Transcriptional profiling of zearalenone-induced inhibition of IPEC-J2 cell proliferation.
Mounting evidence has shown that zearalenone (ZEA) can have toxic effects on the intestinal epithelial cells (IECs) of mammals and humans, but the mechanism of ZEA-induced toxicity on IECs is unclear. The aim of this study was to reveal the mechanism of action of ZEA on intestinal epithelial cells via RNA-seq technology. We measured the effects of ZEA on the viability and lactate dehydrogenase (LDH) activity of the pig intestinal epithelial cell line J2 (IPEC-J2). The results showed ZEA can decrease the IPEC-J2 cell viability and increase LDH activity. Appropriate treatment concentrations were determined (40 μM ZEA) to study the toxic effect of ZEA on IPEC-J2. The results showed that 40 μM ZEA significantly inhibited IPEC-J2 proliferation and arrested the cell cycle at the G2/M phase. A total of 783 differentially expressed genes (DEGs) were identified after ZEA treatment. KEGG pathway analysis revealed that PERK regulates gene expression, Toll-like receptor cascades signaling pathway, mitosis, mitotic metaphase and anaphase, DNA replication and G2/M checkpoints, were involved in the cell cycle pathway. Eleven key genes involved in G2/M checkpoints were validated by qPCR. Thus, these data highlighted that ZEA caused abnormalities in the G2/M transition in IPEC-J2 cells by altering the cell cycle signaling pathway, thereby inhibiting cell proliferation and inducing injury in IECs. And the study will contribute to get the molecular mechanisms of ZEA inhibition of IECs cell proliferation.


Capturing large genomic contexts for accurately predicting enhancer-promoter interactions.
Enhancer-promoter interaction (EPI) is a key mechanism underlying gene regulation. EPI prediction has always been a challenging task because enhancers could regulate promoters of distant target genes. Although many machine learning models have been developed, they leverage only the features in enhancers and promoters, or simply add the average genomic signals in the regions between enhancers and promoters, without utilizing detailed features between or outside enhancers and promoters. Due to a lack of large-scale features, existing methods could achieve only moderate performance, especially for predicting EPIs in different cell types. Here, we present a Transformer-based model, TransEPI, for EPI prediction by capturing large genomic contexts. TransEPI was developed based on EPI datasets derived from Hi-C or ChIA-PET data in six cell lines. To avoid over-fitting, we evaluated the TransEPI model by testing it on independent test datasets where the cell line and chromosome are different from the training data. TransEPI not only achieved consistent performance across the cross-validation and test datasets from different cell types but also outperformed the state-of-the-art machine learning and deep learning models. In addition, we found that the improved performance of TransEPI was attributed to the integration of large genomic contexts. Lastly, TransEPI was extended to study the non-coding mutations associated with brain disorders or neural diseases, and we found that TransEPI was also useful for predicting the target genes of non-coding mutations.


Characteristics and outcomes of second cancers in patients with childhood cancer: A report from the Taiwan Pediatric Oncology Group.
Patients with childhood cancer are at increased risk for the development of second cancers. A national multicenter survey of second cancers conducted by the Taiwan Pediatric Oncology Group retrieved retrospective data from the database at the Children Cancer Foundation in Taiwan beginning in 1995. The characteristics of second cancers and associations of patient demographic and clinical characteristics with time to death due to a second cancer were analyzed. We examined the records of 8782 patients with a primary cancer diagnosed between January 1, 1995 and December 31, 2013, and a total of 99 patients with a second cancer were identified. The most common type of second cancer was acute myeloid leukemia (n = 35), followed by acute lymphoblastic leukemia (n = 15), central nervous system (CNS) tumors (n = 15), and sarcomas (n = 10). Secondary hematological malignancies occurred earlier than other secondary cancers. The frequencies of second CNS tumors and second bone cancers and sarcomas were notably increased when prior radiation doses increased from zero, low dose to high dose. The overall 5-year survival of patients with a second cancer was poor (33.7%). Multivariate survival analysis revealed that the year of primary diagnosis ≤2002, secondary hematological malignancies, and age at second cancer diagnosis ≤9.3 years or >26.8 years increased the risk of death following second cancer. Children who develop a second cancer have an unfavorable outcome. Early detection and improved treatment for second cancers are needed.


Tobacco smoking, alcohol drinking, and the risk of different histological types of nasopharyngeal cancer in a low-risk population.
Nasopharyngeal carcinoma (NPC) is rare in western Countries. Tobacco smoking is a well-recognised risk factor, whereas the role of alcohol drinking is still in debate. We conducted a hospital-based case-control study in Italy on 150, histologically-confirmed, NPC cases of Caucasian ethnicity, aged 18-76years, including 118 undifferentiated NPCs and 22 differentiated squamous-cell NPC. Controls were 450 Caucasian cancer-free patients admitted to general hospitals for acute conditions. Cases and controls were matched according to sex, age, and place of residence. Logistic regression was used to estimate odds ratios (OR) and the corresponding 95% confidence intervals (CI) while adjusting for known confounders. No significant association emerged between tobacco smoking and all NPCs (OR for current vs. never smokers=1.52; 95% CI: 0.89-2.60). Conversely, for differentiated NPC only, statistically significant elevated OR were associated with increasing smoking intensity (OR for ⩾15cigarettes/day=5.40; 95% CI: 1.34-21.76) and duration of the habit (OR for ⩾32years=4.48; 95% CI: 1.11-18.04). Although alcohol drinking was not, per se, significantly associated to NPC risk, the combination of tobacco smoking and alcohol drinking accounted for 57% of differentiated NPCs, whereas it accounted for only 14% of undifferentiated carcinomas. Our findings suggest that, in western populations, NPC includes two separate entities: the differentiated NPC, associated with tobacco smoking like other cancers of head and neck, and the undifferentiated NPC, upon which tobacco smoking has little or no influence.


The anti-cancer agent guttiferone-A permeabilizes mitochondrial membrane: ensuing energetic and oxidative stress implications.
Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with cytotoxic action in vitro and anti-tumor action in rodent models. We addressed a potential involvement of mitochondria in GA toxicity (1-25 μM) toward cancer cells by employing both hepatic carcinoma (HepG2) cells and succinate-energized mitochondria, isolated from rat liver. In HepG2 cells GA decreased viability, dissipated mitochondrial membrane potential, depleted ATP and increased reactive oxygen species (ROS) levels. In isolated rat-liver mitochondria GA promoted membrane fluidity increase, cyclosporine A/EGTA-insensitive membrane permeabilization, uncoupling (membrane potential dissipation/state 4 respiration rate increase), Ca²⁺ efflux, ATP depletion, NAD(P)H depletion/oxidation and ROS levels increase. All effects in cells, except mitochondrial membrane potential dissipation, as well as NADPH depletion/oxidation and permeabilization in isolated mitochondria, were partly prevented by the a NAD(P)H regenerating substrate isocitrate. The results suggest the following sequence of events: 1) GA interaction with mitochondrial membrane promoting its permeabilization; 2) mitochondrial membrane potential dissipation; 3) NAD(P)H oxidation/depletion due to inability of membrane potential-sensitive NADP+ transhydrogenase of sustaining its reduced state; 4) ROS accumulation inside mitochondria and cells; 5) additional mitochondrial membrane permeabilization due to ROS; and 6) ATP depletion. These GA actions are potentially implicated in the well-documented anti-cancer property of GA/structure related compounds.


Broadly Applicable Ion Pair-Assisted Nucleophilic Substitution of sp3-Carbon Electrophiles with Alkynyltrifluoroborates.
Alkynyltrifluoroborate nucleophiles react smoothly with a wide range of sp3-carbon electrophiles, including propargyl methanesulfonates and unactivated alkyl triflates, to give Sonogashira-type products, via a novel ion pair-assisted nucleophilic substitution mechanism. An ion pair-organic complex, investigated using computational chemistry and in situ NMR experiments, may play a crucial role in this reaction.


Imported Dengue Case Numbers and Local Climatic Patterns Are Associated with Dengue Virus Transmission in Florida, USA.
Aedes aegypti mosquitoes are the main vector of dengue viruses globally and are present throughout much of the state of Florida (FL) in the United States of America. However, local transmission of dengue viruses in FL has mainly occurred in the southernmost counties; specifically Monroe and Miami-Dade counties. To get a better understanding of the ecologic risk factors for dengue fever incidence throughout FL, we collected and analyzed numerous environmental factors that have previously been connected to local dengue cases in disease-endemic regions. We analyzed these factors for each county-year in FL, between 2009-2019, using negative binomial regression. Monthly minimum temperature of 17.5-20.8 °C, an average temperature of 26.1-26.7 °C, a maximum temperature of 33.6-34.7 °C, rainfall between 11.4-12.7 cm, and increasing numbers of imported dengue cases were associated with the highest risk of dengue incidence per county-year. To our knowledge, we have developed the first predictive model for dengue fever incidence in FL counties and our findings provide critical information about weather conditions that could increase the risk for dengue outbreaks as well as the important contribution of imported dengue cases to local establishment of the virus in Ae. aegypti populations.


SPARC synthesis in pre-implantation and early post-implantation mouse embryos.
SPARC (secreted protein acidic and rich in cysteine), also known as osteonectin and BM-40, is a secreted protein associated with a variety of embryonic and adult tissue and cell types, including placenta, parietal and visceral endoderm, certain epithelia (e.g. gut, skin, glandular epithelia), and regions of active chondrogenesis and osteogenesis. Although much is known concerning the tissue distribution of this protein, neither the time and location of its initial appearance nor its functions during embryogenesis have been clearly established. We identified the location of SPARC on two-dimensional protein gels. By using two-dimensional gel analysis of both pre- and post-implantation stage mouse embryos, we find that SPARC is initially synthesized between 3.5 and 4.5 days of embryogenesis. This is the earliest time during development at which synthesis of SPARC has been demonstrated. Inner cell masses isolated from 4.5 day blastocysts synthesize SPARC indicating that either primitive ectoderm, primitive endoderm, or both produce this protein. SPARC synthesis is also detectable in isolated trophoblast vesicles. Thus, SPARC is synthesized not only in placenta, parietal endoderm, and visceral endoderm, but in the precursors of these tissues as well. Examination of 7.5 day embryos reveals that SPARC is synthesized in isolated parietal yolk sac and in whole extraembryonic and embryonic regions. Relative to other proteins, synthesis of SPARC was most prevalent in the parietal yolk sac. The possible implications of SPARC synthesis as early as 4.5 days are discussed.


