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Hereditary uterine cancer (UC) is traditionally associated with pathogenic/likely pathogenic germline variants (PGVs) in Lynch syndrome genes or PTEN; however, growing evidence supports a role for other genes that may reveal new clinical management options. In this study we assessed the prevalence and potential clinical impact of PGVs identified in UC patients referred for comprehensive germline genetic testing that combined testing for Lynch syndrome, PTEN, and other cancer predisposition genes.Prevalence of PGVs in patients referred to a single clinical lab for germline genetic testing with an indication of uterine or endometrial cancer were retrospectively assessed and compared by syndrome type, patient age at testing, and self-reported ancestry. Potential clinical actionability of PGVs was based on established guidelines for clinical management, targeted therapies, and clinical trial eligibility.PGVs were detected in 13.6% of the cohort (880/6490). PGVs were most frequently observed in Lynch syndrome genes (60.4%) and PTEN (1.5%), with 38.1% in another cancer predisposition gene (i.e., CHEK2, BRCA1/BRCA2). PGV prevalence was similar for patients50 years and those ≥50 years (15.1% vs 13.2%). Nearly all PGVs (97.2%) were associated with guideline-recommended management, including cascade testing; 60.5% were associated with FDA-approved therapies; and 35.2% were associated with clinical trials.Focusing germline testing on Lynch syndrome genes and PTEN and limiting testing to patients50 years of age at diagnosis may overlook a substantial proportion of UC patients who harbor actionable PGVs. Universal comprehensive genetic testing of UC patients could benefit many patients and at-risk family members.

Perinatal depression (PND) screening recommendations are made by national, state-based and professional organisations; however, there is disagreement regarding screening timing, provider responsible, screening setting, screening tool as well as the follow-up and referral pathways required post-screening. This systematic review aimed to identify, describe and compare PND screening recommendations from member countries of the Organisation for Economic Co-operation and Development (OECD). Publications were identified through systematically searching PubMed, Google and the Guidelines International Network (GIN). Recommendations regarding PND screening endorsement, timing, frequency, responsible provider, tools/assessments and follow-up and referral were extracted. Twenty-one publications, including guidelines, from five countries were included. Most made recommendations in support of PND screening using the Edinburgh Postnatal Depression Scale. Details differed regarding terminology used, as well as frequency of screening, follow-up mechanisms and referral pathways. A broad range of health providers were considered to be responsible for screening. This is the first review to identify and compare PND screening recommendations from OECD member countries; however, only online publications published in English, from five countries were included. Heterogeneity of publication types and inconsistency in definitions rendered quality assessment inappropriate. While most publications generally endorsed PND screening, there are exceptions and the associated details pertaining to the actual conduct of screening vary between and within countries. Developing clear, standardised recommendations based on current evidence is necessary to ensure clarity amongst healthcare providers and a comprehensive approach for the early detection of PND.

Symptomatic subsequent vertebral compression fracture (VCF; SVCF) is a common complication associated with poor outcomes. Accumulating evidence shows that demographic factors and incidences of symptomatic SVCFs differ during different periods after the primary vertebroplasty (VP).To investigate the incidence and demographic factors of symptomatic SVCFs after the primary VP in different periods using registry data in the Taiwan National Health Insurance Research Database.This retrospective cohort study included 28,343 patients aged ≥ 50 years with painful VCF treated with VP from 2002 to 2016. Symptomatic SVCF was defined as SVCF requiring another VP or re-admission. During the 2-year follow-up, 1955 patients received subsequent VP while 1,407 were readmitted. Cox proportional hazard models were used to compare the risks of subsequent VP or readmission.The cumulative incident rate of subsequent VP and re-hospitalization was 0.87 [95% confidence interval (CI), 0.82 ~ 0.92] and 0.62 (95% CI, 0.58 ~ 0.66) per 100 person-months, respectively, within the first 6 months after the primary VP, and it decreased over time. A multiple Cox regression model showed that age, osteopenia or osteoporosis, Charlson comorbidity index (CCI) were significant independent risk factors of subsequent VP or readmission within the first 6 months.This study demonstrated that the incidence of symptomatic SVCF peaked in the first 6 months after the primary VP. Age, osteoporosis or osteopenia, and CCI were determined to be risk factors in the first 6 months, but only osteoporosis or osteopenia and CCI were risk factors thereafter.

Immune checkpoint inhibitors (ICIs) have been widely used in cancer treatment; however, some case reports suggested that ICIs treatment might result in ileus. This study aims to comprehensively reveal the relationship between ileus and ICIs treatment in real-world cases from Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).Reports from January 1, 2011 to December 31, 2020 were extracted from the FAERS. ICIs-related adverse events in patients were defined as related to use of anti-programmed cell death protein 1 antibodies (PD-1, nivolumab and pembrolizumab), anti-programmed cell death-ligand 1 inhibitors (PD-L1, atezolizumab, durvalumab, avelumab, and cemiplimab), and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, ipilimumab and tremelimumab). ICIs-related ileus cases were identified to characterize their clinical features. Reporting odds ratios (ROR) and information component (IC) were used to assess the relationship between ICIs and ileus.Among the 105 001 cases related to ICIs, 245 were reported with ICI-related ileus. The affected patients were mainly elderly (median age, 64.5 years) and male (58%, n = 143). The median onset for all cases was 36 (range 0-880) days, and no statistical difference was observed between monotherapy and combination therapy (PD-1 or PD-L1 plus CTLA-4) (p = 0.21). Most patients required drug withdrawal treatment (n = 113, 74%) and can achieve a recovered-resolved state (n = 72, 46%). All ICIs were significantly associated with ileus (ROR = 4.27, 95%Cl: 3.75-4.85; IC = 2.04, 95%Cl: 1.79-2.31). Ileus events were most commonly reported in PD-1 treatment (n = 164, ROR = 3.83, 95%Cl: 3.28-4.48; IC = 1.90, 95%Cl: 1.62-2.21).This pharmacovigilance database analysis suggested that ICIs are related to ileus. However, combination therapy may not speed up the onset of ileus.

This study trained and evaluated algorithms to detect, segment, and classify simple and complex pleural effusions on computed tomography (CT) scans.For detection and segmentation, we randomly selected 160 chest CT scans out of all consecutive patients (January 2016-January 2021, n = 2659) with reported pleural effusion. Effusions were manually segmented and a negative cohort of chest CTs from 160 patients without effusions was added. A deep convolutional neural network (nnU-Net) was trained and cross-validated (n = 224; 70%) for segmentation and tested on a separate subset (n = 96; 30%) with the same distribution of reported pleural complexity features as in the training cohort (eg, hyperdense fluid, gas, pleural thickening and loculation). On a separate consecutive cohort with a high prevalence of pleural complexity features (n = 335), a random forest model was implemented for classification of segmented effusions with Hounsfield unit thresholds, density distribution, and radiomics-based features as input. As performance measures, sensitivity, specificity, and area under the curves (AUCs) for detection/classifier evaluation (per-case level) and Dice coefficient and volume analysis for the segmentation task were used.Sensitivity and specificity for detection of effusion were excellent at 0.99 and 0.98, respectively (n = 96; AUC, 0.996, test data). Segmentation was robust (median Dice, 0.89; median absolute volume difference, 13 mL), irrespective of size, complexity, or contrast phase. The sensitivity, specificity, and AUC for classification in simple versus complex effusions were 0.67, 0.75, and 0.77, respectively.Using a dataset with different degrees of complexity, a robust model was developed for the detection, segmentation, and classification of effusion subtypes. The algorithms are openly available at https://github.com/usb-radiology/pleuraleffusion.git.

