GADEM: a genetic algorithm guided formation of spaced dyads coupled with an EM algorithm for motif discovery.
Genome-wide analyses of protein binding sites generate large amounts of data; a ChIP dataset might contain 10,000 sites. Unbiased motif discovery in such datasets is not generally feasible using current methods that employ probabilistic models. We propose an efficient method, GADEM, which combines spaced dyads and an expectation-maximization (EM) algorithm. Candidate words (four to six nucleotides) for constructing spaced dyads are prioritized by their degree of overrepresentation in the input sequence data. Spaced dyads are converted into starting position weight matrices (PWMs). GADEM then employs a genetic algorithm (GA), with an embedded EM algorithm to improve starting PWMs, to guide the evolution of a population of spaced dyads toward one whose entropy scores are more statistically significant. Spaced dyads whose entropy scores reach a pre-specified significance threshold are declared motifs. GADEM performed comparably with MEME on 500 sets of simulated "ChIP" sequences with embedded known P53 binding sites. The major advantage of GADEM is its computational efficiency on large ChIP datasets compared to competitors. We applied GADEM to six genome-wide ChIP datasets. Approximately, 15 to 30 motifs of various lengths were identified in each dataset. Remarkably, without any prior motif information, the expected known motif (e.g., P53 in P53 data) was identified every time. GADEM discovered motifs of various lengths (6-40 bp) and characteristics in these datasets containing from 0.5 to >13 million nucleotides with run times of 5 to 96 h. GADEM can be viewed as an extension of the well-known MEME algorithm and is an efficient tool for de novo motif discovery in large-scale genome-wide data. The GADEM software is available at (www.niehs.nih.gov/research/resources/software/GADEM/).


Vectors through a cross-sectional image (VCI): A visualization method for four-dimensional motion analysis for cardiac computed tomography.
Cardiac computed tomography (CT) has the potential for fully four-dimensional (4D for 3D plus time) motion analysis of the heart. We aimed at developing a method for assessment and presentation of the 4D motion for multi-phase, contrast-enhanced cardiac CT data sets and demonstrating its clinical applicability. Four patients with normal cardiac function, old myocardial infarction (OMI), takotsubo cardiomyopathy, and hypertrophic cardiomyopathy (HCM) underwent contrast-enhanced cardiac CT for one heartbeat using a 320-row CT scanner with no tube current modulation. CT images for 10 cardiac phases (with a 10%-increment of the R-R interval) were reconstructed with the isotropic effective resolution of (0.5 mm)3 An image-based motion-estimation (iME) algorithm, developed previously, has been used to estimate a time series of 3D cardiac motion, from the end-systole to the other nine phases. The iME uses down-sampled images with a resolution of (1.0 mm)3 deforms the end-systole images non-rigidly to match images at other phases. Once the agreement is maximized, iME outputs a 3D motion vector defined for each voxel for each phase, that smoothly changes over voxels and phases. The proposed visualization method, which is called "vectors through a cross-sectional image (VCI)," presents 3D vectors from the end-diastole to the end-systole as arrows with an end-diastole CT slice. We performed visual assessment of the VCI with calculated the mean vector lengths to evaluate regional left ventricular (LV) contraction. The VCI images showed the magnitude and direction of systolic 3D vectors, including the through-plane motion, and successfully visualized the relations of LV wall segments and abnormal regional wall motion. Decreased regional motion and asymmetric motion due to hypokinetic infarct segment, takotsubo cardiomyopathy, and hyper trophic cardiomyopathy was clearly observed. It was easy to appreciate the relation of the abnormal regional wall motion to the affected LV wall segments. The mean vector lengths of the affected segments with pathologies were clearly smaller than the other unaffected segments (1.2-1.7 mm versus 2.5-4.7 mm). VCI images could capture the magnitude and direction of through-plane motion and show the relations of LV wall segments and abnormal wall motion.


Prevalence, consequences and factors associated with drug use among individuals over 50 years of age in the family perspective.
The aim of this study was to investigate the prevalence, consequences and factors associated with drug use among individuals over 50 years of age, from the perspective of their families, with particularly reference to cocaine use. Cross-sectional study based on secondary data with 624 family members of substance users who sought family support in 14 units of the Recomeço Família Program in São Paulo, Brazil. The participants were predominately men, aged 50 to 59 years (68%); cocaine users (inhaled and/ or smoked); living alone; with a low level of education and were unemployed. They were likely to use family money to pay for their substance use, with a history of theft and aggression against strangers, and were not in treatment. Unlike other participants [≥ 60 years (31.1%)]; who were better educated and retired. In this latter group, 32.8% are alcohol users, 14.8% cocaine users (inhaled and smoked), 32.6% has physically assaulted their family, 39.7% had assaulted someone else and 18.3% had stolen objects or money from home. The population has peculiar characteristics of vulnerability (cocaine use and violence) that remain under investigated; not only do routes into treatment for older adults (≥ 60) but appropriate treatment packages need to be developed too.


Analyzing Digital Evidence From a Telemental Health Platform to Assess Complex Psychological Responses to the COVID-19 Pandemic: Content Analysis of Text Messages.
The novel COVID-19 disease has negatively impacted mortality, economic conditions, and mental health. These impacts are likely to continue after the COVID-19 pandemic ends. There are no methods for characterizing the mental health burden of the COVID-19 pandemic, and differentiating this burden from that of the prepandemic era. Accurate illness detection methods are critical for facilitating pandemic-related treatment and preventing the worsening of symptoms. We aimed to identify major themes and symptom clusters in the SMS text messages that patients send to therapists. We assessed patients who were seeking treatment for pandemic-related distress on Talkspace, which is a popular telemental health platform. We used a machine learning algorithm to identify patients' pandemic-related concerns, based on their SMS text messages in a large, digital mental health service platform (ie, Talkspace). This platform uses natural language processing methods to analyze unstructured therapy transcript data, in parallel with brief clinical assessment methods for analyzing depression and anxiety symptoms. Our results show a significant increase in the incidence of COVID-19-related intake anxiety symptoms (P<.001), but no significant differences in the incidence of intake depression symptoms (P=.79). During our transcript analyses, we identified terms that were related to 24 symptoms outside of those included in the diagnostic criteria for anxiety and depression. Our findings for Talkspace suggest that people who seek treatment during the pandemic experience more severe intake anxiety than they did before the COVID-19 outbreak. It is important to monitor the symptoms that we identified in this study and the symptoms of anxiety and depression, to fully understand the effects of the COVID-19 pandemic on mental health.


Vertical coupling between gap plasmon waveguides.
This work examines vertical coupling between gap plasmon waveguides for use in high confinement power transfer and power splitting applications at 1.55 microm free space wavelength. The supermode interference method is used to obtain key coupler performance parameters such as coupling length, extinction ratio, net coupled output power, radiated power, and reflected power as a function of waveguide center-to-center spacing, core refractive index, and gap width. The initial power distribution among the two coupler supermodes is obtained via the mode matching method for a single input waveguide feed. Excellent agreement with three-dimensional finite difference time domain simulations is observed for the case of square 50 nm gaps with core refractive indices of 2.50 and a center-to-center spacing of 112 nm. Local maxima in the net coupled output power are found to coincide with local minima in the coupling length. An increase in the core refractive index from 1.00 to 2.5 increases the local maximum net coupled output power from 6.4% to 49% but decreases the extinction ratio from 12.7 to 6.94. A sweep of the width of the core from 25 to 100 nm increases the net coupled output power from 43.7% to 52.0%, but increases the coupling length from 1.58 to 3.19 ???m and decreases the extinction ratio from 7.39 to 6.57.


Adenovirus-mediated expression of an elastase-specific inhibitor (elafin): a comparison of different promoters.
This report describes the design and construction of three recombinant adenoviruses of serotype 5 (Ad5) expressing elafin (EL), also called elastase-specific inhibitor. Three promoters were chosen to drive the synthesis of elafin: the small (380 bp) human cytomegalovirus promoter (HCMV), the Ad2 major late promoter (MLP) and the mouse cytomegalovirus (MCMV) promoter. Human alveolar epithelial cells (A549), as well as rat and human primary pulmonary fibroblasts were infected with Ad5-HCMV-EL, Ad5-MLP-EL, Ad5-MCMV-EL and with the control Ad5-dl70/3. The MCMV promoter was the most efficient promoter in all cells studied. MLP was the least efficient promoter Intermediate between MCMV and MLP was HCMV which was able to induce significant amounts of elafin, particularly in human A549 cells. When compared in vivo in rat lungs, results were similar; MCMV was the only promoter which induced significant amounts of elafin as assessed by Northern blot analysis and ELISA, even with a low dose of virus (3 x 10(8) p.f.u.). Our data indicate that the MCMV promoter is the promoter of choice for the strong induction of adenovirus-mediated transgenes in the lung and suggest its suitability both in rodent experimental models and in humans for investigative and therapeutic purposes.


Biosorption of copper (II) from chemical mechanical planarization wastewaters.
Copper Chemical Mechanical Planarization (Cu-CMP) is a critical step in integrated circuit (IC) device manufacturing. CMP and post-CMP cleaning processes are projected to account for 30-40% of the water consumed by IC manufacturers in 2003. CMP wastewater is expected to contain increasing amounts of copper as the industry switches from Al-CMP to Cu-CMP causing some IC manufacturers to run the risk of violating discharge regulations. There are a variety of treatment schemes currently available for the removal of heavy metals from CMP wastewater, however, many introduce additional chemicals to the wastewater, have large space requirements, or are expensive. This work explores the use of microorganisms for waste treatment. A Staphylococcus sp. of bacteria was isolated and studied to determine the feasibility for use in removing copper from Cu-CMP wastewater. A model Cu-CMP wastewater was developed and tested, as well as actual Cu-CMP wastes. Continuous-flow packed column experiments were performed to obtain adsorption data and show copper recovery from the waste. A predictive, empirical model was used to accurately describe Cu removal. Additionally, the immobilized cells were regenerated, allowing for the concentration and potential recovery of copper from the wastewater.