Childhood leukemia near nuclear sites in Belgium: An ecological study at small geographical level.
A previous investigation of the occurrence of childhood acute leukemia around the Belgian nuclear sites has shown positive associations around one nuclear site (Mol-Dessel). In the following years, the Belgian Cancer Registry has made data available at the smallest administrative unit for which demographic information exists in Belgium, i.e. the statistical sector. This offers the advantage to reduce the potential misclassification due to large geographical scales. The current study performed for the period 2006-2016 uses Poisson models to investigate (i) the incidence of childhood acute leukemia within 20 km around the four Belgian nuclear sites, (ii) exposure-response relationships between cancer incidence and surrogate exposures from the nuclear sites (distance, wind direction frequency and exposure by hypothetical radioactive discharges taking into account historical meteorological conditions). All analyses are carried out at statistical sector level. Higher incidence rate ratios were found for children <15 years (7 cases, RR = 3.01, 95% CI: 1.43;6.35) and children <5 years (< 5 cases, RR = 3.62, 95% CI: 1.35;9.74) living less than 5 km from the site of Mol-Dessel. In addition, there was an indication for positive exposure-response relationships with the different types of surrogate exposures. Results confirm an increased incidence of acute childhood leukemia around Mol-Dessel, but the number of cases remains very small. Random variation cannot be excluded and the ecological design does not allow concluding on causality. These findings emphasize the need for more in-depth research into the risk factors of childhood leukemia, for a better understanding of the etiology of this disease.


Ethical dilemmas: a comment on Jacob, Krahn, and Leonard (1991)
The initial review of Jacob et al. (1991) instigated a dialogue regarding ethics in alcoholism research. This article introduces a series of papers that describe and discuss several issues raised by this study.


Uncemented porous-coated anatomic total hip replacement in Chinese patients.
Primary uncemented Porous-Coated Anatomic total hip replacement was carried out in 72 hips in 62 Chinese patients. Their average age was 50 years and the average follow up was 3 1/2 years. The most common diagnosis was avascular necrosis. The average preoperative Harris score of 36.3 points improved to 83.2 at the last follow up. The pain score improved from 13.7 out of 44 to an average of 42. Seven of 8 hips with thigh pain had an inadequately fitting stem which had subsided. Only one cup was revised because of a technical error and one femoral component for loosening. Uncemented Porous-Coated Anatomic total hip replacement gave good early results in Chinese patients.


Evaluation of LDL receptor and Scavenger Receptor, Class B, Type 1 in the malignant and benign breast tumors: The correlation with the expression of miR-199a-5p, miR-199b-5p and miR-455-5p.
The purpose of present study was to examine the correlations of LDL (LDLR) and HDL (SR-B1) receptors with lipoproteins, miR-199a-5p, miR-199b-5p, miR-455-5p in the malignant and benign breast tumors. Total cholesterol-rich-lipoproteins and the receptors were determined using enzymatic-homogeneous and ELISA methods. The expression levels of miRNAs were detected by qRT-PCR. Receptor expressions and lipoproteins concentration were significantly higher in the malignant tumors (p < 0.05). Positive correlation was found for LDLR with Ki67% and Her2+. HDL-C content of TNBC tumors was higher than those of Non-TNBC (p < 0.05). The expression level of miR-199a-5p was found to be downregulated significantly in the malignant tumors of <2 cm, TNBC, HER2- or stage3. The expression of miR-199b-5p was downregulated in the malignant tumors and was negatively associated with TNBC, stage and Her2+. The expression of miR-455-5p was significantly correlated with Her2- (p < 0.05). A positive correlation was observed for SR-B1 or LDLR with HDL-C or LDL-C and also for SR-B1 with LDLR, although a reverse association was detected for the expression of miR-199b-5p with LDLR in the malignant tumors (p < 0.05). No significant correlations were found for miR-199a-5p or miR-455-5p with LDLR or SR-B1 expressions and also for LDL-C and SR-B1 with clinicopathological features (p ≥ 0.05). Mechanisms potentially involved in the present findings may be due to the lipid internalization and lipoprotein consumption through LDLR and SR-B1 over expression. It is noteworthy that the expression of miR-199b-5p is negatively correlated with LDLR which may suggest it as a suppressor for LDLR expression in the breast cancer.


[Exercise Testing in Respiratory Medicine - DGP Recommendations].
This document replaces the DGP recommendations published in 1998 and 2013. Based on recent studies and a consensus conference, the indications, choice and performance of the adequate exercise testing method and its necessary technical and staffing setting are discussed. Detailed recommendations are provided: for blood gas analysis and right heart catheterization during exercise, walk tests, spiroergometry, and stress echocardiography. The correct use of different exercise tests is discussed for specific situations in respiratory medicine: exercise induced asthma, obesity, monitoring of rehabilitation or therapeutical interventions, preoperative risk stratification, and evaluation in occupational medicine.


Heart failure is associated with an increased incidence of cancer diagnoses.
The prognosis and quality of life of heart failure patients is determined to a significant extent by co-morbidities. New data suggest that heart failure may be associated with an increased incidence of cancer. The present retrospective study investigates this association in a large collective of outpatients with heart failure. This retrospective cohort study assessed the incidence of cancer in patients with an initial diagnosis of heart failure and a matched non-heart failure cohort in 1274 general practices in Germany between January 2000 and December 2018. The study is based on the Disease Analyser database (IQVIA), which contains drug prescriptions, diagnoses, and basic medical and demographic data. Hazard regression models were used to study the association between heart failure and the incidences of different cancers. A total of 100 124 patients with heart failure and 100 124 patients without heart failure were included in the analysis. Patients were matched individually by sex, age, diabetes, obesity, and yearly consultation frequency. Within the 10 year observation period, 25.7% of patients with heart failure and 16.2% of patients without heart failure had been diagnosed with cancer (log-rank P < 0.001). These proportions were 28.6% vs. 18.8% in female and 23.2% vs. 13.8% in male patients. Heart failure was significantly associated with the incidence of cancer [hazard ratio (HR), 95% confidence interval: 1.76, 1.71-1.81; P < 0.001 in total; HR: 1.85, 1.77-1.92, P < 0.001 in women; HR: 1.69, 1.63-1.76, P < 0.001 in men]. A significant association was found between heart failure and all cancer sites assessed. The strongest association was observed for cancer of lip, oral cavity, and pharynx (HR: 2.10, 95% confidence interval: 1.66-2.17; P < 0.001), followed by respiratory organs (HR: 1.91, 1.74-2.10; P < 0.001) and genital organs of female patients (HR: 1.86, 1.56-2.17; P < 0.001). The association for skin tumours was 1.83 (1.72-1.94; P < 0.001), for cancer of lymphoid and haematopoietic tissue 1.77 (1.63-1.91; P < 0.001), for cancer of the digestive tract 1.75 (1.64-1. 87; P < 0.001), for breast cancer 1.67 (1.52-1.84; P < 0.001), for cancer of the genitourinary tract 1.64 (1.48-1.81; P < 0.001), and for male genital organ cancer 1.52 (1.40-1.66; P < 0.001). Our study indicates that heart failure patients experience a significantly higher incidence of cancer during the course of the disease.


Effect of periodontal treatment in pregnancy on perinatal outcomes: a systematic review and meta-analysis.
To assess the effect of periodontal treatment during pregnancy on maternal, fetal and neonatal outcomes. This is a systematic review and meta-analysis of randomized controlled trials that evaluated the effect of treatment of periodontal diseases on pregnancy outcomes. Primary outcome was perinatal mortality. Secondary outcomes were maternal and neonatal morbidity. Outcomes were pooled using fix-effect or random effects models and presented as risk ratio (RR), or mean difference (MD), and 95% confidence interval (CI). Twenty randomized controlled trials involving 8171 participants were included in this study. Periodontal treatment during pregnancy was associated with significantly decreased risk of perinatal mortality [N = 5942; RR = 0.53 (0.30-0.93); p = .03; heterogeneity (I2) = 0%, Number needed to treat (NNT): 162]. Periodontal treatment during pregnancy reduced risks of preterm birth [N = 7335; RR = 0.78 (0.62-0.98); p = .03; I2 = 72%, NNT = 37]. Periodontal treatment during pregnancy significantly increased birthweight (gram) [N = 4708; MD = 200.79 (63.34-337.24); p = .004; I2 = 93%]. Periodontal treatment during pregnancy was not associated with preeclampsia, gestational diabetes, cesarean section, small for gestational age, or congenital malformations. Periodontal treatment during pregnancy reduces the risks of perinatal mortality and preterm birth, and improves birth weight.


Retraction of: abstract P134, Increased beta-adrenergic inotropy in ventricular myocardium from Trpm4 knockout mice.
The publication of this meeting abstract has been retracted at the request of the authors because of prior publication of the full report in Circulation Research.


Interventions in an Ambulatory Setting to Prevent Progression to Severe Disease in Patients With COVID-19: A Systematic Review.
To conduct a systematic review on the effectiveness and safety of pharmacological and nonpharmacological interventions, in the ambulatory setting, aimed at preventing severe disease in patients with COVID-19. Electronic databases (PubMed, EMBASE, and EuropePMC) were searched on January 6, 2021. A systematic review was conducted, adhering to PRISMA guidelines. The quality of individual trials was assessed using the Cochrane Risk-of-Bias Tool 2, and the certainty of evidence was assessed using GRADE. The collective search retrieved 3818 citations. Eight trials relating to 9 pharmacological interventions were identified. No evidence for nonpharmacological interventions was identified. Low certainty evidence of effectiveness in preventing severe disease was found for fluvoxamine (absolute difference: -8.7%; 95% CI: -1.8% to -16.4%) and bamlanivimab plus etesevimab (absolute difference: -4.9%; 95% CI: -0.8% to -8.9%). Both trials were limited by small sample sizes and short durations of follow-up. In addition, very low certainty evidence of effect was found for ivermectin plus doxycycline and sulodexide. Based on published data, insufficient evidence of effect was found for bamlanivimab (monotherapy), casirivimab plus imdevimab, ivermectin (monotherapy), nitazoxanide, and peginterferon lambda. This review assessed all ambulatory treatments for COVID-19 that may improve patient outcomes and reduce hospitalizations. Recent trials have shown promising results for a number of pharmacological agents to treat COVID-19 in the ambulatory setting. However, larger, more robust trials are needed to support the routine use of these agents outside of monitored clinical trials.


Exploring suicide risk factors among Japanese individuals: The largest case-control psychological autopsy study in Japan.
This case-control psychological autopsy study explored suicide risk factors among Japanese individuals. We targeted 102 suicide completers over 20 years of age and 334 living controls matched to suicide cases by gender, age, and residential municipality in Japan. After controlling for other factors, we found significant associations between suicide and mental disorders, sleeping problems, and verbal communication of one's own death. We discuss the importance of sensitive responses to verbal expressions of suicidal ideation.