The clinical utility of Dixon water-fat separation coronary MR angiography (CMRA) with compressed sensing (CS) reconstruction has not been determined in a patient population. This study was designed to evaluate the performance of 3.0 T non-contrast-enhanced Dixon water-fat separation CS whole-heart CMRA sequence in vitro and in vivo.In vitro phantom MRI, we compared key parameters of the SENSE and CS images. And in this prospective in vivo study, from November 2019 to October 2020, 94 participants were recruited for 3.0 T non-contrast-enhanced Dixon water-fat separation CS whole-heart CMRA. The accuracy of CMRA for detecting a ≥ 50% reduction in diameter was determined using X-ray coronary angiography (CA) as the reference method.Compared with SENSE, CS with an appropriate acceleration factor offers both higher SNR/CNR (p0.05) and a shortened acquisition. Fifty-eight patients successfully completed the CMRA and CA. The sensitivity, specificity, positive predictive values, negative predictive values, and accuracy of 3.0 T non-contrast-enhanced Dixon water-fat separation CS whole-heart CMRA according to a patient-based analysis were 96.4%, 66.7%, 73.0%, 95.2% and 81.0%, respectively. The area under the receiver-operator characteristic (ROC) curve (AUC) of 3.0 T non-contrast-enhanced Dixon water-fat separation CS whole-heart CMRA for detecting significant coronary artery stenosis is 0.908, 0.895, and 0.904 in patient-, vessel-, and segment-based analyses respectively.3.0 T non-contrast-enhanced Dixon water-fat separation whole-heart CMRA using appropriate CS is a promising noninvasive and radiation-free technique to detect clinically significant coronary stenosis on patients with suspected CAD.

Purpose We aimed to develop and prospectively validate a risk score model to guide individualized concurrent chemoradiotherapy (CCRT) for patients with stage II nasopharyngeal carcinoma (NPC) in intensity‐modulated radiotherapy (IMRT) era. Materials and Methods In total, 1220 patients who received CCRT or IMRT alone were enrolled in this study, including a training cohort (n = 719), a validation cohort (n = 307), and a prospective test cohort (n = 194). Patients were stratified into different risk groups by a risk score model based on independent prognostic factors, which were developed in the training cohort. Survival rates were compared by the log‐rank test. The validation and prospective test cohorts were used for validation. Results Total tumor volume, Epstein–Barr virus DNA, and lactate dehydrogenase were independent risk factors for failure‐free survival (FFS, all p

Objectives We aimed to develop and validate radiologic scores from [18F]FDG PET/CT and MRI to guide individualized induction chemotherapy (IC) for patients with T3N1M0 nasopharyngeal carcinoma (NPC). Methods A total of 542 T3N1M0 patients who underwent pretreatment [18F]FDG PET/CT and MRI were enrolled in the training cohort. A total of 174 patients underwent biopsy of one or more cervical lymph nodes. Failure-free survival (FFS) was the primary endpoint. The radiologic score, which was calculated according to the number of risk factors from the multivariate model, was used for risk stratification. The survival difference of patients undergoing concurrent chemoradiotherapy (CCRT) with or without IC was then compared in risk-stratified subgroups. Another cohort from our prospective clinical trial (N = 353, NCT03003182) was applied for validation. Results The sensitivity of [18F]FDG PET/CT was better than that of MRI (97.7% vs. 87.1%, p p n = 329) stratified by radiologic score benefited from IC (5-year FFS: IC + CCRT 83.5% vs. CCRT 70.5%; p = 0.0044), while low-risk patients (n = 213) did not. These results were verified again in the validation cohort. Conclusions T3N1M0 patients were accurately staged by both [18F]FDG PET/CT and MRI. The radiologic score can correctly identify high-risk patients who can gain additional survival benefit from IC and it can be used to guide individualized treatment of T3N1M0 NPC. Key Points • [18F]FDG PET/CT was more accurate than MRI in diagnosing histologically proven cervical lymph nodes. • Radiologic lymph node characteristics were reliable independent risk factors for FFS in T3N1M0 nasopharyngeal carcinoma patients. • High-risk patients identified by the radiologic score based on [18F]FDG PET/CT and MRI could benefit from the addition of induction chemotherapy.

To develop and validate a radiomics nomogram for differentiating between malignant pulmonary nodules and benign nodules.56 benign and 51 malignant nodules from 96 patients were analyzed using manual segmentation of the T2-fBLADE-TSE, while the nodules signal intensity (SIlesion), lesion muscle ratio (LMR) and nodule size were all measured and recorded. The maximum relevance and minimum redundancy (mRMR) and the least absolute shrinkage and selection operator (LASSO) were used to select nonzero coefficients and develop the model in pulmonary nodules diagnosis. The radiomics nomogram was also developed. The clinical prediction value was determined by the decision curve analysis (DCA).The nodule size, SIlesion and LMR of the benign group were 1.78 ± 0.57 cm, 227.50 ± 81.39 and 2.40 ± 1.27 respectively, in contrast to the 2.00 ± 0.64 cm, 232.87 ± 82.21 and 2.17 ± 0.91, respectively, in the malignant group (P = 0.09, 0.60 and 0.579). A total of 13 radiomics features were retained. The Rad-score of the benign nodules group was lower than that of the malignant nodules group (P0.0010.049, trainingtest set). The AUC of radiomics signature for nodules diagnosis was 0.82 (95% CI, 0.73-0.91) in the training set and 0.71 (95% CI, 0.51-0.90) in the test set. A nomogram, consisting of 13 radiomics features and nodule size, produced good prediction in the training set (AUC, 0.82; 95% CI, 0.73-0.91), which was significantly better than that of T2-based quantitative parameters (AUC, 0.62; 95% CI, 0.50-0.75, P = 0.003). In the test set, the performance of radiomics nomogram (AUC, 0.70; 95% CI, 0.51-0.90) was also better than that of T2-based quantitative parameters (AUC, 0.46; 95% CI, 0.25-0.67) (P = 0.145). The DCA showed that radiomics nomogram and T2-based quantitative parameter had overall net benefits, while the performance of nomogram was better.We constructed and validated a T2-fBLADE-TSE-based radiomics nomogram that can help to differentiate between malignant pulmonary nodules and benign nodules.

Tumor cells show deregulated metabolism leading to an enrichment of lactate in the tumor microenvironment (TME). This lactate-rich environment has been reported to impair effector T cells. However, T-regulatory cells (Tregs) show metabolic advantages in lactate-rich TME that maintain a strong suppression of effector T cells, which leads to tumor immune evasion. Therefore, the glycolytic process of tumors could represent a therapeutic target, and agents that modify the energy metabolism of tumor cells have therapeutic potential. Resveratrol is a naturally occurring polyphenol that has been confirmed to suppress tumor cells' glycolytic metabolism. In this study, we show that resveratrol induces metabolic reprogramming in ovarian cancer cells. Resveratrol increases oxidative and decreases glycolysis, in association with decreased lactate production both in vitro and in vivo. Lactate reduction in TME weakens the suppressive function of Tregs, and subsequently restores anti-tumor immunity. Significantly, combined resveratrol and PD-1 blockade promote anti-tumor efficacy. These data suggest that resveratrol's anti-tumor actions in ovarian cancer could be explained, in part, through modification of the anti-tumor immunity, and indicate a novel treatment strategy for improving immune checkpoint blockade therapy using resveratrol.

Detrimental tumor microenvironment (TME) relies on distorted tumor vasculature for further tumor expansion. Vascular normalization therapy partly improves TME through vessel repairing, while these therapies enter an unbreakable Mobius ring due to each attempt hindered by pro-angiogenic factors from TME, leading to limited duration and extent of vascular normalization. Here, we developed a nanosystem including FLG and MAR/MPA nanodrugs to regulate both tumor vasculature and TME. FLG nanodrugs were constructed by connecting VEGF/VEGFR2 inhibitory low molecular weight heparin and gambogic acid with F3 peptide decoration for directly regulating on vascular endothelial cells and inducing vascular normalization. Meanwhile, MAR/MPA nanodrugs encapsulating CCL5/CCR5 blocker maraviroc were designed to restrict cytokine functions of angiogenesis and TME deterioration, contributing to vasculature repairing and TME reconstruction. Our results demonstrated this combined nanosystem synergistically induced vascular normalization window lasting 9 days and restored vascular permeability and oxygen supply in Panc-1 tumor. Furthermore, in melanoma, our nanosystem achieved immune improvements with increased infiltration of CD4+ and CD8+T cells in a remodeled TME. The two nanodrugs assisting each other in terms of both vascular repairing and TME improvements successfully reversed the vicious crosstalk to a positive one, achieving overall TME remodeling and promoting therapeutic efficiency.