Influence of dietary concentrate to forage ratio on the development of rumen mucosa in calves.
Effects of structural and non-structural carbohydrates on the development of rumen fermentation and ruminal mucosa in calves were examined during the weaning period. Barley/soybean meal (SBM) group was fed a concentrate starting from 2 weeks of age, whereas alfalfa group received a mixture of concentrate and alfalfa hay in which the proportion of the latter was gradually increased from 20% to 70% between weeks 2 and 9 of age. The total volatile fatty acid concentration in rumen fluid of calves increased with age, but at 9 weeks there were no significant differences between the two diets (barley/SBM group 153 mmol/l, alfalfa group 150 mmol/l). Rumen papillae at 9 weeks of age, as compared to 6 weeks of age, were longer and fewer in number per square centimetre mucosa, with larger cut surface. This resulted in a higher surface of papillae per square centimetre mucosa at 9 weeks (barley/SBM group 286 mm2/cm2, alfalfa group 245 mm2/cm2) than at 6 weeks of age (barley/SBM group 217 mm2/cm2, alfalfa group 198 mm2/cm2). At 9 weeks of age, the pH (barley/SBM 5.0, alfalfa 5.7), the acetate to propionate ratio (barley/SBM 2.2, alfalfa 3.2) as well as the length of the papillae in the ventral ruminal sac (barley/SBM 1.96 mm, alfalfa 2.37 mm) were increased in the alfalfa group when compared to the barley/SBM group (P < 0.1). In the former group, the proportion of butyrate revealed significantly increased values at 4 and 6 weeks of age. In animals of the barley/SBM group at 9 weeks of age, characteristic protrusions with proliferated thick epithelium occurred on the papillae and increased the surface for absorption. On the epithelium (Stratum corneum) desquamating cells with parakeratosis could be observed. In the alfalfa group the papillae of the ventral ruminal sac were longer, without protrusions. The morphotypes of the adhering rumen microflora differed between the groups. It can be concluded that feeding greater amounts of non-structural carbohydrates increases the surface for absorption of the rumen epithelium in calves. The absence of hyperkeratosis and rumenitis in the barley/SBM group indicated that there is no reason to limit high starch diets in the early weaning period of calves.


Orthophosphate vs. bicarbonate used as a buffering substance for optimizing the bromide-enhanced ozonation process for ammonia nitrogen removal.
Bromide-enhanced ozonation (BEO) process can be a fast and effective solution for the complete removal of total nitrogen (TN) from wastewaters containing from moderate to high concentrations of ammonia nitrogen (AN). Like the traditional biological process of AN oxidation, even BEO requires the presence of buffering agents, in order to oppose the progressive acidification induced by the reaction. This study compares the effect of two buffering substances (namely bicarbonate and mixtures of orthophosphates) in hindering the acidification caused by AN oxidation and, consequently, optimizing the overall efficiency of the process. Tests were carried out with on-purpose made solutions containing concentrations of AN of 5-10 mM. The range of [Br-]/[O3] ratio values was from 12 to 18, so as to make ozone the limiting factor in HOBr generation. The results of this study proved that, in the absence of natural buffering agents, mixtures of orthophosphates must be preferred to the more traditionally employed bicarbonate to control the pH evolution of BEO process. In fact, orthophosphates proved to be capable to guarantee an initial pH of the wastewater in the order of 7.5, thus making the zero-order AN removal rates 15% faster than those observed in the presence of bicarbonate. Furthermore, in the presence of mixtures of orthophosphates, the generation of ozonation byproducts in the oxidized form (nitrate, bromate) was reduced by over 70%. Finally, the fine control of pH obtained with orthophosphates in the BEO of AN makes that process an attractive solution for the treatment of effluents containing AN, thus preventing the discharge of residual nitrogen into aquatic environments and avoiding eutrophication of receiving water bodies.


MicroRNA-sensitive oncolytic measles viruses for cancer-specific vector tropism.
Oncolytic measles viruses (MV) derived from the live attenuated vaccine strain have been engineered for increased tumor-cell specificity, and are currently under investigation in clinical trials including a phase I study for glioblastoma multiforme (GBM). Recent preclinical studies have shown that the cellular tropism of several viruses can be controlled by inserting microRNA-target sequences into their genomes, thereby inhibiting spread in tissues expressing cognate microRNAs. Since neuron-specific microRNA-7 is downregulated in gliomas but highly expressed in normal brain tissue, we engineered a microRNA-sensitive virus containing target sites for microRNA-7 in the 3'-untranslated region of the viral fusion gene. In presence of microRNA-7 this modification inhibits translation of envelope proteins, restricts viral spread, and progeny production. Even though highly attenuated in presence of microRNA-7, this virus retained full efficacy against glioblastoma xenografts. Furthermore, microRNA-mediated inhibition protected genetically modified mice susceptible to MV infection from a potentially lethal intracerebral challenge. Importantly, endogenous microRNA-7 expression in primary human brain resections tightly restricted replication and spread of microRNA-sensitive virus. This is proof-of-concept that tropism restriction by tissue-specific microRNAs can be adapted to oncolytic MV to regulate viral replication and gene expression to maximize tumor specificity without compromising oncolytic efficacy.


Foundation and methodologies in computer-aided diagnosis systems for breast cancer detection.
Breast cancer is the most prevalent cancer that affects women all over the world. Early detection and treatment of breast cancer could decline the mortality rate. Some issues such as technical reasons, which related to imaging quality and human error, increase misdiagnosis of breast cancer by radiologists. Computer-aided detection systems (CADs) are developed to overcome these restrictions and have been studied in many imaging modalities for breast cancer detection in recent years. The CAD systems improve radiologists' performance in finding and discriminating between the normal and abnormal tissues. These procedures are performed only as a double reader but the absolute decisions are still made by the radiologist. In this study, the recent CAD systems for breast cancer detection on different modalities such as mammography, ultrasound, MRI, and biopsy histopathological images are introduced. The foundation of CAD systems generally consist of four stages: Pre-processing, Segmentation, Feature extraction, and Classification. The approaches which applied to design different stages of CAD system are summarised. Advantages and disadvantages of different segmentation, feature extraction and classification techniques are listed. In addition, the impact of imbalanced datasets in classification outcomes and appropriate methods to solve these issues are discussed. As well as, performance evaluation metrics for various stages of breast cancer detection CAD systems are reviewed.


Isolation and Immunocharacterization of Lactobacillus salivarius from the Intestine of Wakame-Fed Pigs to Develop Novel "Immunosynbiotics".
Emerging threats of antimicrobial resistance necessitate the exploration of effective alternatives for healthy livestock growth strategies. 'Immunosynbiotics', a combination of immunoregulatory probiotics and prebiotics with synergistic effects when used together in feed, would be one of the most promising candidates. Lactobacilli are normal residents of the gastrointestinal tract of pigs, and many of them are able to exert beneficial immunoregulatory properties. On the other hand, wakame (Undaria pinnafida), an edible seaweed, has the potential to be used as an immunoregulatory prebiotic when added to livestock feed. Therefore, in order to develop a novel immunosynbiotic, we isolated and characterized immunoregulatory lactobacilli with the ability to utilize wakame. Following a month-long in vivo wakame feeding trial in 8-week-old Landrace pigs (n = 6), sections of intestinal mucous membrane were processed for bacteriological culture and followed by identification of pure colonies by 16S rRNA sequence. Each isolate was characterized in vitro in terms of their ability to assimilate to the wakame and to differentially modulate the expression of interleukin-6 (IL-6) and interferon beta (IFN-β) in the porcine intestinal epithelial (PIE) cells triggered by Toll-like receptor (TLR)-4 and TLR-3 activation, respectively. We demonstrated that feeding wakame to pigs significantly increased the lactobacilli population in the small intestine. We established a wakame-component adjusted culture media that allowed the isolation and characterization of a total of 128 Lactobacilli salivarius colonies from the gut of wakame-fed pigs. Interestingly, several L. salivarius isolates showed both high wakame assimilation ability and immunomodulatory capacities. Among the wakame assimilating isolates, L. salivarius FFIG71 showed a significantly higher capacity to upregulate the IL-6 expression, and L. salivarius FFIG131 showed significantly higher capacity to upregulate the IFN-β expression; these could be used as immunobiotic strains in combination with wakame for the development of novel immunologically active feeds for pigs.


Detection of radiotherapy-related damage in head and neck cancer patients by evaluating volumetric changes in lacrimal gland, nasolacrimal duct and computed tomography attenuation changes in lens.
In our study, we aimed to evaluate the change in attenuation of lens in CT images, volumetric changes, in lacrimal gland (LG) and nasolacrimal duct (NLD) of the patients receiving radiotherapy for brain or head & neck tumor. Additionally, the correlation between these changes and radiation dose data were investigated. Patient simulation CT images and control CT images were used to evaluate the volume and attenuation changes. Pre- and post-treatment MR and CT images were used to evaluate radiation-induced volumetric alterations in NLD and LG, respectively. Radiation therapy was given to a total dose of 54-70 Gy with conventional fractionated scheme using intensity-modulated radiotherapy technique (IMRT). Dose volume parameters were evaluated via dose volume histograms (DVHs). Dose volume parameters, volume and densities of 59 lenses (L), 60 LG and 60 NLD of 30 patients were retrospectively assessed. The median LG volume was significantly lower in the post-treatment images (p < 0.001), whereas the median volumes of NLD in pre- and post-RT images were similar. The Hounsfield unit (HU) numbers of lenses were significantly lower on post-RT CT images (p < 0.001). No statistically significant correlation was found between dose parameters and volume or HU changes (p = 0.054-0.817). It was observed that the attenuation of lenses and lacrimal gland volume significantly lowers following radiation. However, these alterations were not found to be correlated with dose.


Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease.
DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstream of IRGM was recently shown to be in strong linkage disequilibrium (LD) with the CD-associated single nucleotide polymorphisms and is itself associated with CD (P < 0.01). The deletion was correlated with increased or reduced expression of IRGM in transformed cells in a cell line-dependent manner, and has been proposed as a likely causal variant. We report here that small insertion/deletion polymorphisms in the promoter and 5' untranslated region of IRGM are, together with the CNV, strongly associated with CD (P = 1.37 x 10(-5) to 1.40 x 10(-9)), and that the CNV and the 5'-untranslated region variant -308(GTTT)(5) contribute independently to CD susceptibility (P = 2.6 x 10(-7) and P = 2 x 10(-5), respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 10(-12)) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case-control sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires gene-gene or gene-environment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the European-Asian split.


