EDST: a decision stump based ensemble algorithm for synergistic drug combination prediction.
There are countless possibilities for drug combinations, which makes it expensive and time-consuming to rely solely on clinical trials to determine the effects of each possible drug combination. In order to screen out the most effective drug combinations more quickly, scholars began to apply machine learning to drug combination prediction. However, most of them are of low interpretability. Consequently, even though they can sometimes produce high prediction accuracy, experts in the medical and biological fields can still not fully rely on their judgments because of the lack of knowledge about the decision-making process. Decision trees and their ensemble algorithms are considered to be suitable methods for pharmaceutical applications due to their excellent performance and good interpretability. We review existing decision trees or decision tree ensemble algorithms in the medical field and point out their shortcomings. This study proposes a decision stump (DS)-based solution to extract interpretable knowledge from data sets. In this method, a set of DSs is first generated to selectively form a decision tree (DST). Different from the traditional decision tree, our algorithm not only enables a partial exchange of information between base classifiers by introducing a stump exchange method but also uses a modified Gini index to evaluate stump performance so that the generation of each node is evaluated by a global view to maintain high generalization ability. Furthermore, these trees are combined to construct an ensemble of DST (EDST). The two-drug combination data sets are collected from two cell lines with three classes (additive, antagonistic and synergistic effects) to test our method. Experimental results show that both our DST and EDST perform better than other methods. Besides, the rules generated by our methods are more compact and more accurate than other rule-based algorithms. Finally, we also analyze the extracted knowledge by the model in the field of bioinformatics. The novel decision tree ensemble model can effectively predict the effect of drug combination datasets and easily obtain the decision-making process.


Public health research systems in the European union.
Strengthening health research is an important objective for international health organisations, but there has been less attention to support for health research in Europe. We describe the public-health (population and organisational level) research systems in the 27 European Union countries. We developed a typology for describing health research structures based on funding streams and strategies. We drew data from internet sources and asked country informants to review these for consistency and completeness. The structures were described as organograms and narratives in country profiles for each of the 27 EU member states. National public-health research structures included public and independent funding organisations, 'mixed' institutions (which receive funds, and both use and allocate them) and provider institutions. Most health research is funded through ministries of science or science councils (and sometimes foundations), while parliaments and regions may also contribute. National institutes of public health are usually funded by ministries of health. Many national research organisations both determine research programmes and undertake health research, but there is a move towards public-health sciences within the universities, and a transition from internal grants to competitive funding. Of 27 national research strategies, 17 referred to health and 11 to public health themes. Although all countries had strategies for public health itself, we found little coherence in public-health research programmes. The European Commission has country contact points for both EU research and health programmes, but they do not coordinate with national health-research programmes. Public-health research is broadly distributed across programmes in EU countries. Better understanding of research structures, programmes and results would improve recognition for public health in Europe, and contribute to practice. EU ministries of health should give greater attention to national public-health research strategies and programmes, and the European Union and the World Health Organisation can provide coordination and support.


Analysis of structure-activity and structure-mechanism relationships among thyroid stimulating hormone receptor binding chemicals by leveraging the ToxCast library.
The thyroid stimulating hormone receptor (TSHR) is crucial in thyroid hormone production in humans, and dysregulation in TSHR activation can lead to adverse health effects such as hypothyroidism and Graves' disease. Further, animal studies have shown that binding of endocrine disrupting chemicals (EDCs) with TSHR can lead to developmental toxicity. Hence, several such chemicals have been screened for their adverse physiological effects in human cell lines via high-throughput assays in the ToxCast project. The invaluable data generated by the ToxCast project has enabled the development of toxicity predictors, but they can be limited in their predictive ability due to the heterogeneity in structure-activity relationships among chemicals. Here, we systematically investigated the heterogeneity in structure-activity as well as structure-mechanism relationships among the TSHR binding chemicals from ToxCast. By employing a structure-activity similarity (SAS) map, we identified 79 activity cliffs among 509 chemicals in TSHR agonist dataset and 69 activity cliffs among 650 chemicals in the TSHR antagonist dataset. Further, by using the matched molecular pair (MMP) approach, we find that the resultant activity cliffs (MMP-cliffs) are a subset of activity cliffs identified via the SAS map approach. Subsequently, by leveraging ToxCast mechanism of action (MOA) annotations for chemicals common to both TSHR agonist and TSHR antagonist datasets, we identified 3 chemical pairs as strong MOA-cliffs and 19 chemical pairs as weak MOA-cliffs. In conclusion, the insights from this systematic investigation of the TSHR binding chemicals are likely to inform ongoing efforts towards development of better predictive toxicity models for characterization of the chemical exposome.


Low transcriptional activity haplotype of matrix metalloproteinase 1 is less frequent in bicuspid aortic valve patients.
Bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly which affects 0.5-2% of the population. It can be associated with other cardiac congenital lesions such as aortic aneurysms or aortic coarctation. Some genetic abnormalities have been suggested as the underlying cause of BAV and aortic root dilatation, but no clear genetic substrate and no specific pathogenic gene variant have already been identified. Increased matrix metalloproteinase activity has been described in the aortic wall of thoracic aortic aneurysms (TAA). 87 patients with BAV and 77 controls with normal tricuspid aortic valve were prospectively assessed. We analysed three functional polymorphisms (-1607 1G/2G, -519 A/G, and -340 T/C) in the matrix metalloproteinase (MMP)-1 gene using polymerase chain reaction and restriction fragment length analysis. We found a haplotype composed of the lower activity allele from each polymorphism (-1607 1G/-519 A/-340 C) significantly less frequent in BAV group (p=0.016; OR [95% CI]=0.37 [0.16-0.85]), association even more clear when we consider only men (p=0.0005, OR [95% CI]=0.24 [0.10-0.56]). We also found a borderline statistical significance in the distribution of the -1607 alleles, being 2G allele more frequent in patients with TAA (p=0.053). This association was stronger and statistically significant when we consider only men (p=0.013; OR [95% CI]=2.0 [1.16-3.50]). In addition, genotype -1607 2G2G, theoretically the more active transcriptionally, was also significantly more frequent in TAA group, independently of aortic valve morphology. Our study suggests that specific genotypes of MMP1 gene could be in part responsible of the complications of BAV pathology, like TAA.


Microglial Metabolic Reprogramming: Emerging Insights and Therapeutic Strategies in Neurodegenerative Diseases.
Microglia, the resident immune cells of the central nervous system, play a critical role in maintaining brain homeostasis. However, in neurodegenerative conditions, microglial cells undergo metabolic reprogramming in response to pathological stimuli, including Aβ plaques, Tau tangles, and α-synuclein aggregates. This metabolic shift is characterized by a transition from oxidative phosphorylation (OXPHOS) to glycolysis, increased glucose uptake, enhanced production of lactate, lipids, and succinate, and upregulation of glycolytic enzymes. These metabolic adaptations result in altered microglial functions, such as amplified inflammatory responses and diminished phagocytic capacity, which exacerbate neurodegeneration. This review highlights recent advances in understanding the molecular mechanisms underlying microglial metabolic reprogramming in neurodegenerative diseases and discusses potential therapeutic strategies targeting microglial metabolism to mitigate neuroinflammation and promote brain health. Microglial Metabolic Reprogramming in Neurodegenerative Diseases This graphical abstract illustrates the metabolic shift in microglial cells in response to pathological stimuli and highlights potential therapeutic strategies targeting microglial metabolism for improved brain health.


HbA1c level may be a risk factor for oxygen therapy requirement in patients with coronavirus disease 2019.
Many clinical studies have identified significant predictors or risk factors for the severity or mortality of coronavirus disease 2019 (COVID-19) cases. However, there are very limited reports on the risk factors for requiring oxygen therapy during hospitalization. In particular, we sought to investigate whether plasma glucose and HbA1c levels could be risk factors for oxygen therapy requirement. A single-center, retrospective study was conducted of 131 COVID-19 patients hospitalized at Saitama Medical University Hospital between March 2020 and November 2020. To identify the risk factors for oxygen therapy requirement during hospitalization, a stepwise multivariate binary logistic regression analysis was performed using several clinical parameters commonly obtained on admission, including plasma glucose and HbA1c levels. Of the 131 patients with COVID-19, 33.6% (44/131) received oxygen therapy during hospitalization. According to the logistic regression analysis, male sex (odds ratio [OR]: 8.76, 95% confidence interval [CI]: 1.65-46.5, P < 0.05), age (OR: 1.07, 95% CI: 1.02-1.12, P < 0.01), HbA1c levels (OR: 1.94, 95% CI: 1.09-3.44, P < 0.05), and serum C-reactive protein (CRP) levels (OR: 2.22, 95% CI: 1.54-3.20, P < 0.01) emerged as independent variables associated with oxygen therapy requirement during hospitalization. In addition to male sex, age, and serum CRP levels, HbA1c levels on admission may serve as a risk factor for oxygen therapy requirement during the clinical course of COVID-19, irrespective of diabetes history and status. This may contribute to the efficient delegation of limited numbers of hospital beds to patients at risk for oxygen therapy requirement.


Screening for aberrantly methylated and differentially expressed genes in nonalcoholic fatty liver disease of hepatocellular carcinoma patients with cirrhosis.
Nonalcoholic fatty liver disease (NAFLD) as the leading chronic liver disease worldwide causes hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The aim of this study was to find potential aberrantly methylated and differentially expressed genes in NAFLD of HCC patients with cirrhosis. DNA methylation data, mRNA expression data, and the corresponding clinical information of HCC were downloaded from the Cancer Genome Atlas (TCGA, tissue sample) database. HCC patients with cirrhosis were divided into two groups according to the presence of NAFLD. The differentially expressed genes (DEGs) and differentially methylated genes (DMGs) were obtained. By overlapping 79 up-regulated genes and 1020 hypomethylated genes, we obtained 5 hypomethylated-highly expressed genes (Hypo-HGs). By overlapping 365 down-regulated genes and 481 hypermethylated genes, we identified 13 hypermethylated-lowly expressed genes (Hyper-LGs). Survival analysis of these 18 MDEGs indicated that the expression of DGKK and HOXD9 was significantly correlated with the overall survival time of NAFLD patients. We identified several candidate genes whose expressions were regulated by DNA methylation of NAFLD of HCC with cirrhosis, which may provide a new field in understanding the clinical pathological mechanism of NAFLD of HCC with cirrhosis.