Background The long-term prognostic value of coronary CT angiography (CCTA) in asymptomatic adults with hepatic steatosis (HS) remains unknown. Purpose To evaluate the long-term prognostic value of CCTA in asymptomatic adults with HS. Materials and Methods Between January 2009 and December 2013, consecutive asymptomatic adults who underwent CCTA evaluation and unenhanced abdominal CT were prospectively enrolled. All participants were divided into two groups-with HS and without HS according to abdominal CT results. The primary end point was major adverse cardiovascular events (MACEs), defined as cardiac death, stroke, myocardial infarction, and angina requiring hospitalization. Multivariable Cox regression analysis and Kaplan-Meier analysis were used to compare survival rates. Results One thousand thirteen participants with HS and 1940 participants without HS who completed the follow-up were included (mean age, 66 years ± 10 [standard deviation] [range, 29-90 years]; 1940 men). During a median of 7.2 years of follow-up (interquartile range, 6.3-8.1), MACEs were observed in 96 of 1013 participants with HS (10%), whereas 80 of 1940 participants without HS (4%) had MACEs. In participants with a Coronary Artery Disease Reporting and Data System (CAD-RADS) category of 0, both participants with and without HS had a similar 8.8-year event-free survival rate (99.2% event-free survival rate in participants with HS vs 99.0% event-free survival rate in participants without HS, P = .77). As for participants with CAD-RADS categories 1 or 2 or 3-5, the 8.8-year event-free survival rate was lower in participants with HS than in those without HS (70.6% vs 85.2%, P < .001; 51.4% vs 71.7%, P = .03, respectively). The risk of MACEs was higher for participants with HS than for those without HS in CAD-RADS categories 1 and 2 (adjusted hazard ratio = 2.3; 95% CI: 1.4, 3.9; P < .001) and CAD-RADS categories 3-5 (adjusted HR = 2.1; 95% CI: 1.2, 3.6; P = .006) but not in the setting of CAD-RADS category 0 (adjusted HR = 5.1; 95% CI: 0.1, 398; P = .47). Conclusion Asymptomatic participants with hepatic steatosis (HS) had a worse prognosis than those without HS in the presence of coronary artery disease (CAD) at coronary CT angiography, whereas participants with HS and without CAD might have excellent clinical outcomes during a median follow-up of 7.2 years. © RSNA, 2021 Online supplemental material is available for this article.

Background Artificial intelligence can assist in cardiac image interpretation. Here, we achieved a substantial reduction in time required to read a cardiovascular magnetic resonance (CMR) study to estimate left atrial volume without compromising accuracy or reliability. Rather than deploying a fully automatic black-box, we propose to incorporate the automated LA volumetry into a human-centric interactive image-analysis process. Methods and results Atri-U, an automated data analysis pipeline for long-axis cardiac cine images, computes the atrial volume by: (i) detecting the end-systolic frame, (ii) outlining the endocardial borders of the LA, (iii) localizing the mitral annular hinge points and constructing the longitudinal atrial diameters, equivalent to the usual workup done by clinicians. In every step human interaction is possible, such that the results provided by the algorithm can be accepted, corrected, or re-done from scratch. Atri-U was trained and evaluated retrospectively on a sample of 300 patients and then applied to a consecutive clinical sample of 150 patients with various heart conditions. The agreement of the indexed LA volume between Atri-U and two experts was similar to the inter-rater agreement between clinicians (average overestimation of 0.8 mL/m2 with upper and lower limits of agreement of − 7.5 and 5.8 mL/m2, respectively). An expert cardiologist blinded to the origin of the annotations rated the outputs produced by Atri-U as acceptable in 97% of cases for step (i), 94% for step (ii) and 95% for step (iii), which was slightly lower than the acceptance rate of the outputs produced by a human expert radiologist in the same cases (92%, 100% and 100%, respectively). The assistance of Atri-U lead to an expected reduction in reading time of 66%—from 105 to 34 s, in our in-house clinical setting. Conclusions Our proposal enables automated calculation of the maximum LA volume approaching human accuracy and precision. The optional user interaction is possible at each processing step. As such, the assisted process sped up the routine CMR workflow by providing accurate, precise, and validated measurement results.

PURPOSE Strict clinical criteria used by Medicare for germline testing for Lynch syndrome (LS) could lead to missed diagnoses of hereditary cancer syndromes given variable individual and family phenotypes. The aim of this study was to compare rates and spectrum of pathogenic or likely pathogenic (P/LP) variants in LS and other hereditary cancer genes on the basis of meeting Medicare LS testing criteria. METHODS Retrospective review of Medicare beneficiaries who had multigene panel testing with an indication of personal or family history of colorectal cancer (CRC) was performed. Ordering providers determined if Medicare LS criteria were met. The results of genetic testing were compared on the basis of whether or not Medicare testing criteria were met. RESULTS Among 639 Medicare beneficiaries, 495 (77.5%) met testing criteria. Overall rates of P/LP variant identification were similar between those meeting and not meeting testing criteria (18.4% v 11.8%; P = .06). LS was diagnosed more frequently among those meeting testing criteria (10.1% v 4.9%; P = .05). No statistical differences were found in rates of P/LP variant identification for non-LS CRC genes (5.3% v 5.6%; P = .89) or non-CRC genes (4.2% v 2.1%; P = .23). PMS2, MUTYH, and ATM P/LP variants were found at higher rates among those outside of criteria. CONCLUSION Among Medicare beneficiaries undergoing genetic testing for suspected LS, rates of P/LP variants in actionable cancer genes were similar regardless of whether testing criteria were met. Current testing criteria fail to identify individuals with P/LP variants in PMS2 and other actionable cancer genes. Relaxing LS testing criteria could improve identification of individuals with hereditary cancer syndromes among Medicare beneficiaries.

There are around 300 million adolescent pregnancies worldwide, accounting for 11% of all births worldwide. Accumulating evidence demonstrates that many adverse perinatal outcomes are associated with adolescent pregnancies. However, how and why these abnormalities occur remain to be defined. In this study, pregnancy at different stages was compared between 25- and 30- day-old and mature female mice. We found that the litter size of adolescent pregnancy is significantly decreased from F1 to F3 generations compared to mature pregnancy. On days 8 and 12 of pregnancy, multiple abnormalities in decidual and placental development appear in F3 adolescent pregnancy. On days 5 and 8, uterine endoplasmic reticulum stress is dysregulated in F3 adolescent pregnancy. Embryo implantation and decidualization are also compromised in adolescent pregnancy. Many genes are abnormally expressed in adolescent estrous uteri. The abnormal endocrine environment and abnormal implantation from uterine immaturity may result in multiple pregnancy failures in adolescent pregnancy. The aim of this study is to shed light on human adolescent pregnancy.

Computerized interpretation of electrocardiogram plays an important role in daily cardiovascular healthcare. However, inaccurate interpretations lead to misdiagnoses and delay proper treatments. In this work, we built a high-quality Chinese 12-lead resting electrocardiogram dataset with 15,357 records, and called for a community effort to improve the performances of CIE through the China ECG AI Contest 2019. This dataset covers most types of ECG interpretations, including the normal type, 8 common abnormal types, and the other type which includes both uncommon abnormal and noise signals. Based on the Contest, we systematically assessed and analyzed a set of top-performing methods, most of which are deep neural networks, with both their commonalities and characteristics. This study establishes the benchmarks for computerized interpretation of 12-lead resting electrocardiogram and provides insights for the development of new methods. Graphical AbstractA community effort to assess and improve computerized interpretation of 12-lead resting electrocardiogram Supplementary information The online version contains supplementary material available at 10.1007/s11517-021-02420-z.

Background To test the advantages of positron emission tomography and computed tomography (PET/CT) for diagnosing lymph nodes and staging nasopharyngeal carcinoma and to investigate its benefits for survival and treatment decisions. Methods The performance of PET/CT and magnetic resonance imaging (MRI) in diagnosis was compared based on 460 biopsied lymph nodes. Using the propensity matching method, survival differences of T3N1M0 patients with (n = 1093) and without (n = 1377) PET/CT were compared in diverse manners. A radiologic score model was developed and tested in a subset of T3N1M0 patients. Results PET/CT performed better than MRI with higher sensitivity, accuracy, and area under the receiver operating characteristic curve (96.7% vs. 88.5%, p p p p p = 0.006) for the high-risk patients selected by the model but not for those without risk stratification (p = 0.78). Conclusion PET/CT showed advantages in staging nasopharyngeal carcinoma due to a more accurate diagnosis of lymph nodes and this contributed to a survival benefit. PET/CT combined with MRI provided prognostic factors that could identify high-risk patients and guide individualized treatment.