Angiopoietin-2 in white adipose tissue improves metabolic homeostasis through enhanced angiogenesis.
Despite many angiogenic factors playing crucial roles in metabolic homeostasis, effects of angiopoietin-2 (ANG-2) in adipose tissue (AT) remain unclear. Utilizing a doxycycline-inducible AT-specific ANG-2 overexpression mouse model, we assessed the effects of ANG-2 in AT expansion upon a high-fat diet (HFD) challenge. ANG-2 is significantly induced, with subcutaneous white AT (sWAT) displaying the highest ANG-2 expression. ANG-2 overexpressing mice show increased sWAT vascularization and are resistant to HFD-induced obesity. In addition, improved glucose and lipid metabolism are observed. Mechanistically, the sWAT displays a healthier expansion pattern with increased anti-inflammatory macrophage infiltration. Conversely, ANG-2 neutralization in HFD-challenged wild-type mice shows reduced vascularization in sWAT, associated with impaired glucose tolerance and lipid clearance. Blocking ANG-2 causes significant pro-inflammatory and pro-fibrotic changes, hallmarks of an unhealthy AT expansion. In contrast to other pro-angiogenic factors, such as vascular endothelial growth factor-A (VEGF-A), this is achieved without any enhanced beiging of white AT.


Molecular and cellular mechanisms of anthracycline cardiotoxicity.
The molecular and cellular mechanisms that cause cumulative dose-dependent anthracycline-cardiotoxicity remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes inA vitro have demonstrated several forms of cellular injury. Cell death in response to anthracyclines can be observed by one of several mechanisms including apoptosis and necrosis. Cell death by apoptosis can be inhibited by dexrazoxane, the iron chelator that is known to prevent clinical development of heart failure at high cumulative anthracycline exposure. Together with clinical evidence for myocyte death after anthracycline exposure, in the form of elevations in serum troponin, make myocyte cell death a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular \'sarcopenia\' characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. Titin is an entropic spring element in the sarcomere that regulates length-dependent calcium sensitivity. Thus titin degradation may lead to impaired diastolic as well as systolic dysfunction, as well as potentiate the effect of suppression of transcription of sarcomere proteins. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. Studies of erbB2 function in viro suggest that signaling through erbB2 by the growth factor neuregulin may regulate cardiac myocyte sarcomere turnover, as well as myocyte-myocyte/myocyte-matrix force coupling. A combination of further in vitro studies, with more careful monitoring of cardiac function after exposure to these cancer therapies, may help to understand to what extent these mechanisms are at work during clinical exposure of the heart to these important pharmaceuticals.


Identification of distant Agouti-like sequences and re-evaluation of the evolutionary history of the Agouti-related peptide (AgRP).
The Agouti-like peptides including AgRP, ASIP and the teleost-specific A2 (ASIP2 and AgRP2) peptides have potent and diverse functional roles in feeding, pigmentation and background adaptation mechanisms. There are contradictory theories about the evolution of the Agouti-like peptide family as well the nomenclature. Here we performed comprehensive mining and annotation of vertebrate Agouti-like sequences. We identified A2 sequences from salmon, trout, seabass, cod, cichlid, tilapia, gilt-headed sea bream, Antarctic toothfish, rainbow smelt, common carp, channel catfish and interestingly also in lobe-finned fish. Moreover, we surprisingly found eight novel homologues from the kingdom of arthropods and three from fungi, some sharing the characteristic C-x(6)-C-C motif which are present in the Agouti-like sequences, as well as approximate sequence length (130 amino acids), positioning of the motif sequence and sharing of exon-intron structures that are similar to the other Agouti-like peptides providing further support for the common origin of these sequences. Phylogenetic analysis shows that the AgRP sequences cluster basally in the tree, suggesting that these sequences split from a cluster containing both the ASIP and the A2 sequences. We also used a novel approach to determine the statistical evidence for synteny, a sinusoidal Hough transform pattern recognition technique. Our analysis shows that the teleost AgRP2 resides in a chromosomal region that has synteny with Hsa 8, but we found no convincing synteny between the regions that A2, AgRP and ASIP reside in, which would support that the Agouti-like peptides were formed by whole genome tetraplodization events. Here we suggest that the Agouti-like peptide genes were formed through classical subsequent gene duplications where the AgRP is the most distantly related to the three other members of that group, first splitting from a common ancestor to ASIP and A2, and then later the A2 split from ASIP followed by a split resulting in ASIP2 and AgRP2.


New method for fMRI investigations of language: defining ROIs functionally in individual subjects.
Previous neuroimaging research has identified a number of brain regions sensitive to different aspects of linguistic processing, but precise functional characterization of these regions has proven challenging. We hypothesize that clearer functional specificity may emerge if candidate language-sensitive regions are identified functionally within each subject individually, a method that has revealed striking functional specificity in visual cortex but that has rarely been applied to neuroimaging studies of language. This method enables pooling of data from corresponding functional regions across subjects rather than from corresponding locations in stereotaxic space (which may differ functionally because of the anatomical variability across subjects). However, it is far from obvious a priori that this method will work as it requires that multiple stringent conditions be met. Specifically, candidate language-sensitive brain regions must be identifiable functionally within individual subjects in a short scan, must be replicable within subjects and have clear correspondence across subjects, and must manifest key signatures of language processing (e.g., a higher response to sentences than nonword strings, whether visual or auditory). We show here that this method does indeed work: we identify 13 candidate language-sensitive regions that meet these criteria, each present in >or=80% of subjects individually. The selectivity of these regions is stronger using our method than when standard group analyses are conducted on the same data, suggesting that the future application of this method may reveal clearer functional specificity than has been evident in prior neuroimaging research on language.


Effects of Low-Dose Ketamine Infusion on Alleviating the Opioid Burden for Patients Undergoing Myomectomy Surgery.
Recent research has focused on the use of N-methyl-D-aspartate (NMDA) receptor antagonists for pain management. Several drugs are known to have this action, including ketamine, which exerts its main analgesic effect through NMDA receptor antagonism. This study aimed to evaluate the effect of low-dose ketamine infusion on opioid exposure for patients undergoing myomectomy surgery under general anaesthesia. A total of 70 women were included in this prospective double-blind trial study. The patients included in this study were American Society of Anaesthesiologists physical status I-II, aged between 18 and 50 years and scheduled for laparotomy myomectomy surgery. Patients were randomised to receive either a bolus of 0.2 mg kg-1 of ketamine followed by a continuous infusion of 0.2 mg kg-1 hr-1 during the operation or a placebo of normal saline. Both groups also received morphine as needed for pain relief. The primary outcome was the total amount of morphine used during the intraoperative and postoperative periods. Intraoperative and postoperative mean blood pressure, heart rate and postoperative visual analogue scale for pain were assessed. Total mean morphine consumption was significantly lower in the ketamine group than in the control group (26±3.5 mg vs. 34.7±3.3 mg, respectively, p<0.05). However, there were no statistical differences between the groups regarding haemodynamics, postoperative pain score and complications. The use of ketamine in low infusion doses intraoperatively during an elective myomectomy procedure produced an opioid-sparing effect by reducing perioperative morphine consumption without significant side effects.


An updated cost-effectiveness analysis of axicabtagene ciloleucel in second-line large B-cell lymphoma patients in the United States.
Aims: This economic evaluation of axicabtagene ciloleucel (axi-cel) versus previous standard of care (SOC; salvage chemotherapy followed by high-dose therapy with autologous stem cell rescue) in the second line (2L) large B-cell lymphoma population is an update of previous economic models that contained immature survival data.Methods: This analysis is based on primary overall survival (OS) ZUMA-7 clinical trial data (median follow-up of 47.2 months), from a United States (US) payer perspective, with a model time horizon of 50 years. Mixture cure models were used to extrapolate updated survival data; subsequent treatment data and costs were updated. Patients who remained in the event-free survival state by 5 years were assumed to have achieved long-term remission and not require subsequent treatment.Results: Substantial survival and quality of life benefits were observed despite 57% of patients in the SOC arm receiving subsequent cellular therapy: median model-projected (ZUMA-7 trial Kaplan-Meier estimated) OS was 78 months (median not reached) for axi-cel versus 25 months (31 months) for SOC, resulting in incremental quality-adjusted life year (QALY) difference of 1.63 in favor of axi-cel. Incrementally higher subsequent treatment costs were observed in the SOC arm due to substantial crossover to cellular therapies, thus, when considering the generally accepted willingness to pay threshold of $150,000 per QALY in the US, axi-cel was cost-effective with an incremental cost-effectiveness ratio of $98,040 per QALY.Conclusions: Results remained consistent across a wide range of sensitivity and scenario analysis, including a crossover adjusted analysis, suggesting that the mature OS data has significantly reduced the uncertainty of axi-cel's cost-effectiveness in the 2L setting in the US. Deferring treatment with CAR T therapies after attempting a path to transplant may result in excess mortality, lower quality of life and would be an inefficient use of resources relative to 2L axi-cel.


[Insulin therapy at the hospital setting].
Hyperglycemia is defined in different studies as a poor prognostic factor relating with higher risk for post-surgical infections, neurological complications, increased hospital staying, and admission to intensive care units. Appropriate use of insulin therapy is one of the key factors assuring the best management of hospitalized patients. The aim of this review was to discuss the most important aspects of insulin use at the hospital setting. We analyzed the different types of insulin commercially available and the factors determining their efficacy, as well as the different regimens and administration routes available at the hospital according to the type of patient and the type of feeding or exogenous intake of carbohydrates. The fear of inducing hypoglycemic episodes at the hospital contributes to an inappropriate prescription of the programmed insulin doses, the use of flexible rapid insulin doses in monotherapy, and setting excessively high glycemia levels. Currently, individualized management of hospital hyperglycemias should replace obsolete insulin regimens in order to reach more stringent glycemia goals and decreasing the number of complications in the hospitalized patient.