Reflective practice "If your illness were a landscape: What would it look like?"
"If we want something to change with our patients, maybe we should ask the questions differently?" Maybe it helps if we get more creative in asking questions. If we ask patients, "If your illness was a landscape: What would it look like?" or encourage them to name their illnesses, just like you name things that stay, like pets, cars, objects.


The life cycles of six multi-center adaptive clinical trials focused on neurological emergencies developed for the Advancing Regulatory Science initiative of the National Institutes of Health and US Food and Drug Administration: Case studies from the Adaptive Designs Accelerating Promising Treatments Into Trials Project.
Clinical trials are complicated, expensive, time-consuming, and frequently do not lead to discoveries that improve the health of patients with disease. Adaptive clinical trials have emerged as a methodology to provide more flexibility in design elements to better answer scientific questions regarding whether new treatments are efficacious. Limited observational data exist that describe the complex process of designing adaptive clinical trials. To address these issues, the Adaptive Designs Accelerating Promising Treatments Into Trials project developed six, tailored, flexible, adaptive, phase-III clinical trials for neurological emergencies, and investigators prospectively monitored and observed the processes. The objective of this work is to describe the adaptive design development process, the final design, and the current status of the adaptive trial designs that were developed. To observe and reflect upon the trial development process, we employed a rich, mixed methods evaluation that combined quantitative data from visual analog scale to assess attitudes about adaptive trials, along with in-depth qualitative data about the development process gathered from observations. The Adaptive Designs Accelerating Promising Treatments Into Trials team developed six adaptive clinical trial designs. Across the six designs, 53 attitude surveys were completed at baseline and after the trial planning process completed. Compared to baseline, the participants believed significantly more strongly that the adaptive designs would be accepted by National Institutes of Health review panels and non-researcher clinicians. In addition, after the trial planning process, the participants more strongly believed that the adaptive design would meet the scientific and medical goals of the studies. Introducing the adaptive design at early conceptualization proved critical to successful adoption and implementation of that trial. Involving key stakeholders from several scientific domains early in the process appears to be associated with improved attitudes towards adaptive designs over the life cycle of clinical trial development.


Recent Technological Advances and Strategies for Arbovirus Vector Control.
In recent decades, we have seen the emergence and re-emergence of many arthropod-transmitted viruses (arboviruses) that pose important public health challenges worldwide [...].


Longitudinal changes in prostate volume in a community-based cohort study of middle-aged and elderly men in rural China.
Prostate volume (PV) and its change rate are important for the progression of prostate disease, but studies on their estimates are inconsistent. To investigate whether age, prostate-specific antigen (PSA), and other specific characteristics are associated with PV and its change rate. A community-based cohort study was conducted in a rural area of China among male residents aged 40-80 years. PV was estimated at baseline and at 4 years of follow-up by trans-abdominal ultrasound. Annual PV change rate (PVCR) was calculated as change in volume divided by time interval. Baseline characteristics, including age, serum PSA, and hormones, were evaluated. And their relationships with PV or PVCR were assessed with Pearson correlation and multivariate linear regression analyses. Totally, 462 participants completed the follow-up with baseline PV (PV0 ) of 15.6 ± 5.5 ml. PV0 was highly correlated with age and PSA in pairwise correlations (Pearson r = 0.35 and 0.34, respectively, p < 0.01). Multivariate linear regression showed similar associations that PV0 tended to increase with age and PSA. The average PVCR was 0.7 ± 1.8 ml/year. In pairwise correlations, PVCR was inversely correlated with PV0 and positively correlated with PSA, while it was not significantly related to baseline age. Linear regression of PVCR on age and PSA in groups classified by PV0 quartile showed that age was not a significant estimator of PVCR, whereas PSA was. In each PV0 group, PVCR tended to increase with PSA. PV was positively associated with age and PSA, and it tended to grow faster in men with smaller baseline PV and higher PSA. PSA can be a valuable parameter for estimating both the size and the growth speed of prostate. Although age is associated with prostate enlargement, it does not appear to be related to the longitudinal change rate of PV.


Detection of tmRNA-mediated trans-translation products in Bacillus subtilis.
Bacterial tmRNA (10Sa RNA) is involved in a trans-translation reaction, which contributes to the degradation of incompletely synthesized peptides and the recycling of stalled ribosomes. To investigate the physiological roles of this reaction in Bacillus subtilis, we devised a system for detecting the proteins that are subject to in vivo trans-translation. The wild-type tmRNA gene (ssrA) in the genome was replaced by a variant ssrA encoding a tag-peptide sequence containing six histidine residues (His-tag) and two aspartic acids at the C-terminus. The His-tagged proteins that accumulated in the cells without degradation were fractionated by Ni2+-NTA column and gel electrophoresis and were detected by Western blotting with an anti-His-tag antibody. The results showed that the trans-translation occurred more frequently at a high temperature (50 degrees C) than at a low temperature (37 degrees C). Two-dimensional (2D) gel electrophoresis of the products revealed many distinct spots, which represent specific target proteins for the trans-translation reaction. Furthermore, the 2D gel patterns of the products from cells cultured at high and low temperatures were apparently different. Several tagged proteins were identified by the N-terminal amino acid sequences of the products. Trans-translation occurs more frequently at high temperature than at low temperature, and different proteins are tagged at different temperatures.


The cerebro-hepato-renal (Zellweger) syndrome: prenatal detection based on impaired biosynthesis of plasmalogens.
Prenatal diagnosis of the cerebro-hepato-renal (Zellweger) syndrome has been performed in 10 pregnancies at risk by measuring both the activity of acyl CoA: dihydroxyacetone-phosphate acyltransferase (DHAP-AT) and the de novo plasmalogen biosynthesis, either in cultured amniotic fluid cells or in fibroblasts cultured from a chorionic villus biopsy. In 7 of the pregnancies both tests indicated no abnormality. All 7 continued to term and normal infants were delivered. However, in amniotic fluid cells from 2 fetuses affected by Zellweger syndrome unequivocal differences from control values were found. The activity of DHAP-AT was clearly deficient and the de novo plasmalogen biosynthesis was impaired. In one pregnancy at risk prenatal diagnosis was performed during the first trimester by measuring both the DHAP-AT activity and the de novo plasmalogen biosynthesis in fibroblasts cultured from a chorionic villi biopsy. From the deficient DHAP-AT activity and the impaired de novo plasmalogen biosynthesis it was concluded that the fetus was affected. This was confirmed biochemically after induced abortion. It can be concluded that measurement of the DHAP-AT activity and the de novo plasmalogen biosynthesis provides convenient methods for the early prenatal detection of Zellweger syndrome.


Feasibility of brackish water and landfill leachate treatment by GO/MoS2-PVA composite membranes.
Two-dimensional (2D) based layered materials with tunable chemical functionalities and surface charge properties have emerged for on-demand applications including membrane technology. However, the process control, time and energy-efficient production of non-swelling graphene oxide (GO) with retaining physicochemical properties are still challenging. In this work, we have fabricated highly ordered GO membrane on cellulose acetate supporting membrane filters of 1.2 μm pore size using molybdenum disulphide (MoS2) as a nano-spacer and polyvinyl alcohol (PVA) as an adhesive for the first time with limited swelling. The fabricated membranes were used for NaCl rejection and removal of toxic heavy metal ions, and the radioactive element from landfill leachate water. The introduction of hydrophilic PVA, thickness control using a various amount of nanospacer and graphene oxide played a vital role in the transport mechanism, permeability, and selectivity index. The composition of PVA and MoS2 in the coating solution was optimized to tune the d-spacing of graphene oxide layers. The newly developed composite membranes have 89% rejection rate to NaCl and 3.96 L/m2h water flux at low operating pressures of 5 bar. Also, the prepared membranes have a high rejection of multivalent metal ions in landfill leachate. 86.5% to 99.8% rejection rate of multivalent metal ions in landfill leachate was observed for the M3 (GO (10): MoS2 (10): PVA (0.5)) membrane. The excellent rejection performance is ascribed to the combined impact of size exclusion, ion adsorption, electrostatic interaction and Gibbs-Donnan exclusion mechanism. The excellent stability and high rejection rate even after 216 h of operation make the fabricated membranes promising for use in practical water separation applications.


Second Generation G-Quadruplex Stabilizing Trimethine Cyanines.
G-Quadruplex DNA has been recognized as a highly appealing target for the development of new selective chemotherapeutics, which could result in markedly reduced toxicity toward normal cells. In particular, the cyanine dyes that bind selectively to G-quadruplex structures without targeting duplex DNA have attracted attention due to their high amenability to structural modifications that allows fine-tuning of their biomolecular interactions. We have previously reported pentamethine and symmetric trimethine cyanines designed to effectively bind G-quadruplexes through end stacking interactions. Herein, we are reporting a second generation of drug candidates, the asymmetric trimethine cyanines. These have been synthesized and evaluated for their quadruplex binding properties. Incorporating a benz[c,d]indolenine heterocyclic unit increased overall quadruplex binding, and elongating the alkyl length increases the quadruplex-to-duplex binding specificity.


Galactolipid formation in chloroplast envelopes. II. Isolation-induced changes in galactolipid composition.
Spinach envelopes were isolated at pH 8.5, which is inhibitory to interlipid galactosyl transfer, and at pH 7.2, which is close to values used in most recent work on chloroplast envelopes. Peptide patterns were identical, but galactolipid compositions differed markedly. These changes are such as could be explained by interlipid galactosyl transfer during isolation at pH 7.2, i.e. a strong decrease in monogalactolipid and a corresponding increase in tri- and tetragalactolipids and diacylglycerol. Digalactolipid was little affected. It was further observed that the interlipid galactosyl transfer was restricted to lipids rich in hexadecatrienoic acid. Arguments are presented that the lipid composition of envelopes in vivo is better represented by the results obtained at high pH. The results will be discussed in relation to previous data on galactolipid composition and biosynthesis in envelopes.


Interactions of Yersinia enterocolitica with polarized human intestinal Caco-2 cells.
The in vitro interactions of Yersinia enterocolitica, Salmonella typhimurium and Escherichia coli with polarized human colonic carcinoma (Caco-2) cells are described. Invasion of a confluent Caco-2 cell monolayer by Yersinia and Salmonella took place within 4 h after contact, which was in marked contrast to E. coli which did not invade Caco-2 cells. Cytoplasmic extrusions developed on the apical membrane and indicated the site of entrance of bacteria into the Caco-2 cells. Intracellular Yersinia and Salmonella were surrounded by a vacuolar membrane. Single as well as multiple bacteria were enclosed within a single vacuole. At 6 h after contact some of the intracellular yersiniae were found free in the cytoplasm. Furthermore, morphological signs of degeneration of Caco-2 cells such as vacuolization and autophagy were observed. Caco-2 cells infected with Salmonella also showed degenerative changes but the salmonellae resided within membrane-bound vacuoles in contrast to Yersinia. These observations are in contrast to those described for the invasion of other cells lines (not derived from intestinal epithelium) by Yersinia and may reflect more closely the interactions between Yersinia and the intestinal epithelium during gastrointestinal infection.