Summary Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.

New hypoglycemic agents include sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide 1 receptor agonists (GLP1RAs), and dipeptidyl peptidase-4 inhibitors (DPP4is). The association between each class of these new hypoglycemic drugs and the risks of various digestive system diseases is unknown. We aimed to explore this relationship by performing a meta-analysis.We included large randomized trials of SGLT2is, GLP1RAs, and DPP4is. Outcomes of interest were 91 kinds of digestive diseases including 75 kinds of gastrointestinal disorders and 16 kinds of hepatobiliary disorders. Meta-analysis was done to generate pooled risk ratio (RR) and 95% confidence interval (CI). Subgroup analysis was conducted according to 3 different drug classes.We included 21 large trials in this meta-analysis. Compared with placebo, GLP1RAs were associated with the higher risks of gastric ulcer hemorrhage (RR 2.68, 95% CI 1.07-6.68; Pdrug = .035; I2 = 0), pancreatitis (RR 1.48, 95% CI 1.02-2.15; Pdrug = .041; I2 = 0), cholangitis acute (RR 5.96, 95% CI 1.04-34.08; Pdrug = .045; I2 = 0), and cholecystitis acute (RR 1.52, 95% CI 1.08-2.15; Pdrug = .017; I2 = 1.5%), but were not significantly associated with the occurrences of the other 87 kinds of digestive diseases (Pdrug ranged from .064 to .999). SGLT2is versus placebo were not significantly associated with the occurrences of 91 kinds of digestive diseases (Pdrug ranged from .077 to .995). DPP4is versus placebo were not significantly associated with the occurrences of 91 kinds of digestive diseases (Pdrug ranged from .085 to .999).Neither SGLT2is nor DPP4is are associated with the occurrences of various kinds of digestive diseases, whereas GLP1RAs are associated with the higher risks of 4 kinds of digestive diseases, namely, gastric ulcer hemorrhage, pancreatitis, cholangitis acute, and cholecystitis acute. These findings seem to suggest that GLP1RAs are not applicable for patients at high risk of 4 specific digestive diseases, whereas SGLT2is and DPP4is are safe for patients susceptible to digestive diseases. However, our findings require to be further verified by future studies with sufficient statistical power.

Background The aim of this work was to determine whether patients with intermediate-risk head and neck squamous cell carcinoma (HNSCC) can benefit from postoperative chemoradiotherapy (POCRT). Methods Patients without extracapsular extension (ECE) or positive margins (PMs) who received POCRT or postoperative radiotherapy (PORT) at our center were retrospectively (December 2009 to October 2018) included for analysis, in particular, using a propensity score-matching method. Results After matching, 264 patients were enrolled, including 142 (41.2%) patients with pT3-4, 136 (38.3%) patients with pN2-3, 68 (21.1%) patients with perineural invasion, and 45 (12.8%) patients with lymphatic/vascular space invasion. With a median follow-up of 52 months, 3-year overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS) and disease-free survival (DFS) rates were 72.4%, 79.3%, 83.5% and 62.5%, respectively. pN2-3 was an independent risk factor for OS (p p p p = 0.002), while pT3-4 was a poor prognostic factor for DMFS (p = 0.005). Overall, patients receiving POCRT had no significant differences from those receiving PORT in OS (p = 0.062), DFS (p = 0.288), LRFS (p = 0.076) or DMFS (p = 0.692). But notably, patients with pN2-3 achieved better outcomes from POCRT than PORT in 3-year OS (p = 0.050, 63.9% vs. 47.9%) and LRFS (p = 0.019, 74.6% vs. 54.9%). And patients with pT3-4 also had higher 3-year LRFS (p = 0.014, 88.5% vs. 69.1%) if receiving POCRT. Conclusions Among all intermediate-risk pathological features, pN2-3 and pT3-4 were independent unfavorable prognostic factors for patients with HNSCC without PMs or ECE. POCRT can improve the survival outcomes of patients with pN2-3 or pT3-4.

This study was a systematic review comparing the clinical outcomes of using the nonirradiated and irradiated allograft for anterior cruciate ligament (ACL) reconstruction.A comprehensive literature search was conducted using multiple databases, including Medline, Embase, and Cochrane. All databases were searched from the earliest records through August 2019 using the following Boolean operators: irradiated AND nonirradiated AND ACL AND allograft. All prospective and retrospective controlled trials were retrieved that directly compared physical examination and knee function scores and patient-rated outcomes between the nonirradiated and irradiated allograft for ACL reconstruction.Three prospective and 2 retrospective articles were identified by the search, and the findings suggested that the nonirradiated allografts were superior to the irradiated allografts based on improved knee joint functional scores and decreased failure rate, even though there was no significantly difference with respect to overall IKDC, range of motion, vertical jump test, and one-leg hop test.Irradiated allograft should be limited to be used in ACL surgery and further research into new alternative sterilization techniques are needed to avoiding the disease transmission without interference with the biomechanical properties of the grafts.

Nanoparticles and antibiotics are toxic to humans and ecosystems, and they inevitably coexist in the wastewater treatment plants. Hence, the co-existence effects and stress mechanism of copper (II) oxide nanoparticles (CuO NPs) and ciprofloxacin (CIP) on simultaneous nitrification, endogenous denitrification and phosphorus removal (SNEDPR) by aerobic granular sludge (AGS) were investigated here. The co-existence stress of 5 mg/L CuO NPs and 5 mg/L CIP resulted in the synergistic inhibitory effect on nutrient removal. Transformation inhibition mechanisms of carbon (C), nitrogen (N) and phosphorus (P) with CuO NPs and CIP addition were time-dependent. Furthermore, the long-term stress mainly inhibited PO

Primary effusion lymphoma (PEL) is a fatal B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Inducing KSHV lytic replication that causes the death of host cells is an attractive treatment approach for PE; however, combination therapy inhibiting viral production is frequently needed to improve its outcomes. We have previously shown that the KSHV lytic protein K-bZIP can SUMOylate histone lysine demethylase 4A (KDM4A) at lysine 471 (K471) and this SUMOylation is required for virus production upon KSHV reactivation. Here, we demonstrate that SUMOylation of KDM4A orchestrates PEL cell survival, a major challenge for the success of PEL treatment; and cell movement and angiogenesis, the cell functions contributing to PEL cell extravasation and dissemination. Furthermore, integrated ChIP-seq and RNA-seq analyses identified interleukin-10 (IL-10), an immunosuppressive cytokine, as a novel downstream target of KDM4A. We demonstrate that PEL-induced angiogenesis is dependent on IL-10. More importantly, single-cell RNA sequencing (scRNA-seq) analysis demonstrated that, at the late stage of KSHV reactivation, KDM4A determines the fates of PEL cells, as evidenced by two distinct cell populations; one with less apoptotic signaling expresses high levels of viral genes and the other is exactly opposite, while KDM4A-K417R-expressing cells contain only the apoptotic population with less viral gene expression. Consistently, KDM4A knockout significantly reduced cell viability and virus production in KSHV-reactivated PEL cells. Since inhibiting PEL extravasation and eradicating KSHV-infected PEL cells without increasing viral load provide a strong rationale for treating PEL, this study indicates targeting KDM4A as a promising therapeutic option for treating PEL.

MicroRNA-221 (miRNA-221) is upregulated in several malignant tumors and is associated with poor patient prognosis. Therefore, the present study aimed to investigate the role and underlying mechanism of miRNA-221 in doxorubicin (DOX) resistance in osteosarcoma cells. We constructed DOX-resistant Saos-2/DOX cells and treated them with DOX. Cell viability was determined by performing a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cells were transfected with either miRNA-221 mimic or miRNA-221 inhibitor; quantitative (q)RT-PCR was performed to detect the expression of miRNA-221. Flow cytometry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling (TUNEL) staining were used to detect cell apoptosis. The immunofluorescence method was also used to detect cell signal transduction and activator of transcription 3 (Stat3) protein expression distribution. In addition, Western blotting was used to detect changes in the expression of each protein. We found that miRNA-221 was upregulated in Saos-2/DOX cells. Moreover, the miRNA-221 mimic induced DOX resistance in Saos-2 cells, whereas the miRNA-221 inhibitor enhanced DOX sensitivity in Saos-2/DOX cells. The miRNA-221 mimic upregulated the expression of phosphorylated-Stat3, P-glycoprotein (P-gp), and B-cell lymphoma-2 (Bcl-2) proteins in Saos-2 cells and induced the entry of Stat3 into the nucleus, whereas the miRNA-221 inhibitor exerted the opposite effect. Pretreatment with the Stat3 chemical inhibitor, STAT3-IN-3, significantly inhibited the upregulation of P-gp and Bcl-2 protein expression induced by the miRNA-221 mimic in Saos-2 cells; it also caused the Saos-2 cells to overcome DOX resistance induced by the miRNA-221 mimic. Thus, miRNA-221 increased the expression of P-gp and Bcl-2 by activating the Stat3 pathway to promote DOX resistance in osteosarcoma cells, indicating a potential use of miRNA-221 in osteosarcoma treatment.