Dissociation of solid tumor tissues with cold active protease for single-cell RNA-seq minimizes conserved collagenase-associated stress responses.
Single-cell RNA sequencing (scRNA-seq) is a powerful tool for studying complex biological systems, such as tumor heterogeneity and tissue microenvironments. However, the sources of technical and biological variation in primary solid tumor tissues and patient-derived mouse xenografts for scRNA-seq are not well understood. We use low temperature (6 °C) protease and collagenase (37 °C) to identify the transcriptional signatures associated with tissue dissociation across a diverse scRNA-seq dataset comprising 155,165 cells from patient cancer tissues, patient-derived breast cancer xenografts, and cancer cell lines. We observe substantial variation in standard quality control metrics of cell viability across conditions and tissues. From the contrast between tissue protease dissociation at 37 °C or 6 °C, we observe that collagenase digestion results in a stress response. We derive a core gene set of 512 heat shock and stress response genes, including FOS and JUN, induced by collagenase (37 °C), which are minimized by dissociation with a cold active protease (6 °C). While induction of these genes was highly conserved across all cell types, cell type-specific responses to collagenase digestion were observed in patient tissues. The method and conditions of tumor dissociation influence cell yield and transcriptome state and are both tissue- and cell-type dependent. Interpretation of stress pathway expression differences in cancer single-cell studies, including components of surface immune recognition such as MHC class I, may be especially confounded. We define a core set of 512 genes that can assist with the identification of such effects in dissociated scRNA-seq experiments.


Cannabidiol in inflammatory bowel diseases: a brief overview.
This minireview highlights the importance of cannabidiol (CBD) as a promising drug for the therapy of inflammatory bowel diseases (IBD). Actual pharmacological treatments for IBD should be enlarged toward the search for low-toxicityand low-cost drugs that may be given alone or in combination with the conventional anti-IBD drugs to increase their efficacy in the therapy of relapsing forms of colitis. In the past, Cannabis preparations have been considered new promising pharmacological tools in view of their anti-inflammatory role in IBD as well as other gut disturbances. However, their use in the clinical therapy has been strongly limited by their psychotropic effects. CBD is a very promising compound since it shares the typical cannabinoid beneficial effects on gut lacking any psychotropic effects. For years, its activity has been enigmatic for gastroenterologists and pharmacologists, but now it is evident that this compound may interact at extra-cannabinoid system receptor sites, such as peroxisome proliferator-activated receptor-gamma. This strategic interaction makes CBD as a potential candidate for the development of a new class of anti-IBD drugs.


Evaluating Indices for Non-invasive Myocardial Recovery Assessment in LVAD-Supported Heart Failure Patients.
Accurate assessment of myocardial recovery (MR) under left ventricular assist device (LVAD) support is essential for clinicians to manage heart failure patients. However, current techniques for assessing MR are time-consuming, invasive, and infrequent. Measuring MR using indices derived from LVAD operating data instead provides a potential real-time alternative. Several of these indices for assessing the MR of LVAD-supported heart failure patients were collated from the literature and subject to a comprehensive comparative analysis. The objective of this analysis was to determine the most accurate index for assessing systolic cardiac function under LVAD-support, characterized by maximal end-systolic elastance (Emax), while remaining insensitive to preload & afterload. The indices were compared in computational simulation, utilizing an LVAD + cardiovascular system model to sweep through a large array of Emax and resistance conditions. Results demonstrated the index that correlated best with Emax, showing the highest accuracy, was the ratio between maximum flow acceleration and flow pulsatility (average R2 =0.9790). The same index also exhibited the lowest % variation (sensitivity) to preload & afterload (1.32% & 13.53% respectively). However, opportunities for improvement remain among current recovery assessment indices, with this study providing a baseline of performance for potential future indices to improve upon.Clinical relevance- This study presents a potential real-time measure of native cardiac function in LVAD-supported heart failure patients to support patient management and further recovery.


[Group education for asthmatic children: our experience].
Asthma is a chronic disease of great prevalence among children and with complex treatment. Health education is considered a very important therapeutic tool, but it has been poorly assessed in our environment. The main objectives of this work were to assess the utility of the education in groups of asthmatic children and parents in order to improve the knowledge about the disease, to raise the profile of the self-management concept and to improve the clinical evolution. Sixty-one asthmatic children and their parents were distributed into groups according to the age of the patients (less than 2 years, between 2 and 5 years and more than 5 years) and each group attended 6 theoretical and practical sessions on asthma. Theoretical knowledge about the disease and its management was evaluated by using questionnaires before and after the sessions. The clinical evolution of the children was assessed for a period of two years, from the year before the training started until 1 year after it ended. Theoretical knowledge about the disease clearly improved both in children (p = 0.2) and their tutors (p < 0.00001). The yearly number of crises and hospitalizations were not reduced by the training; however, the number of visits to the outpatient clinic significantly decreased (p < 0.001). Patients started using the flow-meter (p < 0.001) and started proper treatment (p < 0.00001) more frequently after attending the group session. Group health education for asthmatic children improves both the knowledge and the self-management of the disease by the patients and their parents, but does not modify the clinical evolution.


The induction of lamellar stacking by cholesterol in lecithin-bile salt model systems and human bile studied by synchrotron X-radiation.
Small angle X-ray scattering (SAXS) with synchroton radiation was used to investigate interactions among lipid particles in lecithin-bile salt model systems and in native gallbladder biles. In model systems in the absence of cholesterol, isotropic, continuous spectra were found, indicating the absence of periodic structures. In the presence of excess cholesterol, interaction in the form of lamellar stacking was detected by the appearance of discrete diffraction peaks. In the supersaturated cholesterol region of the commonly accepted phase diagram [1], where cholesterol crystals were expected, we found lamellar stacking. The high proportion of cholesterol to bile salts seems to be the common denominator of these models. The lamellar stacking was also found in native unprocessed bile. This effect of cholesterol on lipid structure has not been previously described. Lamellar stacking may contribute to cholesterol solubilization. Its influence on the kinetics of cholesterol crystallization is presently unknown.


An exploration of the current use and benefit of nursing student portfolios.
This study aims to identify the structure and of student portfolios and to ascertain their views on their usefulness. Portfolios are in common use in undergraduate nursing programmes although there are considerable variations in approaches. As a result a wide variety exists in the quality of work presented and students are often unclear as to constituent contents. This latter, while a reflection of the current status and development of portfolio use within the discipline is a source of dissatisfaction for students, and warrants further investigation. This project aimed to quantitatively capture student views using an on line survey approach utilizing a previously validated questionnaire (McMullen, 2006) [McMullen, M. 2006. Students' perceptions on the use of portfolios in pre-registration nursing education: A questionnaire survey. International Journal of Nursing Studies 43 (3), 333-343]. A survey tool is used to examine the structure, process and content of portfolios (n=481) in current use in one school. The study provides an evidence base for hitherto anecdotal comments and provides useful information for future development. While students see potential value in the portfolio use there are several areas of dissatisfaction including lack of clear guidelines. As an evolving structure within universities and practice there is much room for process improvement.


COVID-19 Outcomes in Inflammatory Bowel Disease Hospitalized Patients: A Comprehensive Analysis Using the National Inpatient Sample.
There is no uniformity in the available literature concerning the effects of coronavirus disease 2019 (COVID-19) viral illness on people with inflammatory bowel disease (IBD). We conducted an analysis using the 2020 National Inpatient Sample (NIS) database to compare the outcomes of COVID-19 hospitalized patients with and without IBD. Of 1,050,040 patients admitted with COVID-19, 5,750 (0.5%) also had IBD. The group with COVID-19 and IBD had higher percentages of females and White individuals and a greater prevalence of chronic lung disease, peripheral vascular disease, and liver disease. However, after accounting for confounding variables, there was no significant difference in mortality rates, length of hospital stays, or hospitalization costs between the two groups. According to our findings, the presence of IBD does not appear to elevate the risk of COVID-19 complications.


Coagulopathy associated with dilatation and evacuation for intrauterine fetal death.
Dilatation and evacuation was reported recently to be a safe and effective method for the treatment of intrauterine fetal death. The current authors have treated ten cases of intrauterine fetal death with dilatation and evacuation. Five patients (50%) developed coagulopathy, one of whom also developed endometritis. Patients who developed coagulopathy were significantly older than those who did not. Previous pregnancy also was associated with the development of coagulopathy. Five of six multigravidas developed coagulopathy, whereas none of the four primigravidas developed this complication. Other factors that may have contributed to the development of coagulopathy are discussed. The authors conclude that dilatation and evacuation for midtrimester intrauterine fetal death may not be as safe as has been reported.


Classification and staging of dementia of the Alzheimer type: a comparison between neural networks and linear discriminant analysis.
To examine the utility of artificial neural networks (ANNs) for differentiating patients with Alzheimer disease from healthy control subjects and for staging the degree of dementia. Comparison of the classification abilities of ANNs with the statistical technique of linear discriminant analysis (LDA) using the results of 11 neuropsychological tests as predictors. Ninety-two patients with a diagnosis of probable Alzheimer disease (referred from a geriatric clinic) and 43 elderly control subjects (independently solicited). The patients met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable dementia, with clinical ratings of dementia severity derived from the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX). Classifications between and within groups were determined by using LDA and ANNs, and more detailed comparisons of the 2 methods were performed by using chi2 analyses and unweighted and weighted kappa statistics. Linear discriminant analysis correctly identified 71.9% of cases. Artificial neural networks, trained to classify the subjects using the same data, correctly classified 91.1% of the cases. Subsidiary analyses showed that although both techniques effectively discriminated between the control subjects and patients with dementia, the ANNs were more powerful in discriminating severity levels within the dementia population. The analyses for goodness of fit revealed that the ANN classification produced a better fit to the actual data. A comparison of the weighted proportion of agreement between the criterion and predictor variables also showed that the ANNs clearly outperformed LDA in classification accuracy for the full data set and patients-only data set. The results demonstrate the utility of ANNs for group classification of patients with Alzheimer disease and elderly controls and for staging dementia severity using neuropsychological data.