Evidence for the presence of endothelin ETA receptors in endothelial cells in situ on the aortic side of porcine aortic valve.
1. In the present study, we determined whether ETA receptors are present on endothelial cells in situ, by use of front-surface fluorometry of fura-2-loaded porcine aortic valvular strips and reverse transcription polymerase chain reaction (RT-PCR). 2. Although endothelin-1 (ET-1) and endothelin-3 (ET-3) induced maximum elevations of cytosolic Ca2+ concentrations ([Ca2+]i) at 10(-7) M, the peak elevations of [Ca2+]i induced by ET-1 were much greater than those induced by ET-3. 3. The application of ET-1 after ET-3 induced an additional increase in [Ca2+]i, while the application of ET-3 after ET-1 had no effect. A selective ETA receptor antagonist, BQ-123, partially inhibited the ET-1-induced Ca2+ transient but had no effect on ET-3-induced Ca2+ transients. These experiments indicated the presence of functioning ETA receptors in addition to ETB receptors in endothelial cells in situ. 4. The sequence of pig lung ETA receptor complimentary DNA (cDNA) was determined by PCR. RT-PCR, using specific primers for pig ETA receptor sequence and total RNA from endothelial cells on the aortic side of the aortic valve, gave the expected size of band. This PCR product was sequenced and was found to be identical to the sequence of the pig lung ETA receptor. 5. The partial sequence of the pig lung ETB receptor was also determined. RT-PCR for the pig ETB receptor revealed that endothelial cells of the aortic valve express ETB receptor messenger RNA (mRNA). 6. We confirmed that functioning ETA receptors and expression of ETA receptor mRNA exist in the endothelial cells on the aortic side of porcine aortic valves.


"Remembering" emotional words is based on response bias, not recollection.
Recent studies have demonstrated that emotional stimuli result in a higher proportion of recognized items that are "remembered" (e.g., Kensinger & Corkin, 2003; Ochsner, 2000), leading to greater estimates of recollection by the dual-process model (Yonelinas, 1994). This result suggests that recognition judgments to emotional stimuli depend on a recollection process. We challenge this conclusion with receiver operating characteristic (ROC) curve data from two experiments. In both experiments, subjects studied neutral and emotional words. During the recognition test, subjects made old-new confidence ratings as well as remember-know judgments. Four models of remember-know judgments were fit to individual subjects' data: two versions of a one-dimensional signal-detection-based model (Donaldson, 1996; Wixted & Stretch, 2004), the dual-process model (Yonelinas, 1994), and the two-dimensional signal-detection-based model known as STREAK (Rotello, Macmillan, & Reeder, 2004). Consistent with the literature, we found that emotion increases subjective reports of "remembering:" However, our ROC analyses and modeling work reveal that the effect is due to response bias differences rather than sensitivity change or use of a high-threshold recollection process.


The effect of function-focused care on long-term care workers in South Korea.
The purpose of this study was to identify the effects of the Korean Function-Focused Care Program (K-FFCP) for residents of long-term care facilities (LTCRs) on long-term care workers' (LTCWs) knowledge, self-efficacy, and outcome expectations about function-focused care, as well as on their job satisfaction. The study adopted a quasi-experimental repeated-measures design. Participants included 50 LTCWs from two long-term care facilities (24 in the experimental group and 26 in the control group). Multivariate analysis of covariance showed that the effects of K-FFCP were significant on knowledge, efficacy, outcome expectation, and job satisfaction. Outcomes that could not be measured using scales were assessed through a focus group interview. The results suggest that LTCWs would benefit from a long-term educational program on function-focused care.


Spousal Concordance in the Development of Functional Limitations Among Married Adults in China.
Functional limitation is increasingly common as people age and is often associated with negative consequences. Evidence of the dynamics of functional limitation within couples in China is still inadequate. To examine whether functional limitation was associated within middle-aged and older couples and to explore sex differences in spousal associations. In this nationwide, population-based cohort study performed from January 1, 2011, to December 31, 2018, participants were selected using multistage probability sampling, and 5207 community-dwelling couples (10 414 individuals) 45 years or older were included in the nationally representative China Health and Retirement Longitudinal Study. Data analysis was performed from January 1 to February 28, 2021. The exposure variable was the presence of functional limitation in spouses. Functional limitation was measured by the activities of daily living (ADLs) and instrumental activities of daily living (IADLs) scales and was defined as having difficulty in independently performing at least 1 ADL or IADL item. The main outcome was functional limitation in index participants. Multivariable logistic regression with generalized estimating equations was used to estimate the reciprocal association of functional limitation within couples over time. A total of 5207 married, different-sex couples (mean [SD] age, 59.1 [8.8] years for husbands and 57.0 [8.2] years for wives) were included in the study. For husbands, the number (percentage) of participants classified with baseline functional limitation was 1140 (21.9%), the number (percentage) with ADL limitation was 684 (13.1%), and the number (percentage) with IADL limitation was 834 (16.0%). For wives, the number (percentage) of participants classified with baseline functional limitation was 1502 (28.8%), the number (percentage) with ADL limitation was 887 (17.0%), and the number (percentage) with IADL limitation was 1183 (22.7%). Longitudinal results demonstrated an association in spouses developing functional limitation (adjusted odds ratio [OR], 2.55; 95% CI, 2.41-2.69; P < .001), ADL limitation (adjusted OR, 2.26; 95% CI, 2.11-2.41; P < .001), and IADL limitation (adjusted OR, 2.58; 95% CI, 2.43-2.73; P < .001). Subgroup analyses by sex revealed similar patterns of spousal health concordance in terms of all studied outcomes, indicating no sex specificity. This population-based cohort study suggests that among Chinese middle-aged and older couples there is significant concordance in the development of functional limitation. This study of spousal functional ability from a dyadic perspective may help in the understanding of health risks within a wider familial context and offers novel insights for prioritizing policy focus from individual centered to couple based.


Isolation, characterization and identification of antigenotoxic and anticancerous indigenous probiotics and their prophylactic potential in experimental colon carcinogenesis.
Colorectal cancer, the third most commonly diagnosed cancer, is a lifestyle disease where diet and gut microbiome contribute intricately in its initiation and progression. Prophylactic bio-interventions mainly probiotics offer an alternate approach towards reducing or delaying its progression. Therefore, the present study was designed wherein a robust protocol for the isolation, characterization, and identification of indigenous probiotics having antigenotoxic and anticancerous activity was followed along with their prophylactic potential assessment in early experimental colorectal carcinogenesis. Among forty-six isolated lactic acid bacterial strains, only three were selected on the basis of antigenotoxicity against N,N-Dimethyl dihydrazine dihydrochloride and 4-Nitroquinoline 1-oxide and probiotic attributes. All three selected probiotic strains exhibited anticancerous potential as is evident by the reduced Aberrant Crypt Foci, reduced fecal pH, enhanced fecal lactic acid bacteria and altered fecal enzymes (β-glucuronidase, nitroreductase, β-glucosidase) that modulated gut microbiota and microenvironment resulting into restored histoarchitecture of the colon. The results are a clear indicator of the prophylactic potential of selected indigenous probiotics which may be used as an alternative prophylactic biological therapy against colon carcinogenesis particularly in highly susceptible individuals.


Antioxidant and anticoagulant effects of phenylpropanoid glycosides isolated from broomrapes (Orobanche caryophyllacea, Phelipanche arenaria, and P. ramosa).
Holoparasitic plants of the Orobanchaceae, including Cistanche, Orobanche, and Phelipanche spp, are known for their richness of phenylpropanoid glycosides (PPGs). Many PPG compounds have been found to possess a wide spectrum of activities, such as antimicrobial, anti-inflammatory, antioxidant, and memory-enhancing. To better explore the bioactivity potential of European broomrapes (O. caryophyllacea - OC, P. arenaria - PA, P. ramosa - PR) and ten single isolated phenylpropanoid constituents, we investigated their antiradical action, protective effect against oxidation in plasma in vitro system, and influence on coagulation parameters. The tested extracts showed a scavenging activity of 50-70% of Trolox's power. The OC extract, rich in acteoside, had over 20% better antiradical potential than PR extract which was the only one containing PPGs lacking a B-ring catechol moiety in the acyl unit. Moreover, it was found that only eight tested PPGs demonstrated antioxidant potential in human plasma treated with H2O2/Fe; however, the three tested PPGs possessed anticoagulant potential in addition to antioxidant properties. It appears that the structure of PPGs, especially the presence of acyl and catechol moieties, is mainly related to their antioxidant properties. The anticoagulant potential of these compounds is also related to their chemical structure. Selected PPGs exhibit the potential for treating cardiovascular diseases associated with oxidative stress.


Preparation, Characterization and Cytotoxic Effects of Pegylated Nanoliposomal Containing Carboplatin on Ovarian Cancer Cell Lines.
Carboplatin is a chemotherapeutic agent used against various malignancies such as ovarian carcinoma. The aim of this study is to improve the therapeutic efficacy of carboplatin using pegylated liposomal nanocarriers. Nanoparticles were synthesized using thin film hydration technique and characterized for shape morphology, particle size, zeta potential and drug-release properties. In the next step, A2780S and A2780CP ovarian cancer cell lines were used to determine the efficacy of nanodrug by MTT assay. The particle size and zeta potential of nanodrug were measured 244.3 ± 19.6 nm and -22.9 ± 1.7 mV, respectively. High encapsulation capacity (78.6 ± 3.7 %) confirmed the efficiency of technique. The cytotoxicity results also showed that nanodrug compared to free drug improve the efficacy of carboplatin against both A2780S (P < 0.01) and A2780CP (P < 0.05) cell lines. In conclusion, the findings of our study suggested pegylated liposomal nanocarriers are proper for carboplatin delivery to ovarian cancer cell lines A2780S and A2780CP.


Tidal continuous cycling peritoneal dialysis in children.
About 10% of all home peritoneal dialysis regimens in children with chronic kidney disease stage 5 are reported to involve some form of a tidal peritoneal dialysis (TPD) prescription. Despite this, there remain several gaps in how pediatric nephrologists approach the use of TPD. This stems from a combination of factors such as the confusing technical terminology pertaining to TPD, seemingly conflicting data on the risks, benefits, and indications for TPD, and lastly, limited published guidelines on the practical aspects of how to write a TPD prescription, based on the indication, in children. Our educational review, using evidence-based data, attempts to bridge this gap and provide an easy-to-use guide on the key practical aspects of TPD in children.