Background: Increased IL-6 level, M2 macrophages and PD-1+CD8+ T cells in tumor microenvironments (TME) have been identified to correlate with resistance to checkpoint blockade immunotherapy, yet the mechanism remains poorly understood. Rab small GTPase-mediated trafficking of cytokines is critical in immuno-modulation. We have previously reported dysregulation of Rab37 in lung cancer cells, whereas the roles of Rab37 in tumor-infiltrating immune cells and cancer immunotherapy are unclear. Methods: The tumor growth of the syngeneic mouse allograft in wild type or Rab37 knockout mice was analyzed. Imaging analyses and vesicle isolation were conducted to determine Rab37-mediated IL-6 secretion. STAT3 binding sites at PD-1 promoter in T cells were identified by chromatin immunoprecipitation assay. Multiplex fluorescence immunohistochemistry was performed to detect the protein level of Rab37, IL-6 and PD-1 and localization of the tumor-infiltrating immune cells in allografts from mice or tumor specimens from lung cancer patients. Results: We revealed that Rab37 regulates the secretion of IL-6 in a GTPase-dependent manner in macrophages to trigger M2 polarization. Macrophage-derived IL-6 promotes STAT3-dependent PD-1 mRNA expression in CD8+ T cells. Clinically, tumors with high stromal Rab37 and IL-6 expression coincide with tumor infiltrating M2-macrophages and PD1+CD8+ T cells that predicts poor prognosis in lung cancer patients. In addition, lung cancer patients with an increase in plasma IL-6 level are found to be associated with immunotherapeutic resistance. Importantly, combined blockade of IL-6 and CTLA-4 improves survival of tumor-bearing mice by reducing infiltration of PD1+CD8+ T cells and M2 macrophages in TME. Conclusions: Rab37/IL-6 trafficking pathway links with IL-6/STAT3/PD-1 transcription regulation to foster an immunosuppressive TME and combined IL-6/CTLA-4 blockade therapy exerts potent anti-tumor efficacy.

Airway wall thickening is a consequence of chronic inflammatory processes and usually only qualitatively described in CT radiology reports. The purpose of this study is to automatically quantify airway wall thickness in multiple airway generations and assess the diagnostic potential of this parameter in a large cohort of patients with Chronic Obstructive Pulmonary Disease (COPD).This retrospective, single-center study included a series of unenhanced chest CTs. Inclusion criteria were the mentioning of an explicit COPD GOLD stage in the written radiology report and time period (01/2019-12/2021). A control group included chest CTs with completely unremarkable lungs according to the report. The DICOM images of all cases (axial orientation; slice-thickness: 1 mm; soft-tissue kernel) were processed by an AI algorithm pipeline consisting of (A) a 3D-U-Net for det detection and tracing of the bronchial tree centerlines (B) extraction of image patches perpendicular to the centerlines of the bronchi, and (C) a 2D U-Net for segmentation of airway walls on those patches. The performance of centerline detection and wall segmentation was assessed. The imaging parameter average wall thickness was calculated for bronchus generations 3-8 (AWTAirway wall thickness increases in patients suffering from COPD and is automatically quantifiable. AWTQuantitative measurements considering the complete visible bronchial tree instead of qualitative description could enhance radiology reports, allow for precise monitoring of disease progression and diagnosis of early stages of disease.

Background and Purpose As magnetic resonance imaging (MRI) signs of normal pressure hydrocephalus (NPH) may precede clinical symptoms we sought to evaluate an algorithm that automatically detects this pattern. Methods A support vector machine (SVM) was trained in 30 NPH patients treated with ventriculoperitoneal shunts and 30 healthy controls. For comparison, four neuroradiologists visually assessed sagittal MPRAGE images and graded them as no NPH pattern, possible NPH pattern, or definite NPH pattern. Results Human accuracy to visually detect a NPH was between 0.85 and 0.97. Interobserver agreement was substantial (κ = 0.656). Accuracy of the SVM algorithm was 0.93 and AUROC 0.99. Among 272 prespecified regions, gray matter and CSF volumes of both caudate, the right parietal operculum, the left basal forebrain, and the 4th ventricle showed the highest discriminative power to separate a NPH and a no NPH pattern. Conclusion A NPH pattern can be reliably detected using a support vector machine (SVM). Its role in the work-up of asymptomatic patients or neurodegenerative disease has to be evaluated.

Increasing circRNAs have attracted a lot of attention because of their significant biological effects in many diseases. It has been reported that circ_0008305 can modulate lung cancer progression. However, the association between circ_0008305 and hepatocellular carcinoma (HCC) needs to be well explored. In this current research, we studied the molecular function and potential mechanism of circ_0008305 in HCC progression. First, it was demonstrated that circ_0008305 was greatly increased in HCC tissues and cells. Moreover, we observed silencing circ_0008305 markedly repressed HCC cells in vitro growth and reduced tumor growth in vivo. Additionally, it was identified that circ_0008305 can act as a sponge of miR‐660 while miR‐660 targeted Bcl‐2‐associated athanogene 5 (BAG5). BAG5 belongs to a member of BAG family and it is involved in multiple diseases. We reported that circ_0008305 contributed to the inhibition of miR‐660, which resulted in an upregulated expression of BAG5 in HCC. Subsequently, rescue assays were conducted and it was indicated that loss of BAG5 reversed the effects of miR‐660 inhibitors on HCC partially. To sum up, it was illustrated by our study that circ_0008305‐mediated miR‐660‐5p/BAG5 axis triggered HCC progression, which could provide a novel insight on the underlying mechanism of HCC progression., circ_0008305 was greatly increased in HCC tissues and cells. circ_0008305 can act as a sponge of miR‐660. miR‐660 targeted Bcl‐2‐associated athanogene 5 (BAG5).

The failure to treat and control the growth of metastases is the main cause of death in breast cancer (BC) patients. Compared to the traditional method of analyzing circulating tumor DNA (ctDNA), capturing intact circulating tumor cells (CTCs) allows us to more accurately characterize mutations and identify suitable targeted therapies. We used CellCollector to collect peripheral CTCs. Thirty metastatic breast cancer (MBC) patients were enrolled, and 17 were analyzed with next-generation sequencing (NGS) methods. Clinical characteristics were analyzed along with the CTCs enumeration and detection rates. Whole-genome amplification (WGA) was used to amplify the CTC genomic DNA of 127 genes. Patients younger than 45 years old, with brain metastasis, with three or more metastatic sites, or with HER2-positive had the highest number of CTCs collected. The CTCs detection rate was also correlated to the number of metastasis sites. Different metastasis sites such as the brain, viscus, bone, and soft tissue contained specific high-frequency gene mutations. AKT3, MYC, and NT5C2 mutations were only found in brain metastases. APC, BCL2L11, ESRP1, FLT3 mutations were only in the visceral metastases. KEAP1, KIT, MET were the specific mutation genes in patients with bone and soft tissue metastases. These findings provide evidence that we can detect gene mutation information for obtaining the biological characteristics by CTCs using CellCollector. Different metastasis sites contain specific high-frequency mutation genes, which provide guidance to the accurate gene therapy.