Does size matter? Modelling the cooling effect of green infrastructures in a megacity during a heat wave.
The vulnerability of urban ecosystems to global climate change becomes a key issue in research and political agendas. Urban green infrastructures (UGIs) are widely considered as a nature-based solution to mitigate climate change and adapt to local urban climate anomalies in cities. However, UGI-induced cooling effect depends on the size, location and geometry of green spaces, and such dependencies remain overlooked. This research aimed to investigate the cooling effect of UGIs of different size under extreme conditions of 2021 summer heat wave for the case of Moscow megacity (Russia) using a numerical mesoclimatic model COSMO. UGIs objects were assigned to one of the four size categories (S, M, L and XL) based on their area. Their cooling effects at the local, non-local and city scales were evaluated based on comparison between the model outcomes for the realistic land cover and simulations for which UGI of a particular size category were replaced by the built-up areas typical for their surroundings. The highest cooling effect was observed for XL size UGIs, which reduced the local heat-wave-averaged air temperatures by up to 3.4 °C, whereas for the S size UGIs it did not exceed 2 °C. The cooling effectiveness for XL category was higher than for S category by 23 % inside the green spaces (locally), by 40-90 % in the buffer zones around the green space (non-locally) and by 35 % for the whole city. More effective cooling of large UGIs is partially explained by their stronger park breeze effect, i.e., impact on the airflow increasing the divergence over green spaces. However, when standardized to the population affected by cooling, the M size UGIs made the strongest contribution to the thermal environment where people live and work. The stronger non-local cooling induced by the largest UGI objects cannot compensate for their remoteness from the built environment.


Distribution characteristics and main influencing factors of selenium in surface soil of natural selenium-rich area: a case study in Langao County, China.
In order to study the distribution of selenium in surface soil and its main influencing factor, we collected 360 surface soil samples and four groups of soil profiles with 210 corresponding parent rock samples in Langao County, Shaanxi Province (a typical high-selenium area of Daba Mountain). Samples were analyzed for trace elements by using ICP-MS, ICP-OES and HG-AFS. The results show the following. (1) selenium content in surface soils of Langao County varies greatly (0.03-16.96 mg/kg). The mean selenium content in surface soils of Langao County is 0.99 mg/kg, higher than the global (0.4 mg/kg) and China (0.29 mg/kg) soil average, and 3.4 times the mean of soil selenium in China. (2) Selenium content of bedrock in Langao County also varies greatly (0.01-56.22 mg/kg), with an average selenium content of 2.02 mg/kg, which is 40 times higher than the upper crust (0.05 mg/kg). (3) Selenium content in the strata of the Late Precambrian-Early Paleozoic and its variation is an important factor affecting the spatial variation of soil selenium content. The black rock series (carbonaceous slate and silicon-bearing carbonaceous slate) of the Upper Ediacaran-Cambrian on the north side has the highest mean selenium content (> 7.92 mg/kg), and the selenium content of the surface soil in the distribution area can reach up to 16.96 mg/kg. The Middle Cambrian, Upper Cambrian, Ordovician and Silurian (limestone and marl) in the south has the lowest mean selenium content (< 2 mg/kg), and the selenium content of surface soil in the distribution area is lower than 0.8 mg/kg mostly. (4) Soil samples at different depths in the same soil profile have similar composition of rare earth elements (REE), and bedrock and corresponding topsoil has similar composition of REE. This study indicates the selenium content in the topsoil varies greatly, even in high-selenium area. And the difference of selenium distribution is closely related to the original selenium content of the bedrock.


Diagnostic significance of IgG-synthesizing activated B cells in acute inflammatory diseases of the central nervous system.
An immunohistological technique was used to identify activated, i.e. IgG-synthesizing, B cells in cerebrospinal fluid. A total of 177 patients suffering from inflammatory diseases of the central nervous system were investigated. Activated B cells were found in 61% of patients with bacterial meningitis, especially in lethal or prolonged cases. The number of activated B lymphocytes was low in most cases of viral meningitis, whereas in tick-borne meningopolyneuritis Bannwarth, a very strong B cell activation was detectable. In all inflammatory diseases investigated, the B cell response was restricted to the mononuclear phase. Comparing the number of activated B cells and the amount of locally synthesized IgG, there was a loose correlation between these inflammation parameters in meningopolyneuritis Bannwarth. In acute viral and bacterial meningitis more than 50% of the patients exhibited activated B cells without any detectable intrathecal IgG synthesis.


Outcomes in adolescent and young adult patients (16 to 30 years) compared to younger patients treated for high-risk B-lymphoblastic leukemia: report from Children's Oncology Group Study AALL0232.
Adolescent and young adult (AYA) patients 16-30 years old with high-risk acute lymphoblastic leukemia (HR-ALL) have inferior outcomes compared to younger HR-ALL patients. AALL0232 was a Phase 3 randomized Children's Oncology Group trial for newly diagnosed HR B-ALL (1-30 years). Between 2004 and 2011, 3154 patients enrolled with 3040 eligible and evaluable for induction. AYA patients comprised 20% of patients (16-21 years, n = 551; 22-30 years, n = 46). 5-year event-free survival and overall survival was 65.4 ± 2.2% and 77.4 ± 2.0% for AYA patients compared to 78.1 ± 0.9% and 87.3 ± 0.7% for younger patients (p < 0.0001). Five-year cumulative incidence of relapse was 18.5 ± 1.7% for AYA patients and 13.5 ± 0.7% for younger patients (p = 0.006), largely due to increased marrow relapses (14.0 ± 1.5% versus 9.1 ± 0.6%; p < 0.0001). Additionally, induction failure rate was higher in AYA (7.2 ± 1.1% versus 3.5 ± 0.4%; p < 0.001) and post-induction remission deaths were significantly higher in AYA (5.7 ± 1.0% versus 2.4 ± 0.3%; p < 0.0001). AALL0232 enrolled the largest number of AYA B-ALL patients to date, demonstrating significantly inferior survival and greater rates of treatment-related toxicities compared to younger patients. Although treatment intensification has improved outcomes in younger patients, they have not been associated with the same degree of improvement for older patients.


Neuropharmacological activity of Nigella sativa L. extracts.
Pharmacological studies have been conducted on the aqueous and methanol extracts of defatted Nigella sativa L. seeds to evaluate their effects on the central nervous system (CNS) and on analgesic activity. The observations suggest that the two extracts of Nigella sativa possesses a potent CNS and analgesic activity (depressant action especially in the case of the methanolic extract).


Instrumentation for direct observation of frozen hydrated specimens in the electron microscope.
Instrumentation and techniques are described for the transfer and observation of frozen hydrated specimens in the transmission electron microscope. The transfer is accomplished without the complexity of a vacuum transfer device but also without significant sublimation of specimen ice or frosting. Examples are given of the transfer and observation of thin sections of rapidly frozen muscle and of rapidly frozen thin film preparations of isolated cells.


Intrinsic signal amplification in the application of 2D SENSE parallel imaging to 3D contrast-enhanced elliptical centric MRA and MRV.
The relative signal-to-noise ratio (SNR) provided by 2D sensitivity encoding (SENSE) when applied to 3D contrast-enhanced MR angiography (CE-MRA) is studied. If an elliptical centric phase-encoding order is used to map the waning magnetization of the contrast bolus to k-space, the application of SENSE will reduce the degree of k-space signal modulation, providing a signal amplification A over corresponding nonaccelerated acquisitions. This offsets the SNR loss in R-accelerated SENSE due to suquare root R and the geometry (g) factor. The theoretical bound on A is R and is reduced from this depending on the properties of the bolus profile and the duration over which it is imaged. In this work a signal amplification of 1.14-1.23 times that of nonvascular background tissue is demonstrated in a study of 20 volunteers using R = 4 2D SENSE whole-brain MR venography (MRV). The effects of a nonuniform g-factor and inhomogeneity of background tissue are accounted for. The observed amplification compares favorably with the value of 1.31 predicted numerically from a measured bolus curve.


Atrial fibrillation, cognitive impairment, and neuroimaging.
The objective of our study was to investigate cross-sectional associations of atrial fibrillation with neuroimaging measures of cerebrovascular disease and Alzheimer's disease and their interactions with mild cognitive impairment (MCI). Magnetic resonance imaging scans of individuals from a population-based study were analyzed for infarctions, total gray matter, and hippocampal and white matter hyperintensity volumes. A subsample underwent positron emission tomography imaging. Atrial fibrillation was associated with infarctions and lower total gray matter volume. Compared with subjects with no atrial fibrillation and no infarction, the odds ratio (95% confidence intervals) for MCI was 2.99 (1.57-5.70; P = .001) among participants with atrial fibrillation and infarction, 0.90 (0.45-1.80; P = .77) for atrial fibrillation and no infarction, and 1.50 (0.96-2.34; P = .08) for no atrial fibrillation and any infarction. Participants with both atrial fibrillation and infarction are more likely to have MCI than participants with either infarction or atrial fibrillation alone.


Cross-lagged model of bullying victimization and mental health problems in children with autism in middle to older childhood.
Youth with autism spectrum disorders are disproportionately at risk for bullying victimization compared to typically developing children and adolescents. While internalizing and externalizing mental health problems have been linked to victimization experiences, few studies have examined the longitudinal effects bullying victimization experiences may have on youth mental health outcomes. The present study investigated longitudinal associations between bullying victimization and mental health problems in a sample of children with autism in middle childhood to early adolescence (aged 5 to 12 years). Findings from our study suggest that youth with autism who experienced bullying victimization (versus no victimization) were older in age, had more severe autism symptoms, and higher levels of internalizing and externalizing mental health problems at study onset. Though externalizing mental health problems at study onset (Time 1) did not relate to change in the likelihood of being bullied one year later (Time 2), experiences of bullying victimization did relate to an increase in parent reports of internalizing mental health problems. This study expanded on previous cross-sectional studies by including two waves of data in a relatively large sample of youth with autism and highlights important information that may be helpful in adapting approaches to intervention at the individual level. Moreover, our findings support the need for bullying programs that may need to focus particular attention to subgroups of youth with autism who may be most at-risk for bullying victimization such as those with more autism symptoms and those with past experiences of victimization (given the chronic nature of bullying).


Aberrant cGMP-binding activity in non-chemotactic Dictyostelium discoideum mutants.
The kinetics of cGMP-binding to the major cGMP-binding activity in Dictyostelium were investigated in 10 non-chemotactic mutants (KI mutants; KI-1 approximately 10). A wild-type cell contains about 3000 binding sites with a Kd of 1.5 nM. cGMP may dissociate from these binding sites with fast (F-type) or slow (S-type) kinetics, and DNA has been shown to promote the conversion of F- to S-type of cGMP-binding. The 10 mutants were placed in 4 classes, based on equilibrium and non-equilibrium binding properties and the effect of DNA. Class I mutants (KI-1, 3 and 8) have normal cGMP-binding properties. Class II mutants (KI-2, 6 and 7) show increased Kd values but nearly normal Bmax, normal F/S ratio and normal effects of DNA. Class III mutants (KI-4, 5 and 10) have a strongly decreased Kd and increased Bmax, nearly all binding sites are of the S-type and DNA does not affect the binding; apparently these mutants have a cGMP-binding protein locked in the S-form. cGMP-binding in class IV mutant (KI-9) is normal except that the number of binding sites is increased about 3-fold. The finding of seven mutants with altered cGMP-binding in 10 non-chemotactic mutants suggests that the cGMP-binding activity plays an important role in the chemotactic signal transduction pathway.


