor constitute the Ewing family of tumors (EFT). EFTs primarily arising in the ovary are extremely rare. We report the case of a 22-yr-old nulliparous woman with a primary EFT in the ovary that initially presented as a 3-cm teratoma-like ovarian tumor, with rapid progression to a 15-cm-sized tumor with liver metastasis in 3 mo. The patient underwent suboptimal debulking surgery and salvage chemotherapy with vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide. In conclusion, primary EFT in the ovary is extremely rare with highly aggressive behavior and poor outcome for metastatic disease. Demonstration of EWSR1 rearrangement, observed in a variety of soft tissue tumors, is very helpful in the diagnosis of EFT when interpreted on the basis morphology and immunohistochemistry.

OBJECTIVE To examine the risk of ocular complications following radiotherapy in patients with nasopharyngeal carcinoma (NPC). METHODS We adopted 1:1 propensity score matching and identified an NPC cohort (n = 736) and a comparison cohort (n = 736) that comprised non-NPC head and neck cancer patients who received radiotherapy in the National Health Insurance Research Database from 1997 to 2010. The follow-up period was terminated upon developing ocular complications (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]360-379) or on December 31, 2010. RESULTS After adjusting for the confounding factors of the study, the NPC cohort had a higher adjusted hazard ratio (HR) for developing ocular complications than the comparison cohort (adjusted HR = 2.786, 95% confidence interval [CI] = 1.805-4.112, P

Uterine mesenchymal tumors are genetically heterogenous; those with uniform cytomorphology, best exemplified by endometrial stromal tumors, often contain various fusion genes. Novel fusions involving ESR1 and GREB1, key factors in sex hormone pathways, have been implicated in rare uterine mesenchymal tumors. Particularly, the fusions between 5'-ESR1/GREB1 and 3'-NCOA2/NCOA3 were recently identified in 4 uterine tumors resembling ovarian sex-cord tumor (UTROSCT). By RNA sequencing, pathology review, and FISH screening, we identified 4 uterine sarcomas harboring rearranged GREB1, including GREB1-NCOA2 and the novel GREB1-NR4A3, GREB1-SS18, and GREB1-NCOA1, validated by RT-PCR and/or FISH. They occurred in the myometrium of postmenopausal women and were pathologically similar despite minor differences. Tumor cells were generally uniform and epithelioid, with vesicular nuclei and distinct to prominent nucleoli. Growth patterns included solid sheets, trabeculae/cords, nests, and fascicles. Only 1 tumor showed small foci of definitive sex-cord components featuring well-formed tubules, retiform structures, Leydig-like cells, and lipid-laden cells and exhibiting convincing immunoreactivity to sex-cord markers (calretinin, α-inhibin, and Melan-A). In contrast, all the 4 classic UTROSCT we collected occurred in premenopausal patients, consisted predominantly of unequivocal sex-cord elements, prominently expressed multiple sex-cord markers, and harbored ESR1-NCOA3 fusion. Combined with previously reported cases, GREB1-rearranged tumors involved significantly older women (P=0.001), tended to be larger and more mitotically active, showed more variable and often inconspicuous sex-cord differentiation, and appeared to behave more aggressively than ESR1-rearranged UTROSCT. Therefore, these 2 groups of tumors might deserve separate consideration, despite some overlapping features and the possibility of belonging to the same disease spectrum.

Influenza is an infectious disease caused by an RNA virus that affects birds and mammals. It is a leading cause of morbidity, mortality and economic loss worldwide. Under influenza A virus infection, an uncontrolled inflammatory response in the lungs frequently leads to severe pneumonia. The anti-inflammatory and immune modulatory effects of melatonin may provide a beneficial effect for this disease. In this study, we found that melatonin treatment significantly decreases the expression of TNF-α, IL-6 and IFN-γ, and increases the production of IL-10 and TGF-β. The induction of IL-10 by melatonin occurs via the upregulation of IL-27 expression in dendritic cells. Melatonin also significantly inhibits the production of TNF-α in CD8 T cells. Co-treatment of melatonin and ribavirin significantly increases the survival of virus-infected mice compared to ribavirin alone. Our study suggests that melatonin possesses a therapeutic potential in influenza-induced pneumonia as an adjuvant treatment with anti-viral drugs.

