Complications of central venous catheter insertion in a teaching hospital.
Central venous catheters are fundamental to daily clinical practice. This procedure is mainly performed by residents, often without supervision or structured training. To describe the characteristics of central venous catheterization and the complication rate related to it. Retrospective cohort study. Adult patients undergoing central venous catheter insertion out of the intensive care unit (ICU) of a teaching hospital were selected from March 2014 to February 2015. Data were collected from medical charts using an electronic form. Clinical and laboratory characteristics from patients, procedure characteristics, and mechanical and infectious complications rates were assessed. Patients with and without complications were compared. Three hundred and eleven (311) central venous catheterizations were evaluated. The main reasons to perform the procedure were lack of peripheral access, chemotherapy and sepsis. There were 20 mechanical complications (6% of procedures). Arterial puncture was the most common. Procedures performed in the second semester were associated with lower risk of complications (odds ratio 0.35 [95CI 0.12-0.98; p=0.037]). Thirty-five (35) catheter-related infection cases (11.1%) were reported. They were related to younger patients and procedures performed by residents with more than one year of training. Procedures performed after the first trimester had a lower chance of infection. These results show that the rate of mechanical complications of central venous puncture in our hospital is similar to the literature, but more attention should be given to infection prevention measures.


Correcting the cystic fibrosis disease mutant, A455E CFTR.
Cystic fibrosis is caused by more than 1000 mutations, the most common being the ΔF508 mutation. These mutations have been divided into five classes [1], with ΔF508 CFTR in class II. Here we have studied the class V mutation A455E. We report that the mature and immature bands of A455E are rapidly degraded primarily by proteasomes; the short protein half-life of this mutant therefore resembles that of ΔF508 CFTR. A455E could be rescued by treatment of the cells with proteasome inhibitors. Furthermore, co-transfection of A455E with the truncation mutant Δ264 CFTR also rescued the mature C band, indicating that A455E can be rescued by transcomplementation. We found that Δ264 CFTR bound to A455E, forming a bimolecular complex. Treatment with the compound correctors C3 and C4 also rescued A455E. These results are significant because they show that although ΔF508 belongs to a different class than A455E, it can be rescued by the same strategies, offering therapeutic promise to patients with Class V mutations.


Reliability-Weighted Integration of Audiovisual Signals Can Be Modulated by Top-down Attention.
Behaviorally, it is well established that human observers integrate signals near-optimally weighted in proportion to their reliabilities as predicted by maximum likelihood estimation. Yet, despite abundant behavioral evidence, it is unclear how the human brain accomplishes this feat. In a spatial ventriloquist paradigm, participants were presented with auditory, visual, and audiovisual signals and reported the location of the auditory or the visual signal. Combining psychophysics, multivariate functional MRI (fMRI) decoding, and models of maximum likelihood estimation (MLE), we characterized the computational operations underlying audiovisual integration at distinct cortical levels. We estimated observers' behavioral weights by fitting psychometric functions to participants' localization responses. Likewise, we estimated the neural weights by fitting neurometric functions to spatial locations decoded from regional fMRI activation patterns. Our results demonstrate that low-level auditory and visual areas encode predominantly the spatial location of the signal component of a region's preferred auditory (or visual) modality. By contrast, intraparietal sulcus forms spatial representations by integrating auditory and visual signals weighted by their reliabilities. Critically, the neural and behavioral weights and the variance of the spatial representations depended not only on the sensory reliabilities as predicted by the MLE model but also on participants' modality-specific attention and report (i.e., visual vs. auditory). These results suggest that audiovisual integration is not exclusively determined by bottom-up sensory reliabilities. Instead, modality-specific attention and report can flexibly modulate how intraparietal sulcus integrates sensory signals into spatial representations to guide behavioral responses (e.g., localization and orienting).


Botulinum toxin A submucosal injection for refractory non-neurogenic overactive bladder: early outcomes.
The objective of the present study was to assess the short-term effects of botulinum toxin A (BTX-A) injection for refractory non-neurogenic overactive bladder (OAB) in the setting of a prospective multicenter clinical trial. Refractory OAB was defined as persistent urgency urinary incontinence (UUI) ≥ once a week despite taking anticholinergic agents, or the incapability to continue the agents because of the adverse effects. A total of 100 U of BTX-A were reconstituted in 15 mL of normal saline and an aliquot of 0.5 mL was injected at 30 submucosal sites of the bladder wall. Nine men and eight women aged 67 ± 12 years were included. Subjective daytime frequency, urgency and UUI significantly decreased after treatment. On a 3-day frequency-volume chart, the daytime and night-time frequency of UUI significantly decreased from 5.5 and 0.5 pre-injection to 2.0 and 0.3 postinjection, respectively. Daytime urinary incontinence completely disappeared in six subjects. A urodynamic study showed the disappearance of detrusor overactivity in eight patients and a decrease in five patients. Maximum bladder capacity significantly increased from 179.9 to 267.3 mL. Difficulty on micturition or feeling of incomplete emptying was reported by 23.5% and 43.8% of patients at weeks 2 and 4, respectively. Postvoid residual urine increased to >100 mL in seven patients and >200 mL in one patient after injection; however, none of the patients required clean intermittent catheterization. These findings suggest promising efficacy of BTX-A in Japanese OAB patients.


Hemp to limit diffusion of difenoconazole in vegetable garden soils.
Triazole molecules are used to manage invasive aspergillosis, a fungal infection mainly due to Aspergillus fumigatus. A. fumigatus is not a phytopathogen, but, as it is widespread in soils, triazole fungicides have an unintended impact on it, selecting resistant populations' in environment. Thus, to maintain our ability to control fungal infections, whether in human health or agriculture, reduce the impact of the use of triazoles in the environment is important, notably limiting their diffusion in soils. Here we tested a hemp-based material as adsorbent to limit the spread of difenoconazole, a triazole fungicide, in vegetable soils. We studied the effects of contact time, material dose, difenoconazole concentration, and organic content of the soil using batch mode and percolation methods. Batch experiments showed that the material exhibited high adsorption capacities toward difenoconazole. Removal from the soil water increased from 46.6% using 0.35 g hemp per kg of soil to 77.0% using 1.75 g hemp per kg, for a contact time of 15 min and an initial difenoconazole concentration of 1.2 mg/L. For a contact time of 240 min, the removal was 93.5%. Percolation experiments showed that the quantity of difenoconazole removed was greater than the amount obtained by batch method: 41.9% of removal with only one passes of solution at a concentration of 12 mg/L is obtained through percolation technique whereas, with similar conditions, only 20% of removal is obtained by batch method, i.e. after 1 min of contact. The removal was strongly dependent on the number of passes: the values increased from 57.0% to 91.0% with increasing the number of passes from 1 to 15. Addition of hemp to soils allows to remove efficiently the difenoconazole fungicide from soil water. Hemp-based felt is a new and safe adsorbent that can be applied in agriculture to limit crop contamination.