Supporting Children's Initiative: Appreciating Family Contributions or Paying Children for Chores.
Collaborative initiative is an important aspect of Learning by Observing and Pitching In (LOPI), and many interrelated family and community practices in LOPI may support children's initiative. In this chapter, we examine two cultural ways of supporting children's helpfulness and responsibility that draw on different cultural paradigms for organizing children's participation in everyday work in U.S. Mexican-heritage and European American communities. European American university students reported having received allowances as a contractual enticement to do assigned chores. In contrast, although U.S. Mexican-heritage university students reported having received pocket money from their families, this was as a gift, noncontingent on completed chores or good behavior. They reported that this noncontingent support for children's responsibility focuses children on collaborating with the family, and contributing to shared work with initiative, consistent with LOPI, in which children are integrated in family and community endeavors and are eager to contribute. The chapter challenges traditional dichotomies in motivational theory that attempt to specify the "source" of children's motivation to learn and help within either individuals or social contexts.


Effects of basic fibroblast growth factor (bFGF) on choline acetyltransferase activity and astroglial reaction in adult rats after partial fimbria transection.
Adult rats received a partial and unilateral transection of the fimbria. They received then intracerebroventricular (i.c.v.) injections of 5 microliters of Tris, half of them containing 2.5 ng of basic fibroblast growth factor (bFGF). They were injected twice a week for 4 weeks. At the end of this period, choline acetyltransferase (ChAT) activity was measured in the hippocampus. ChAT activity, which was decreased by the fimbria transection, was higher (by about 20%) in medial hippocampus of the bFGF group compared with the Tris group. In addition, bFGF enhanced the lesion-induced astroglial reaction by changing the morphology of the astrocytes and increasing the apparent number of these reactive astrocytes.


[Influence of compatibility on content of berberine in Maxingganshi decoction].
To set up the quantitative method of herberine in decoctions prepared from various combinations of Maxingganshi decotion by HPLC and to determine the change of general contents in different decoction. The study was designed by L8 (2(7)) orthogonal and to determine the change of general contents in different decoction by HPLC. In full formula remove Glycyrrhiza uralensis group, the contents of L-ephedrine, d-pseudephedrine and the amygdaloside cut down significantly. In full formula remove armeniacae semen group, the content of glycyrrhetic acid cut down significantly. Four chemical composition in full formula group had higher contents. Armeniacae semen can decrease the content of L-ephedrine, D-pseudephedrine. Glycyrrhiza uralensis can help decoctum amygdaloside and armeniacae semen can help decoctum glycyrrhizic acid.


Modulation of epithelial innate immunity by autocrine production of nitric oxide.
Mechanisms of innate immunity especially with relevance to epithelial tissue, are currently the focus of intense research, as epithelial immunity greatly impacts on health and disease. However, many findings regarding innate immunity signalling pathways in vertebrates stems from research using the genetic model Drosophila melanogaster. Here we discuss the central importance of epithelial tissues in innate immunity in Drosophila; the modulation of the Imd pathway via autocrine production of nitric oxide (NO); and the central importance of the Malpighian (renal) tubule in immune function of the whole animal.


Immunosenescence profile and expression of the aging biomarker (p16INK4a) in testicular cancer survivors treated with chemotherapy.
Cytotoxic chemotherapy can cure advanced germ cell tumors. Nevertheless, cancer treatment may induce cellular senescence and accelerate molecular aging. The aging process implies an increase of cells expressing p16INK4a and changes in lymphocyte subpopulations. Our aim was to study the potential induction of premature immunosenescence in testicular cancer survivors (TCS) exposed to chemotherapy. Case-control exploratory study of TCS treated with chemotherapy (≥3 BEP cycles, disease-free ≥3 months) compared with age matched healthy controls. Peripheral blood mononuclear cells were isolated, and lymphocyte subpopulations were analyzed by flow cytometry. CDKN2A/p16INK4a expression in T cells was measured using qPCR. The percentage of lymphocyte subpopulations and the CDKN2A/p16INK4a expression in TCS were compared with the control group using the Wilcoxon signed-rank test. We included 16 cases and 16 controls. The median age was 27 years (minimum 24, maximum 54) and the median time on surveillance was 26.5 months (minimum 3, maximum192). TCS had a lower percentage of total T cells and CD4+ T cells in total lymphocytes. Among the CD4+ T lymphocytes, TCS had less naïve CD4+ and increased memory CD4+ cells. Within the CD8+ T lymphocytes, TCS exhibited a decrease in the percentage of naïve cells and an increase in CD8 + CD45RA + CD57+ cells. TCS also exhibited decreased memory CD19+ B cells compared to the controls. The relative expression of CDKN2A/p16INK4a in T cells was increased in TCS (mean 1.54; 95% CI of the mean: 1.074-2.005; p = 0.048). In this exploratory study, TCS showed increased expression of CDKN2A/p16INK4a and a lymphocyte phenotype that has been associated with immunosenescence. Further studies are warranted to define the clinical implications of these alterations in TCS.


Benign thyroid disease and upper airway obstruction: case presentations, pathophysiology, and management.
Investigations of three cases with large goiters and marked respiratory stridor showed different mechanisms of airflow limitations. This report describes the flow volume loop and Machida fiberoptic tracheoscopy as newer methods for evaluating the larynx and trachea. Indications for tracheotomy in benign thyroid disease are discussed.


Intraoperative cardiovascular crisis caused by glucagon.
Glucagon use as a muscle relaxant is common in radiologic and endoscopic examinations in which smooth-muscle spasm has interfered. Glucagon also provokes catecholamine release from an unsuspected pheochromocytoma, as occurred in a 60-year-old patient undergoing biliary tract surgery. To prevent hypertensive crisis and ventricular tachyarrhythmia after intraoperative glucagon administration, appropriate pharmacologic catecholamine antagonists must be immediately available.


Eliminating Fc N-Linked Glycosylation and Its Impact on Dosing Consideration for a Transferrin Receptor Antibody-Erythropoietin Fusion Protein in Mice.
Erythropoietin (EPO), a hematopoietic growth factor and a promising therapy for Alzheimer's disease, has low permeability across the blood-brain barrier. The transferrin receptor antibody fused to EPO (TfRMAb-EPO) is a chimeric monoclonal antibody that ferries EPO into the brain via the transvascular route. However, TfRMAbs have Fc-effector function-related adverse effects including reticulocyte suppression. To overcome this, we recently developed an effectorless TfRMAb-EPO fusion protein, designated TfRMAb-N292G-EPO, by eliminating the Fc N-linked glycosylation site at position 292 of the antibody heavy chain. The mutant fusion protein showed enhanced plasma clearance and dramatically reduced plasma concentrations compared with the wild-type (WT) nonmutant fusion protein. This increased clearance of the aglycosylated TfRMAb is expected to increase the injection dose of the mutant fusion protein. To provide a basis for future therapeutic uses of this IgG-neurotrophin fusion protein, the current study aimed to characterize the pharmacokinetic profile of this effectorless TfRMAb-N292G-EPO at different doses following different routes of administration in the mouse. Adult C57BL/6J male mice were injected with a single dose (3, 6, 9, or 20 mg/kg; n = 3-6 per dose) of TfRMAb-N292G-EPO through either the subcutaneous (SQ) or intraperitoneal (IP) route. TfRMAb-N292G-EPO plasma concentrations were determined using an enzyme-linked immunosorbent assay. Mice were sacrificed 24 h after injection, and terminal blood was used for a complete blood count. Brain concentrations in the WT- and mutant fusion protein-treated mice were compared. We observed stark differences in the plasma pharmacokinetics of TfRMAb-N292G-EPO between the IP and SQ routes of administration. Dose escalation from 3 to 20 mg/kg increased the plasma Cmax only 3.5-fold for the SQ route, compared with a 35-fold increase for the IP route. The plasma Cmax was 15.0 ± 2.0, 21.3 ± 4.1, 21.3 ± 6.4, and 52.8 ± 27.9 ng/mL following SQ injection and 288 ± 47, 389 ± 154, 633 ± 194, and 10,066 ± 7059 ng/mL following IP injection for 3, 6, 9, and 20 mg/kg doses, respectively. The plasma Cmax following the SQ route was therefore 19- to 190-fold lower than that following the IP route. This finding is consistent with a 31-fold higher apparent clearance following the SQ route compared with the IP route at the highest dose administered. The brain concentrations in the mice treated with a 3 mg/kg dose of the mutant fusion protein were lower than those in the nonmutant WT-treated mice. No reticulocyte suppression was observed at the 3 mg/kg SQ dose of TfRMAb-N292G-EPO. However, reticulocyte suppression increased with an increase in dose and area under the plasma concentration-time curve (AUC) for both the IP and SQ routes. Overall, elimination of Fc N-linked glycosylation, to mitigate TfRMAb effector function side effects, has a profound effect on the plasma exposure of TfRMAb-N292G-EPO at therapeutic as well as high doses (3-20 mg/kg). This effect is more pronounced following SQ injection. The low plasma concentrations of the mutant fusion protein following a 3 mg/kg dose resulted in negligible brain uptake. The beneficial rescue of reticulocyte reduction by the N292G mutation is a function of AUC and is negated at high doses of the N292G mutant.


AKT supports the metabolic fitness of multiple myeloma cells by restricting FOXO activity.
Metabolic alterations are important cancer-associated features that allow cancer cell transformation and survival under stress conditions. Multiple myeloma (MM) plasma cells show increased glycolysis and oxidative phosphorylation (OXPHOS), which are characteristics associated with recurrent genetic aberrations that drive the proliferation and survival of MM cells. The protein kinase B/AKT acts as a central node in cellular metabolism and is constitutively active in MM cells. Despite the known role of AKT in modulating cellular metabolism, little is known about the downstream factors of AKT that control the metabolic adaptability of MM cells. Here, we demonstrate that negative regulation of the forkhead box O (FOXO) transcription factors (TFs) by AKT is crucial to prevent the metabolic shutdown in MM cells, thus contributing to their metabolic adaptability. Our results demonstrate that the expression of several key metabolic genes involved in glycolysis, the tricarboxylic acid (TCA) cycle, and OXPHOS are repressed by FOXO TFs. Moreover, the FOXO-dependent repression of glycolysis- and TCA-associated genes correlates with a favorable prognosis in a large cohort of patients with MM. Our data suggest that repression of FOXO by AKT is essential to sustain glycolysis and the TCA cycle activity in MM cells and, as such, predicts patient survival.