SB-706375 is a selective receptor antagonist of human urotensin-II (hU-II), which can block the aorta contraction induced by hU-II in rats. The effect of SB-706375 on myocardial ischaemia–reperfusion (I/R) injury is unclear. The major objective of this study was to investigate whether SB-706375 has a protective effect on myocardial I/R injury in rats and explore its possible mechanisms. Isolated hearts of Adult Sprague–Dawley were perfused in a Langendorff apparatus, and haemodynamic parameters, lactate dehydrogenase (LDH), creatine phosphokinase-MB (CK-MB), cardiac troponin I (cTnI), RhoA, and the protein expressions of U-II receptor (UTR), receptor-interacting protein 3 (RIP3), Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) and Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) were assessed. We found that SB-706375 (1 × 10−6 and 1 × 10−5 mol/L) significantly inhibited the changes of haemodynamic parameters and reduced LDH and CK-MB activities and also cTnI level in the coronary effluents in the heart subjected to myocardial I/R injury. Further experiments studies showed that SB-706375 obviously prevented myocardial I/R increased RhoA activity and UTR, RIP3, ROCK1, and ROCK2 protein expressions. ROCK inhibition abolished the improving effect of SB-706375 on myocardial I/R-induced haemodynamic change in the isolated perfused rat heart. These findings suggested that SB-706375 provides cardio-protection against I/R injury in isolated rats by blocking UTR-RhoA/ROCK-RIP3 pathway.

Background: Whether the weaning outcome of solid cancer patients receiving mechanical ventilation (MV) in the intensive care unit (ICU) is comparable to that in non-cancer patients is unknown. The aim of this study was to compare the weaning outcomes between non-cancer patients and patients with different types of cancer. Methods: We studied patients requiring MV during ICU stay for medical reasons between 2012 and 2014. Cancer patients were grouped into those with lung cancer (LC), head and neck cancer (HNC), hepatocellular carcinoma (HCC), and other cancers (OC). The primary endpoint was successful weaning at day 90 after the initiation of MV, and the main secondary endpoints were 28-day and 90-day mortality after ICU admission. Results: Five hundred and eighteen patients with solid cancers and 1362 non-cancer patients were recruited. The rate of successful weaning at day 90 was 57.9% in cancer patients, which was lower than 68.9% in non-cancer patients (p

Seedlessness is a primary breeding objective for citrus fresh fruit market, and triploids have been proven to have great value to produce seedless fruits. In this study, aiming to produce triploid plants for developing some seedless cultivars, four 2x × 4x interploid crosses were conducted using three elite but seedy cultivars as seed parents and one newly flowered doubled diploid and two allotetraploid somatic hybrids as pollen parents. As a result, a total of 1454 developed and 3409 undeveloped seeds from 341 fruits were obtained. Using an optimized embryo rescue approach, 669 developed and 1301 undeveloped seeds germinated in vitro, with an average germination rate as 52.5% for the crosses using ‘Nadorcott’ tangor and ‘Bendizao’ tangerine (polyembryonic) as seed parents and 31.0% for the crosses using ‘Orah’ mandarin (monoembryonic) as seed parent. Then by shoot and root induction, totally 1354 plantlets were regenerated, among which 401 and 54 plants were proved to be triploids and tetraploids by flow cytometry (FCM) analysis and chromosome counting. Hybrid nature of the selected triploid progenies, as well as two different origins (doubled diploid and hybrid origins) for the selected tetraploid progenies was further confirmed by single nucleotide polymorphism (SNP) markers.