Mechanisms of action of 6-thioguanine, 6-mercaptopurine, and 8-azaguanine.
The effects of 6-thioguanine on purine biosynthesis and cell viability have been examined in H.Ep. 2 cells grown in culture. Toxicity is not reversed by aminoimidazolecarboxamide, suggesting that inhibition of purine biosynthesis de novo is not the sole mechanism of toxicity. Also, 6-(methylmercapto)purine ribonucleoside, a potent inhibitor of purine biosynthesis de novo, produces more marked reductions in cellular pools of purines than does 6-thioguanine without killing cells. There is no apparent inhibition by 6-thioguanosine 5'-monophosphate of other enzymes leading to the synthesis of guanosine 5'-triphosphate as determined in whole cells by measurements of radioactive hypoxanthine or guanine incorporation. Inhibition of DNA synthesis by 1 mM thymidine protects cells from 6-mercaptopurine or 6-thioguanine but fails to protect cells from 8-azaguanine toxicity. On the other hand, inhibition of RNA synthesis by 6-azauridine plus deoxycytidine protects cells against 8-azaguanine but does not protect against 6-thioguanine or 6-mercaptopurine toxicity. In agreement with the in vitro data, arabinosylcytosine (a potent inhibitor of DNA synthesis) fails to protect mice against 8-azaguanine but has previously been shown to protect mice from 6-mercaptopurine or 6-thioguanine toxicity. The results support the hypotheses of others that incorporation into DNA (as 6-thioguanine nucleotide) is a mechanism of toxicity for these thiopurines, whereas 8-azaguanine is toxic due to its incorporation into RNA.


Response shift in patients with multiple sclerosis: an application of three statistical techniques.
With the evolution of theory and methods for detecting recalibration, reprioritization, and reconceptualization response shifts, the time has come to evaluate and compare the current statistical detection techniques. This manuscript presents an overview of a cross-method validation done on the same patient sample. Three statistical techniques were used: Structural Equation Modeling, Latent Trajectory Analysis, and Recursive Partitioning and Regression Tree modeling. The study sample (n = 3,008) was drawn from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry to represent patients soon after diagnosis, classified as having either a self-reported relapsing, progressive, or stable disease trajectory. Patient-reported outcomes included the disease-specific Performance Scales and the Patient-Derived Disease Steps, and the generic SF-12v2 measure. Small response shift effect sizes were detected by all of the methods. Recalibration response shift was detected by Structural Equation Modeling, Recursive Partitioning Regression Tree demonstrated patterns consistent with all three types of response shift, and Latent Trajectory Analysis, although unable to distinguish types of response shift, did detect response shift in less than 1% of the sample. The methods and their findings were discussed for operationalization, interpretability, assumptions, ability to use all data points from the study sample, limitations, and strengths. Directions for future research are discussed.


Absolute quantification of targeted rabbit liver- and meat tissue-specific peptide markers in highly processed food products.
A highly sensitive and selective method for the simultaneous absolute quantification of peptides unique to rabbit meat- and liver-specific tissue was developed using liquid chromatography - triple quadrupole mass spectrometry. Two rabbit skeletal muscle-specific peptides (SSVFVADPK and PHSHPALTPEQK), three rabbit liver tissue-specific peptides (FNLEALVTHTLPFEK, AILNYVANK, and TELAEPTSTR) and one peptide specific to both rabbit offal and skeletal muscle tissue (AFFGHYLYEVAR) were monitored. Analyses were performed using peptides labelled with stable isotopes (13C and 15N) as internal standards. Fifteen food samples containing rabbit meat and/or liver were analysed to verify compliance of the rabbit meat and liver composition with product labelling. One sample was adulterated with undeclared rabbit liver. The limit of detection and limit of quantification for the selected peptides of interest were in the range of 0.17 to 0.35 ng/mg and 0.57 to 1.17 ng/mg, respectively. The method may be useful for the determination of rabbit meat and liver tissue in highly processed food samples.


Evaluation of primary haemostasis in people with neurofibromatosis type 1.
Assessment of haemostasis in people with neurofibromatosis type 1 (NF-1) is essentially lacking, despite case reports of an association with von Willebrand disorder (VWD) and reported excessive bleeding post-surgery. We assessed routine blood haematology, routine coagulation parameters [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen], coagulation factors II, V, VII, VIII, IX, X, XI and XII, von Willebrand (VWF) factor antigen and activity, and platelet function [using the platelet function analyser (PFA-100)] in a group of individuals with NF-1 (n = 30). Their perceived haemorrhagic bleeding risk was also graded by means of a structured clinical assessment and physical examination. Routine blood assessments including platelet counts were generally normal, as were the routine coagulation tests PT, TT and fibrinogen, and most coagulation factors. Elevated APTTs were detected in 11 individuals, reduced factor XII levels in three, reduced VWF levels in four, and elevated PFA closure times (CTs) in 13. Laboratory results correlated with each other in some but not all cases. For example, elevated APTTs were identified in two of three individuals with a reduced factor XII level and prolonged CTs were identified in three individuals who also showed reduced aggregation responses in classical platelet function studies. Moreover, all individuals with VWF results below the normal reference range showed elevated CTs with both PFA test cartridges, and those with VWF results identified as borderline normal (i.e. 50-65%) also showed elevated CTs with both PFA test cartridges in three of five cases. The relationship between VWF and CTs was also identified by linear regression analysis (P-values of <0.05, for all comparisons). However, as clinically perceived bleeding risk did not appear to be correlated with laboratory test results in most cases, blanket screening of NF-1 individuals for evaluation of laboratory haemostasis may not be warranted.