The fine structure of the developing human choriocapillaris during the first trimester.
In human embryos with a gestational age ranging from 6.5 to 13 weeks the development of the choriocapillaris was studied by electron microscopy. A continuous maturation process was observed over the whole period, which was most pronounced between weeks 6.5 and 9.7. During the earlier weeks, the endothelium appeared to be rather thick and contained many cytoplasmic vesicles; it was markedly flattened and less vesiculated than at week 9.7. This process was accompanied by an enlargement in the vascular lumina. Fenestrations directed towards the primitive Bruch's layer were found to be already present at week 7.2 but increased in number from week 9.7 to week 13. In the early weeks, basement membrane structures were present in small, discontinuous tufts of cloudy material adjacent to the endothelium. These structures became continuous at week 9.7 and increased in thickness towards week 13. In the earlier weeks, punctate junctions were seen. Beginning with week 9.7, adultlike tight junctions between the endothelial cells became observable. Pericytes were already present at week 6.5. It is suggested that both pericytes and endothelial cells are derived from the differentiating mesenchymal cells of the surrounding ocular stroma.


Two decades of experience with the Haemophilus influenzae serotype b conjugate vaccine in the United Kingdom.
The Haemophilus influenzae serotype b (Hib) conjugate vaccine was introduced into the UK national childhood immunization program in 1992 after clinical trials reported the vaccine to be highly immunogenic in infants as young as two months of age. The goal of this study was to describe and comment on the impact of routine Hib immunization on the epidemiology of invasive Hib disease in the United Kingdom. In addition, the development of Hib polysaccharide and conjugate vaccines was reviewed. A literature search was conducted of PubMed for invasive Hib disease epidemiology in the United Kingdom. The UK Health Protection Agency Web site was also searched for relevant publications. The incidence of invasive Hib incidence in children aged <5 years fell from 21/100,000 to 44/100,000 in the prevaccine era to 0.63/100,000 in 1998, with an estimated vaccine failure rate of 2.2/100,000 vaccinees. After 1999, however, invasive Hib disease increased, particularly in toddlers, and peaked in 2003. Potential reasons for the resurgence included a greater-than-expected decline in Hib antibodies after primary immunization, waning of herd immunity offered by the initial catch-up campaign, and use of a less immunogenic Hib combination vaccine containing acellular pertussis in 2000-2001. In response to the resurgence, a Hib combination vaccine containing whole-cell pertussis was reintroduced in 2002, followed by a childhood Hib booster campaign in 2003. In 2004, the recommended infant vaccine was changed to a different Hib/acellular pertussis combination vaccine containing inactivated polio, which had a satisfactory Hib response, was less reactogenic, and eliminated the risk of vaccine-associated paralytic poliomyelitis. This action was followed by introduction of a routine 12-month Hib booster in 2006. Together, these measures led to a decline in invasive Hib disease across all age groups. In 2010, there were only 30 invasive Hib cases, with 6 reported in children aged <5 years and no deaths in this age group since 2007. Control of Hib disease is currently the best that has been achieved since the introduction of the routine Hib vaccination almost 20 years ago.


Laryngitis--diagnosis and management.
Laryngeal inflammation includes a broad spectrum of pathologies, from infectious processes that need to be managed as airway emergencies, to indolent diseases that mimic head and neck cancer. The importance of a thorough history cannot be emphasized enough as it is the most important step toward developing a differential diagnosis. Vocal pathologies often have a noticeable impact on a person's quality of life and daily activities; therefore, it is key to counsel patients on the course of the disease process. Treatment of specific pathologies depends on the causative pathogen or etiology, as well as the age, vocal demands, and clinical characteristics of the individual.


Anticancer effects of clinically acceptable colchicine concentrations on human gastric cancer cell lines.
Colchicine is a very cheap microtubule destabilizer. Because microtubules are an ideal target for anticancer drugs, the purpose of this study was to investigate whether clinically acceptable colchicine concentrations have anticancer effects on gastric cancer cells, and its possible anticancer mechanisms. Two human gastric cancer cell lines (i.e., AGS and NCI-N87) were investigated by proliferative assay, microarray, quantitative reverse transcriptase-polymerase chain reaction, and a nude mice study using clinically acceptable colchicine concentrations (2 ng/mL and 6 ng/mL for in vitro tests and 0.07 mg colchicine/kg/d for in vivo tests). Our results showed that colchicine had the same inhibitory effects on the proliferation of both cell lines. The antiproliferative effects of colchicine on both cell lines were achieved only at the concentration of 6 ng/mL (p < 0.0001). In both cell lines, 18 genes were consistently upregulated and 10 genes were consistently downregulated by 6 ng/mL colchicine, compared with 2 ng/mL colchicine. Among these genes, only the upregulated DUSP1 gene may contribute to the antiproliferative effects of colchicine on gastric cancer cells. The nude mice (BALB/c-nu) experiment showed that colchicine-treated mice after 14 days of treatment had lower increased tumor volume ratios (p = 0.0199) and tumor growth rates (p = 0.024) than the control mice. In conclusion, colchicine has potential for the palliative treatment of gastric cancer. However, the anticancer effects are achieved only at high clinically acceptable colchicine concentrations. Monitoring the colchicine plasma concentration is mandatory if this drug is applied for the palliative treatment of gastric cancer.


Triple nuclear NMR studies of cerebral metabolism during generalized seizure.
Noninvasive NMR spectroscopy of 1H, 31P, and 23Na is performed simultaneously to study brain metabolism during grand mal seizures. Decreases in PCr and increases in lactate associated with seizure as well as an intracellular shift of the Na+ ion pool are demonstrated. A close correlation between the phosphate potential and the intensity of the seizure, as well as the intra/extracellular ionic gradient, is shown.


Investigation on the improvement of activated sludge dewaterability using different iron forms (ZVI vs. Fe(II))/peroxydisulfate combined vertical electro-dewatering processes.
The high moisture content (MC) of activated sludge dewatered by traditional vertical electro-dewatering (VED) is unable to meet the disposal requirements. Therefore, different iron forms (ZVI vs. Fe(II))/peroxydisulfate (PDS) combined VED (ZVI/PDS-VED and Fe(II)/PDS-VED) were employed to enhance the dewaterability of activated sludge. The dewatering behaviors of the two combined dewatering processes and the underlying mechanism related to the sludge characteristics were investigated and compared. Sludge was conditioned using ZVI/PDS and Fe(II)/PDS, respectively, and then dewatered by the VED in the experiment. Experimental results showed that with 0.3 g (g dry solids (DS))-1 of iron activators, 0.583 g (g DS) -1 of PDS, and 30 V of voltage, the MC of sludge after ZVI/PDS-VED and Fe(II)/PDS-VED reached the minimum values of 50.6 ± 1.2% and 32.1 ± 1.5%, respectively. ZVI/PDS and Fe(II)/PDS conditioning reduced the MC difference of sludge between the anode and the cathode during the VED, facilitating the water homogenization in the sludge cake. ZVI/PDS-VED and Fe(II)/PDS-VED could effectively reduce the bound water and the free water. Free water had high correlations with α-helix (r = 0.999, p < 0.05) and CO (r = 0.998, p < 0.05). Compared with the traditional VED and the ZVI/PDS-VED, the Fe(II)/PDS-VED had a greater improvement of sludge dewaterability due to the more efficient degradation of extracellular polymeric substances and the increase of sludge surface hydrophobicity. This study promoted the development of the new sludge deep-dewatering technology.


Value of single photon absorptiometry in osteoporosis screening.
Radial bone mineral content and bone mineral density were measured in 1515 women referred for osteoporosis screening. A detailed questionnaire allowed the selection of 1069 normal white women for further analysis who had no historical evidence of bone disease or predisposing factors for bone disease. The nondominant radius was measured at two locations: the midradial bone density (MRBD) composed of predominantly cortical bone and the distal radial bone density at the 5 mm site (DRBD) composed of a mixture of cortical and trabecular bone. Women considered at risk were defined as those whose bone density values fell below fracture risk levels (0.550 g/cm2 for the MRBD and 0.325 g/cm2 for the DRBD). Between the ages of 20 and 70 years, the DRBD showed significantly greater sensitivity in defining subjects at risk (N = 223) than than MRBD (N = 80); P less than 0.001. Analysis of all ages showed that 684 women were above the fracture risk value (FRV) at both sites (64.0%), 260 were below the FRV at the DRBD 5 mm site (24.3%), 14 were below the FRV at the MRBD site (1.3%), and 111 were below the FRV at both sites (10.4%). Postmenopausal women age 50 to 70 years receiving estrogen replacement therapy (N = 221) had significantly higher values at both sites (P less than 0.001) than age-matched postmenopausal women not receiving replacement therapy (N = 239). Hereditary factors significantly correlated with both sites but neither site showed that calcium intake, activity level, or cigarette smoking were significant variables.(ABSTRACT TRUNCATED AT 250 WORDS)


Endovascular Intervention for the Treatment of Trans-Atlantic Inter-Society Consensus (TASC) D Femoropopliteal Lesions: A Systematic Review and Meta-Analysis.
Advancements in the endovascular treatment of femoropopliteal atherosclerotic lesions have led to treatment of more complex lesions, particularly long lesions. The aim of this study was to determine the meta-analytic primary patency and need for re-intervention among patients treated for very long lesions (>200 mm) at the femoropopliteal segment and to identify potential risk factors for loss of patency. This study was performed according to the PRISMA guidelines. A random effects model meta-analysis was conducted, and the I-square was used to assess heterogeneity. Fifty-one studies comprised of 3029 patients were included. The mean lesion length was 269 mm. The primary patency rate at 30 days, 6 m, 1-, 2- and 5-years of follow-up was 98%, 76%, 62%, 55%, and 39% respectively. The incidence of TLR was 16% at one year and 32% at two years. The secondary patency rate at 1, 2, 3 and 5 years was 85%, 71%, 64%, and 64% respectively. Heparin bonded ePTFE covered stents (69%) and paclitaxel eluting stents (73%) demonstrated higher 1-year primary patency rates than self-expanding nitinol stents (55%) or uncoated percutaneous transluminal angioplasty (PTA) with provisional stenting (54%). Lesions treated with a heparin bonded ePTFE covered stent had statistically significant higher odds of remaining patent at 1-year of follow-up (OR: 2.74; 95%CI: 1.63-4.61; p < 0.001) than lesions treated with BMS or PTA. Patients with long femoropopliteal lesions causing critical limb ischemia (CLI) developed restenosis or occlusion more often than patients treated for claudication (HR: 1.63; 95%CI: 1.06-2.49; p = 0.026) during an average follow-up of 26 months. Primary stenting of femoropopliteal TASC D lesions using drug eluting stents or covered stents results in sustained patency over time. PTA or uncoated nitinol stents demonstrated lower patency rates. However, additional comparative studies are needed to determine the efficacy of newer technologies for the treatment of complex femoropopliteal lesions and provide evidence for the most optimal treatment approach.