Transferase-deficiency galactosemia: evidence for the lack of a transferase protein in galactosemic red cells.
Red blood cell lysates from normal individuals, a homozygous Duarte variant, and a patient with transferase-deficiency galactosemia were challenged with rabbit antibody to pure human placental galactose-1-phosphate uridylyltransferase. Although the antibody quantitatively precipitated the enzymatically active proteins in the normal and Duarte hemolysates, the Duarte sample absorbed only about one-half as much antibody as did the normal. In contrast, the antibody did not react with the galactosemic hemolysate.


Fast on-line rubidium DPAL atomic concentration measurement by 420 nm probe laser: erratum.
We present an erratum to our recent work [Appl. Opt.60, 10862 (2021)APOPAI0003-693510.1364/AO.440435] that corrects errors in Fig. 4 and the body of the paper. The corrections do not affect the results and conclusions of the original paper.


Musculoskeletal outcomes and the effect of radiation to the vertebral bodies on growth trajectories for long-term survivors of high-risk neuroblastoma.
Here, we report musculoskeletal outcomes and the impact of radiotherapy dose on vertebral body growth for an institutional series of long-term survivors of high-risk neuroblastoma. We conducted a retrospective study of 23 patients who were disease-free and at least 36 months from the end of treatment. The patients were initially treated from July 2003 to May 2012. Patient records were reviewed for growth percentiles (obtained at approximately 6-month intervals from onset of treatment to the last follow-up) and musculoskeletal comorbidities. RT plans and most recent surveillance CT scans were reviewed for locations of in-field vertebral bodies and corresponding vertebral growth patterns. The median follow-up was 7.93 years. The median prescribed radiation dose was 21.6 Gy. Musculoskeletal abnormalities included scoliosis (5 patients), muscular hypoplasia (3), and hypodontia (1). The median growth percentile at treatment onset was 35.5 (range, 4.7-100) versus 10 (0-94.1) at the last follow-up. The median numbers of vertebral bodies encompassed (by at least half of their volume) by the 5-, 10-, 15-, and 20-Gy isodose lines were 7 (mean, 6.78), 7 (6.56), 6 (6.17), and 6 (5.52), respectively. Sixteen patients (70.0%) had in-field abnormalities in vertebral body growth, manifesting as stretches of successive vertebral bodies at the same height, while normally there is a gradual vertebral body height increase progressing caudally down the spinal column. Musculoskeletal abnormalities, below average height, and stunted in-field vertebral body growth are routine in long-term survivors of high-risk neuroblastoma. Sparing vertebral bodies when feasible may lead to improvement in patient growth trajectories.


Investigation of Adsorption Behavior of Anticancer Drug on Zinc Oxide Nanoparticles: A Solid State NMR and Cyclic Voltammetry (CV) Analysis.
The present study aims to comprehend the adsorption behavior of a set of anticancer drugs namely 5-fluorouracil (5-FU), doxorubicin and daunorubicin on ZnO nanoparticles (ZnO NPs) proposed as drug delivery systems employing solid state (ss) NMR, FTIR and Cyclic Voltammetry (CV) analysis. FTIR and 1H MAS ssNMR data recorded for bare ZnO nanoparticle confirmed the presence of adsorbed -OH groups on the surface. 13C CP-MAS NMR spectra recorded for free and ZnO surface adsorbed drug samples exhibited considerable line broadening and chemical shift changes that complemented our earlier report on UV-DRS and XRD data of surface adsorption in case of 5-FU. Moreover, a remarkable enhancement of 13C signal intensity in case of loaded 5-FU was observed. This clearly indicated rigid nature of the drug on the surface allowing efficient transfer of 1H polarization from the hetero nitrogen of 5-FU to ZnO to form surface hydroxyl (-OH) groups and the same has been observed in the quantum chemical calculations. To further analyze the motional dynamics of the surface adsorbed 5-FU, longitudinal relaxation times (T1) were quantified employing Torchia method that revealed significant enhancement of 13C relaxation rate of adsorbed 5-FU. The enhanced rate suggested an effective role of quadrupolar contribution from 67Zn to the 13C relaxation mechanism of ZnO_5-FU. The heterogeneous rate constant (khet), average free energy of activation (∆G≠) and point of zero charge (PZC) measured for free and drug loaded ZnO NPs samples using CV further support the SS-NMR results.


A method for evaluating parameters of reinforcement during parent-child interactions.
We conducted functional analyses and identified reinforcers for problem behavior for three individuals with developmental disabilities. Based on results of the functional analysis, we evaluated the rate, probability, delay, and duration of reinforcement for problem and appropriate behavior during descriptive parent-child observations. Results showed that parameters of reinforcement, including rate, probability, delay, and duration may interact, and that evaluations of a single reinforcement parameter may be insufficient in describing response allocation. Hence, this study represents a movement toward a method for analyzing reinforcer dimensions, other than rate and probability, in a descriptive analysis.


Heart/heart-lung transplantation. The domino procedure.
Orthotopic heart transplantation has become an accepted therapeutic modality limited only by availability of donor organs. Heart-lung transplantation is also being performed with increasing frequency due to improvements in distant procurement techniques. Although the majority of patients requiring heart-lung transplantation have cardiac dysfunction, there is a subset with no cardiac compromise that can serve as donors of cardiac allografts before heart-lung transplantation. We report a technique for sequential heart/heart-lung transplantation in such a subset of patients.


Decentralization of care for adults with congenital heart disease in the United States: a geographic analysis of outpatient surgery.
Guidelines recommend that adults with congenital heart disease (CHD) undergo noncardiac surgery in regionalized centers of expertise, but no studies have assessed whether this occurs in the United States. We hypothesized that adults with CHD are less likely than children to receive care at specialized CHD centers. Using a comprehensive state ambulatory surgical registry (California Ambulatory Surgery Database, 2005-2011), we calculated the proportion of adult and pediatric patients with CHD who had surgery at a CHD center, distance to the nearest CHD center, and distance to the facility where surgery was performed. Patients with CHD accounted for a larger proportion of the pediatric population (n = 11,254, 1.0%) than the adult population (n = 10,547, 0.07%). Only 2,741 (26.0%) adults with CHD had surgery in a CHD center compared to 6,403 (56.9%) children (p<0.0001). Adult CHD patients who had surgery at a non-specialty center (11.9 ± 15.4 miles away) lived farther from the nearest CHD center (37.9 ± 43.0 miles) than adult CHD patients who had surgery at a CHD center (23.2 ± 28.4 miles; p<0.0001). Pediatric CHD patients who had surgery at a non-specialty center (18.0 ± 20.7 miles away) lived farther from the nearest CHD center (35.7 ± 45.2 miles) than pediatric CHD patients who had surgery at a CHD center (22.4 ± 26.0 miles; p<0.0001). Unlike children with CHD, most adults with CHD (74%) do not have outpatient surgery at a CHD center. For both adults and children with CHD, greater distance from a CHD center is associated with having surgery at a non-specialty center. These results have significant public health implications in that they suggest a failing to achieve adequate regional access to specialized ACHD care. Further studies will be required to evaluate potential strategies to more reliably direct this vulnerable population to centers of expertise.


Characteristics of noise complaints and the associations with urban morphology: A comparison across densities.
This study aimed to characterise spatial-temporal distribution of noise complaints across urban areas with different densities and to analyse the associations between urban morphology and noise complaints. Taking New York City as the study area, crowdsourced noise complaint and urban morphology datasets from the government's open data source were statistically analysed. The results suggest that between boroughs the characteristics of noise complaints are different, in terms of their spatial-temporal distribution, their relation to transport network, land use, and building morphology. Noise complaints were clustered around the highest density area (Manhattan). The rate of noise complaints showed a year-on-year increase, peaking in autumn and spring. The rate of noise complaints is higher in areas with higher densities and roads that are 20-40 m wide, closer to road crossings, and in enclosed blocks. The relationships between noise complaints and urban morphology are weaker in high-density boroughs than in other boroughs.


Conduction Disturbances and Pacing in Transcatheter Aortic Valve Replacement.
Conduction disturbances (CDs) after transcatheter artic replacement remain a clinical concern and relatively common complication. A recent meta-analysis showed both new-onset persistent left bundle branch block and new permanent pacemaker implantation were related to all-cause death with risk ratio 1.32 (95% confidence interval [CI] 1.17 to 1.49; P<.001) and 1.17 (95% CI 1.11-1.25; P<.001) at 1 year, respectively. Preprocedural computed tomography imaging can highlight potential risk factors for CDs, such as membranous septum length, device landing zone calcium, and the annulus size/degree of device oversizing.


Tomato SlYTH1 encoding a putative RNA m6A reader affects plant growth and fruit shape.
N6-methyladenosine (m6A), the most abundant and common modification on eukaryotic mRNA, plays crucial roles in multiple biological processes through controlling endogenous gene activity in organisms. The m6A reader specifically recognizes the m6A mark to mediate the regulation of m6A on mRNA, and determines the fate of its target mRNA. In plants, the currently confirmed m6A readers are YTH (YT521B homology) domain-containing proteins. We previously reported that tomato contains 9 YTH genes, of which SlYTH1 has the strongest expression. The present study reports the functional characterization of SlYTH1 in tomato. SlYTH1 mutants generated via CRISPR/Cas9 technology exhibited pleiotropic phenotypes, including low seed germination rate, shortened seedling root, retarded plant growth and development during vegetative development, and elongated and longitudinally flattened fruit with reduced the locule number. SlYTH1 knockout reduced GA3 content and downregulated the expression of related genes in gibberellin biosynthesis pathway. Moreover, exogenous GA3 application could partially restore the phenotypic defects caused by SlYTH1 mutations. SlYTH1 knockout could alleviate the inhibition of seedling root elongation by exogenous GA3 application at relatively low concentration. These facts indicated SlYTH1 is involved in regulating gibberellin biosynthesis and plays important roles in multiple physiological processes in tomato.


Toxicity and influences of the alkaloids from Cynanchum komarovii AL. Iljinski (Asclepiadaceae) on growth and cuticle components of Spodoptera litura Fabricius (Noctuidae) larvae.
The acute lethal toxicity of the extracted and purified gross alkaloids from Cynanchum komarovii has been demonstrated on the insect pest, Spodoptera litura. The toxic regression equation of the gross alkaloids for S. litura larvae was Y = -2.69701 + 0.78711X and the LC(50) value 2669.88 mg L(-1). The growth disruptions of S. litura caused by the alkaloids from C. komarovii were also evaluated. The rates of growth inhibition, malformation, developmental duration (from third instar to pupation), pupation and emergence inhibition of S. litura caused by the gross alkaloids at dose rates between 50 and 800 mg L(-1) were 30.13-91.71%, 0.00-20.00%, 12-72 h, 16.66-36.66% and 16.66-50.00%, respectively. The alkaloids caused the modification of the cuticular components of S. litura. The relative contents of cuticular lipids, proteins and chitins showed a 3.02-17.11% rise before exposure, followed by 2.29-12.96% and 0.75-4.13% declines 72 h after treatment with gross alkaloids with concentrations between 50 and 800 mg L(-1). Initial studies on the insecticidal properties of C. komarovii gross alkaloids indicate these to be very potent insect growth inhibitors.