As an extension of the conventional diffusion weighted imaging, diffusion kurtosis imaging (DKI) is based on the non-Gaussian diffusion model that can inherently account for restricted water diffusion within the complex microstructure of most tissues. This study aimed to investigate association of liver DKI derived parameter with stage of liver fibrosis.Fifty-six healthy New Zealand white rabbits were enrolled into this study, among which 48 rabbits were randomly given carbon tetrachloride to model liver fibrosis, and 8 rabbits treated with normal saline served as control subjects. All rabbits underwent liver DKI followed by biopsy to stage fibrosis (stages F0-F4) on 6th, 8th, 10th, and 12th weekends after initiation of modeling fibrosis. Mean kurtosis (MK), fractional anisotropy (FA), and mean diffusion (MD) were derived from DKI data. Statistical analysis was to evaluate association of DKI derived parameter with stage of fibrosis.FA (r = 0.512) and MK (r = 0.567) increased, and MD (r = -0.574) decreased with increasing stage of fibrosis from F0 to F4 (all p values0.05). Significant differences were found in all parameters between F0 and F3 or F4, F1 and F4, F0 and F1-4, and F0-1 and F2-4 (all p values0.05). FA and MD could distinguish between F0 from F2, MD, and MK could distinguish F1 from F3, F0-2 from F3-4, and F1-2 from F3-4, and MK and FA could distinguish F2 from F4, and F0-3 from F4 (all p values0.05). According to receiver operating characteristic analysis, MK could best predict stage ≥F1, ≥F2, ≥F3, and F4, and discriminate F1-2 from F3-4 with areas under receiver operating characteristic curve of 0.766-0.930.DKI derived parameters can help stage fibrosis.

Background Computed tomography (CT) or MR images may cause the severity of early acute pancreatitis (AP) to be underestimated. As an innovative image analysis method, radiomics may have potential clinical value in early prediction of AP severity. Purpose To develop a contrast-enhanced (CE) MRI-based radiomics model for the early prediction of AP severity. Study type Retrospective. Subjects A total of 259 early AP patients were divided into two cohorts, a training cohort (99 nonsevere, 81 severe), and a validation cohort (43 nonsevere, 36 severe). Field strength/sequence 3.0T, T1 -weighted CE-MRI. Assessment Radiomics features were extracted from the portal venous-phase images. The "Boruta" algorithm was used for feature selection and a support vector machine model was established with optimal features. The MR severity index (MRSI), the Acute Physiology and Chronic Health Evaluation (APACHE) II, and the bedside index for severity in acute pancreatitis (BISAP) were calculated to predict the severity of AP. Statistical tests Independent t-test, Mann-Whitney U-test, chi-square test, Fisher's exact tests, Boruta algorithm, receiver operating characteristic analysis, DeLong test. Results Eleven potential features were chosen to develop the radiomics model. In the training cohort, the area under the curve (AUC) of the radiomics model, APACHE II, BISAP, and MRSI were 0.917, 0.750, 0.744, and 0.749, and the P value of AUC comparisons between the radiomics model and scoring systems were all less than 0.001. In the validation cohort, the AUC of the radiomics model, APACHE II, BISAP, and MRSI were 0.848, 0.725, 0.708, and 0.719, respectively, and the P value of AUC comparisons were 0.96 (radiomics vs. APACHE II), 0.40 (radiomics vs. BISAP), and 0.46 (radiomics vs. MRSI). Data conclusion The radiomics model had good performance in the early prediction of AP severity. Level of evidence 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:397-406.

Influenza A virus mutates rapidly, allowing it to escape natural and vaccine-induced immunity. Neuraminidase (NA) is a surface protein capable of cleaving the glycosidic linkages of neuraminic acids to release newly formed virions from infected cells. Genetic variants within a viral population can influence the emergence of pandemic viruses as well as drug susceptibility and vaccine effectiveness. In the present study, 55 clinical specimens from patients infected with the 2009 pandemic influenza A/H1N1 virus, abbreviated as A(H1N1)pdm09, during the 2015-2016 outbreak season in Taiwan were collected. Whole genomes were obtained through next-generation sequencing. Based on the published sequences from A(H1N1)pdm09 strains worldwide, a mixed population of two distinct variants at NA position 151 was revealed. We initially reasoned that such a mixed population may have emerged during cell culture. However, additional investigations confirmed that these mixed variants were detectable in the specimens of patients. To further investigate the role of the two NA-151 variants in a dynamic population, a reverse genetics system was employed to generate recombinant A(H1N1)pdm09 viruses. It was observed that the mixture of the two distinct variants was characterized by a higher replication rate compared to the recombinant viruses harbouring a single variant. Moreover, an NA inhibition assay revealed that a high frequency of the minor NA-151 variant in A(H1N1)pdm09 was associated with a reduced susceptibility to NA inhibitors. We conclude that two distinct NA-151 variants can be identified in patient specimens and that such variants may increase viral replication and NA activity.