Effect of pII key nitrogen regulatory gene on strain growth and butenyl-spinosyn biosynthesis in Saccharopolyspora pogona.
PII signal transduction proteins are widely found in bacteria and plant chloroplast, and play a central role in nitrogen metabolism regulation, which interact with many key proteins in metabolic pathways to regulate carbon/nitrogen balance by sensing changes in concentrations of cell-mediated indicators such as α-ketoglutarate. In this study, the knockout strain Saccharopolyspora pogona-ΔpII and overexpression strain S. pogona-pII were constructed using CRISPR/Cas9 technology and the shuttle vector POJ260, respectively, to investigate the effects on the growth and secondary metabolite biosynthesis of S. pogona. Growth curve, electron microscopy, and spore germination experiments were performed, and it was found that the deletion of the pII gene inhibited the growth to a certain extent in the mutant. HPLC analysis showed that the yield of butenyl-spinosyn in the S. pogona-pII strain increased to 245% than that in the wild-type strain while that in S. pogona-ΔpII decreased by approximately 51%. This result showed that the pII gene can promote the growth and butenyl-spinosyn biosynthesis of S. pogona. This research first investigated PII nitrogen metabolism regulators in S. pogona, providing significant scientific evidence and a research basis for elucidating the mechanism by which these factors regulate the growth of S. pogona, optimizing the synthesis network of butenyl-spinosyn and constructing a strain with a high butenyl-spinosyn yield. KEY POINTS: • pII key nitrogen regulatory gene deletion can inhibit the growth and development of S. pogona. • Overexpressed pII gene can significantly promote the butenyl-spinosyn biosynthesis. • pII gene can affect the amino acid circulation and the accumulation of butenyl-spinosyn precursors in S. pogona.


Open versus Endovascular Repair of Arch and Descending Thoracic Aneurysms: A Retrospective Comparison.
Thoracic aortic aneurysms (TAAs) contribute significant mortality if left untreated, but surgical repair has historically carried substantial risks. We sought to observe trends and outcomes of open and endovascular thoracic endovascular aneurysm repair thoracic aortic repairs, so conducted a retrospective review of all patients who presented for management of TAAs from 2003 to 2013 at 2 hospitals in Sydney, Australia. A total of 179 patients presented with TAAs over the study period, including 5 ruptures. Fifty-two were treated nonoperatively, with 127 surgically repaired. Operative duration was significantly shorter in endovascular than open repair of arch (193 ± 108 vs. 396 ± 98 min, P = 0.0001) and descending aneurysms (242 ± 116 vs. 422.5 ± 161 min, P = 0.003). There were no differences in mortality or complication rates (including paraplegia), duration of hospital or intensive care unit stay, or transfusion requirements between endovascular and open TAA repairs. Apart from reduced surgical duration, this study revealed no benefits of endovascular over open TAA repair. Overall morbidity and mortality were low, even in elderly patients.


Earthworms can mobilize soil arsenic through their casts.
The mobilization of arsenic (As) in paddy soil has received much attention because it might accelerate the transfer of As from soil to rice. This study aims to elucidate whether earthworms can mobilize As through their casts. Cast samples were collected from 23 different paddy fields in the Red River delta. We first analysed different forms of As through fractionation and then performed batch experiments under reducing conditions to identify factors that govern the mobility of As in casts. Because the dissociation of casts may induce colloids that carry As, the colloidal properties of cast suspensions were also examined. The median value of As in casts (obtained from aqua regia digestion) was 5.11 mg kg-1, which was lower than that in the surrounding soil (6.7 mg kg-1). Compared with the surrounding soil, casts contain less As, possibly because cast As is more labile and more easily lost due to leaching. Various processes, including the reductive dissolution of Fe oxides, decomposition of organic matter, and sorption competition of soluble anionic substances, such as P, Si and DOC, were found to strongly correlate with the release of As from casts. We propose that earthworms, via their casts, may accelerate the As cycle in paddy soils, potentially intensifying As exposure to human health. The dissociation of cast could release colloids containing As; therefore, the cotransport of As with cast-induced colloids should also be considered in future works.


Depletion from a hard wall induced by aggregation and gelation.
Diffusion-limited cluster aggregation and gelation of hard spheres is simulated using off-lattice Monte Carlo simulations. A comparison is made of the wall-particle correlation function with the particle-particle correlation function over a range of volume fractions, both for the initial system of randomly distributed spheres and for the final gel state. For randomly distributed spheres the correlation functions are compared with theoretical results using the Ornstein-Zernike equation and the Percus-Yevick closure. At high volume fractions (phi > 40%) gelation has little influence on the correlation function, but for phi < 10% it is a universal function of the distance normalized by correlation length (xi) of the bulk. The width of the depletion layer is about 0.5xi. The concentration increases as a power law from the wall up to r approximately = xi, where it reaches a weak maximum before decreasing to the bulk value.


Telehealth physician oversight over direct to consumer testing: doctors working with patients towards patient empowerment.
Patient empowerment has increased the demand for direct to consumer (DTC) laboratory testing. Multiple professional societies and advocacy groups have raised concerns over how DTC laboratory testing is being offered to consumers without proper physician oversight. Physician telehealth services can properly oversee DTC laboratory testing in a safe and medically sound manner. Using telehealth protocols and standards established by professional health organizations and state regulators, physician telehealth oversight in DTC laboratory test ordering can be effective to increase patient access to healthcare services. With proper physician oversight in test interpretation, post-test counseling, and information collaboration, DTC laboratory testing can remain a reliable and convenient option for consumers. Working within the channel of distribution of most DTC laboratory testing, physician telehealth services can properly oversee DTC laboratory testing in a safe and medically sound manner to ensure that proper test interpretation, counseling, and information collaboration are achieved. Physician telehealth services can properly oversee DTC laboratory testing to ensure that proper test interpretation, counseling, and information collaboration are achieved.


The role of exfoliative cytology in the management of bladder carcinoma.
Cytological analyses of bladder washings from 974 patients with disorders of the urinary tract are reported. The cytological findings were compared with the clinical and histological diagnoses. The histological grading of bladder tumours was based on the classification proposed by Bergkvist et al. No false positive diagnosis of malignancy was made in the 320 patients without tumour growth. The five cases with positive cytology had histologically verified carcinoma in situ. The frequency of cytological diagnosis of cancer increased with the histological grade of malignancy in the 428 patients with bladder neoplasm. Carcinoma was graded in smears according mainly to the degree of epithelial atypia. A comparison with the histological grading was attempted. Of 226 cases of bladder carcinoma treated with supervoltage irradiation, 108 had persistence or recurrence of carcinoma. The clinical diagnosis was cytologically confirmed in 92 per cent of these cases.


Antibiotic prophylaxis in posterior colporrhaphy does not reduce postoperative infection: a nationwide observational cohort study.
The aim of this study was to explore if antibiotic prophylaxis prevents postoperative infection after a posterior colporrhaphy. In this register-based nationwide cohort study data were collected from the "The Swedish National Quality Register of Gynecological Surgery" (GynOp). Women 18 years or older who underwent a primary posterior colporrhaphy between 1 January 2015 and 31 December 2020 were included. Patients undergoing any concomitant prolapse procedure, mesh surgery, or incontinence procedure were excluded. The cohort was divided into two groups based on administration of antibiotic prophylaxis (n = 1,218) or not (n = 4,884). The primary outcome of this study was patient-reported infectious complication requiring antibiotic treatment. Secondary outcome measures included patient satisfaction and prolapse-related symptoms at 1 year postoperatively. A total of 7,799 patients who underwent posterior colporrhaphy and met the inclusion criteria and did not meet the exclusion criteria were identified in the register database. Of these patients 6,102 answered the primary outcome question (79%). In the antibiotic prophylaxis group a total of 138 reported a postoperative infection (11%) and in the no antibiotic prophylaxis group the corresponding data were 520 (11%). There were no significant differences regarding either the primary or the secondary outcomes between the study groups. In this nationwide Swedish register study antibiotic prophylaxis was not associated with a reduced risk of postoperative infection after a posterior colporrhaphy.


Establishment and characterization of a new endometrial cancer cell line (SCRC-1).
A new human endometrial cell line, SCRC-1, has been established from a uterine adenocarcinoma. During a period of 57 weeks in culture, the SCRC-1 cells have been passaged over 100 times. Cultures have an epitheloid morphology, high mitotic activity, and a tendency to form multiple cell layers. The cells are polygonal and are arranged in pavement-like fashion. Most have multiple nucleoli, some are multinucleated, and all have heavily vacuolated cytoplasm. Pretreatment with iododeoxyuridine did not reveal viral markers by cocultivation or immunofluorescence techniques. Karyologic studies indicate that the SCRC11 cell line is essentially diploid with a small subpopulation of tetraploid cells. Over a period of 20 weeks, 1 of 14 athymic nude mice inoculated with SCRC-1 cells developed a tumor which histologically closely resembled the original human tumor. Cells were subsequently propagated from this tumor and the resulting epitheloid-like cell line was designated SCRC-1, Tu 1.


Classification, diagnosis, and interventional radiologic management of vascular malformations.
Vascular anomalies are comprised of either hemangiomas or vascular malformations.Low-flow vascular malformations can be divided into capillary, venous, and lymphatic types and are usually present at birth, undergo pari passu growth, and produce symptoms related to mass effect or stasis. High-flow malformations are comprised pre-dominantly of arteriovenous malformations that follow a more aggressive clinical course of hyperemia, adjacent mass effect, steal phenomenon, tissue destruction, and ultimately high output failure. Ultrasound, CT, nuclear medicine, angiography, and particularly MRI have greatly enhanced diagnostic accuracy and provide detailed information for percutaneous and surgical treatment planning and an objective means of following therapeutic efficacy. Interventional radiologic percutaneous sclerotherapy for low-flow lesions and embolosclerotherapy for high-flow lesions with or without adjunctive surgical intervention have become the mainstay of therapy.