Background. Methylene blue is the most commonly used tracer for sentinel lymph node (SLN) biopsy (SLNB) in China. This study aimed to investigate the feasibility of clinical application of SLNB using methylene blue dye (MBD) for early breast cancer and the prognosis of patients with different SLN and non-SLN statuses. Methods. We retrospectively analyzed the clinicopathological data of patients with early breast cancer treated at the Peking University First Hospital between 2013 and 2018. We calculated the SLN identification rate (IR) in SLNB with MBD and the false-negative rate (FNR), and analyzed the prognosis of patients with different SLN and non-SLN statuses using Kaplan-Meier curves. Results. Between January 2013 and December 2018, 1603 patients with early breast cancer underwent SLNB with MBD. The SLN IR was 95.8% (1536/1603). Two SLNs (median) were detected per patient. There were significant differences in FNR between patients with SLN micrometastasis and macrometastasis (19.0% vs. 4.5%, χ2 = 12.771, P

Tryptophan (Trp) is one of the essential amino acids, which plays important roles in biological systems and the normal growth of human beings, and it is of great significance to be able to detect Trp in a rapid, efficient, and sensitive way. Herein, a 3D network metal–organic framework ([Sm2(BTEC)1.5(H2O)8]·6H2O) with excellent thermal and water stability was synthesized by a hydrothermal method. Interestingly, it could discriminate Trp from other natural amino acids in aqueous solution through a significant fluorescence enhancement effect, and showed high detection sensitivity (LOD = 330 nM) and outstanding anti-interference ability. The sensor system was successfully applied to the detection of Trp in practical samples, so it was expected to be a sensitive and efficient Trp sensor. In addition, the sensing mechanism was explained in detail by a series of characterization methods combined with density functional theory (DFT). There were many coordination water molecules in the crystal structure of the complex. Based on the small steric hindrance and molecular structure of water molecules, it provided the possibility for coordination interaction between Trp and Sm3+. On the other hand, the triplet energy level (T1) of Trp matched with the 4G5/2 vibrational energy level of Sm3+, so Trp could be used as the second “antenna molecule” besides 1,2,4,5-benzenetetracarboxylic acid (H4BTEC). Therefore, it effectively broadened the way for Sm-MOF to absorb excitation light.

Background Atrial fibrillation (AF) has been linked to left atrial (LA) enlargement. Whereas most studies focused on 2D-based estimation of static LA volume (LAV), we used a fully-automatic convolutional neural network (CNN) for time-resolved (CINE) volumetry of the whole LA on cardiac MRI (cMRI). Aim was to investigate associations between functional parameters from fully-automated, 3D-based analysis of the LA and current classification schemes in AF. Methods We retrospectively analyzed consecutive AF patients who underwent cMRI on 1.5T systems including a stack of oblique-axial CINE series covering the whole LA. The LA was automatically segmented by a validated CNN. In the resulting volume-time curves, maximum, minimum and LAV before atrial contraction were automatically identified. Active, passive and total LA emptying fractions (LAEF) were calculated and compared to clinical classifications (AF Burden score (AFBS), increased stroke risk (CHA2DS2VASc≥2), AF type (paroxysmal/persistent), EHRA score, and AF risk factors). Moreover, multivariable linear regression models (mLRM) were used to identify associations with AF risk factors. Results Overall, 102 patients (age 61±9 years, 17% female) were analyzed. Active LAEF (LAEF_active) decreased significantly with an increase of AFBS (minimal: 44.0%, mild: 36.2%, moderate: 31.7%, severe: 20.8%, p Conclusions Fully-automatic morphometry of the whole LA derived from cMRI showed significant relationships between LAEF_active with increased stroke risk and severity of AFBS. Furthermore, higher age, higher AFBS and presence of heart failure were independent predictors of reduced LAEF_active, indicating its potential usefulness as an imaging biomarker.

PURPOSE An inherited basis for presumed sporadic neuroendocrine tumor (NET) has been suggested by evidence of familial clustering of NET and a higher incidence of second malignancies in patients and families with NET. To further investigate a potential heritable basis for sporadic neuroendocrine tumors, we performed multigene platform germline analysis to determine the frequency of hereditary susceptibility gene variants in a cohort of patients with sporadic small intestine NET (SI-NET). METHODS We performed a multigene platform germline analysis with Invitae's 83-gene, next-generation sequencing panel using DNA from 88 individuals with SI-NET from a clinically annotated database of patients with NET evaluated at Dana-Farber Cancer Institute (DFCI) who are considered high risk for inherited variants. Additionally, we evaluated the prevalence of pathogenic variants in an unselected cohort of patients with SI-NET who underwent testing with Invitae. RESULTS Of the 88 patients in the DFCI cohort, a pathogenic germline variant was identified in eight (9%) patients. In an independent cohort of 120 patients with SI-NET, a pathogenic germline variant was identified in 13 (11%) patients. Pathogenic variants were identified in more than one patient in the following genes: ATM, RAD51C, MUTYH, and BLM. Somatic testing of tumors from the DFCI cohort was suboptimal because of insufficient coverage of all targeted exons, and therefore, analysis was limited. CONCLUSION We demonstrate a 9%-11% incidence of pathogenic germline variants in genes associated with inherited susceptibility for malignancy not previously described in association with SI-NET. The association of these germline variants with neuroendocrine carcinogenesis and risk is uncertain but warrants further characterization.

Background This study aimed to explore the correlations between continuous positive airway pressure (CPAP) treatment-related self-efficacy and family support among patients with obstructive sleep apnoea (OSA) to provide a basis for improving patients' CPAP treatment compliance. Methods From May to Dec 2017, a cross-sectional study was conducted in the emergency wards, otorhinolaryngology wards, respiratory wards, and outpatient clinic of our hospital. A total of 112 patients with OSA treated with home ventilators were administered with the Self-efficacy Measure for Sleep Apnoea (SEMSA) and Perceived Social Support from Family (PSS-Fa) Scale. Results On the SEMSA, participants had a disease risk perception score of 2.61±0.31, an outcome expectation score of 2.44±0.17, and a self-efficacy score of 2.55±0.13. Mean total score on PSS-Fa was 10.15±2.73, with 10.7%, 45.5% and 43.8% of participants showing a low level, a medium level, and a high level of family support, respectively. Outcome expectation and self-efficacy were positively correlated with family support. Conclusions The self-efficacy and outcome expectation of patients with OSA are positively correlated with their level of family support.

Clinical studies have indicated that the long-term use of topical antiglaucoma drugs, such as carbonic anhydrase inhibitors (CAIs), may lead to meibomian gland dysfunction (MGD). We hypothesize that these adverse effects involve a direct influence on human MG epithelial cells (HMGECs). The purpose our present investigation was to test our hypothesis and determine whether exposure to dorzolamide, a CAI, impacts the proliferation, intracellular signaling and differentiation of HMGECs.We cultured immortalized (i) HMGECs with vehicle or various concentrations of dorzolamide for 6 days. Cells were enumerated with a hemocytometer, and examined for their morphology, Akt signaling activity, accumulation of neutral lipids, phospholipids and lysosomes, and the expression of protein biomarkers for lipogenesis regulation, lysosomes and autophagosomes.Our results show that a high, 500 µg/ml concentration of dorzolamide causes a significant decrease in Akt signaling and the proliferation of iHMGECs. However, the high dose of dorzolamide also promotes the differentiation of iHMGECs. This response features increases in the number of lysosomes, the accumulation of phospholipids, and the expression of the light chain 3A biomarker for autophagosomes. In contrast, the therapeutic amount (50 µg/ml) of dorzolamide has no impact on the proliferative or differentiative abilities of iHMGECs.Our results support our hypothesis and demonstrate that the CAI dorzolamide does exert a direct influence on the proliferation and differentiation of iHMGECs. However, this effect is elicited only by a high, and not a therapeutic, amount of dorzolamide.

Attention based end-to-end speech synthesis achieves better performance in both prosody and quality compared to the conventional "front-end"-"back-end" structure. But training such end-to-end framework is usually time-consuming because of the use of recurrent neural networks. To enable parallel calculation and long-range dependency modeling, a solely self-attention based framework named Transformer is proposed recently in the end-to-end family. However, it lacks position information in sequential modeling, so that the extra position representation is crucial to achieve good performance. Besides, the weighted sum form of self-attention is conducted over the whole input sequence when computing latent representation, which may disperse the attention to the whole input sequence other than focusing on the more important neighboring input states, resulting in generation errors. In this paper, we introduce two localness modeling methods to enhance the self-attention based representation for speech synthesis, which maintain the abilities of parallel computation and global-range dependency modeling in self-attention while improving the generation stability. We systematically analyze the solely self-attention based end-to-end speech synthesis framework, and unveil the importance of local context. Then we add the proposed relative-position-aware method to enhance local edges and experiment with different architectures to examine the effectiveness of localness modeling. In order to achieve query-specific window and discard the hyper-parameter of the relative-position-aware approach, we further conduct Gaussian-based bias to enhance localness. Experimental results indicate that the two proposed localness enhanced methods can both improve the performance of the self-attention model, especially when applied to the encoder part. And the query-specific window of Gaussian bias approach is more robust compared with the fixed relative edges.