Summary Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colony-stimulating factor 1 receptor. This phase I, nonrandomized, open-label multiple-dose study evaluated pexidartinib safety and efficacy in Asian patients with symptomatic, advanced solid tumors. Materials and Methods Patients received pexidartinib: cohort 1, 600 mg/d; cohort 2, 1000 mg/d for 2 weeks, then 800 mg/d. Primary objectives assessed pexidartinib safety and tolerability, and determined the recommended phase 2 dose; secondary objectives evaluated efficacy and pharmacokinetic profile. Results All 11 patients (6 males, 5 females; median age 64, range 23–82; cohort 1 n = 3; cohort 2 n = 8) experienced at least one treatment-emergent adverse event; 5 experienced at least one grade ≥ 3 adverse event, most commonly (18%) for each of the following: increased aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyl transferase, and anemia. Recommended phase 2 dose was 1000 mg/d for 2 weeks and 800 mg/d thereafter. Pexidartinib exposure, area under the plasma concentration-time curve from zero to 8 h (AUC0-8h), and maximum observed plasma concentration (Cmax) increased on days 1 and 15 with increasing pexidartinib doses, and time at Cmax (Tmax) was consistent throughout all doses. Pexidartinib exposure and plasma levels of adiponectin and colony-stimulating factor 1 increased following multiple daily pexidartinib administrations. One patient (13%) with tenosynovial giant cell tumor showed objective tumor response. Conclusions This was the first study to evaluate pexidartinib in Asian patients with advanced solid tumors. Pexidartinib was safe and tolerable in this population at the recommended phase 2 dose previously determined for Western patients (funded by Daiichi Sankyo; clinicaltrials.gov number, NCT02734433).

In this study, effects of icariin (Ica) on were examined in a mouse model of d -galactose (D-gal)-induced ovarian aging. Kunming white mice were divided into three groups: aging group induced with D-gal, experiment group treated with Ica at low (50 mg/kg), middle (100 mg/kg) and high (200 mg/kg) concentrations, and control group with no treatment. Ovarian histomorphology, serum FSH, LH and E2 levels, and reproductive function were compared among the groups. Ovarian expression of Amh, Bax and Bcl-2 was examined by qPCR and western blotting. Our results showed that diameters of secondary and tertiary follicles were significantly reduced in the aging group when compared with control group (P

Purpose To determine whether gross tumour volume (GTV) of adenocarcinoma of oesophagogastric junction (AOG) measured on fat-suppression T2-weighted imaging (FS-T2WI) and diffusion-weighted imaging (DWI) correlates with regional lymph node metastasis and N stage. Materials and methods The study was approved by the institutional ethics committee, and written informed consent was obtained. Forty-six patients with AOG underwent preoperative magnetic resonance scans including FS-T2WI and DWI with b-values of 500 and 800 s/mm2. GTV was measured on FS-T2WI and DWI. Statistical analyses were performed to determine association of GTV with N stage. Results Univariate analysis showed GTV measured on FS-T2WI and DWI with b-values of 500 and 800 s/mm2 were correlated with lymph node metastasis (all Ps Conclusion There is a trend toward an increase in GTV obtained on FS-T2WI and DWI sequences with increasing N stage.