Investigation of Neuroprotective and Therapeutic Effects of Hesperidin in Experimental Spinal Cord Injury.
To investigate the neuroprotective and therapeutic efficacy of hesperidin against secondary damage following traumatic spinal cord injury. A total of 32 male Wistar albino rats weighing 250?300 g were randomly divided into four groups (n=4): group I, control group; group II, sham group; group III, preconditioning group, and group IV, treatment group. A rat model of spinal cord injury was established by dropping a weight of 100 g/cm on the spinal cord exposed at T7?T10 with dorsal laminectomy. In neurological examination after the trial period, inclined planed test, modified Tarlov scale, and finger extension test were performed. Furthermore, the bioefficacy of hesperidin was investigated histopathologically, biochemically, and immunohistochemically using blood and tissue samples obtained from the experimental animals. Neurological examination following spinal cord injury revealed that hesperidin significantly contributed to improvement in the 24-hour period. Biochemical analyses revealed that hesperidin showed anti-inflammatory effects by decreasing IL-1? and TNF-? levels at the 24th hour as well as strong antioxidant activity by increasing TAS levels in groups III and IV. Histopathologically, hesperidin reduced hemorrhage, laceration, axonal and neuronal degeneration, necrosis, inflammatory reaction, and edema in groups III and IV. Immunohistochemically, hesperidin reduced the number of caspase 3-positive apoptotic cells in groups III and IV. Hesperidin showed antioxidant, anti-inflammatory, and anti-apoptotic effects during the acute period following spinal cord injury; thus, hesperidin shows neuroprotective and therapeutic efficacy in spinal cord injury.


Preparation of cupric sulfate-based self-emulsifiable nanocomposites and their application to the photothermal therapy of colon adenocarcinoma.
Nanocomposites (NCs) of cupric sulfate monohydrate (CuSO4) were fabricated by hot-melt extrusion (HME) system equipped with twin screws. Micron-sized bulk powder of CuSO4 was dispersed in the mixture of surfactants (Span 80 and Tween 80) and hydrophilic polymer (polyethylene glycol (PEG) 6000) by HME process. Reduction of surface tension by surfactants and homogeneous dispersion in hydrophilic polymer along with HME technique were introduced to prepare CuSO4 NCs. Dispersion of CuSO4 NCs exhibited approximately 204 nm hydrodynamic size, unimodal size distribution, and positive zeta potential values. Encapsulation of CuSO4 in CuSO4 NCs and the physicochemical interactions between CuSO4 and pharmaceutical excipients were investigated by solid-state studies. Of note, CuSO4 NCs group exhibited higher antiproliferation efficacies, compared with bulk CuSO4, in Caco-2 (human adenocarcinoma) cells at 75 and 100 μg/mL CuSO4 concentrations (p < 0.05). Also, near-infrared laser irradiation to CuSO4 NCs group elevated the antiproliferation efficacies, compared with non-irradiation group, in Caco-2 cells. After intravenous injection in mice, CuSO4 NCs did not show severe in vivo toxicities. Developed CuSO4 NCs can be one of promising candidates of photothermal therapeutic agents for colon cancers.


[Screening of Mothers in a COVID-19 Low-Prevalence Region: Determination of SARS-CoV-2 Antibodies in 401 Mothers from Rostock by ELISA and Confirmation by Immunofluorescence].
In children, the infection with SARS-CoV-2, the cause of COVID-19, tends to be clinically inapparent more often or less severe than in adults. The spread of this infection from children poses a danger to vulnerable adults. Therefore, child care institutions and schools currently are widely closed. Since the status of infection tends to be congruent in mothers and their children, we tested 401 mothers of children between 1 and 10 years in the city of Rostock (State of Mecklenburg-Westpomerania, northeast of Germany), for the presence of RNA of SARS-CoV-2 in throat swabs, and of antibodies against SARS-CoV-2 in serum. In none of the mothers tested, RNA of this virus was detected in the throat swab. In the ELISA test, IgG antibodies were positive in one serum sample, IgA antibodies were positive in 11, and borderline in 3 serum samples. All 401 sera were negative in the indirect immunofluorescence test (IIFT) with FITC-labeled IgG, IgA, und IgM antibodies. At the time of this study, neither SARS-CoV-2 RNA, nor specific antibodies against SARS-CoV-2 were detectable in the mothers tested in Rostock.


Association between measured teamwork and medical errors: an observational study of prehospital care in the USA.
The goal of this study was to examine the relationship between measured teamwork and adverse safety events in the prehospital emergency care of children using high-fidelity simulation. We posit that non-technical skills such as leadership, teamwork, situation awareness and decision-making are associated with the clinical success of teams. Observational study. Emergency medical services (EMS) responders were recruited from public fire and private transport agencies in Oregon State to participate in four simulations of paediatric emergencies using high-fidelity patient simulators, scene design, and professional actors playing parents and bystanders. Forty-four fire/transport teams consisting of 259 EMS professionals consented to participate and completed simulations. Teams were assessed using the Clinical Teamwork Scale (CTS), a validated instrument that measures overall teamwork and 15 specific elements in five overarching domains: communication, decision-making, role responsibility (leadership and followership), situational awareness/resource management and patient-friendliness. We used generalised estimating equations to estimate the odds of error with increasing overall CTS teamwork score while adjusting for clinical scenario and potential clustering by team. Across 176 simulations, the mean overall score on the CTS was 6.04 (SD 2.10; range 1=poor to 10=perfect) and was normally distributed. The distribution of scores was similar across the four clinical scenarios. At least one error was observed in 82% of the simulations. In simulations with at least one observed error, the mean CTS score was 5.76 (SD 2.04) compared with 7.16 (SD 1.95) in scenarios with no observed error. Logistic regression analysis accounting for clustering at the team level revealed that the odds of an error decreased 28% with each unit increase in CTS (OR 0.72, 95% CI 0.59 to 0.88). This study found that overall teamwork among care delivery teams was strongly associated with the risk of serious adverse events in simulated scenarios of caring for critically ill and injured children.


Cost Consequences of Age and Comorbidity in Accelerated Postoperative Discharge After Colectomy.
Prospective payment models have incentivized reductions in length of stay after surgery. The benefits of abbreviated postoperative hospitalization could be undermined by increased readmissions or postacute care use, particularly for older adults or those with comorbid conditions. The purpose of this study was to determine whether hospitals with accelerated postsurgical discharge accrue total episode savings or incur greater postdischarge payments among patients stratified by age and comorbidity. This was a retrospective cross-sectional study. National data from the 100% Medicare Provider Analysis and Review files for July 2012 to June 2015 were used. We included Medicare beneficiaries undergoing elective colectomy and stratified the cohort by age (65-69, 70-79, ≥80 y) and Elixhauser comorbidity score (low: ≤0; medium: 1-5; and high: >5). Patients were categorized by the hospital's mode length of stay, reflecting "usual" care. In a multilevel model, we compared mean total episode payments and components thereof among age and comorbidity categories, stratified by hospital mode length of stay. Among 88,860 patients, mean total episode payments were lower in shortest versus longest length of stay hospitals across all age and comorbidity strata and were similar between age groups (65-69 y: $28,951 vs $30,566, p = 0.014; 70-79 y: $31,157 vs $32,044, p = 0.073; ≥80 y: $33,779 vs $35,771, p = 0.005) but greater among higher comorbidity (low: $23,107 vs $24,894, p = 0.001; medium: $30,809 vs $32,282, p = 0.038; high: $44,097 vs $46641, p < 0.001). Postdischarge payments were similar among length-of-stay hospitals by age (65-69 y: ∆$529; 70-79 y: ∆$291; ≥80 y: ∆$872, p = 0.25) but greater among high comorbidity (low: ∆$477; medium: ∆$480; high: ∆$1059; p = 0.02). Administrative data do not capture patient-level factors that influence postacute care use (preference, caregiver availability). Hospitals achieving shortest length of stay after surgery accrue lower total episode payments without a compensatory increase in postacute care spending, even among patients at oldest age and with greatest comorbidity. See Video Abstract at http://links.lww.com/DCR/B624. ANTECEDENTES:Los modelos de pago prospectivo, han sido un incentivo para reducir la estancia hospitalaria después de la cirugía. Los beneficios de una hospitalización posoperatoria "abreviada" podrían verse afectados por un aumento en los reingresos o en la necesidad de cuidados postoperatorios tempranos luego del periodo agudo, particularmente en los adultos mayores o en aquellos con comorbilidades.OBJETIVO:Determinar si los hospitales que han establecido protocolos de alta posoperatoria "acelerada" generan un ahorro en cada episodio de atención o incurren en mayores gastos después del alta, entre los pacientes estratificados por edad y por comorbilidades.DISEÑO:Estudio transversal retrospectivo.AJUSTE:Revisión a partir de la base de datos nacional del 100% de los archivos del Medicare Provider Analysis and Review desde julio de 2012 hasta junio de 2015.PACIENTES:Se incluye a los beneficiarios de Medicare a quienes se les practicó una colectomía electiva. La cohorte se estratificó por edad (65-69 años, 70-79, ≥80) y por la puntuación de comorbilidad de Elixhauser (baja: ≤0; media: 1-5; y alta: > 5). Los pacientes se categorizaron de acuerdo con la modalidad de la duración de la estancia hospitalaria del hospital, lo que representa lo que se considera es una atención usual para dicho centro.PRINCIPALES MEDIDAS DE RESULTADO:En un modelo multinivel, comparamos la media de los pagos por episodio y los componentes de los mismos, entre las categorías de edad y comorbilidad, estratificados por la modalidad de la duración de la estancia hospitalaria.RESULTADOS:En los 88,860 pacientes, los pagos promedio por episodio fueron menores en los hospitales con una modalidad de estancia más corta frente a los de mayor duración, en todos los estratos de edad y comorbilidad, y fueron similares entre los grupos de edad (65-69: $28,951 vs $30,566, p = 0,014; 70-79: $31,157 vs $32,044, p = 0,073; ≥ 80 $33,779 vs $35,771, p = 0,005), pero mayor entre los pacientes con comorbilidades más altas (baja: $23,107 vs $24,894, p = 0,001; media $30,809 vs $32,282, p = 0,038; alta: $44,097 vs $46,641, p <0,001). Los pagos generados luego del alta hospitalaria fueron similares con relación a la estancia hospitalaria de los diferentes hospitales con respecto a la edad (65-69 años: ∆ $529; 70-79 años: ∆ $291; ≥80 años: ∆ $872, p = 0,25), pero mayores en aquellos con más alta comorbilidad (baja ∆ $477, medio ∆ $480, alto ∆ $1059, p = 0,02).LIMITACIONES:Las bases de datos administrativas no capturan los factores del paciente que influyen en el cuidado luego del estado posoperatorio agudo (preferencia, disponibilidad del proveedor del cuidado).CONCLUSIONES:Los hospitales que logran una estancia hospitalaria más corta después de la cirugía, acumulan pagos más bajos por episodio, sin un incremento compensatorio del gasto en la atención pos-aguda, incluso entre pacientes de mayor edad y con mayor comorbilidad. Consulte Video Resumen en http://links.lww.com/DCR/B624. (Traducción-Dr Eduardo Londoño-Schimmer).