Chevalier Jackson lecture. Esophagology: an update.
Because of the great interest in the problem of gastroesophageal reflux, much emphasis has been placed on factors which control the competence of the lower esophageal sphincter (LES). Much study has been devoted to the effect of hormones and drugs on the LES. Of the various diagnostic methods available, 24-hour pH testing seems to offer the most information regarding reflux and its complications. Medical therapy should be given a careful trial before surgical procedures for reflux are considered. Diagnostic esophagoscopy is usually performed with fiberoptic instruments. Open-tube esophagoscopes are still preferable for most types of endoscopy is usually performed with fiberoptic instruments. Open-tube esophagoscopes are still preferable for most types of endoscopic therapy. However, flexible fiberscopes may be used for injection of esophageal varices and for laser coagulation of bleeding lesions or even tumors. Guide wires may be introduced through flexible scopes to aid in the dilation of esophageal strictures and also to aid in the placement of prosthetic tubes in patients with obstructing cancers. The performance of esophagoscopy by practitioners of several disciplines has resulted in fragmentation of the specialty. Ideally, all esophagoscopists should be competent with both open-tube and fiberoptic scopes and should be familiar with all of the newer knowledge of the physiology and pharmacology of the esophagus and its sphincters.


Phylogenomic Subsampling and the Search for Phylogenetically Reliable Loci.
Phylogenomic subsampling is a procedure by which small sets of loci are selected from large genome-scale data sets and used for phylogenetic inference. This step is often motivated by either computational limitations associated with the use of complex inference methods or as a means of testing the robustness of phylogenetic results by discarding loci that are deemed potentially misleading. Although many alternative methods of phylogenomic subsampling have been proposed, little effort has gone into comparing their behavior across different data sets. Here, I calculate multiple gene properties for a range of phylogenomic data sets spanning animal, fungal, and plant clades, uncovering a remarkable predictability in their patterns of covariance. I also show how these patterns provide a means for ordering loci by both their rate of evolution and their relative phylogenetic usefulness. This method of retrieving phylogenetically useful loci is found to be among the top performing when compared with alternative subsampling protocols. Relatively common approaches such as minimizing potential sources of systematic bias or increasing the clock-likeness of the data are found to fare worse than selecting loci at random. Likewise, the general utility of rate-based subsampling is found to be limited: loci evolving at both low and high rates are among the least effective, and even those evolving at optimal rates can still widely differ in usefulness. This study shows that many common subsampling approaches introduce unintended effects in off-target gene properties and proposes an alternative multivariate method that simultaneously optimizes phylogenetic signal while controlling for known sources of bias.


Early in vivo signaling profiles in MUC1-specific CD4+ T cells responding to two different MUC1-targeting vaccines in two different microenvironments.
Vaccines are beginning to be explored for as measures to prevent cancer. Since determining the efficacy of vaccines by evaluating disease outcome requires a long time, there is an urgent need for early predictive biomarkers. To this end, immunological endpoints that can be assessed weeks or months post-vaccination are currently being evaluated. However, when multiple vaccines are available, waiting for the development of humoral and cellular immunity could still cause delays, whereas early assessments would allow for a timely shift to more effective prevention modalities. Applying the phospho-flow technique to primary T cells, we examined the phosphorylation status of various proteins that shape the activation, proliferation, and differentiation of mucin 1 (MUC1)-specific CD4+ T cells within the first 24 hours post-immunization. It is known that a vaccine composed of a MUC1-derived peptide loaded on dendritic cells is more effective in eliciting T-cell responses than a vaccine including the same peptide plus an adjuvant. Both these vaccines stimulate T cells more effectively in wild-type (WT) than in MUC1-transgenic mice. We examined if the signaling events downstream of the TCR or linked to various proliferative and survival pathways, monitored in two different hosts as early as 3, 6, 12 and 24 hours post-immunization, could predict the differential potential of these two MUC1-targeting vaccines. The signaling signatures that we obtained primarily reflect differences between the vaccines rather than between the hosts. We demonstrate the feasibility of using a phospho-flow-based approach to evaluate the potential of a given vaccine to elicit a desired immune response.


Incidence and mortality due to thromboembolic events during the COVID-19 pandemic: Multi-sourced population-based health records cohort study.
Evidence supports an excess of deaths during the COVID-19 pandemic. We report the incidence and mortality of thrombo-embolic events (TE) during the COVID-19 pandemic. Multi-sourced nationwide cohort study of adults (age ≥18 years) admitted to hospital with TE and deaths from TE in England (hospital and community) between 1st February 2018 and 31st July 2020. Relative risks, adjusted for age, sex, atrial fibrillation, co-morbidities and time trend comparing before and during the COVID-19 pandemic were estimated using Poisson regression. Of 272,423 patients admitted with TE to 195 hospitals, 86,577 (31.8%) were admitted after 2nd March 2020 (first COVID-19 death in the UK). The incidence of TE hospitalised increased during the COVID-19 pandemic from 1090 to 1590 per 100,000 (absolute risk change 45.9% [95% CI 45.1-46.6%], adjusted relative risk [ARR] 1.43 [95% CI 1.41-1.44]) driven particularly by pulmonary embolism; 1.49, 95% CI 1.46-1.52. TE were more frequent among those with COVID-19; 1.9% vs. 1.6%, absolute risk change 21.7%, 95% CI 21.0-22.4%, ARR 1.20, 95% CI 1.18-1.22. There was an increase in the overall mortality from TE during the pandemic (617, 6.7% proportional increase compared with the historical baseline), with more TE deaths occurring in the community compared with the historical rate (44% vs. 33%). The COVID-19 pandemic has resulted in an increase in the incidence of hospitalised TE. There were more deaths from TE in the community highlighting a number of mechanisms including the hypercoagulable state associated with COVID-19 infection and potential impact of delays in seeking help. Evidence before this study We searched PubMed on 16 November 2020 for articles that documented the incidence and mortality of thrombo-embolic events (TE) during the COVID-19 pandemic using the search terms "COVID-19" OR "Coronavirus*" OR "2019-nCOV" OR "SARS-CoV" AND ("Thromboembolism" OR "Venous Thromboembolism" OR "thromboembol*") with no language or time restrictions. The majority of data on TE in COVID-19 pertains to hospitalised patients from retrospective cohort studies. One study found that TE in hospitalised patients was associated with an increased mortality rate (adjusted hazard ratio 1.82; 95% CI 1.54-2.15). A systematic review and meta-analysis of 35 studies in 9249 hospitalised patients calculated an overall pooled incidence of TE of 17.8% (95% CI: 9.9-27.4%), rising to 22.9% (95% CI: 14.5-32.4%) in patients admitted to intensive care (ICU). The most contemporary data are from a cohort of 1114 patients (715 outpatient, 399 hospitalised, 170 admitted to ICU). With robust COVID-19-specific therapies and widespread thromboprophylaxis the prevalence of venous TE in ICU patients was reported as 7% (n = 12) when catheter-/device-related events were excluded, and among the outpatients there was no TE reported. No published studies have used nationwide data to investigate TE during the pandemic or the effect of the pandemic on outcomes of patients with TE but without Covid-19. Added value of this study This retrospective multi-sourced nationwide unlinked cohort study compares the overall incidence and mortality of TE prior to and during the COVID-19 pandemic. We found an increased incidence of TE despite only a small proportion having a diagnosis of COVID-19. This may highlight the lack of testing, particularly in the community during the initial phase of the pandemic, and the possibility of other factors contributing to TE risk, such as decreased daily activity mandated by home quarantine and alterations in medication concordance. Mortality from TE was higher in the community during the pandemic and this highlights that adverse societal effects of the pandemic, such as aversion to seeking medical assessment, may precipitate worse outcomes related to TE. Implications of all the available evidence Evidence suggests that COVID-19 produces a hypercoagulable state and thromboprophylaxis is recommended in hospitalised patients to prevent excess mortality from TE. Whether to anticoagulate non-hospitalised ambulatory patients with COVID-19 will be answered by ongoing trials. Clinicians should consider the risks posed by decreased daily activity and fear of medical contact, and provide appropriate advice to patients.