BACKGROUND The purpose of this study was to present our comparison of the clinical outcome of patients with nasopharyngeal carcinoma (NPC) treated with whole-field intensity-modulated radiotherapy (whole-field-IMRT) or split-field-IMRT. METHODS We retrospectively studied 388 patients with M0 NPC. The median lower neck doses were 50 Gy in 1.35 Gy/fractions for the 240 whole-field-IMRT patients, and 50.4 Gy in 1.8 to 2.0 Gy/fractions for the 148 split-field-IMRT patients. RESULTS The IMRT technique did not affect the overall survival (OS; P = .077) and locoregional control (P = .231) rates. However, the split-field-IMRT group had more locoregional recurrences at the whole neck (P = .005) but not at the nasopharynx (P = .968) or the lower neck (P = .485). The patients treated with split-field-IMRT (43.2%) had more grade III neck fibrosis than the patients who received whole-field-IMRT (18.3%; P < .001). Only 1 patient had temporal lobe necrosis in our study. CONCLUSION Our study shows that whole-field-IMRT using a lower dose/fraction for the lower neck results in at least comparable locoregional control and less fibrosis compared to conventional fraction with split-field-IMRT.

It is important to address the periodontitis-associated bacteria in the residual subgingival plaque after scaling and root planing to successfully treat periodontitis. In this study, we explored the possibility of exploiting the ion pairing/complexation of minocycline, Ca2+, and sulfate/sulfonate-bearing biopolymers to develop an intrapocket delivery system of minocycline as an adjunct to scaling and root planing. Minocycline-calcium-dextran sulfate complex microparticles were synthesized from minocycline, CaCl2, and dextran sulfate. They were characterized using Fourier-transform infrared spectroscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. An in vitro release study was conducted to evaluate the release kinetics of minocycline from these microparticles. Agar disk diffusion assays and biofilm-grown bacteria assays were used to assess antibacterial capability. High loading efficiency (96.98% ± 0.12%) and high loading content (44.69% ± 0.03%) for minocycline were observed for these complex microparticles. Mino-Ca-DS microparticles achieved sustained release of minocycline for at least 9 days at pH 7.4 and 18 days at pH 6.4 in phosphate-buffered saline, respectively. They also demonstrated potent antimicrobial effects against Streptococcus mutans and Aggregatibacter actinomycetemcomitans in agar disk diffusion and biofilm assays. These results suggested that the ion pairing/complexation of minocycline, Ca2+, and sulfonate/sulfate-bearing biopolymers can be exploited to develop complex microparticles as local delivery systems for periodontitis treatment.

The role of CSE-produced H2S on cerebrovascular relaxation and cerebral ischemia-reperfusion (I/R) injury was investigated using CSE knockout (CSE-/-) and wild-type (CSE+/+) mice. The relaxation of the cerebral basilar artery (BA) to CSE-produced H2S and its mechanism were detected. The results revealed that both NaHS, a donor of exogenous H2S, and ROCK inhibitor Y27632 could induce significant relaxation of the BA, but the relaxation of the BA to NaHS was significantly attenuated by Y27632. In addition, removal of endothelium could reduce the relaxation of the BA to Y27632; CSE knockout also significantly attenuated Y27632-induced BA relaxation with endothelium rather than without endothelium. By contrast, the contraction of the BA from CSE-/- mice to RhoA agonist LPA or U46619 was stronger than that from CSE+/+ mice. Furthermore, RhoA activity and ROCK protein expression remarkably increased in the BA vascular smooth muscle cells (VSMCs) from CSE-/- mouse, which were inhibited by NaHS pretreatment. These findings revealed that the CSE-produced H2S induced cerebrovascular relaxation is generated from endothelial cells and the mechanism of vascular relaxation may relate to inhibition of RhoA-ROCK pathway. We next sought to confirm the protective effect of CSE-produced H2S on cerebral I/R injury produced by middle cerebral artery occlusion and bilateral common carotid artery occlusion in mice. We investigated the changes of neurological deficit, cerebral infarct, brain water content, LDH decrease, MDA increase as well as impairment of learning and memory function. The results showed that the cerebral injury became more grievous in CSE-/-mice than that in CSE+/+mice, which could be remarkably alleviated by NaHS pretreatment.