Refracture of cemented vertebrae occurs commonly after vertebroplasty (VP) for osteoporotic vertebral compression fracture (OVCF). It can result in severe pain or neurological deficit, but no preventive medication is available. Owing to the bone anabolic benefits of teriparatide (TP), this study was aimed to compare the outcomes of cemented vertebrae with TP to those without TP. Patients who received VP for OVCF with at least 1 year follow-up were included. The anterior body height (ABH) and middle body height (MBH) and kyphotic angle (KA) were measured before VP and 1 week and at least 1 year after VP. Refracture was defined as a 15% decrease in ABH or MBH and 8° decrease in KA compared with those at postoperative 1 week. The clinical outcomes were evaluated. 35 VP procedures in 21 patients treated with TP (TP group), and, matched to that, 29 out of 133 patients treated with VP alone (VP group) were included. One year after VP, ABH and MBH were significantly greater, except KA, in the TP group (VP group vs. TP group: KA − 4.97° ± 12.1 vs. −2.85° ± 12.21°, p = 0.462, ABH 1.56 ± 0.48 cm vs. 1.84 ± 0.56 cm, p = 0.027, MBH 1.49 ± 0.39 cm vs. 1.73 ± 0.41 cm, p = 0.017). The refracture rates of KA, ABH, and MBH were significantly lower in the TP group (VP group vs. TP group: KA 42.11% vs.8.57%, p p p

Background Limited data are available regarding the current microbiological characteristics of bloodstream infections (BSIs) in intensive care units (ICUs) in China. This retrospective study aimed to determine the epidemiology of early- and late-onset BSIs in our ICU. Methods We retrospectively collected data about ICU patients with BSI from 2013 to 2017. The patients were divided into the early- and late-onset BSI groups according to if BSI occurred within or beyond 48 hours after ICU admission. Univariate and multivariate logistic regression analyses were used to assess the risk factors for infection with multidrug resistant organisms (MDROs). Results Of 5474 ICU admissions, 486 (8.9%) patients with BSIs and with 500 microorganisms were included in this study, 246 (50.6%) of whom had early-onset BSIs. Two hundred and seventy patients were infected with MDROs. The proportion of MDRO infections was significantly higher among patients with late-onset BSIs than among those with early-onset BSIs (57.9% vs. 41.5%, P = .017). The ICU mortality rate was significantly higher in the late-onset BSI group (44.6% vs. 33.8%, P = .014) and early and appropriate antimicrobial treatment significantly improved the survival rate among patients with BSI (P < .001). Conclusions MDROs affected more than half of patients with BSI in the ICU. Early appropriate empirical antimicrobial therapy could improve clinical outcome of patients with BSIs.

BackgroundThe key to modern drug discovery is to find, identify and prepare drug molecular targets. However, due to the influence of throughput, precision and cost, traditional experimental methods are difficult to be widely used to infer these potential Drug-Target Interactions (DTIs). Therefore, it is urgent to develop effective computational methods to validate the interaction between drugs and target.MethodsWe developed a deep learning-based model for DTIs prediction. The proteins evolutionary features are extracted via Position Specific Scoring Matrix (PSSM) and Legendre Moment (LM) and associated with drugs molecular substructure fingerprints to form feature vectors of drug-target pairs. Then we utilized the Sparse Principal Component Analysis (SPCA) to compress the features of drugs and proteins into a uniform vector space. Lastly, the deep long short-term memory (DeepLSTM) was constructed for carrying out prediction.ResultsA significant improvement in DTIs prediction performance can be observed on experimental results, with AUC of 0.9951, 0.9705, 0.9951, 0.9206, respectively, on four classes important drug-target datasets. Further experiments preliminary proves that the proposed characterization scheme has great advantage on feature expression and recognition. We also have shown that the proposed method can work well with small dataset.ConclusionThe results demonstration that the proposed approach has a great advantage over state-of-the-art drug-target predictor. To the best of our knowledge, this study first tests the potential of deep learning method with memory and Turing completeness in DTIs prediction.

Aim: This study investigated the molecular mechanism underlying the involvement of miR-885 in the signaling pathways of VDR. Results: Based on their rs739837 genotype, the subjects were divided into a case group and a control group. Logistic regression was carried out to study the impact of rs739837 genotypes on the severity of asthma, and it was found that the minor allele (T) of rs739837 significantly increased the severity of asthma. Using a luciferase assay, VDR was confirmed as a miR-885 target, with a negative regulatory relationship established between VDR and miR-885. Conclusion: The findings of this study demonstrated that VDR is an miR-885 target, while the presence of rs739837 minor allele (T) in miR-885 interferes with the interaction between miR-885 and VDR to affect the severity of asthma.

Background Despite speckle tracking echocardiography (STE) has emerged as a sensitive technique for identifying myocardial dysfunction, there are little data available on the appropriate timing to perform STE in the serial assessment after anthracycline administration. Moreover, further uncertainty is increased in the context of STE application in diffuse large B-cell lymphoma (DLBCL) research, as most recommendations are inferred by studies conducted primarily in breast cancer. Objective This study aimed to determine whether early measurement of strain parameters derived by STE could predict the development of cardiotoxicity. Methods Sixty-five patients were included in the final analysis. The patients were evaluated at baseline, after the third cycle and sixth-eighth cycle, and during follow-up. Global longitudinal strain (GLS) was analyzed using STE, and left ventricular ejection fraction (LVEF) was calculated by real time 3D echocardiography (RT3DE). Results There was a significant decrease in GLS after the third cycle of chemotherapy and remained decreased during subsequent follow-up, whereas LVEF decreased only at follow-up. A percentage reduction in GLS of 13.8% between baseline and the third cycle of chemotherapy was the best predictor of further LVEF reduction. Conclusion Earlier monitoring timing and more accurate assessment methods might be helpful in the prevention of irreversible heart failure.

Due to the circadian rhythm regulation of almost every biological process in the human body, physiological and biochemical conditions vary considerably over the course of a 24-h period. Thus, optimal drug delivery and therapy should be effectively controlled to achieve the desired therapeutic plasma concentrations and therapeutic drug responses at the required time according to chronopharmacological concepts, rather than continuous maintenance of constant drug concentrations for an extended time period. For many drugs, it is not always necessary to constantly deliver a drug into the human body under disease conditions due to rhythmic variations. Pulsatile drug delivery systems (PDDSs) have been receiving more attention in pharmaceutical development by providing a predetermined lag period, followed by a fast or rate-controlled drug release after application. PDDSs are characterized by a programmed drug release, which may release a drug at repeatable pulses to match the biological and clinical needs of a given disease therapy. This review article focuses on thermoresponsive gating membranes embedded with liquid crystals (LCs) for transdermal drug delivery using PDDS technology. In addition, the principal rationale and the advanced approaches for the use of PDDSs, the marketed products of chronotherapeutic DDSs with pulsatile function designed by various PDDS technologies, pulsatile drug delivery designed with thermoresponsive polymers, challenges and opportunities of transdermal drug delivery, and novel approaches of LC systems for drug delivery are reviewed and discussed. A brief overview of all academic research articles concerning single LC- or binary LC-embedded thermoresponsive membranes with a switchable on-off permeation function through topical application by an external temperature control, which may modulate the dosing interval and administration time according to the therapeutic needs of the human body, is also compiled and presented. In the near future, since thermal-based approaches have become a well-accepted method to enhance transdermal delivery of different water-soluble drugs and macromolecules, a combination of the thermal-assisted approach with thermoresponsive LCs membranes will have the potential to improve PDDS applications but still poses a great challenge.