Combination of 177Lu-PSMA-617 and External Radiotherapy for the Treatment of Cerebral Metastases in Patients With Castration-Resistant Metastatic Prostate Cancer.
Two castration-resistant prostate cancer patients, both with cerebral and visceral and lymphatic metastases, received multiple cycles of Lu-PSMA-617 treatments. The prognosis of both cases is dependent on brain metastases. Between Lu-PSMA-617 treatment cycles, local radiotherapy was also applied to the brain metastases. Prior to the combined therapy, all systemic metastases, including cerebral lesions, showed PSMA expression using Ga-PSMA PET/CT. Under the combined therapy, all the metastases, particularly the cerebral lesions, showed significant regression in size and PSMA expression over time.


Access to emergency surgical treatment for congenital heart diseases in the state of São Paulo.
To analyze access to surgical care for congenital heart diseases in public specialized centers in the state of São Paulo before and during the COVID-19 pandemic and availability of surgical care in specialized hospitals, to identify bottlenecks in the care path for neonatal cardiac surgery. This study included 1,437 children, under one year old, with congenital heart disease and formal referral to heart surgery between February 1, 2019, and February 28, 2021. Quantitative data analysis was performed using t-tests or the Mann-Whitney test. Approximately 30 % of children with urgent congenital heart disease could not access recommended care, mainly those needing complex surgeries (categories RACHS 4 to 6). The main diagnoses of neonates accessing care were patency of the ductus arteriosus (10.5 %) and coarctation of the aorta (10.1 %). Referral time for children in RACHS 1 to 3 was 4 days (median), while for those in categories 4 to 6, it was 7 days (p < 0.001). Longer referral time (20 days) was associated with court orders. During the pandemic, referral time decreased to 3 days, compared to 5 days (median) in the pre-pandemic period (p < 0.001). The emergency surgical treatment supply for congenital heart diseases is insufficient compared to the current demand. Future research should evaluate if access to care in publicly funded hospitals could be improved by better access to prenatal care for pregnant women, increased diagnostic and therapeutic capacity in pediatric cardiology, and financial incentives for complex cardiac surgeries.


Nucleocytoplasmic shuttling of p53 is essential for MDM2-mediated cytoplasmic degradation but not ubiquitination.
As a shuttling protein, p53 is constantly transported through the nuclear pore complex. p53 nucleocytoplasmic transport is carried out by a bipartite nuclear localization signal (NLS) located at its C-terminal domain and two nuclear export signals (NES) located in its N- and C-terminal regions, respectively. The role of nucleocytoplasmic shuttling in p53 ubiquitination and degradation has been a subject of debate. Here we show that the two basic amino acid groups in the p53 bipartite NLS function collaboratively to import p53. Mutations disrupting individual amino acids in the NLS, although causing accumulation of p53 in the cytoplasm to various degrees, reduce but do not eliminate the NLS activity, and these mutants remain sensitive to MDM2 degradation. However, disrupting both parts of the bipartite NLS completely blocks p53 from entering the nucleus and causes p53 to become resistant to MDM2-mediated degradation. Similarly, mutations disrupting four conserved hydrophobic amino acids in the p53 C-terminal NES block p53 export and prohibit it from MDM2 degradation. We also show that colocalization of a nonshuttling p53 with MDM2 either in the nucleus or in the cytoplasm is sufficient for MDM2-induced p53 polyubiquitination but not degradation. Our data provide new insight into the mechanism and regulation of p53 nucleocytoplasmic shuttling and degradation.


Methods for isolation of cell-free plasma DNA strongly affect DNA yield.
Extracellular nucleic acids are present in plasma, serum, and other body fluids and their analysis has gained increasing attention during recent years. Because of the small quantity and highly fragmented nature of cell-free DNA in plasma and serum, a fast, efficient, and reliable isolation method is still a problem and so far there is no agreement on a standardized method. We used spin columns from commercial suppliers (QIAamp DNA Blood Midi Kit from Qiagen; NucleoSpin Kit from Macherey-Nagel; MagNA Pure isolation system from Roche Diagnostics) to isolate DNA from 44 plasma samples in parallel at laboratories in Berlin and Munich. DNA in all samples was quantified by real-time PCR on a LightCycler 480 using three different targets (GAPDH, ß-globin, ERV). The quantities of cell-free DNA for the different isolation methods and genes varied between medians of 1.6 ng/mL and 28.1 ng/mL. This considerable variation of absolute DNA values was mainly caused by the use of different isolation methods (p<0.0001). Comparable results were achieved by the use of the genes GAPDH and ERV while higher values were obtained by use of ß-globin. The laboratory site had only minor influence on DNA yield when manual extraction methods were used.


Connectome-based individualized prediction of temperament trait scores.
Temperament consists of multi-dimensional traits that affect various domains of human life. Evidence has shown functional connectome-based predictive models are powerful predictors of cognitive abilities. Putatively, individuals' innate temperament traits may be predictable by unique patterns of brain functional connectivity (FC) as well. However, quantitative prediction for multiple temperament traits at the individual level has not yet been studied. Therefore, we were motivated to realize the individualized prediction of four temperament traits (novelty seeking [NS], harm avoidance [HA], reward dependence [RD] and persistence [PS]) using whole-brain FC. Specifically, a multivariate prediction framework integrating feature selection and sparse regression was applied to resting-state fMRI data from 360 college students, resulting in 4 connectome-based predictive models that enabled prediction of temperament scores for unseen subjects in cross-validation. More importantly, predictive models for HA and NS could be successfully generalized to two relevant personality traits for unseen individuals, i.e., neuroticism and extraversion, in an independent dataset. In four temperament trait predictions, brain connectivities that show top contributing power commonly concentrated on the hippocampus, prefrontal cortex, basal ganglia, amygdala, and cingulate gyrus. Finally, across independent datasets and multiple traits, we show person's temperament traits can be reliably predicted using functional connectivity strength within frontal-subcortical circuits, indicating that human social and behavioral performance can be characterized by specific brain connectivity profile.