Challenges of asthma management for school nurses in districts with high asthma hospitalization rates.
School nurses play a central role in assisting elementary school children in managing their asthma, especially those in higher-risk school districts that are at increased risk of uncontrolled asthma. Study purposes are to (1) identify barriers to asthma management by school nurses in higher-risk school districts; and (2) assess the extent to which National Asthma Education and Prevention Program (NAEPP) recommendations are followed in these districts. School districts containing at least one zipcode with high asthma hospitalization rates among children (0-14 years) in a New York State county were identified. Nurses in 44 elementary schools were surveyed about asthma management during 2008. Both quantitative and qualitative data were collected. Study nurses learned of children with asthma mainly through school records and when students presented with symptoms rather than through parents. The major obstacles to asthma management were communication with parents and parental support. Reluctance of some physicians to diagnose asthma in these children presented a barrier and contributed to the nurses' ability to gain parental cooperation. Adherence to the NAEPP school recommendations was inconsistent. Improvement in the communication among parents, school nurses, and providers is critical to the improvement of asthma management for children in high-risk school districts.


Management of leishmanial osteolytic lesions in a hypothyroid dog by partial tarsal arthrodesis.
A five-year-old male boxer, previously diagnosed with leishmaniasis and hypothyroidism, had gradually become unable to bear weight on its left hindlimb. Physical examination revealed a left popliteal lymphadenopathy, mild crepitus, and severe swelling of the left tarsal joint, a radiographic examination of which revealed severe bone destruction of the talus and a periosteal reaction of the calcaneus. Laboratory findings and serological tests suggested an active leishmanial infection, and a Leishmania species was identified by direct cytology of a sample from the osteolytic area and by indirect immunohistochemistry of a bone biopsy. The dog's condition improved when it was treated with meglumine antimonate and allopurinol. Because of the large osteolytic area and the increased use of the affected leg, a partial tarsal arthrodesis was performed to prevent a fracture. Five months after the surgery, the osteolytic area had healed completely and the calcaneus periosteal reaction had disappeared.


Growth hormone effects on hepatic glutamate handling in vivo.
Growth hormone administration affects growth in hypophysectomized animals by depressing urea synthesis and redistributing nitrogen into protein. Because the liver is the site of ureagenesis and glutamine is the major interorgan nitrogen vehicle, we studied hepatic glutamine uptake in relation to urea release in hypophysectomized and growth hormone-supplemented, 100 micrograms/100 g body wt hypophysectomized rats. In vivo hepatic balances for glutamine, glutamate, alanine, and urea were performed on anesthetized animals by simultaneous measurement of flow through the liver and the respective arteriovenous and portovenous concentration differences. On the whole animal level, growth hormone-administered hypophysectomized rats exhibited restored growth and decreased urea excretion associated with a reduction in arterial urea and elevation in arterial glutamate, but glutamine and alanine concentrations were unchanged. On the organ level, growth hormone treatment reduced hepatic urea release from 3,145 +/- 432 to 1,954 +/- 320 nmol.min-1.100 g-1. However, neither glutamine uptake, 342 +/- 110 and 494 +/- 135 nmol.min-1.100 g-1 nor alanine uptake, 522 +/- 120 vs. 363 +/- 109 nmol.min-1.100 g-1 were altered by growth hormone treatment. In marked contrast, net glutamate uptake by the hypophysectomized rat liver, 71 +/- 15 nmol.min-1.100 g-1, was reversed by growth hormone administration to a striking net release rate of 960 +/- 229 nmol.min-1.100 g-1, suggesting that glutamine nitrogen is spared incorporation into urea by shunting into glutamate and release into the blood.


Strategies to distinguish new synthetic cannabinoid FUBIMINA (BIM-2201) intake from its isomer THJ-2201: metabolism of FUBIMINA in human hepatocytes.
Since 2013, a new drugs-of-abuse trend attempts to bypass drug legislation by marketing isomers of scheduled synthetic cannabinoids (SCs), e.g., FUBIMINA (BIM-2201) and THJ-2201. It is much more challenging to confirm a specific isomer's intake and distinguish it from its structural analog because the isomers and their major metabolites usually have identical molecular weights and display the same product ions. Here, we investigated isomers FUBIMINA and THJ-2201 and propose strategies to distinguish their consumption. THJ-2201 was scheduled in the US, Japan, and Europe; however, FUBIMINA is easily available on the Internet. We previously investigated THJ-2201 metabolism in human hepatocytes, but human FUBIMINA metabolism is unknown. We aim to characterize FUBIMINA metabolism in human hepatocytes, recommend optimal metabolites to confirm its consumption, and propose strategies to distinguish between intakes of FUBIMINA and THJ-2201. FUBIMINA (10 μM) was incubated in human hepatocytes for 3 h, and metabolites were characterized with high-resolution mass spectrometry (HR-MS). We identified 35 metabolites generated by oxidative defluorination, further carboxylation, hydroxylation, dihydrodiol formation, glucuronidation, and their combinations. We recommend 5'-OH-BIM-018 (M34), BIM-018 pentanoic acid (M33), and BIM-018 pentanoic acid dihydrodiol (M7) as FUBIMINA specific metabolites. THJ-2201 produced specific metabolite markers 5'-OH-THJ-018 (F26), THJ-018 pentanoic acid (F25), and hydroxylated THJ-2201 (F13). Optimized chromatographic conditions to achieve different retention times and careful selection of specific product ion spectra enabled differentiation of isomeric metabolites, in this case FUBIMINA from THJ-2201. Our HR-MS approach should be applicable for differentiating future isomeric SCs, which is especially important when different isomers have different legal status.


Diet and eczema: a review of dietary supplements for the treatment of atopic dermatitis.
In the context of increasing popularity of "natural" alternatives to conventional medicine, several dietary supplements have gained the attention of researchers and consumers alike in the treatment of atopic dermatitis (AD). Readily available without a prescription and frequently perceived to have fewer side effects than traditional medications, these "natural" remedies may be featured in discussions with patients, and clinicians should therefore be familiar with their efficacy and safety. Based on trials to date, no dietary supplements can be recommended for routine use in the treatment of AD. However, some promising results have been noted from the use of probiotics and prebiotics taken in combination. Given significant differences in study design to date, however, further studies would be needed to clarify dose and strains of probiotics. Studies of vitamin D have been limited and have produced conflicting results, although further trials in selected subsets of patients may be indicated. Very limited data is available on fish oil supplements, while future studies on Chinese herbal medicine would require evaluation of comparable herbs and formulations. Finally, multiple trials of evening primrose oil and borage seed oil have shown improvement similar to placebo, and neither is currently recommended in eczema therapy.


Molecular landscape of recurrent cervical cancer.
Cervical cancer (CC) is a major gynecological problem in developing and underdeveloped countries. Despite the significant advancement in early detection and treatment modalities, several patients recur. Moreover, the molecular mechanisms responsible for CC recurrence remains obscure. The patients with CC recurrence often show poor prognosis and significantly high mortality rates. The clinical management of recurrent CC depends on treatment history, site, and extent of the recurrence. Owing to poor prognosis and limited treatment options, recurrent CC often presents a challenge to the clinicians. Several in vitro, in vivo, and patient studies have led to the identification of the critical molecular changes responsible for CC recurrence. Both aberrant genetic and epigenetic modifications leading to altered cell signaling pathways have been reported to impact CC recurrence. Researchers are currently trying to dissect the molecular pathways in CC and translate these findings for better management of disease. This article attempts to review the existing knowledge of disease relapse, accompanying challenges, and associated molecular players in CC.


Statistical Change Detection by the Pool Adjacent Violators Algorithm.
In this paper, we present a statistical change detection approach aimed at being robust with respect to the main disturbance factors acting in real-world applications such as illumination changes, camera gain and exposure variations, noise. We rely on modeling the effects of disturbance factors on images as locally order-preserving transformations of pixel intensities plus additive noise. This allows us to identify within the space of all of the possible image change patterns the subspace corresponding to disturbance factors effects. Hence, scene changes can be detected by a-contrario testing the hypothesis that the measured pattern is due to disturbance factors, that is, by computing a distance between the pattern and the subspace. By assuming additive Gaussian noise, the distance can be computed within a maximum likelihood nonparametric isotonic regression framework. In particular, the projection of the pattern onto the subspace is computed by an O(N) iterative procedure known as Pool Adjacent Violators algorithm.


Statistical analysis plan for the Head Position in Stroke Trial (HeadPoST): An international cluster cross-over randomized trial.
Background There is evidence to indicate that the lying flat head position increases cerebral blood flow and oxygenation in patients with acute ischemic stroke, but how these physiological effects translate into clinical outcomes is uncertain. The Head Position in Stroke Trial aims to determine the comparative effectiveness of lying flat (0°) compared to sitting up (≥30°) head positioning, initiated within 24 h of hospital admission for patients with acute stroke. Design An international, pragmatic, cluster-randomized, crossover, open, blinded outcome assessed clinical trial. Each hospital with an established acute stroke unit (cluster) site was required to recruit up to 140 consecutive cases of acute stroke (one phase of head positioning before immediately crossing over to the other phase of head positioning), including both acute ischemic stroke and intracerebral hemorrhage, in each randomized head position as a 'business as usual' policy. Objective To outline in detail the predetermined statistical analysis plan for the study. Methods All accumulated data will be reviewed and formally assessed. Information regarding baseline characteristics of patients, their process of care and management will be outlined, and for each item, statistically relevant descriptive elements will be described. For the trial outcomes, the most appropriate statistical comparisons are described. Results A statistical analysis plan was developed that is transparent, verifiable, and predetermined before completion of data collection. Conclusions We developed a predetermined statistical analysis plan for Head Position in Stroke Trial to avoid analysis bias arising from prior knowledge of the findings, in order to reliably quantify the benefits and harms of lying flat versus sitting up early after the onset of acute stroke. Trial registration ClinicalTrials.gov identifier NCT02162017; ANZCTR identifier ACTRN12614000483651.