As small conserved RNAs without a coding function, microRNAs are expressed in multicellular organisms and contribute to the modulation of multiple cellular reactions, such as viral replication, as well as autophagy. microRNAs can regulate host gene expression and inhibit or reinforce hepatitis B virus (HBV) replication. Hepatic cells express miR-155 noticeably. Consequently, our study explored miR-155 modulation of HBV replication and investigated the potential mechanism involved. miR-155 was inhibited on HBV infection. miR-155 transfection remarkably reinforced HBV replication, antigen expression, and progeny secretion in HepG2215 cells. Moreover, miR-155 impaired the inhibition of the cytokine signalling 1 (SOCS1)/Akt/mTOR axis and reinforced HepG2215 autophagy. Additionally, the autophagy inhibitor (3-MA) eliminated HBsAg secretion triggered by miR-155. Taken together, miR-155 reinforced HBV replication by reinforcing SOCS1-triggered autophagy. SIGNIFICANCE OF THE STUDY: The research studied the potential mechanism involved in HBV replication and miR-155 that miR-155 reinforces HBV replication by reinforcing the SOCS1/Akt/mTOR axis-stimulated autophagy, and therefore, it can provide medical practitioners with the inspiration that chronic HBV might be cured or improved by regulating the activation of miR-155 in cells. In the study, the experiments show that autophagy inhibitors (3-MA) counteracted miR-155 contribution to HBV replication, and it might be a practicable way to improve HBV through some therapies that can repress the autophagy in related cells.

This study compared the surgical outcomes of the 120-W Thulium laser (Vela™ XL) enucleation of the prostate and bipolar transurethral resection of the prostate (TURP) in terms of efficacy, safety, and improvements of quality of life (QoL) in patients with benign prostate hyperplasia (BPH). Records were obtained from January 2014 to September 2018 for selected patients with symptomatic BPH who underwent 120-W Thulium laser (Vela™XL) prostate enucleation and bipolar TURP in our institution. All the patients selected met the surgical criteria for TURP and had received medical treatment for at least 3 months. Patients were excluded if their ECOG performance status was >1, if they had active malignant disease, of if they had a history of prostate surgery or reconstruction surgery of the urinary system. Patients decided which treatment option would be performed. Both the procedures were conducted by a single surgeon. Clinical outcomes such as changes in the International Prostate Symptom Score (IPSS) score, urodynamic parameters, drug consumption, pain scores, and QoL were evaluated. The rate of urinary tract infection, recatheterization, additional analgesic requirement, return to the emergency department for treatment, and other surgical complications was analyzed and compared between the two cohorts. A total of 276 patients met the inclusion criteria. Among them, 141 patients received bipolar TURP, where as 135 decided to receive laser vaporesection. No significant difference was observed in age, PSA level, prostate volume, and comorbidities between the two cohorts. Pre-operative (pre-op) urodynamic parameters were also identical, except that the laser surgery group had a higher rate of admission with a urinary catheter (24.4% vs. 14.2%, p=0.044). The operating time was longer in the laser surgery group (79.3 minutes vs. 62.4 minutes, p

Purpose. In this study, we aim to evaluate the prognostic role of serum uric acid and gamma-glutamyltransferase in advanced gastric cancer patients. Methods. A total of 180 patients pathologically diagnosed with advanced gastric cancer were included in this retrospective study. We used time-dependent receiver operating characteristic (ROC) curves to identify the optimal cut-off value of serum uric acid (UA) and gamma-glutamyltransferase (GGT). Survival analysis was performed using the Kaplan–Meier method and log-rank test, and multivariate Cox regression analyses were applied. A nomogram was formulated, and the calibration and discrimination of the nomogram were determined by calibration curve and concordance index (C-index). We validated the results using bootstrap resampling and a separate study on 60 patients collected from 2015 to 2017 using the same criteria in other medical center. Results. Both higher serum uric acid (>228 μmol/L) and higher gamma-glutamyltransferase (>14 U/L) had worse OS and PFS. Univariate analysis indicated that serum uric acid (UA) (p<0.001 and p<0.001) and gamma-glutamyltransferase (GGT) (p<0.001 and p=0.044) were significantly related to overall survival (OS) and progression-free survival (PFS), respectively. Multivariate analysis revealed serum uric acid (UA) and gamma-glutamyltransferase (GGT) were independent prognostic factors for OS (p=0.012, p=0.001). The optimal agreement between actual observation and nomogram prediction was shown by calibration curves. The C-indexes of the nomogram for predicting OS and PFS were 0.748 (95% CI: 0.70-0.79) and 0.728 (95% CI: 0.6741-0.7819), respectively. The results were confirmed in the validation cohort. Conclusion. We observed that both serum UA and GGT were poor prognostic factors in patients with advanced gastric cancer. And we also formulated and validated a nomogram which can predict individual survival for advanced gastric cancer patients.

Purpose To date, there has not been a large, systematic evaluation of the prevalence of germline risk variants in urothelial carcinoma (UC). Methods We evaluated the frequency of germline pathogenic and likely pathogenic variants in 1038 patients with high-risk UC who underwent targeted clinical germline testing. Case–control enrichment analysis was performed to screen for pathogenic variant enrichment in 17 DNA repair genes in 1038 UC patients relative to cancer-free individuals. Results Among 1038 patients with UC, the cumulative frequency of patients with pathogenic variants was 24%; 18.6% of patients harbored ≥1 actionable germline variant with preventive or therapeutic utility. MSH2 (34/969, 3.5%) and BRCA1/2 (38/867, 4.4%) germline variants had the highest frequency. Germline variants in DNA damage repair genes accounted for 78% of pathogenic germline variants. Compared to the cancer-free cohort, UC patients had significant variant enrichment in MSH2 (odds ratio [OR]: 15.4, 95% confidence interval [CI]: 7.1–32.7, p

Low-molecular-weight heparin (LMWH) has attracted increasing attention as a tumor treatment because of its board range of physiological functions. Over the past decade, diverse LMWH derivatives have increased the variety of antitumor strategies available, serving not only as anti-tumor agents, but also as drug delivery platforms. In this review, we introduce the basic strategy for structural modification of LMWH to attenuate its antitumor activity while reducing its risk of bleeding and immune responses, as well as highlighting current applications of LMWH and its derivatives in cancer therapy. We select representative drug delivery systems involving LMWH derivatives and discuss the construction principles and therapeutic effects associated with their use. We also analyze progress made in the development of antitumor combination therapies, in which LMWH has shown synergistic or combined effects with other treatment strategies.

Research suggests that genetic variants that regulate the hypothalamic-pituitary-adrenal (HPA) axis function moderate the association between parenting and anxiety symptoms, but these studies have primarily focused on (i) individual genes with very small and unreliable effect and (ii) the role of mothers as opposed to fathers. Using a multilocus genetic profile score approach, the current study is the first to examine the moderation effect of HPA-axis multilocus genetic variants on the associations of both maternal and paternal parenting with adolescent anxiety symptoms. In a sample of Chinese Han adolescents (N = 772; 50.1% girls; M

For ST-segment elevation myocardial infarction (STEMI) patients presenting 24 to 48 hours from symptom onset, whether early invasive strategy should be performed still remains controversial.This is a prospective, open-label, multicenter, investigator initiated, randomized controlled trial (NCT04962178) to evaluate the efficacy of early invasive strategy for STEMI patients within 24 to 48 hours of symptom onset. A total of 366 patients will be included from 10 hospitals in mainland China. They will be randomly (1:1) divided into 2 groups: the early invasive strategy group (primary percutaneous coronary intervention, PPCI) and conservative strategy group (optimal medical therapy with primary PCI not performed). All patients will be followed for 1 month. The primary end point is myocardial infarction size on cardiac magnetic resonance (CMR). The secondary end points are as follows: (1) major adverse cardiovascular events (MACE), which is defined as a composite of cardiac death, recurrent myocardial infarction, ischemic driven target vessel revascularization and stroke; (2) other CMR end points, including microvascular obstruction, intramyocardial hemorrhage, myocardial area at risk, left ventricular ejection fraction, left ventricular end diastolic volume and left ventricular end systolic volume.This study is designed to evaluate the efficacy of early invasive strategy for STEMI patients within 24 to 48 hours of symptom onset and will add more evidence for clinical practice.ClinicalTrials.gov Identifier: NCT04962178. Registered on July 14, 2021.

Three new limonoids, walsurauias A-C (1-3), along with four known ones, were isolated from the leaves and twigs of Walsura yunnanensis C. Y. Wu. Their structures were determined on the basis of comprehensive spectroscopic data analysis. The new limonoids were screened for their cytotoxic activity (IC