Relationship of body mass index and prostate specific antigen in a population-based study.
This study was designed to use a prospectively analyzed, population-based, multiethnic cohort of men to determine if there is a relationship between one measure of obesity/overweight (Body Mass Index) and Prostate Specific Antigen (PSA). A total of 1565 men without a prior diagnosis of prostate cancer were prospectively enrolled in the San Antonio study of Biomarkers Of Risk (SABOR) Clinical and Epidemiologic Center of the Early Detection Research Network of the National Cancer Institute. Body Mass Index (BMI) was compared with serum PSA levels, stratifying by ethnic group. No relationship was found between BMI and PSA in any ethnic group or in the cohort as a whole. This study suggests that there is no increased risk of overdetection of prostate cancer among obese men due to an elevation in PSA.


An aid to the management of pediatric trauma in peripheral centers--a proposal for a pediatric trauma board.
In 1986, 630,000 children under the age of 15 were living in Queensland. This accounted for 17% of Australia's pediatric population. That year there were 39 pediatric deaths in Queensland resulting from road traffic incidents. Another 408 injured children were admitted to hospital. Less than 20% of these children were treated in an accident and emergency (A&E) department staffed by a qualified pediatrician. Only 35% of the A&E departments were staffed by a qualified emergency physician. A Pediatric Trauma Board is proposed, which will lead to improvement in the care of injured or critically ill pediatric patients. This board is made of pre-marked whiteboard and includes normal pediatric values and replacement fluid flow charts; it is approximately three feet in height and six feet in width. The Board is aimed primarily at nonpediatric clinicians who may or may not be specifically trained or interested in emergency medicine. It provides quick, easy access to the normal values of vital signs for children of different ages and sizes. It enables accurate calculation of the fluid requirements for resuscitation and provides a means for following the response to this therapy. Drug doses per weight are provided. A copy of the board can be made on size A4 photostats for inclusion in the hospital chart as part of the admission notes.


Research in college health. I: An introduction to the research process.
College health professionals are often intimidated by the research process and thus miss opportunities to develop and communicate their ideas. The present article, the first in a series on college health research, describes the basics of the research process, including the purpose and nature of research and the ways in which ideas are developed into research hypotheses. The process of reviewing research literature is described in detail, including methods for computerized searching.


Narratives of Gender, Sexuality, and Community in Three Generations of Genderqueer Sexual Minorities.
Genderqueer identities-those that challenge a strict binary between woman and man-are increasingly visible within mainstream culture and psychological research. However, little is known about generational differences in the lived experience of genderqueer people. Inductive thematic analysis of interviews with 30 genderqueer sexual minorities of 3 distinct generations living the United States revealed 3 major themes: (a) unintelligibility: genderqueer people face challenges in identifying, naming, and expressing their gender due to the constraints of everyday language and material culture; (b) managing stigma through challenging oppression: genderqueer people manage stigma by naming and challenging the gender binary, often in relation to other forms of oppression; and (c) connection beyond mainstream LGBTQ communities: genderqueer people often find connection outside of mainstream LGBTQ spaces, such as through ethnicity-based or sexual subcommunities (e.g., kink/BDSM, polyamorous). Within these themes, key generational patterns included (a) greater challenges among the middle and older generations in naming and expressing a genderqueer identity, especially in relation to their sexual identity; (b) intensified critique of mainstream LGBTQ politics among the younger generation; and (c) greater challenges in finding and maintaining community among the middle and older generations. Across generations, participants emphasized the need to create more inclusive environments by changing language and social structures to deemphasize the gender binary.


Cognitive effort decreases beta, alpha, and theta coherence and ends afterdischarges in human brain.
Mental activation has been reported to modify the occurrence of epileptiform activity. We studied its effect on afterdischarges. In 15 patients with implanted electrodes we presented cognitive tasks when afterdischarges occurred. We developed a wavelet cross-coherence function to analyze the electrocorticography before and after the tasks and compared findings when cognitive tasks did or did not result in afterdischarge termination. Six patients returned for functional MRI (fMRI) testing, using similar tasks. Cognitive tasks often could terminate afterdischarges when direct abortive stimulation could not. Wavelet cross-coherence analysis showed that, when afterdischarges stopped, there was decreased coherence throughout the brain in the 7.13-22.53 Hz frequency ranges (p values 0.008-0.034). This occurred a) regardless of whether an area activated on fMRI and b) regardless of whether there were afterdischarges in the area. It is known that cognitive tasks can alter localized or network synchronization. Our results show that they can change activity throughout the brain. These changes in turn can terminate localized epileptiform activity. Cognitive tasks result in diffuse brain changes that can modify focal brain activity. Combined with a seizure detection device, cognitive activation might provide a non-invasive method of terminating or modifying seizures.


The role of color cues in facilitating accurate and rapid location of aided symbols by children with and without down syndrome.
This research examined how the color distribution of symbols within a visual aided augmentative and alternative communication array influenced the speed and accuracy with which participants with and without Down syndrome located a target picture symbol. Eight typically developing children below the age of 4 years, 8 typically developing children over the age of 4 years, and 10 children with Down syndrome participated. Participants were asked to find a target line drawing among an array of 12. Line drawings represented either foods (e.g., grapes, cherries), clothing (e.g., a red shirt, a yellow shirt), or activities (e.g., soccer, swimming). In one condition, symbols that shared a color were clustered together, creating a subgroup within which to search. In another condition, symbols that shared a color were distributed across the display, allowing each to appear individually. Dependent measures were accuracy and speed of finding the target symbol. Clustering same-color symbols facilitated the speed of locating the target for all participants, and facilitated search accuracy in the younger preschool children and participants with Down syndrome. These effects held when targets were foods, clothing, or activities. Clinicians should consider the internal color of visual symbols when constructing aided symbol displays, at least for children with Down syndrome. Further research is needed on a number of dimensions, however, including visual processing in other etiological categories, the role of background color, and the relation of color to other stimulus dimensions.