Emotional dysregulation mediates the impact of childhood trauma on psychological distress: First Italian data during the early phase of COVID-19 outbreak.
The coronavirus disease 2019 pandemic represents an unprecedented traumatic stressor to mental health. Psychological distress is considered a reliable proxy for psychopathology and can be negatively influenced by childhood trauma through sensitization effects. Emotion dysregulation has been proposed as a potential mediator of this mechanism. We aimed to test this hypothesis in a national Italian sample assessed in the early phase of the coronavirus disease 2019 outbreak. We investigated the relationship between psychological distress and childhood trauma in 500 healthy participants assessed through a survey-based study, after the coronavirus disease 2019 pandemic lockdown in Italy. Levels of psychological distress and history of childhood trauma were obtained using the Kessler-10 (K10) and the Childhood Trauma Questionnaire, respectively. We used bootstrapped mediation analysis to test the mediator role of emotional dysregulation, measured through the Difficulties in Emotion Regulation Scale, on the effect of childhood trauma on psychological distress. In total, 190 (38%) reported psychological distress related to the coronavirus disease 2019 outbreak. Individuals with psychological distress experienced more childhood trauma, specifically emotional abuse (F = 23.51, df = 1, p < 0.001) and neglect (F = 10.98, df = 1, p = 0.001). After modelling the effect of emotional dysregulation, the impact of childhood trauma on coronavirus disease 2019-related psychological distress resulted in indirect effects and mediated by deficits in emotion regulation mechanisms (bootstrapped lower level of confidence interval = 0.345, upper level of confidence interval = 0.598). Childhood trauma is associated with increased vulnerability to the stressful effect of the coronavirus disease 2019 outbreak. Our data suggest that emotional dysregulation may represent a dimension mediating the impact of childhood trauma on coronavirus disease 2019-related psychological distress and may be considered as specific target for interventions aiming at empowering resilience.


Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain.
Neural stem cells (NSCs, B1 cells) are retained in the walls of the adult lateral ventricles but, unlike embryonic NSCs, are displaced from the ventricular zone (VZ) into the subventricular zone (SVZ) by ependymal cells. Apical and basal compartments, which in embryonic NSCs play essential roles in self-renewal and differentiation, are not evident in adult NSCs. Here we show that SVZ B1 cells in adult mice extend a minute apical ending to directly contact the ventricle and a long basal process ending on blood vessels. A closer look at the ventricular surface reveals a striking pinwheel organization specific to regions of adult neurogenesis. The pinwheel's core contains the apical endings of B1 cells and in its periphery two types of ependymal cells: multiciliated (E1) and a type (E2) characterized by only two cilia and extraordinarily complex basal bodies. These results reveal that adult NSCs retain fundamental epithelial properties, including apical and basal compartmentalization, significantly reshaping our understanding of this adult neurogenic niche.


The choice of arterial access for percutaneous coronary intervention and its impact on outcome: An expert opinion perspective.
The prevention of major bleeding during percutaneous coronary intervention is one of the most widely discussed and often controversial topics within interventional cardiology. The choice of arterial access should be considered a mechanism for bleeding avoidance, and various strategies have been proposed to prevent or lower major bleeding and vascular complications with varying levels of strength. Herein, we review the current literature on arterial access as a bleeding avoidance strategy during percutaneous coronary intervention and its impact on outcome and provide a consensus opinion based on the strength of the evidence supporting various techniques.


Object lessonsSo Much Stuff: How Humans Discovered Tools, Invented Meaning, and Made More of Everything Chip Colwell University of Chicago Press, 2023. 304 pp.
An anthropologist confronts the history and ubiquity of human-made items.


Nonlinear photonic lattices in anisotropic nonlocal self-focusing media.
We analyze theoretically and generate experimentally two-dimensional nonlinear lattices with periodic phase modulation in a photorefractive medium. The light-induced periodically modulated nonlinear refractive index is highly anisotropic and nonlocal, and it depends on the lattice orientation relative to the crystal axis. We discuss the stability of such induced photonic structures and their guiding properties.


A structural equation model of the relationship between insomnia, negative affect, and paranoid thinking.
A growing body of evidence points to relationships between insomnia, negative affect, and paranoid thinking. However, studies are needed to examine (i) whether negative affect mediates the relation between insomnia and paranoid thinking, (ii) whether different types of insomnia exert different effects on paranoia, and (iii) to compare the impact of objective and self-reported sleeping difficulties. Structural equation modelling was therefore used to test competing models of the relationships between self-reported insomnia, negative affect, and paranoia. n = 348 participants completed measures of insomnia, negative affect and paranoia. A subset of these participants (n = 91) went on to monitor their sleep objectively (using a portable sleep monitor made by Zeo) for seven consecutive nights. Associations between objectively recorded sleep, negative affect, and paranoia were explored using linear regression. The findings supported a fully mediated model where self-reported delayed sleep onset, but not self-reported problems with sleep maintenance or objective measures of sleep, was directly associated with negative affect that, in turn, was associated with paranoia. There was no evidence of a direct association between delayed sleep onset or sleep maintenance problems and paranoia. Taken together, the findings point to an association between perceived (but not objective) difficulties initially falling asleep (but not maintaining sleep) and paranoid thinking; a relationship that is fully mediated by negative affect. Future research should seek to disentangle the causal relationships between sleep, negative affect, and paranoia (e.g., by examining the effect of an intervention using prospective designs that incorporate experience sampling). Indeed, interventions might profitably target (i) perceived sleep quality, (ii) sleep onset, and / or (iii) emotion regulation as a route to reducing negative affect and, thus, paranoid thinking.


Steps toward the visualization of soft tissue.
The use of tomographic imaging technologies has gained significant importance in recent years due to its capability of showing the internals of the human body. However, some structures of the anatomy are not easily visualized as they are not well-contrasted in the local neighborhood. With the use of apriori models, in the form of atlases of anatomy, physicians can overcome these difficulties and interpret patient data sets. As such, important parts of the head anatomy, like soft tissue, are beginning to be visualized when integrated rendering methods are used for this purpose.


Insidious reintroduction of wild poliovirus into Israel, 2013.
Israel was certified as polio-free country in June 2002, along with the rest of the World Health Organization European Region. Some 11 years later, wild-type polio virus ₁ (WPV₁) was isolated initially from routine sewage samples collected between 7 and 13 April 2013 in two cities in the Southern district. WPV₁-specific analysis of samples indicated WPV₁ introduction into that area in early February 2013. National supplementary immunisation with oral polio vaccine has been ongoing since August 2013.


A repetitive DNA fragment carrying a hot spot for de novo DNA methylation enhances expression variegation in tobacco and petunia.
A 1.6 kb repetitive DNA sequence (RPS) from Petunia hybrida was identified that destabilizes expression of a GUS marker transgene. Following polyethylene glycol (PEG)-mediated tobacco and petunia protoplast transformations, GUS expression patterns analysed on callus and plant levels were clearly more variable when constructs contained the RPS sequence. The effect on transgene expression required chromosomal integration since the two different RPS constructs employed did not exhibit reduced levels of GUS activities in transient assays. DNA methylation analysis implies a hypermethylated default state of endogenous RPS copies present in the petunia genome. Analysis of the transgene DNA in different transgenic tobacco plants showed almost complete hypermethylation of a particular Hhal site of the RPS sequence. It is proposed that, due to the presence of specific signals within the RPS region or based on interaction of RPS with other endogenous homologous sequences, RPS functions as an initiation region for de novo methylation and induces expression variegation in adjacent sequences.


A computational study towards understanding the mechanism of phosphodiester cleavage by two mononuclear Zn(II) complexes.
In this study, the hydrolytic reaction mechanism of HPNP by two effective mononuclear Zn(II) catalysts was explored by using density functional calculations. With the assumption that the active catalyst is in Zn-aqua form, the water-assisted proton transfer mode was found to be energetically the most favorable one for both the catalysts among three possible reaction pathways. The rate-limiting step on this pathway is a concerted double-proton transfer, concomitant with the nucleophilic addition of the deprotonated hydroxyl group to form a five-coordinated phosphorus intermediate. A comparison of potential energy surfaces for both catalysts shows that the three amino groups in the second coordination sphere of one catalyst play an important role in stabilizing the proton transfer (or nucleophilic addition) transition state. The two coordination spheres are found to have almost the same contributions in catalyzing the phosphate ester cleavage reaction. Also, present calculations show that the water-assisted proton transfer mechanism with the catalyst L-Zn-OH(2) is more favorable in energy than the general base pathway with the active catalyst L-Zn-OH suggested previously.


Photodesorption of alkali anions from alkali-halide cluster anions.
Using photoelectron spectroscopy, we have observed alkali anion photodesorption from alkali-halide cluster anions that contain two weakly bound electrons. In the alkali iodides, we have found this type of desorption in almost every (MI)(n)M- cluster we have studied (M=Na, K, Cs; n<9), although it depends on the probe laser frequency and cluster temperature. Using pump-probe techniques, we have shown that the process occurs on a picosecond time scale by way of an electronic excitation of the cluster's spin-paired electrons.


Hippocampal CaMKII inhibition induces reactivation-dependent amnesia for extinction memory and causes fear relapse.
Hippocampal GluN2B subunit-containing NMDAR (GluN2B-NMDAR) activation during recall destabilizes fear extinction memory, which must undergo brain-derived neurotrophic factor (BDNF)-dependent reconsolidation to persist. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a Ser/Thr protein kinase essential for hippocampus-dependent memory processing that acts downstream GluN2B-NMDAR and controls BDNF expression, but its participation in fear extinction memory reconsolidation has not yet been studied. Using a combination of pharmacological and behavioral tools, we found that in adult male Wistar rats, intra dorsal-CA1 administration of the CaMKII inhibitors autocamtide-2-related inhibitory peptide (AIP) and KN-93, but not of their inactive analogs scrambled AIP and KN-92, after fear extinction memory recall impaired extinction and caused GluN2B-NMDAR-dependent recovery of fear. Our results indicate that hippocampal CaMKII is necessary for fear extinction reconsolidation, and suggest that modulation of its activity around the time of recall controls the inhibition that extinction exerts on learned fear.