High dose antithrombin III inhibits HMGB1 and improves endotoxin-induced acute lung injury in rats.
High mobility group box 1 (HMGB1) is an important factor in the development of sepsis. Previous work suggests that antithrombin III (ATIII) inhibits inflammation, but the mechanism of action is still poorly understood. Prospective controlled animal study in a university laboratory. Rats were randomly divided into a lipopolysaccharide (LPS)-induced sepsis control group and an ATIII-treated experimental group. Animals in the experimental group received a bolus of 250 units/kg of ATIII injected into the tail vein. Animals receiving high-dose ATIII (250 units/kg) had significantly improved lung histopathology and survival compared to the control rats. We measured serum and lung levels of various cytokines and HMGB1 at regular intervals from 0 to 12 h after the induction of sepsis and demonstrated lower HMGB1 levels over time in ATIII-treated animals. In an in vitro experiment, we stimulated the mouse macrophage cell line RAW 264.7 with LPS in the presence or absence of ATIII. Subsequent measurement of HMGB1 concentrations in the supernatant and cell signaling molecules in cell lysates revealed an ATIII dose-dependent decrease in HMGB1 release. Furthermore, inhibition of IkB and p42 phosphorylation was observed with the administration of ATIII, suggestive of downstream signaling pathways. High-dose ATIII decreases lung pathology and reduces mortality in a rat sepsis model. This finding may be mediated by the inhibition of HMGB1.


Diagnostic preparedness for infectious disease outbreaks.
Diagnostics are crucial in mitigating the effect of disease outbreaks. Because diagnostic development and validation are time consuming, they should be carried out in anticipation of epidemics rather than in response to them. The diagnostic response to the 2014-15 Ebola epidemic, although ultimately effective, was slow and expensive. If a focused mechanism had existed with the technical and financial resources to drive its development ahead of the outbreak, point-of-care Ebola tests supporting a less costly and more mobile response could have been available early on in the diagnosis process. A new partnering model could drive rapid development of tests and surveillance strategies for novel pathogens that emerge in future outbreaks. We look at lessons learned from the Ebola outbreak and propose specific solutions to improve the speed of new assay development and ensure their effective deployment.


Alginate oligosaccharide protects against enterotoxigenic Escherichia coli-induced porcine intestinal barrier injury.
Alginate oligosaccharide (AOS) possesses various pharmaceutical benefits, making it an attractive candidate for biomedical applications. In the present study, we prepared AOS by depolymerising alginate; its degree of polymerisation mainly ranged from 2 to 8. We confirmed the enteroprotective potential of AOS against enterotoxigenic Escherichia coli (ETEC)-induced intestinal barrier injury in weaned pigs. Next, we illustrated the mechanisms underlying this effect of AOS using the porcine small intestinal epithelial cell line IPEC-J2. AOS potently reduced the binding of the bacteria-deprived endotoxin lipopolysaccharide (LPS) to the IPEC-J2 cell surface. Moreover, it suppressed the LPS-induced production of pro-inflammatory cytokines and the nuclear translocation of nuclear factor-κB (NF-κB) p65 in IPEC-J2 cells. These results indicate that AOS protects the intestinal epithelium from ETEC-induced inflammatory injury by preventing the activation of NF-κB, implying that AOS could be used as an anti-inflammatory agent for treating inflammation-related intestinal diseases in mammals.


Virtual Transformation and the Use of Social Media: Cardiac Electrophysiology Education in the Post-COVID-19 Era.
The COVID-19 pandemic has significantly impacted the delivery of education for all specialties, including cardiac electrophysiology. This review will provide an overview of the COVID-19 spurred digital transformation of electrophysiology education for practicing clinicians and trainees in electrophysiology and cover the use of social media in these educational efforts. Major international, national, and local meetings and electrophysiology fellowship-specific educational sessions have transitioned rapidly to virtual and distanced learning, enhanced by social media. This has allowed for participation in educational activities by electrophysiologists on a wider, more global scale. Social media has also allowed rapid dissemination of new advances, techniques, and research findings in real time and to a global audience, but caution must be exercised as pitfalls also exist. The digital and social media transformation of cardiac electrophysiology education has arrived and revolutionized the way education is delivered and consumed. Continued hybrid in-person and virtual modalities will provide electrophysiologists the flexibility to choose the best option to suit their individual needs and preferences for continuing education.


Inhibitory effects of ventral tegmental area stimulation on the activity of prefrontal cortical neurons: evidence for the involvement of both dopaminergic and GABAergic components.
The medial prefrontal cortex of the rat receives dopamine and non-dopaminergic projections from the ventral tegmental area. Both electrical stimulation of the ventral tegmental area and local application of dopamine induce an inhibition of the spontaneous activity of most prefrontal cortical neurons, including efferent neurons. In the present study, the techniques of extracellular recording and microiontophoresis were used in anesthetized rats in order to determine whether these dopamine- and ventral tegmental area-induced inhibitory responses involve GABAergic components. Prefrontal cortex output neurons were identified by antidromic activation from subcortical structures. The inhibitory responses evoked by the local application of dopamine were blocked by the iontophoretic application of the D2 antagonist sulpiride, and the GABAA antagonist bicuculline in 89 and 57% of the cases, respectively. In addition, sulpiride and bicuculline abolished the inhibition induced by ventral tegmental area stimulation in 54 and 51% of the prefrontal cortical cells tested, respectively. The implication of a non-dopaminergic mesocortical system in the ventral tegmental area-induced inhibition was further analysed using rats pre-treated with alpha-methylparatyrosine to deplete dopamine stores. The proportion of prefrontal cortical cells inhibited by ventral tegmental area stimulation was markedly reduced (39%) in alpha-methylparatyrosine-treated rats, when compared to controls (86%). Remaining ventral tegmental area-induced inhibition was no longer affected by sulpiride, but in all cases blocked by the local microiontophoretic application of bicuculline. The present results suggest that: (1) the dopamine-induced inhibition of prefrontal cortex neurons could involve cortical GABAergic interneurones; (2) the non-dopaminergic mesocortical system exerts also an inhibitory influence on prefrontal cortical cells and appears to be GABAergic.


Transition of lasing modes in disordered active photonic crystals.
The transition from a photonic band-edge laser to a random laser in two-dimensional active photonic crystals is described. The lasing modes in the active photonic crystals shift from the edge of the photonic bandgap to the bulk of the gap when a certain amount of position and size disorder is introduced. The shift of lasing modes is determined with various gain profiles. The results show that the modulation of lasing modes is significant when the lasing transition wavelength overlaps the photonic bandgap.


Determination of transcription factor isoelectric point by two-dimensional native isoelectric focusing and electrophoretic mobility shift analysis.
A rapid, sensitive, and inexpensive assay is described for the determination of isoelectric points of native transcription factors derived from cell nuclei. This assay depends on a transcription factors' ability to bind DNA with high specificity and obviates the need for specific antisera or additional detection methods in identifying a particular protein following isoelectric focusing. This method has been applied to two ubiquitous proteins, the octamer transcription factor, Oct-1, and the multisubunit CCAAT box factor, NF-Y. Isoelectric points have been determined under native conditions using conventional isoelectric focusing in the first dimension, followed by binding to a specific oligonucleotide DNA probe, and separation of specific DNA/protein complexes from unbound DNA in the second dimension using native polyacrylamide gel electrophoresis. Oct-1 from HeLa cell nuclei was shown to have a pI of 9.6, while NF-Y was shown to have a pI of 4.5. This method is applicable to any transcription factor which binds DNA specifically and may be used to identify changes in surface charge characteristics which occur as a result of alternative splicing events and/or following transcription factor post-translational modification(s).


Detection of apoptotic cell death in vitro in the presence of Gd-DTPA-BMA.
Due to variability in patient response to cancer therapy, there is a growing interest in monitoring patient progress during treatment. Apoptotic cell death is one early marker of tumor response to treatment. Using known extracellular concentrations of gadolinium diethylenetriamine pentaacetic acid bismethylamide (Gd-DTPA-BMA) to vary the exchange regime, T(1) and T(2) relaxation data for acute myeloid leukemia (AML) cell samples were obtained and then analyzed using a two-pool model of relaxation with exchange. Leukemia cells treated with cisplatin to induce apoptosis exhibited a statistically significant (P < 0.05) decrease in intracellular longitudinal relaxation time, T(1I), from 1030 ms to 940 ms, a decrease (P < 0.001) in the intracellular water fraction, M(0I), from 0.86 to 0.68 and a statistically significant increase (P < 0.01) in transmembrane water exchange rate, k(IE), from 1.4 s(-1) to 6.8 s(-1). The changes in MR parameters correlated with quantitative histology, such as cellular cross-sectional area and average nuclear area measurements. The results of this study emphasize the importance of accounting for water exchange in dynamic contrast-enhanced MRI (DCE-MRI) studies, particularly those that examine tumor response to therapies in which apoptotic changes occur.


Hepatic cell-sheet fabrication of differentiated mesenchymal stem cells using decellularized extracellular matrix and thermoresponsive polymer.
Liver tissue engineering via cell sheet technology would open new doors for treatment of patients with liver failure. Decellularized tissues could provide sufficient extracellular matrix (ECM) to support development of hepatocytes in in vivo niches. Besides, with the potential of temperature responsive polymer (pNIPAAm) as an intelligent surface for controlling the attachment/detachment of cell, we set out to generate three in vitro microenvironments models including I: pNIPAAm hydrogel (pN hydrogel), II: decellularized ECM incorporated into pNIPAAm hydrogel (dECM + pN hydrogel) and III: decellularized ECM scaffold (dECM scaffold) to investigate the structural and function cues of hepatocyte-like cells after differentiation of adipose tissue-derived mesenchymal stem cells (AT-MSCs) on the surface of these models. dECM scaffold was obtained after decellularization of rat liver, and its efficiency was analyzed. pN hydrogel and dECM + pN hydrogel (1:3 and 2:3 ratios) of were fabricated, and scaffold architecture was characterized. Each well of culturing plates was coated separately with these three constructs and AT-MSCs were instructed to differentiate into hepatocyte-like cells (HLCs). After recellularization, patterns of differentiation, and expression of hepatogenic markers were investigated via biochemical assays and qRT-PCR at different time points. Multipotency of AT-MSCs, after their ability for osteogenesis and adipogenesis was documented. Production of dense and intact cell sheets was reported in dECM + pN hydrogel, as opposed to pN hydrogel and dECM scaffold. Also, statistically significant difference of HLCs functionality in dECM + pN hydrogel was confirmed after evaluation of the expression of hepatocyte markers including, alpha-fetoprotein, cytokeratin 18, cytochrome P450-2E1 and phosphoenolpyruvate carboxykinase. Our results proved dECM + pN hydrogel were able to preserve hepatocyte function in cell sheets owing to the high level of albumin, urea, hepatogenic markers, and glycogenesis potential of HLCs. Accordingly, dECM incorporated in pN hydrogel could remodel microenvironments to guide the AT-MSCs into conducive differentiation and proliferation to give rise to multilayer sheets of cells in their own ECM.