Shortest path choice in zebrafish (Danio rerio).
Many animals regularly move between different locations within their home range. During these journeys, individuals are expected to use the shortest path, because this strategy minimizes energy expenditure and reduces exposure to adverse conditions, such as predation. The ability to find the shortest distance route has been demonstrated in ants, migrating birds and a few mammals. We investigated whether a freshwater fish, Danio rerio, exhibits this ability. Small groups of zebrafish were allowed to move between the two compartments of their tank using two paths differing in length. They developed a preference for the shorter path gradually over the six days of the experiment. Subjects' accuracy in choosing the shorter path varied from below 60%, with a 20% length disparity, to 80% when one path was twice as long as the other. In a second experiment, zebrafish were initially allowed to practice in groups and then tested individually. We found evidence of individual and sex differences in performance, with males performing more accurately than females. However, due to our experimental design, we cannot conclusively determine whether these differences are indeed cognitive or influenced by confounding factors during the group phase of the experiment.


Repeated long-term potentiation induces mossy fibre sprouting and changes the sensibility of hippocampal granule cells to subconvulsive doses of pentylenetetrazol.
Electrical and chemical kindling induces sprouting of the mossy fibre system and potentiation of evoked field potentials in the dentate gyrus. It has been postulated that such changes may also be induced by repeated induction of long-term potentiation (LTP) with tetanic stimulation of the perforant pathway. LTP was induced in rats chronically implanted with stimulation electrodes in the ipsilateral and contralateral angular bundles and with a recording electrode in the ipsilateral dorsal dentate gyrus. The animals were stimulated 10 times on 10 consecutive days but with different tetanization strengths. Sprouting of the mossy fibres terminating in the CA3 region was significantly induced only in the group of 'strongly' tetanized animals, but not in that of 'weakly' tetanized animals, or in low-frequency stimulated animals. Additionally, a novel form of potentiation which was previously found in pentylenetetrazol (PTZ)-kindled animals was also observed in the group of 'strongly' and 'weakly' tetanized rats. Differences in duration of this potentiation were found between the two groups of animals tetanized with different strengths. The results further demonstrate that morphological and functional changes in the hippocampus, similar to those seen after kindling, can also occur in an activation paradigm leading to long-lasting synaptic plasticity but not accompanied by seizure activity.


Ocular disposition, pharmacokinetics, efficacy and safety of nanoparticle-formulated ophthalmic drugs.
Ophthalmic drugs are delivered to ocular tissues predominantly via relatively simple formulations, such as topically dosed water-soluble drug solutions and water-insoluble drug suspensions in ointments. An ideal topical drug delivery system should possess certain desirable properties, such as good corneal and conjunctival penetration, prolonged precorneal residence time, easy instillation, non-irritative and comfortable to minimize lachrymation and reflex blinking, and appropriate rheological properties. In general, ocular efficacy is closely related to ocular drug bioavailability, which may be enhanced by increasing corneal drug penetration and prolonging precorneal drug residence time. To improve ocular bioavailability of topically dosed ophthalmic drugs, a variety of ocular drug delivery systems, such as hydrogels, microparticles, nanoparticles, microemulsions, liposomes and collagen shields, have been designed and investigated. These newer systems may, to some extent, control drug release and maintain therapeutic levels in ocular tissues over a prolonged period of time. This review focuses on the in vitro, ex vivo and in vivo studies of ophthalmic drugs formulated in nanoparticles published over the past two decades. The progress and development issues relating to ocular disposition, pharmacokinetics, efficacy and safety of the nanoparticle-formulated ophthalmic drugs are specifically addressed. Information and discussions summarized in this review are helpful for pharmaceutical scientists to develop better ophthalmic therapeutics.


A novel rind puncture technique to measure rind thickness and diameter in plant stalks.
Measurements of rind and culm thickness and stem radius/diameter are important to biomechanical, ecological and physiological plant studies. However, many methods of measuring rind thickness and diameter are labor intensive and induce plant fatality. A novel rind puncture methodology for obtaining measurements of rind thickness and diameter has been developed. The suitability of the new method for implementation in plant studies is presented. The novel rind puncture technique was used to obtain measurements of rind thickness and diameter for samples of Poison Hemlock (Conium maculatum). The rind puncture measurements were strongly correlated with caliper measurements (R2 > 0.97) and photographic image analysis measurements (R2 > 0.84). The capacity for high throughput measurements using the rind puncture technique was determined to exceed that of caliper measurements and image analysis techniques. The rind puncture technique shows promise as a high throughput method for determining rind thickness and diameter as it is cost effective and non-lethal. The authors are currently working to develop a custom handheld apparatus to allow the novel rind puncture method to be used in field work. High throughput field-based measurements of rind thickness and diameter are needed to help address the problem of stalk lodging (failure of grain crops to remain upright until harvest).


Anthropology in public health emergencies: what is anthropology good for?
Recent outbreaks of Ebola virus disease (2013-2016) and Zika virus (2015-2016) bring renewed recognition of the need to understand social pathways of disease transmission and barriers to care. Social scientists, anthropologists in particular, have been recognised as important players in disease outbreak response because of their ability to assess social, economic and political factors in local contexts. However, in emergency public health response, as with any interdisciplinary setting, different professions may disagree over methods, ethics and the nature of evidence itself. A disease outbreak is no place to begin to negotiate disciplinary differences. Given increasing demand for anthropologists to work alongside epidemiologists, clinicians and public health professionals in health crises, this paper gives a basic introduction to anthropological methods and seeks to bridge the gap in disciplinary expectations within emergencies. It asks: 'What can anthropologists do in a public health crisis and how do they do it?' It argues for an interdisciplinary conception of emergency and the recognition that social, psychological and institutional factors influence all aspects of care.


Ten Years of Simulation in Healthcare: A Thematic Analysis of Editorials.
In this commentary, I review 38 articles published as editorials in Simulation in Healthcare from inception to April 2016. Of the 27 authors, there was a predominance of medical doctors (63%), male authors (67%), and work originating in the United States (86%). The founding Editor-in-Chief Dr David Gaba contributed to half of the editorials. Using inductive thematic analysis, the following five themes were identified: "embedding" simulation, simulation responding to clinical practice, educational considerations for simulation, research practices, and communicating leadership and scholarship about the community. After thematic analysis, the theoretical notion of communities of practice was used to make further meaning of the themes. This theorizing process reveals that editorial content aligns with the features of an evolving community of practice. The editorials seem to have responded to and shaped contemporary simulation practices. The editorial is a powerful forum in which to frame issues relevant to the healthcare simulation community. As the founding Editor-in-Chief, Gaba has made an extraordinary contribution to the Society for Simulation in Healthcare, in these editorials and the broader healthcare simulation community. Under the leadership of the Editor-in-Chief, Dr Mark Scerbo, I am confident that the editorial voice will continue in the true spirit of scholarship.