Simultaneous Computer-Aided Design/Computer-Aided Manufacture Bimaxillary Orthognathic Surgery and Mandibular Reconstruction Using Selective-Laser Sintered Titanium Implant.
This patient report describes simultaneous bimaxillary orthognathic surgery and mandibular reconstruction by means of three-dimensional (3D) planning, 3D printed biocompatible surgical wafers, and 3D selective-laser sintered titanium implant. A 26-year-old male patient presented with a left mandibular defect secondary to trauma. The whole body of the mandible on the left hand side was deficient with a narrow connection with the remaining left condyle. He had undergone orthodontic treatment for 18 months and was ready to undergo bimaxillary orthognathic surgery. Advanced cranio-maxillofacial software was used in processing his cone beam computer tomography scan data, and e-casts of his upper and lower dental arches. Bimaxillary surgery was planned with Le Fort 1 maxillary impaction and mandibular advancement to achieve a class 1 incisor relationship. Intermediate and final surgical wafers were designed following the planned movements and printed using biocompatible resin. The deficient left side of the mandible was reconstructed by means of mirror imaging the contra-lateral right side into the deficient left side with the aim of restoring normal facial symmetry. Biomedical software was then used in designing a reconstruction plate that connected the condylar head and the mandible following the planned bimaxillary surgery and mandibular continuity symmetry reconstruction. The plate was printed in titanium following state-of the-art selective laser sintering technology. The bimaxillary surgery and mandibular reconstruction were done simultaneously as planned along with an iliac-crest bone graft. This patient confirms the advantages of 3D computer-aided design/computer-aided manufacture technologies in optimizing clinical outcomes for cranio-maxillofacial reconstruction, especially when conducting two simultaneous clinical procedures.


Isolated heart responsiveness to beta-simulation after exercise training in obesity.
Exercise training results in many health benefits, but few studies have focused on whether exercise training might attenuate the adverse effects of obesity on heart function. Therefore, the purpose of this study was to determine whether exercise training attenuated obesity-related decreases in systolic contractile function in response to beta-adrenergic stimulation, using the rabbit model of obesity. Female New Zealand white rabbits were divided into four groups: lean sedentary, lean exercise-trained, obese sedentary, and obese exercise-trained. Obese rabbits were fed an ad libitum high-fat diet. Exercise-trained rabbits underwent a 12-wk progressive treadmill exercise training protocol. After 12 wk, the Langendorff isolated heart method was used to study developed pressure, +dP/dt, and -dP/dt responses to increasing concentrations of isoproterenol (10(-9)--3 x 10(-7) M). Log concentration-response data were fit to a sigmoidal function, using a four-parameter (minimum, maximum, EC(50), slope) logistic equation. Groups were compared using a 2 x 2 analysis of variance. Although obesity shifted the concentration-response curves for developed pressure, +dP/dt, and -dP/dt to the right as indicated by an increase in the EC(50) (P < or = 0.05), there was no effect of exercise training on any of the logistic regression parameters. EC(50) (log M) values for combined lean versus combined obese were -8.50 +/- 0.7 vs -8.20 +/- 0.09 (developed pressure), -8.04 +/- 0.06 vs -7.68 +/- 0.07 (+dP/dt), and -8.17 +/- 0.07 vs -7.91 +/- 0.09 (-dP/dt). These results confirm the negative effect of obesity on responsiveness of the isolated heart to beta-adrenergic stimulation but indicate that exercise training does not significantly attenuate obesity-related changes.


Emergency hormonal contraception usage in genitourinary medicine clinic attenders.
To assess the indications for usage of emergency hormonal contraception amongst a population of London genitourinary medicine clinic attenders. In a prospective study, 150 consecutive women receiving emergency hormonal contraception (EHC) were enrolled. The attending doctor completed a questionnaire of patient details and prescribed EHC with prophylactic prochlorperazine. Follow-up was arranged three weeks later, at which time outcomes and side-effects of therapy were recorded. For those women who did not reattended as planned case notes were reviewed at three months. Of 150 women surveyed, 100 (66%) reported contraceptive method failure, 48 (32%) had used no contraception at the time of last sexual intercourse and two requested EHC after sexual assault. Ninety three (62%) reported condom failure, 7 (5%) oral contraceptive pill failure. Seventy five (50%) had used EHC before (range 1-10 times). Seventy one (47%) women reattended within three months. Five (3.3%) of the 150 women were pregnant; none of these cases had experienced nausea or vomiting whilst taking EHC. Side-effects were reported by 22 (31%) of the 71 patients who reattended. Nine (6%) women had been followed-up in the family planning advisory clinic. Of the 71 women who reattended, 39 (55%) reported that their preferred future method of contraception would be condoms. Of the 150 women 19 (13%) underwent tests for sexually transmissible infections within one month of presentation. EHC usage in this population was associated with a failure rate of at least 3.3% and an overall side effect rate of 31%. Despite requests for emergency contraception because of condom failure many elected to continue using condoms as their preferred method of contraception. The majority of women (53%) did not return for follow-up or family planning advice, and so we believe that future contraceptive plans must be addressed at the time EHC is prescribed.


Impact of gout on in-hospital outcomes of acute coronary syndrome-related hospitalizations and revascularizations: Insights from the national inpatient sample.
Previous studies have established a role of gout in predicting risk and prognosis of cardiovascular diseases. However, large-scale data on the impact of gout on inpatient outcomes of acute coronary syndrome (ACS)-related hospitalizations and post-revascularization is inadequate. To evaluate the impact of gout on in-hospital outcomes of ACS hospitalizations, subsequent healthcare burden and predictors of post-revascularization inpatient mortality. We used the national inpatient sample (2010-2014) to identify the ACS and gout-related hospitalizations, relevant comorbidities, revascularization and post-revascularization outcomes using the ICD-9 CM codes. A multivariable analysis was performed to evaluate the predictors of post-revascularization in-hospital mortality. We identified 3144744 ACS-related hospitalizations, of which 105198 (3.35%) also had gout. The ACS-gout cohort were more often older white males with a higher prevalence of comorbidities. Coronary artery bypass grafting was required more often in the ACS-gout cohort. Post-revascularization complications including cardiac (3.2% vs 2.9%), respiratory (3.5% vs 2.9%), and hemorrhage (3.1% vs 2.7%) were higher whereas all-cause mortality was lower (2.2% vs 3.0%) in the ACS-gout cohort (P < 0.001). An older age (OR 15.63, CI: 5.51-44.39), non-elective admissions (OR 2.00, CI: 1.44-2.79), lower household income (OR 1.44, CI: 1.17-1.78), and comorbid conditions predicted higher mortality in ACS-gout cohort undergoing revascularization (P < 0.001). Odds of post-revascularization in-hospital mortality were lower in Hispanics (OR 0.45, CI: 0.31-0.67) and Asians (OR 0.65, CI: 0.45-0.94) as compared to white (P < 0.001). However, post-operative complications significantly raised mortality odds. Mean length of stay, transfer to other facilities, and hospital charges were higher in the ACS-gout cohort. Although gout was not independently associated with an increased risk of post-revascularization in-hospital mortality in ACS, it did increase post-revascularization complications.


Accelerated differentiation of osteoblast cells on polycaprolactone scaffolds driven by a combined effect of protein coating and plasma modification.
A combined effect of protein coating and plasma modification on the quality of the osteoblast-scaffold interaction was investigated. Three-dimensional polycaprolactone (PCL) scaffolds were manufactured by the precision extrusion deposition (PED) system. The structural, physical, chemical and biological cues were introduced to the surface through providing 3D structure, coating with adhesive protein fibronectin and modifying the surface with oxygen-based plasma. The changes in the surface properties of PCL after those modifications were examined by contact angle goniometry, surface energy calculation, surface chemistry analysis (XPS) and surface topography measurements (AFM). The effects of modification techniques on osteoblast short-term and long-term functions were examined by cell adhesion, proliferation assays and differentiation markers, namely alkaline phosphatase activity (ALP) and osteocalcin secretion. The results suggested that the physical and chemical cues introduced by plasma modification might be sufficient for improved cell adhesion, but for accelerated osteoblast differentiation the synergetic effects of structural, physical, chemical and biological cues should be introduced to the PCL surface.


Hypo-osmotic shock-induced subclinical inflammation of skin in a rat model of disrupted skin barrier function.
Aging disrupts skin barrier function and induces xerosis accompanied by pruritus. In many cases, elderly patients complain of pruritus during skin hygiene care, a condition called aquagenic pruritus of the elderly (APE). To date, the pathophysiology and mechanism of action of APE have not been elucidated. We conducted the present study to test the hypothesis that hypo-osmotic shock of epidermal cells induces skin inflammation and elongation of C-fibers by nerve growth factor β (NGFβ) as a basic mechanism of APE. The dorsal skin of HWY rats, which are a model for disrupted skin barrier function, was treated with distilled water (hypotonic treatment [Hypo] group) or normal saline (isotonic treatment [Iso] group) by applying soaked gauze for 7 days. Untreated rats were used as a control (no-treatment [NT] group). Histochemical and immunohistochemical analyses revealed inflammatory responses in the epidermis and the dermal papillary layer in the Hypo group, while no alterations were observed in the Iso or NT groups. Induction of expression and secretion of NGFβ and elongation of C-fibers into the epidermis were found in the Hypo group. In contrast, secretion of NGFβ was significantly lower and elongation of C-fibers was not observed in the Iso group. These results suggest that hypo-osmotic shock-induced inflammatory reactions promote hypersensitivity to pruritus in skin with disrupted barrier function.


Network meta-analysis: application and practice using Stata.
This review aimed to arrange the concepts of a network meta-analysis (NMA) and to demonstrate the analytical process of NMA using Stata software under frequentist framework. The NMA tries to synthesize evidences for a decision making by evaluating the comparative effectiveness of more than two alternative interventions for the same condition. Before conducting a NMA, 3 major assumptions-similarity, transitivity, and consistency-should be checked. The statistical analysis consists of 5 steps. The first step is to draw a network geometry to provide an overview of the network relationship. The second step checks the assumption of consistency. The third step is to make the network forest plot or interval plot in order to illustrate the summary size of comparative effectiveness among various interventions. The fourth step calculates cumulative rankings for identifying superiority among interventions. The last step evaluates publication bias or effect modifiers for a valid inference from results. The synthesized evidences through five steps would be very useful to evidence-based decision-making in healthcare. Thus, NMA should be activated in order to guarantee the quality of healthcare system.