Survival analysis of patients with stage I and II hepatocellular carcinoma after a liver transplantation or liver resection.
Liver transplantation (LT) is a treatment option in select patients with hepatocellular carcinoma (HCC). The aim of the present study was to compare survival in Stage I or II HCC patients undergoing either liver transplant (LT) or a liver resection (LR). The study is a retrospective analysis of the National Cancer Data Base (1998-2011). In total, 148,882 patients with liver cancer were identified, of which 5-year survival data (1998-2006) were available for 64,227 patients. Patients were stratified by the American Joint Committee on Cancer (AJCC) clinical stage I and II. Kaplan-Meier curves and log-rank tests were used for statistical analysis. 3340 HCC patients met analysis criteria. Among stage I HCC, 860 had LT and 871 had LR. Among stage II HCC, 833 had LT and 776 LR. In stage I patients the median survival for LT and LR were 127.9 and 56.7 months, respectively, (P < 0.0001) and in stage II patients the median survival was 110.8 and 42.8 months (P < 0.0001). Unlike LT patients, LR patients with Stage I HCC had a longer median survival compared with Stage II patients (P = 0.0002). Liver transplantation offers a survival advantage compared with a liver resection among patients with Stage I and II HCC. LT is the best surgical treatment for early stage (I/II) HCC in patients with advanced fibrosis or cirrhosis, whereas LR provides equivalent outcomes to LT in patients without advanced fibrosis and should be considered as the first surgical option.


Heparin inhibits the "quasi-lipoxygenase" activity of hemoglobin toward linoleic acid by oxidant scavenging.
Previous studies have shown heparin to have antiinflammatory properties. We have attempted to determine if the mechanism involves the inhibition of lipid oxidation by utilizing a model system where linoleic acid is oxidized in the presence of oxygen and methemoglobin. Heparin inhibits this "quasi-lipoxygenase" activity prolonging the lag phase and slowing the rate of lipid peroxidation. An oxidant scavenging mechanism is also inferred from the fact that heparin is capable of inhibiting luminol-dependent chemiluminescence resulting from the reduction of 15-HPETE by methemoglobin. It is concluded that heparin, in at least this model system, is capable of inhibiting lipoxygenation by an oxidant scavenging mechanism.


Electrodeposition of atmosphere-sensitive ternary sodium transition metal oxide films for sodium-based electrochemical energy storage.
We introduce an intermediate-temperature (350 °C) dry molten sodium hydroxide-mediated binder-free electrodeposition process to grow the previously electrochemically inaccessible air- and moisture-sensitive layered sodium transition metal oxides, NaxMO2 (M = Co, Mn, Ni, Fe), in both thin and thick film form, compounds which are conventionally synthesized in powder form by solid-state reactions at temperatures ≥700 °C. As a key motivation for this work, several of these oxides are of interest as cathode materials for emerging sodium-ion-based electrochemical energy storage systems. Despite the low synthesis temperature and short reaction times, our electrodeposited oxides retain the key structural and electrochemical performance observed in high-temperature bulk synthesized materials. We demonstrate that tens of micrometers thick >75% dense NaxCoO2 and NaxMnO2 can be deposited in under 1 h. When used as cathodes for sodium-ion batteries, these materials exhibit near theoretical gravimetric capacities, chemical diffusion coefficients of Na+ ions (∼10-12 cm2⋅s-1), and high reversible areal capacities in the range ∼0.25 to 0.76 mA⋅h⋅cm-2, values significantly higher than those reported for binder-free sodium cathodes deposited by other techniques. The method described here resolves longstanding intrinsic challenges associated with traditional aqueous solution-based electrodeposition of ceramic oxides and opens a general solution chemistry approach for electrochemical processing of hitherto unexplored air- and moisture-sensitive high valent multinary structures with extended frameworks.


Synergistic Action of Commercially Available Fungicides for Protecting Wheat from Common Root Rot Caused by Bipolaris sorokiniana in China.
Wheat (Triticum aestivum) common root rot (CRR) caused by predominant fungal pathogen Bipolaris sorokiniana occurs in all wheat-growing regions worldwide and is difficult to control. In this study, the efficacy of eight fungicides against Bipolaris sorokiniana was examined in in vitro assays, and we determined that the combined application of two fungicides significantly inhibits the growth of fungal mycelium. Half of the maximal effective concentration of a mixture containing fludioxonil and difenoconazole in the ratio 1:4 was 0.0372 mg/liter, and the cotoxicity coefficient was 160.14. Under an environmentally controlled pot assay, seed treatment with the mixture of fludioxonil and difenoconazole in the 1:4 ratio demonstrated the best control efficiency at seedling and adult stages, respectively. The best synergistic mixture on seed treatment was assessed in a 2-year field experiment at Hebei, China. The best control efficacy achieved at the seedling and adult stages was 82.65% and 68.48%, respectively. Overall, the in vitro mycelial growth inhibition assay and controlled-environment and field studies indicated that the synergistic action of a mixture of fludioxonil and difenoconazole provides effective control against wheat CRR. These findings highlight the potential application of the fungicide combination for controlling CRR and reducing the selection pressure on fungal pathogens by lessening the use of various fungicides in the field.


Effect of diazocine bridgehead modification on the folding of the Wilcox molecular torsion balance: a view from a different angle.
Replacing the methano (NCH(2)N) bridgehead with an ethano (NCH(2)CH(2)N) bridgehead affects the conformational equilibrium of the Wilcox molecular torsion balance. With a NCH(2)CH(2)N bridgehead, the phenyl and the cyclohexyl esters prefer the out conformation, whereas with the NCH(2)N bridgehead, they were found to prefer the folded conformation.


A risk score for iliofemoral patients with deep vein thrombosis.
Deep vein thrombosis (DVT) is a common condition with a high risk of post-thrombotic morbidity, especially in patients with a proximal thrombus. Successful iliofemoral clot removal has been shown to decrease the severity of post-thrombotic syndrome. It is assumed that earlier thrombus lysis is associated with a better outcome. Generally, the earlier IFDVT is confirmed, the earlier thrombus lysis could be performed. d-Dimer levels and Wells score are currently used to assess the preduplex probability for DVT; however, some studies indicate that the d-dimer value varies depending on the thrombus extent and localization. Using d-dimer and other risk factors might facilitate development of a model selecting those with an increased risk of IFDVT that might benefit from early referral for additional analysis and adjunctive iliofemoral thrombectomy. All consecutive adult patients from a retrospective cohort of STAR diagnostic center (primary care) in Rotterdam suspected of having DVT between September 2004 and August 2016 were assessed for this retrospective study. The diagnostic workup for DVT including Wells score and d-dimer were performed as well as complete duplex ultrasound examination. Patients with objective evidence of DVT were categorized according to thrombus localization using the Lower Extremity Thrombolysis classification. Logistic regression analysis was done for a model predicting IFDVT. The cut-off value of the model was determined using a receiver operating characteristic curve. A total of 3381 patients were eligible for study recruitment, of whom 489 (14.5%) had confirmed DVT. We developed a multivariate model (sensitivity of 77% and specificity of 82%; area under the curve, 0.90; 0.86-0.93) based on d-dimer, Wells score, age, and anticoagulation use, which is able to distinguish IFDVT patients from all patients suspected of DVT. This multivariate model adequately distinguishes IFDVT among all suspected DVT patients. Practically, this model could give each patient a preduplex risk score, which could be used to prioritize suspected IFDVT patients for an immediate imaging test to confirm or exclude IFDVT. Further validation studies are needed to confirm potential of this prediction model for IFDVT.


Integrating Physician Services in the Home: evaluation of an innovative program.
To evaluate a new program, Integrating Physician Services in the Home (IPSITH), to integrate family practice and home care for acutely ill patients. Causal model, mixed-method, multi-measures design including comparison of IPSITH and non-IPSITH patients. Data were collected through chart reviews and through surveys of IPSITH and non-IPSITH patients, caregivers, family physicians, and community nurses. London, Ont, and surrounding communities, where home care is coordinated through the Community Care Access Centre. A total of 82 patients receiving the new IPSITH program of care (including 29 family physicians and 1 nurse practitioner), 82 non-randomized matched patients receiving usual care (and their physicians), community nurses, and caregivers. Emergency department (ED) visits and satisfaction with care. Analysis included a process evaluation of the IPSITH program and an outcomes evaluation comparing IPSITH and non-IPSITH patients. Patients and family physicians were very satisfied with the addition of a nurse practitioner to the IPSITH team. Controlling for symptom severity, a significantly smaller proportion of IPSITH patients had ED visits (3.7% versus 20.7%; P = .002), and IPSITH patients and their caregivers, family physicians, and community nurses had significantly higher levels of satisfaction (P < .05). There was no difference in caregiver burden between groups. Family physicians can be integrated into acute home care when appropriately supported by a team including a nurse practitioner. This integrated team was associated with better patient and system outcomes. The gains for the health system are reduced strain on hospital EDs and more satisfied patients.


3-Hy-droxy-1-methyl-2-[4-(piperidin-1-yl)phen-yl]quinolin-4(1H)-one.
There are two structurally similar but crystallographically independent mol-ecules (A and B) in the asymmetric unit of the title compound, C(21)H(22)N(2)O(2), which are linked via two O-H⋯O hydrogen bonds. An intramolecular O-H⋯O hydrogen bond also occurs in each molecule. In the crystal, the A and B mol-ecules are further linked through C-H⋯O inter-actions. The benzene ring is twisted at an angle of 69.9 (1) and 83.4 (1)° relative to the 1,4-dihydro-quinoline skeleton in mol-ecules A and B, respectively. Adjacent 1,4-dihydro-quinoline units of mol-ecules A are parallel, while mol-ecules A and B are oriented at an angle of 32.8 (1)°.


[The nutrition situation of the population in the former East Germany: results of household budget surveys in 1989].
The last representative nutritional surveys in households of the former GDR date back to 1989. Trends towards excessive energy intake have continued, resulting, above all, from high fat consumption. A considerable proportion of employed persons have their meals outside the home. The proportion of food used as animal feed was high in households of members of agricultural cooperatives.