Is it all the X: familial learning dysfunction and the impact of behavioral aspects of the phenotypic presentation of XXY?
The behavioral phenotype of children with XXY has not been extensively studied until recently and this research has been confounded by insufficient study populations and ascertainment biases. The aim of the study was to expand the behavioral aspect of the XXY phenotype as well as investigate the role of existing familial learning disabilities (FLD) on behavioral problems. Behavioral phenotype of XXY includes social anxiety, ADHD, social communication, and atypical peer interactions. The Child Behavior Checklist (CBCL), Social Responsiveness Scale (SRS), and Gilliam Autism Rating Scale (GARS) were completed by the parents of 54 boys with XXY who had not received hormonal replacement prior to participation. Our findings suggest fewer behavioral deficits and lower severity in the general 47,XXY population than previously published and found significant differences between the groups with a positive FLD on the behavioral assessments. Findings demonstrate that boys with FLD exhibit an increased incidence and severity of behavioral problems. Our study expands on the findings of Samango-Sprouse et al. [Samango-Sprouse et al. (2012b) J Intellect Disabil Res] and the significant influence that FLD has on not only neurodevelopment, but also behavioral deficits. Our study suggests that part of the XXY phenotypic profile may be modulated by FLD. Further study is underway to examine the interaction between the many salient factors effecting behavioral and neurodevelopmental progression in XXY and variant forms. © 2013 Wiley Periodicals, Inc.


[Acid-soluble collagen in the skin of rats who received a tryptophan load and were kept on a protein-free diet].
Crystalline preparations of acid-soluble collagen of rat skin in norm and with tryptophan load against a background of the protein-free diet were fractionated by differential salting out using NaCl in concentrations corresponding to precipitation zones of collagen 1,3 and 4. Amino acid composition, electrophoretic mobility in polyacrylamide gel, profiles of elution from CM-cellulose, content of the carbohydrate component and--S--S-bonds were studied in proteins of the mentioned fractions and in the precipitate insoluble after the pepsin action. Essential differences as compared to the normal level in the amino acid composition and elution profiles were detected in the fraction corresponding to collagen I. Quantitative changes in the carbohydrate component and--S--S-bonds occur due to the fraction inaccessible to the persin action.


Reversal of Oral Anticoagulants for Intracerebral Hemorrhage Patients: Best Strategies.
In patients with acute intracerebral hemorrhage (ICH), one of the major concerns is ongoing bleeding or ICH expansion. Anticoagulated patients are at higher risk of ongoing expansion and worse outcome. It may be that rapid anticoagulation reversal can reduce the risk of expansion and improve clinical outcome. For those taking coumarins, the best available evidence suggests that intravenous vitamin K combined with four-factor prothrombin complex concentrate (4F-PCC) is the most rapid and effective regimen to restore hemostasis. For those on dabigatran, the highest quality data available for reversal are for idarucizumab, although it is not yet clear whether patients derive clinical benefit from this reversal. In the absence or failure of idarucizumab, activated prothrombin complex concentrate (aPCC) is recommended. For those on factor Xa inhibitors, the ideal reversal agent is not clear. Many providers use 4F-PCC or aPCC, but more specific agents are in clinical trials and may soon be available. In addition, the half-lives of the non-vitamin K antagonists are relatively short compared with warfarin, and so some patients may not have a clinically relevant coagulopathy at the time of presentation. Overall, the optimal reversal agent, when one is required, is a function of which anticoagulant the patient is taking.


Escherichia coli arabinose isomerase and Staphylococcus aureus tagatose-6-phosphate isomerase: which is a better template for directed evolution of non-natural substrate isomerization?
Metallic and non-metallic isomerases can be used to produce commercially important monosaccharides. To determine which category of isomerase is more suitable as a template for directed evolution to improve enzymes for galactose isomerization, L-arabinose isomerase from Escherichia coli (ECAI; E.C. 18.104.22.168) and tagatose-6-phosphate isomerase from Staphylococcus aureus (SATI; E.C. 184.108.40.206) were chosen as models of a metallic and non-metallic isomerase, respectively. Random mutations were introduced into the genes encoding ECAI and SATI at the same rate, resulting in the generation of 515 mutants of each isomerase. The isomerization activity of each of the mutants toward a non-natural substrate (galactose) was then measured. With an average mutation rate of 0.2 mutations/kb, 47.5% of the mutated ECAIs showed an increase in activity compared with wild-type ECAI, and the remaining 52.5% showed a decrease in activity. Among the mutated SATIs, 58.6% showed an increase in activity, whereas 41.4% showed a decrease in activity. Mutant clones showing a significant change in relative activity were sequenced and specific increases in activity were measured. The maximum increase in activity achieved by mutation of ECAI was 130%, and that for SATI was 190%. Based on these results, the characteristics of the different isomerases are discussed in terms of their usefulness for directed evolution of non-natural substrate isomerization.


Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin.
One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator-activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response.


Metastatic Melanoma With Papillary Features: A Mimic and Possible Diagnostic Pitfall.
Papillary and pseudopapillary features are histopathologic findings typically associated with carcinomas (thyroid, pancreas, breast, prostate, bladder, kidney, or ovary) or mesothelioma. Melanoma is typically composed of nested and variably pigmented atypical cells. Here, we report a case of in-transit metastasis of melanoma presenting with prominent papillary features, and we discuss the differential diagnoses of neoplasms with papillary features. This case report suggests that the spectrum of neoplasms with papillary features should be expanded to include melanoma, a pattern that, to the best of our knowledge, is uncommon.