Sexually Dimorphic Changes of Hypocretin (Orexin) in Depression.
Neurophysiological and behavioral processes regulated by hypocretin (orexin) are severely affected in depression. However, alterations in hypocretin have so far not been studied in the human brain. We explored the hypocretin system changes in the hypothalamus and cortex in depression from male and female subjects. We quantified the differences between depression patients and well-matched controls, in terms of hypothalamic hypocretin-1 immunoreactivity (ir) and hypocretin receptors (Hcrtr-receptors)-mRNA in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex. In addition, we determined the alterations in the hypocretin system in a frequently used model for depression, the chronic unpredictable mild stress (CUMS) rat. i) Compared to control subjects, the amount of hypocretin-immunoreactivity (ir) was significantly increased in female but not in male depression patients; ii) hypothalamic hypocretin-ir showed a clear diurnal fluctuation, which was absent in depression; iii) male depressive patients who had committed suicide showed significantly increased ACC Hcrt-receptor-2-mRNA expression compared to male controls; and iv) female but not male CUMS rats showed a highly significant positive correlation between the mRNA levels of corticotropin-releasing hormone and prepro-hypocretin in the hypothalamus, and a significantly increased Hcrt-receptor-1-mRNA expression in the frontal cortex compared to female control rats. The clear sex-related change found in the hypothalamic hypocretin-1-ir in depression should be taken into account in the development of hypocretin-targeted therapeutic strategies.


Antiproliferative autoantigen CDA1 transcriptionally up-regulates p21(Waf1/Cip1) by activating p53 and MEK/ERK1/2 MAPK pathways.
We previously reported that overexpression of cell division autoantigen 1 (CDA1) in HeLa cells arrests cell growth and inhibits DNA synthesis at S-phase. Here we show that CDA1-induced arrest of cell growth is accompanied by increases in protein and mRNA levels of the cyclin-dependent kinase (Cdk) inhibitor protein, p21(Waf1/Cip1) (p21). Both p21 induction and cell growth arrest are reversed when CDA1 expression is inhibited. CDA1 also increases p53 protein, but not its mRNA, in a time- and dose-dependent manner. MDM2, a ubiquitin ligase regulating p53 degradation, is inactivated by CDA1, suggesting that p53 protein accumulation is due to decreased protein degradation. Knockdown of p53, using siRNA targeting two sites of p53 mRNA, abrogates transcriptional induction of p21 by CDA1. Deletion of the p53 responsive element in the distal region of p21 promoter attenuates promoter activity in response to CDA1. DNA damage caused by camptothecin treatment increases mRNA and protein levels of CDA1, accompanied by induction of p53. The DNA damage-induced p53 induction is markedly attenuated by CDA1 knockdown. CDA1 induces phosphorylation of ERK1/2(p44/42), an activity blocked by PD98059 and U0126, inhibitors of the upstream kinase MEK1/2. The MEK inhibitors also block induction of p21 mRNA and abrogate p21 promoter activity stimulated by CDA1. Cell cycle kinases, Cdk1, -2, -4, and -6 are inhibited by CDA1 overexpression. We conclude that CDA1 induces p53- and MEK/ERK1/2 MAPK-dependent expression of p21 by acting through the p53 responsive element in the p21 promoter and that this contributes to its antiproliferative activity.


Diagnostic approach to pleural effusion.
Pleural effusion affects more than 1.5 million people in the United States each year and often complicates the management of heart failure, pneumonia, and malignancy. Pleural effusion occurs when fluid collects between the parietal and visceral pleura. Processes causing a distortion in body fluid mechanics, such as in heart failure or nephrotic syndrome, tend to cause transudative effusions, whereas localized inflammatory or malignant processes are often associated with exudative effusions. Patients can be asymptomatic or can present with cough, dyspnea, and pleuritic chest pain. Dullness to percussion on physical examination suggests an effusion; chest radiography can confirm the diagnosis. Thoracentesis may be indicated to diagnose effusion and relieve symptoms. Ultrasound guidance is preferred when aspirating fluid. Routine assays for aspirated fluid include protein and lactate dehydrogenase levels, Gram staining, cytology, and pH measurement. Light's criteria should be used to differentiate exudative from transudative effusions. Additional laboratory assays, bronchoscopy, percutaneous pleural biopsy, or thoracoscopy may be required for diagnosis if the initial test results are inconclusive.


A biochip platform for cell transfection assays.
In this paper, we describe the development and characterization of a biochip platform for cell transfection assays. Silicon wafers were surface modified by plasma polymerization of allylamine plasma polymer (ALAPP) and grafting of a protein-resistant layer of poly(ethylene oxide) (PEO) on the plasma polymer surface. Excimer laser ablation was then used to pattern ALAPP-PEO coated samples for spatially controlled protein adsorption and subsequent cell attachment. X-ray photoelectron spectroscopy (XPS) was used to characterize the surface modifications before and after excimer laser ablation. Experiments confirmed the creation of a two-dimensionally controlled surface chemistry on the biochip. Cell culture experiments using human embryonic kidney (HEK 293) cells showed that cells attached exclusively to laser ablated areas. In addition, cells confined to ablated areas were successfully transfected with plasmid DNA containing the gene for green fluorescent protein (GFP). The cell transfection efficiencies of cells growing in a culture flask and cells confined on the biochip were determined to be 21 and 13%, respectively.


Competencies in Pastoral Counseling: The Lived Experiences of Filipino Diocesan Parish Priests.
Pastoral counseling has been a significant part of the priestly ministry in the Philippines. Nonetheless, literature about Filipino priests' lived experiences and competencies in counseling is almost non-existent. Using Interpretative Phenomenological Analysis (IPA), the researcher explored the lived experiences and competencies of Filipino diocesan parish priests in their role as pastoral counselors. The study was framed in Phenomenology, the Philippines Psychology Act of 2009, and the 2009 competencies of the Association for Spiritual, Ethical, and Religious Values in Counseling (ASERVIC), a division within the American Counseling Association (ACA). Data were collected using a semi-structured interview, and the analysis yielded seven (7) themes under three (3) clusters. The findings revealed that the participants lack the prerequisites to be rightfully called pastoral counselors. As priests continue to attend to people in need of counseling, the researcher calls on church leaders, the Psychological Association of the Philippines (PAP), and the Professional Regulation Commission (PRC) to address the practice of pastoral counseling in the country.


Low prevalence of anti-xenobiotic antibodies among the occupationally exposed individuals is associated with a high risk of cancer.
Cancer is one of the major health problem globally, responsible for high morbidity and mortality. Exposure of humans to xenobiotics is associated with the development of cancer. Further, these xenobiotics may combine with the body proteins and can act as a hapten and elicit an antibody response. In this study, we examined whether the regular exposer to xenobiotics evokes anti-xenobiotic antibodies and the presence of these antibodies have any correlation with the prevention of cancer. Interestingly, we noticed that the healthy household contacts showed significantly greater titers of anti-xenobiotic antibodies, as compared to cancer patients. Consequently, suggesting that the higher level of anti-xenobiotic antibodies may be responsible for neutralizing the effect of xenobiotics in the healthy subjects. Thereby, preventing the individuals from disease. In contrast, the presence of a significantly lower level of anti-xenobiotic antibodies in the cancer patients may be a causative factor for disease infliction. In conclusion, immunotherapy employing anti-xenobiotic antibodies may provide a prudent remedial measure to clear xenobiotics from the body of the individuals and thereby protecting from cancer.


Improving Portfolio Assessment: Addressing Challenges in Transition to Eportfolio.
As health care education programs adopt electronic portfolios (eportfolios), a midwestern university baccalaureate nursing program faces challenges in transitioning from a 25-year-old paper-based system to eportfolio. Process improvements and faculty development were implemented through collaboration with the information technology (IT) department and the involvement of students as ambassadors. Pre- and posttransition surveys and portfolio benchmarks were used to evaluate the efficacy of the new eportfolio system. Results of faculty and student surveys revealed improved positive experiences regarding the value, clarity, and ease of use of the eportfolio system. Benchmark deficits decreased from six of eight portfolio criteria in Fall 2017 to none in Fall 2019. Buy-in through faculty and student involvement, along with a user-centered design, are essential for a successful eportfolio transition. Student and faculty engagement would be secured when they are well-informed in the transition process. [J Nurs Educ. 2020;59(12):705-708.].


Colonic phytobezoar as a rare cause of large bowel obstruction.
Bezoars are masses formed by the concretion of stomach contents or debris within the gastrointestinal tract. Bezoars are rare and account for only 0.4-4% of all cases of gastrointestinal obstruction and mainly occur in the stomach or small intestine. Intestinal obstruction caused by colonic bezoars is extremely rare. We report a case of a distal sigmoid obstruction caused by a phytobezoar in a 60-year-old man with no obvious precipitating causes. He presented to the emergency department acutely unwell and a subsequent abdominal CT scan showed a mass within the proximal sigmoid colon suspicious for a bezoar. He proceeded to have an urgent laparotomy and the obstructive intraluminal mass in the sigmoid colon was identified and manually broken down. Subsequent histopathological assessment reported amorphous material and plant cellular matter consistent with the diagnosis of a phytobezoar.


Thyroid activity in desert rodents: a mechanism for lowered metabolic rate.
Desert rodents are known to exhibit three different levels of metabolic rate (MR) when related to the mouse-elephant equation. Several species have an MR that is either higher, lower, or similar to that predicted from the equation. The role of thyroid function as a possible mechanism associated with these different MR was examined in 12 species of desert rodents, representing 3 families and 3 different biotic communities. Thyroidal 131I uptake, ratio of neck-to-thigh 131I counts per minute (N/T ratio), thyroxine secretion rate (TSR), and plasma protein binding sites were used as indices of thyroid function. When relating thyroid function to MR, TSR was found to be low in species exhibiting low MR and vice versa. Other thyroid indices did not show a consistent relationship to MR. Also, TSR seems to be related to ecologic distribution: low TSR in desert areas and high TSR in arid woodland and montane forest areas. TSR was found to be correlated to body weight. The low TSR associated with reduced MR represents a useful adaptive mechanism for survival of desert rodents under their natural stressful environment.