Metastatic melanoma treatment: Combining old and new therapies.
Metastatic melanoma is an aggressive form of cancer characterised by poor prognosis and a complex etiology. Until 2010, the treatment options for metastatic melanoma were very limited. Largely ineffective dacarbazine, temozolamide or fotemustine were the only agents in use for 35 years. In recent years, the development of molecularly targeted inhibitors in parallel with the development of checkpoint inhibition immunotherapies has rapidly improved the outcomes for metastatic melanoma patients. Despite these new therapies showing initial promise; resistance and poor duration of response have limited their effectiveness as monotherapies. Here we provide an overview of the history of melanoma treatment, as well as the current treatments in development. We also discuss the future of melanoma treatment as we go beyond monotherapies to a combinatorial approach. Combining older therapies with the new molecular and immunotherapies will be the most promising way forward for treatment of metastatic melanoma.


The Spencer Op-Site Applicator, a new technique for treating the burned hand.
A technique to apply Op-Site Incise Drape to the burned hand is described using the Spencer Op-Site Applicator. The technique allows for the use of a transparent, flexible, semi-permeable plastic glove in the management of the burned hand in all age-groups. This minimizes excoriation of normal tissue but allows full flexibility of the hand with good healing.


Does the perception of fairness and standard of care in the health system depend on the field of study? Results of an empirical analysis.
The main challenge in the context of health care reforms and priority setting is the establishment and/or maintenance of fairness and standard of care. For the political process and interdisciplinary discussion, the subjective perception of the health care system might even be as important as potential objective criteria. Of special interest are the perceptions of academic disciplines, whose representatives act as decision makers in the health care sector. The aim of this study is to explore and compare the subjective perception of fairness and standard of care in the German health care system among students of medicine, law, economics, philosophy, and religion. Between October 2011 and January 2012, we asked freshmen and advanced students of the fields mentioned above to participate in a paper and pencil survey. Prior to this, we formulated hypotheses. The data were analysed by micro econometric regression techniques. Data from 1,088 students were included in the study. Medical students, freshmen, and advanced students perceive the standard of care significantly as being better than non-medical students. Differences in the perception of fairness are not significant between the freshmen of the academic disciplines; however, they increase with the number of study terms. Besides the field of study, further variables such as gender and health status have a significant impact on perceptions. Our results show that there are differences in the perception of fairness and standard of care between academic disciplines, which might influence the interdisciplinary discussion on health care reforms and priority setting.


Studies of the effects of fragment (25-35) of beta-amyloid peptide on the behavior of rats in a radial maze.
Decreases in cognitive functions, particularly long-term (episodic) and working memory, are among the earliest prognostic signs of Alzheimer's disease. The toxicity of beta-amyloid peptide is regarded as a major cause of neurodegeneration and cognitive impairment in this disease. The present report describes studies of the effects of intracerebroventricular administration of beta-amyloid peptide (25-35) (Abeta(25-35)) on the reproduction of a previously assimilated habit consisting of finding food in an eight-arm radial maze in rats. Abeta(25-35) was given bilaterally at doses of 15 and 30 nmol/animal seven days after preliminary training. Testing was performed 60 days after peptide administration. The results showed that Abeta(25-35) impaired working memory in rats without having any significant effect on the retention of responses. We were unable to demonstrate any relationship between memory impairment and the dose of peptide given. These data provide evidence of the ability of Abeta(25-35) to produce greater degradation of working memory function than long-term memory function.


ZiBuPiYin recipe ameliorates diabetes-associated cognitive decline by improving neuronal mitochondrial function in chronic psychologically stressed zucker diabetic fatty rats.
Zibu Piyin Recipe (ZBPYR) is a traditional Chinese medicine compound composed of 12 kinds of Chinese herbal medicines including red ginseng and yam. Long-term basic and clinical applications have proved that ZBPYR can prevent and treat cognitive dysfunction. Previous studies showed that chronic psychological stress can increase the risk of type 2 diabetes mellitus (T2DM), and lead to cognitive decline. Mitochondrial dysfunction plays a key role in chronic psychological stress-induced diabetes mellitus. While the mechanism of mitochondrial dysfunction and insulin resistance in diabetes-associated cognitive decline (DACD) is unclear. Our previous research found that a ZiBuPiYin recipe (ZBPYR) has significant pharmacological effects against DACD. The present study investigated changes in mitochondrial dysfunction in the brain and the mechanism of insulin resistance and mitochondrial damage to explore the relationship between neuronal mitochondrial dysfunction and insulin resistance in chronic psychologically stressed DACD rats. Zucker diabetic fatty (ZDF) rats with spontaneous T2DM and rats with diabetic cognitive impairment that was induced by chronic psychological stress were used in in vivo experiments. PC12 cells that were damaged by rotenone were used for the in vitro experiment. The findings indicated that the number of mitochondria decreased, morphology and membrane potential were damaged, and reactive oxygen species increased in the cortex and hippocampus in psychologically stressed DACD rats. Protein kinase Cβ2 (PKCβ2) activation and insulin resistance were markedly induced by chronic psychological stress, together with decreases in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial fusion protein 2 (Mfn2). Furthermore, ZBPYR exerted protective effects both in in vivo and in vitro. Mitochondrial damage and insulin resistance were observed in the brain in chronic psychologically stressed DACD rats. The ZBPYR significantly improved brain mitochondrial damage and insulin resistance in chronic psychologically stressed DACD rats. These results provide novel insights for the development of ZBPYR as a traditional Chinese medicine for the treatment of chronic psychological stress and DACD.


Reproductive performance of goats treated with free gonadorelin or nanoconjugated gonadorelin at estrus.
The reproductive performance of goats that received a GnRH analog (gonadorelin) fabricated with or without chitosan-sodium tripolyphosphate (TPP) nanoparticles on the day of estrus (day 0) was evaluated. The chitosan-TPP polymer was conjugated with gonadorelin using an ionic gelation method. Thirty-three multiparous Zaraiebi goats were synchronized for estrus with 2 intramuscular (im) injections of 125 μg prostaglandin F2α 14 d apart. Goats showing signs of estrus were divided equally into 3 experimental groups and received a single im injection of 1 mL physiological saline (placebo; control), 50 μg/mL gonadorelin (GnRH), or 12.5 μg (quarter of GnRH dose)/mL chitosan-TPP-conjugated gonadorelin nanoparticles (NGnRH). Each goat underwent ultrasound imaging of their ovaries at day 0 and at day 10 after mating, and pregnancy was diagnosed 28 and 45 d after mating. The concentrations of estradiol (E2) and progesterone (P4) were determined at day 0 and at days 7, 14, 21, and 42 after mating. NGnRH size, polydispersity, and zeta potential were 93.91 nm, 0.302, and 11.6 mV, respectively. Chitosan-TPP nanoparticles showed 91.2% entrapment efficiency for GnRH. No differences in estrus rate, interval to estrus, or ovarian structure at day 0 were observed among the experimental groups, but the GnRH and NGnRH treatments significantly decreased the duration of estrus compared with the control. At day 10 after mating, both GnRH and NGnRH increased (P = 0.011) the number of corpora lutea compared with the control. Treatment with GnRH increased (P = 0.023) serum E2 concentrations from day 7 to 42 after mating compared with NGnRH and control treatments. The highest (P = 0.043) serum P4 concentration was observed in the GnRH group, followed by the NGnRH and control groups. The increase in serum P4 concentration started earlier a on day 7 in the GnRH group but later on day 14 in the NGnRH group. Compared with the control, GnRH resulted in a higher (P = 0.041) P4-to-E2 ratio, followed by NGnRH. Both gonadorelin treatments significantly increased the twinning rate, the number of embryos at days 28 and 42, and prolificacy and decreased pregnancy losses compared with the control. In conclusion, the administration of GnRH at the time of estrus improved the prolificacy of goats by increasing both the ovulation rate and the number of embryos. In addition, the nanoformulation developed in this study allowed a 75% reduction in the conventional dose of gonadorelin without affecting the fertility and prolificacy of goats, indicating the bioavailability of the reduced GnRH dose after conjugation with developed nanoformula.


A reproducible, clinically relevant, intensively managed, pig model of acute liver failure for testing of therapies aimed to prolong survival.
A clinically relevant, translational large animal model of acute liver failure (ALF) is required for testing of novel therapies to prolong survival in acute liver failure, to permit spontaneous liver recovery or to act as a bridge to transplantation. The aim was to establish a pig model of acetaminophen-induced ALF that mimics the human clinical syndrome, is managed as in a human intensive care unit and has a predictable survival time. Nine female pigs were anaesthetised and instrumented for continuous intensive care monitoring and management using: target-driven protocols for treatment of cardiovascular collapse, metabolic acidosis and electrolyte abnormalities; intermittent positive pressure ventilation; and continuous renal replacement therapy. Six animals were induced to ALF with acetaminophen (paracetamol). Three animals acted as controls. Irreversible acute liver failure, defined as rise in prothrombin time >3 times normal, occurred 19.3 ± 1.8 h after the onset of acetaminophen administration. Death occurred predictably 12.6 ± 2.7 h thereafter, with acute hepatocellular necrosis in all animals. Clinical progression of liver failure mimicked the human condition including development of coagulopathy, intracranial hypertension, hyperammonaemia, cardiovascular collapse, elevation in creatinine, metabolic acidosis and hyperlactataemia. In addition, cardiovascular monitoring clearly demonstrated progressive cardiac dysfunction in ALF. A reproducible, clinically relevant, intensively managed, large animal model of acute liver failure, with death as a result of multi-organ failure, has been successfully validated for translational studies of disease progression and therapies designed to prolong survival in man.