In vitro efficacy of ceftazidime-avibactam, aztreonam-avibactam and other rescue antibiotics against carbapenem-resistant Enterobacterales from the Arabian Peninsula.
Our aim was to assess the susceptibility of carbapenem-resistant Enterobacterales (CRE) from the Arabian Peninsula to a broad spectrum of antibiotics, including fosfomycin, ceftazidime-avibactam, and aztreonam-avibactam. 1192 non-repeat CRE isolated in 2009-2017 from 33 hospitals in five countries of the Arabian Peninsula were tested. The minimum inhibitory concentration of 14 antibiotics was determined. Carbapenemase and 16S methylase genes were detected by PCR. Clonality was assessed by PFGE. The highest rate of susceptibility was detected to aztreonam-avibactam (95.5%) followed by colistin (79.8%), fosfomycin (71.8%) and tigecycline (59.9%). Isolates co-producing two carbapenemases (12.4%) were the least susceptible. Aminoglycoside susceptibility was affected by the frequent production of a 16S methylase. Susceptibility to ceftazidime-avibactam was impacted by the high rate of metallo-beta-lactamase producers (46.3%), while aztreonam-avibactam resistance occurred mostly in clonally unrelated, carbapenemase non-producing Escherichia coli. Of the currently available drugs: colistin, tigecycline, and ceftazidime-avibactam co-administered with aztreonam appear to be the most effective to treat CRE infections. However, the presence of non-clonal CRE isolates, in which avibactam does not lower the aztreonam MIC below the clinical breakpoint, is of notable concern. Based on the relatively high rate of fosfomycin susceptibility, it would be desirable to license parenteral fosfomycin in the region.


The preoperative G8 geriatric screening tool independently predicts survival in older patients with endometrial cancer: results of a retrospective single-institution cohort study.
The aim of this retrospective study was to evaluate the prognostic impact of global health status assessment tools in elderly patients with endometrial cancer (EC) on survival. Preoperative frailty status was assessed by the G8 geriatric screening tool (G8 Score), Lee Schonberg prognostic index, Charlson Comorbidity index and American Society of Anesthesiologists Physical Status System in women older than 60 years with EC. Univariable and multivariable Cox-regression analyses, as well as Kaplan-Meier survival analyses were performed to determine the prognostic impact. Statistical analyses were adjusted for cancer entity-specific risk factors such as conventional histopathological tumor characteristics and relevant anamnestic life style parameters. 153 patients with all stages of EC who were operated at the University Medical Center Mainz between 2008 and 2019 were included. In multivariable analyses, only the G8 Score retained independent significance as a prognostic factor for disease-specific survival (DSS) (HR:4.58; 95% CI [1.35-15.51]) and overall survival (OS) (HR:2.89; 95% CI [1.31-6.39]. 92 patients (61.3%) were classified as G8-non-frail with a significantly increased DSS and OS rate compared to the 58 G8-frail patients (DSS:93.8% vs. 60.8%; p < 0.001 and OS:88.2% vs. 49.7%; p < 0.001; respectively). This is the first study demonstrates the substantial clinical and prognostic impact of the G8 Score on survival in elderly women with EC. Assessing the frailty status to estimate the individual vulnerability of elderly cancer patients could be useful in preoperative decision-making to individualize treatment plans such as the surgical radicality and to improve pre- and postoperative morbidity.


Socioeconomic and gender disparities in anal cancer diagnosis and treatment.
We investigated whether receipt of radiation in patients with anal carcinoma is related to income level and other demographic factors. The SEER database (1988-2011) was queried and linked to the Area Health Resources File (AHRF). We used logistic regression and Kaplan-Meier analyses to correlate receipt of radiation and overall and cancer-specific survival with tumor stage, age, gender, and income. Of 28,028 patients with anal cancer, 14,783 (53%) received radiation. Patients in the lowest quartile for median household income were significantly more likely to present at higher stages, were 1.87 times more likely to receive radiation (95% CI 1.74-2.00, p < 0.001), and 1.27 times more likely to die of anal cancer (95% CI 1.18-1.33, p < 0.001) than those in the highest income quartile. Within most stages, however, the wealthiest patients were more likely to receive radiation therapy than the poorest patients. Additionally, we found that women presented at higher stages (p < 0.001), were 2.67 times more likely to receive radiation (95% CI 2.55-2.81, p < 0.001), and were 1.25 times more likely to die of anal cancer than men (95% CI 1.17-1.32, p < 0.001). Women and poorer patients present with more advanced stages of anal cancer, more commonly receive radiation, and are more likely to die of anal cancer than men and wealthier patients, respectively.


Infection versus cardiovascular disease as leading causes of hospitalisations and associated mortality in vasculitis in the U.S.: a national study.
To assess the top 5 causes of non-vasculitis hospitalisations in people with vasculitis over time. In a national U.S. sample of people with vasculitis hospitalised for reasons other than vasculitis, the rank (and percent) of top 5 causes of hospitalisations and in-hospital mortality were compared in 1998-99 versus 2013-2014. The top 5 ranked disease categories responsible for non-vasculitis hospitalisations in people with vasculitis in 1998-99 versus 2013-14 were as follows, respectively: (#1) circulatory system disease versus the same; (#2) heart disease versus infections/parasitic diseases; (#3) digestive system disease versus bacterial infection; (#4) respiratory disease versus septicaemia; and (#5) musculoskeletal disease versus unspecified septicaemia. The respective top 5 CCS category ranks for in-hospital mortality in people with vasculitis in 1998-1999 versus 2013-2014 were: (#1) respiratory disease versus infections/parasitic diseases; (#2) circulatory system disease versus bacterial infection; (#3) heart disease versus septicaemia; (#4) respiratory infection versus unspecified septicaemia; and (#5) pneumonia versus circulatory system disease. Infections replaced cardio-pulmonary disease among the top 5 causes for non-primary vasculitis hospitalisations and associated in-hospital mortality in people with vasculitis over time. Studies should examine modifiable factors associated with infection in vasculitis and design interventions to reduce this burden.


Genome-wide association approaches for identifying loci for human height genes.
Human height is a very heritable trait as most of other human anthropometric traits. Genome-wide association studies have thus far identified about 200 genes associated with height with a genome-wide significance. Very large meta-analyses were needed to achieve this. These 200 height genes are involved in various biologically plausible pathways for growth, but yet explain only 10% of the variance in height. So it is obvious, that the GIANT-consortium height meta-analysis leaves, as most of GWA studies, a major part of the genetic variation unexplained. Much work utilizing several different strategies and very large study cohorts are needed to identify more genes for growth.


Long-term depression of cortico-striatal synaptic transmission by DHPG depends on endocannabinoid release and nitric oxide synthesis.
In models of early stage Parkinson's disease (PD), motor deficits are accompanied by excessive activation of striatal glutamate receptors. Metabotropic glutamate group I receptors (mGluR I) play an important but not well-understood role in PD progression. In mouse brain slices, bath application of the mGluR I agonist (RS)-DHPG (3,5-dihydroxyphenylglycine, 100 microm for 20 min) caused a long-term depression of corticostriatal transmission (LTD(DHPG)), which was reversed by three mGluR I antagonists: LY 367385, CPCCOEt and MPEP. LTD(DHPG) required nitric oxide (NO) synthesis as it was blocked by the broad-spectrum NO synthase (NOS) inhibitor Nomega-nitro-l-arginine (NL-Arg) and impaired under blockade of neuronal NOS and in endothelial NOS-deficient mice. Release of endocannabinoids (eCB) was critically involved in this form of striatal plasticity givem that the CB1 receptor antagonist AM251 prevented LTD(DHPG), while the CB1 agonist ACEA elicited LTD. The NO synthesis necessary for LTD(DHPG) induction occurred downstream of CB1 activation as ACEA-evoked LTD was also abolished by NL-Arg. These findings are relevant for the pathophysiology of PD, as they link the overactivation of group I mGluRs and striatal NO production.


Conformational Dynamics of Transmembrane Domain 3 of Presenilin 1 Is Associated with the Trimming Activity of γ-Secretase.
γ-Secretase is an intramembrane-cleaving protease that generates the toxic species of the amyloid-β peptide (Aβ) that is responsible for the pathology of Alzheimer disease. The catalytic subunit of γ-secretase is presenilin 1 (PS1), which is a polytopic membrane protein with a hydrophilic catalytic pore. The length of the C terminus of Aβ is proteolytically determined by its processive trimming by γ-secretase, although the precise mechanism still remains largely unknown. Here, we identified that transmembrane domain (TMD) 3 of human PS1 is involved in the formation of the intramembranous hydrophilic pore. Notably, the water accessibility of TMD3 was greatly altered by point mutations and compounds, which modify γ-secretase activity. The changes in the water accessibility of TMD3 was also correlated with Aβ42 production. Moreover, crosslinking between TMD3 and TMD7 resulted in a loss of sensitivity to a γ-secretase modulator that reduces Aβ42 production. Therefore, our findings indicate that the conformational dynamics of TMD3 is a prerequisite for regulation of the Aβ trimming activity of γ-secretase.SIGNIFICANCE STATEMENT Modulation of γ-secretase activity to reduce the level of toxic amyloid-β species is thought to be a therapeutic strategy for Alzheimer disease. However, the detailed mechanism of the regulation of amyloid-β production, as well as the structure-and-activity relationship of γ-secretase remains unclear. Here we identified that the water accessibility around transmembrane domain 3 in presenilin 1 was increased along with a reduction in toxic amyloid-β production. Our findings demonstrate how the structure of presenilin 1 dynamically changes during amyloid-β production, and provides insights toward the development of treatments against Alzheimer disease.


Adiponectin and its receptors in preimplantation embryo development.
Adiponectin can play an important role in regulating the female reproductive function and embryo development and can affect the embryo at very early stages of pregnancy--during the preimplantation period. Disturbances in the maternal adiponectin system are associated with several diseases, including diabetes type 2, obesity, and some female reproductive disorders. Adiponectin receptors are expressed in oocytes and preimplantation embryos and can be activated by adiponectin produced by maternal adipose tissue or organs of the female reproductive tract. Adiponectin can affect proliferation and survival of cells in preimplantation embryos, and these effects are isoform dependent. Experimental results suggest involvement of various protein kinases, including mitogen-activated protein kinases, in the regulation of these processes by adiponectin. Actions of adiponectin on lipid and glucose metabolism can increase the energy supply to the embryo, and final targets of adiponectin signaling are metabolic enzymes, glucose transporters, and fatty acid transporters. The involvement of several signaling molecules, such as AMPK/PRKA, PI3K, or AKT/PKB, in the regulation of metabolic processes by adiponectin has been demonstrated in preimplantation embryos. In summary, adiponectin produced in an endocrine/paracrine/autocrine manner can significantly influence preimplantation embryo development, uterine receptivity, and embryo implantation.