The implication of background anthracosis in the development and progression of pulmonary adenocarcinoma.
In order to characterize the relationship between background anthracosis and pulmonary adenocarcinogenesis, surgically resected tissues of 66 cases of stage I pulmonary adenocarcinoma, 4 cm or less at their greatest dimension, were examined. These cases were diagnosed based on the classification of small-sized adenocarcinoma of the lung (Noguchi et al., Cancer 75, 1995). Thirteen cases were diagnosed as types A (localized bronchioloalveolar adenocarcinoma, LBAC) and B (LBAC with alveolar collapse), 40 cases as type C (LBAC with a focus of fibroblastic proliferation), 8 as type D (poorly differentiated adenocarcinoma) and 5 as types E (bronchial gland type adenocarcinoma) and F (true papillary adenocarcinoma). The 5-year survival rate of types A and B cases was 100%, while those of type C, type D and types E and F were 52%, 48% and 39%, respectively. Nuclear accumulation of abnormal p53 protein in non-replacement type adenocarcinomas (types D, E and F) was detected more frequently than that in replacement type adenocarcinomas (types A, B and C) (P < 0.05). In each case, black dusty material was extracted from tumorous lesions and non-tumorous regions and blotted onto a nitrocellulose membrane. The anthracotic index (AI) was calculated with a densitometer. AIs of non-tumorous regions in early and replacement type adenocarcinomas (types A and B) were significantly less than in relatively advanced (type C) and poorly differentiated (type D) adenocarcinomas (P < 0.05). These results indicated that adenocarcinoma developing in heavily anthracotic lungs readily progresses to an advanced stage, or that adenocarcinoma with a less favorable prognosis tends to develop in severely anthracotic lungs.


Isolation and identification of a pyrrolic glutathione conjugate metabolite of the pyrrolizidine alkaloid monocrotaline.
This report describes the isolation and identification of a monocrotaline-derived, glutathione-conjugated pyrrole obtained from the bile of male Sprague-Dawley rats. Bile obtained from rats given an intravenous bolus of 14C-monocrotaline was fractionated using a series of chromatographic separations. Initial purification with cholestyramine resin removed bile acid and pigment contaminants. Subsequent anion exchange and reversed-phase HPLC separations yielded several fractions that contained the 14C label and tested positive for pyrroles using Ehrlich's reagent. These fractions were analyzed using fast-atom-bombardment tandem mass spectrometry (FAB MS/MS). In addition to glutathione-conjugated dehydroretronecine, at least one other pyrrole present had similar ionic properties. The latter was not present in amounts sufficient for positive identification.


Spinal cord glioblastoma during pregnancy: Case report.
Spinal Cord Glioblastoma Multiforme (SCGBM) is a very rare, debilitating and often fatal tumor. Cases of intracranial GBM during pregnancy have been reported, and as other tumor occurring in this setting, it harbors a great dilemma to attending physicians and families. We report the first case of a SCGBM diagnosed during pregnancy and discuss its management and treatment.


Effect of a standardized fluid management algorithm on acute kidney injury and mortality in pediatric patients on extracorporeal support.
Acute kidney injury (AKI), fluid overload (FO), and mortality are common in pediatric patients supported by extracorporeal membrane oxygenation (ECMO). The aim of this study is to evaluate if using a fluid management algorithm reduced AKI and mortality in children supported by ECMO. We performed a retrospective study of pediatric patients aged birth to 25 years requiring ECMO at a quaternary level children's hospital from 2007 to 2019 In October 2017, a fluid management algorithm was implemented for protocolized fluid removal after deriving a daily fluid goal using a combination of diuretics and ultrafiltration. Daily algorithm compliance was defined as ≥ 12 h on the algorithm each day. The primary and secondary outcomes were AKI and mortality, respectively, and were assessed in the entire cohort and the sub-analysis of children from the era in which the algorithm was implemented. Two hundred and ninety-nine (median age 5.3 months; IQR: 0.2, 62.3; 45% male) children required ECMO (venoarterial in 85%). The fluid algorithm was applied in 74 patients. The overall AKI rate during ECMO was 38% (26% severe-stage 2/3). Both AKI incidence and mortality were significantly lower in patients managed on the algorithm (p = 0.02 and p = 0.05). After adjusting for confounders, utilization of the algorithm was associated with lower odds of AKI (aOR: 0.40, 95%CI: 0.21, 0.76; p = 0.005) but was not associated with a reduction in mortality. In the sub-analysis, algorithm compliance of 80-100% was associated with a 54% reduction in mortality (ref: < 60% compliant; aOR:0.46, 95%CI:0.22-1.00; p = 0.05). Conclusion: Among the entire cohort, the use of a fluid management algorithm reduced the odds of AKI. Better compliance on the algorithm was associated with lower mortality. Multicenter studies that implement systematic fluid removal may represent an opportunity for improving ECMO-related outcomes. What is Known: • Acute kidney injury and fluid overload are associated with morbidity and mortality in children supported by extracorporeal membrane oxygenation. What is New: • A systematic and protocolized approach to fluid removal in children supported by extracorporeal membrane oxygenation reduces acute kidney injury incidence. • Greater adherence to a protocolized fluid removal algorithm is associated with a reduction in mortality.


Comparative biochemical kinase activity analysis identifies rivoceranib as a highly selective VEGFR2 inhibitor.
Vascular endothelial growth factor receptor 2 (VEGFR2), a key regulator of tumor angiogenesis, is highly expressed across numerous tumor types and has been an attractive target for anti-cancer therapy. However, clinical application of available VEGFR2 inhibitors has been challenged by limited efficacy and a wide range of side effects, potentially due to inadequate selectivity for VEGFR2. Thus, development of potent VEGFR2 inhibitors with improved selectivity is needed. Rivoceranib is an orally administered tyrosine kinase inhibitor that potently and selectively targets VEGFR2. A comparative understanding of the potency and selectivity of rivoceranib and approved inhibitors of VEGFR2 is valuable to inform rationale for therapy selection in the clinic. Here, we performed biochemical analyses of the kinase activity of VEGFR2 and of a panel of 270 kinases to compare rivoceranib to 10 FDA-approved kinase inhibitors ("reference inhibitors") with known activity against VEGFR2. Rivoceranib demonstrated potency within the range of the reference inhibitors, with a VEGFR2 kinase inhibition IC50 value of 16 nM. However, analysis of residual kinase activity of the panel of 270 kinases showed that rivoceranib displayed greater selectivity for VEGFR2 compared with the reference inhibitors. Differences in selectivity among compounds within the observed range of potency of VEGFR2 kinase inhibition are clinically relevant, as toxicities associated with available VEGFR2 inhibitors are thought to be partly due to their effects against kinases other than VEGFR2. Together, this comparative biochemical analysis highlights the potential for rivoceranib to address clinical limitations associated with off-target effects of currently available VEGFR2 inhibitors.


The importance of particularising the model to estimate landfill GHG emissions.
Methane generation in landfills can be estimated using mathematical models. One of the most widespread estimation models is that developed by the Intergovernmental Panel on Climate Change (IPCC). Despite its popularity, the simplicity that characterises this model markedly limits the possibility of representing operation alternatives, which can strongly impact surface emissions and hinder the introduction of local data that are sometimes available. In this study, the IPCC model was applied to a case study from which field data on gas emissions were available. To fit the model to the studied landfill conditions, a series of modifications were made, including changes in Degradable Organic Carbon (DOC) and methane generation rate constant (k) values, and degradation times for some waste fractions, and by considering leachate carbon and the inclusion of gas lateral migration phenomena or changes in the methane oxidation factor. The model's Final Version improved the fit of its Initial Version to the experimentally estimated values in the case study by more than 65%. Some modifications, such as considering the carbon dragged by leachate or the contour migration of gas, have a minor impact on the model's fit. However, changes in the degradation time of some fractions according to their particular pretreatment or the modification of parameter k in accordance with the moisture conditions in each landfill phase, strongly influence the model's results. This highlights the importance of particularising estimation models to achieve more accurate results, which allow better estimates of the efficiency of mitigation measures for landfill gas emissions in each facility.


Human Papillomavirus Detection in Oropharyngeal Squamous Cell Carcinoma Using p16 Immunohistochemistry.
Oral cancer ranks third among all cancers in the Indian population with approximately 45% of call cancer cases in India being diagnosed as oral cancer, among which 20%-50% of the cases are observed to be associated with human papillomavirus (HPV) infection. This study aims to detect and evaluate the presence of p16 in oropharyngeal squamous cell carcinoma (OPSCC) patients using immunohistochemistry (IHC). This study was based on samples collected from 21 patients with primary OPSCC who were diagnosed and treated during the period of December 2017-March 2018. Inclusion criteria were complete clinicopathologic data, adequate clinical follow-up, and availability of sufficient paraffin-embedded tumor material. HPV immunoreactivity was further investigated by means of IHC using p16 as a marker. IHC results revealed p16 positivity in six OPSCC cases. There was no statistically significant association of the p16 positivity of HPV with the age, gender, or site. Our results suggest that IHC-based detection of p16 provides a suboptimal prognostic information if not combined with detection of HPV DNA. Although p16 expression and HPV DNA infection are correlated with HPV-associated OPSCCs, neither of the tests alone is the optimal method for HPV status detection.


Dynamics of T2* and deformation in the placenta and myometrium during pre-labour contractions.
Pre-labour uterine contractions, occurring throughout pregnancy, are an important phenomenon involving the placenta in addition to the myometrium. They alter the uterine environment and thus potentially the blood supply to the fetus and may thus provide crucial insights into the processes of labour. Assessment in-vivo is however restricted due to their unpredictability and the inaccessible nature of the utero-placental compartment. While clinical cardiotocography (CTG) only allows global, pressure-based assessment, functional magnetic resonance imaging (MRI) provides an opportunity to study contractile activity and its effects on the placenta and the fetus in-vivo. This study aims to provide both descriptive and quantitative structural and functional MR assessments of pre-labour contractions in the human uterus. A total of 226 MRI scans (18-41 weeks gestation) from ongoing research studies were analysed, focusing on free-breathing dynamic quantitative whole uterus dynamic T2* maps. These provide an indirect measure of tissue properties such as oxygenation. 22 contractile events were noted visually and both descriptive and quantitative analysis of the myometrial and placental changes including volumetric and T2* variations were undertaken. Processing and analysis was successfully performed, qualitative analysis shows distinct and highly dynamic contraction related characteristics including; alterations in the thickness of the low T2* in the placental bed and other myometrial areas, high intensity vessel-like structures in the myometrium, low-intensity vessel structures within the placental parenchyma and close to the chorionic plate. Quantitative evaluation shows a significant negative correlation between T2* in both contractile and not-contractile regions with gestational age (p < 0.05) as well as a significant reduction in T2* during contractions. The T2* values in the myometrium were however not correlated to gestational age (p > 0.5). The quantitative and qualitative description of uterine pre-labour contractions including dynamic changes and key characteristics aims to contribute to the sparsely available in-vivo information and to provide an in-vivo tool to study this important phenomenon. Further work is required to analyse the origins of these subclinical contractions, their effects in high-risk pregnancies and their ability to determine the likelihood of a successful labour. Assessing T2* distribution as a marker for placental oxygenation could thus potentially complement clinically used cardiotocography measurements in the future.