Prevalence of chronic pain after spinal cord injury: a systematic review and meta-analysis.
The reported prevalence of chronic pain after spinal cord injury (SCI) varies widely due, in part, to differences in the taxonomy of chronic pain. A widely used classification system is available to describe subcategories of chronic pain in SCI, but the prevalence of chronic pain in SCI based on this system is unknown. The primary objective of this systematic review and meta-analysis is to determine the prevalence of chronic pain after SCI based on the International Spinal Cord Injury Pain (ISCIP) classification system. A comprehensive search of databases from January 1980 to August 2019 was conducted. The risk of bias was assessed using a modified tool developed for uncontrolled studies. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to assess certainty in prevalence estimates. A total of 1305 records were screened, and 37 studies met inclusion criteria. The pooled prevalence of overall chronic pain was 68% (95% CI 63% to 73%). The pooled prevalence of neuropathic pain in 13 studies was 58% (95% CI 49% to 68%); the pooled prevalence of musculoskeletal pain in 11 studies was 56% (95% CI 41% to 70%); the pooled prevalence of visceral pain in 8 studies was 20% (95% CI 11% to 29%) and the pooled prevalence of nociceptive pain in 2 studies was 45% (95% CI 13% to 78%). Meta-regression of risk of bias (p=0.20), traumatic versus non-traumatic etiology of injury (p=0.59), and studies where pain was a primary outcome (p=0.32) demonstrated that these factors were not significant moderators of heterogeneity. Certainty in prevalence estimates was judged to be low due to unexplained heterogeneity. This systematic review and meta-analysis extends the findings of previous studies by reporting the prevalence of chronic pain after SCI based on the ISCIP classification system, thereby reducing clinical heterogeneity in the reporting of pain prevalence related to SCI.


The dehydrins gene expression differs across ecotypes in Norway spruce and relates to weather fluctuations.
Norway spruce has a broad natural distribution range, which results in a substantial variety of its physiological and genetic variation. There are three distinct altitudinal ecotypes described in this tree species. The physiological optimum of each ecotype may be shifted due to ongoing climate change, especially in traits associated with water demand that might be crucial for adaptation. Dehydrins are proteins that help to mitigate the adverse effects of dehydration. Dehydrin gene expression patterns appeared to be a suitable marker for plant stress assessment. Genetically determined differences in response between individuals and populations were formerly studied, however, mainly in controlled conditions. We evaluated ecotypic variation in dehydrin gene expression in a clonal bank comprised of all three ecotypes. A genetic relationship among targeted trees was uncovered utilizing GBS (Genotyping by Sequencing) platform. We sampled 4-6 trees of each ecotype throughout 15 months period. Subsequently, we assessed the RNA expression of dehydrin genes by qRT-PCR. For this study, we deliberately selected dehydrins from different categories. Our findings detected significant differences among ecotypes in dehydrin expression. The association of recorded climatic variables and individual gene expression across the study period was evaluated and revealed, for certain genes, a correlation between dehydrin gene expression and precipitation, temperature, and day-length.


Physiological, subjective, and behavioural responses during sleep to noise from rail and road traffic.
An interdisciplinary study was performed to examine the difference between road and rail traffic noise with regard to physiological, subjective, and behavioural responses. In 8 areas where either rail or road noise prevailed, a total of 1 600 persons (18 to 70 years of age) were interviewed; a subgroup of 377 persons was examined during 2 times 5 nights each. In this sleep observation period noise impact and body movements were recorded continuously during each night. Every morning the subjects stated the position of the windows during the night, they evaluated the qualitative and quantitative parameters of sleep and performed a 4-choice reaction time test. Only the behaviour to sleep with open or closed windows was significantly associated with the rating level and the windows were significantly more often closed by the residents primarily exposed to road noise. Whether this indicates a reaction to noise or to concomitant pollutants such as odour is, however, debatable. The fact that none of the other data recorded here revealed any difference between the two types of noise is discussed in view of future studies.


Radiation exposure in total ankle replacement.
Radiation exposure from diagnostic imaging procedures is associated with increased cancer risk. No published data currently exist regarding ionizing radiation exposure in total ankle replacement surgery. This study quantified intraoperative fluoroscopic dose and duration during ankle replacement surgery and examined patient and technical factors affecting the level of exposure. Fifty-five patients underwent ankle replacement using STAR, Salto-Talaris, or INBONE total ankles. Intraoperative fluoroscopic dose and duration, patient demographics, implant design, and accompanying additional procedures were documented for each case. The relationship between each relevant variable and radiation dose and time was determined. The mean fluoroscopic dose and duration for all cases were 1.15 ± 0.84 milliGray per case and 77 ± 34 seconds per case, respectively. There was a positive correlation between the absorbed radiation dose and the duration of fluoroscopy (r = .50, P < .001). The mean fluoroscopic doses were 1.53 milliGray, 0.99 milliGray, and 0.88 milliGray for INBONE, STAR, and Salto-Talaris prostheses, respectively. Fluoroscopic dose was significantly influenced by implant design (P = .035), with implants using an intramedullary referencing guide associated with higher radiation doses. After excluding cases requiring additional procedures, the fluoroscopic time and radiation dose associated with intramedullary referencing guide implants continued to exceed those of the other implants, but the differences were no longer statistically significant (P = .22, P = .09, respectively). The average patient radiation dose during total ankle replacement was approximately one-fifth the recommended maximum yearly radiation exposure. The radiation dose was positively associated with fluoroscopy duration. Among factors controllable by the surgeon, selection of an implant with an extramedullary alignment system and conscious effort to minimize duration of fluoroscopy can reduce harmful radiation exposure and decrease cancer risk in total ankle replacement patients and associated operating room personnel. Level III, comparative series.


Structure and Orientation of the SARS-Coronavirus-2 Spike Protein at Air-Water Interfaces.
The SARS coronavirus 2 (SARS-CoV-2) spike protein is located at the outermost perimeter of the viral envelope and is the first component of the virus to make contact with surrounding interfaces. The stability of the spike protein when in contact with surfaces plays a deciding role for infection pathways and for the viability of the virus after surface contact. While cryo-EM structures of the spike protein have been solved with high resolution and structural studies in solution have provided information about the secondary and tertiary structures, only little is known about the folding when adsorbed to surfaces. We here report on the secondary structure and orientation of the S1 segment of the spike protein, which is often used as a model protein for in vitro studies of SARS-CoV-2, at the air-water interface using surface-sensitive vibrational sum-frequency generation (SFG) spectroscopy. The air-water interface plays an important role for SARS-CoV-2 when suspended in aerosol droplets, and it serves as a model system for hydrophobic surfaces in general. The SFG experiments show that the S1 segment of the spike protein remains folded at the air-water interface and predominantly binds in its monomeric state, while the combination of small-angle X-ray scattering and two-dimensional infrared spectroscopy measurements indicate that it forms hexamers with the same secondary structure in aqueous solution.


Calibration of random dot stereograms and correlograms free of monocular cues.
Dynamic random dot stereograms (DRDSs) and correlograms (DRDCs) are cyclopean stimuli containing binocular depth cues that are ideally, invisible by one eye alone. Thus, they are important tools in assessing stereoscopic function in experimental or ophthalmological diagnostic settings. However, widely used filter-based three-dimensional display technologies often cannot guarantee complete separation of the images intended for the two eyes. Without proper calibration, this may result in unwanted monocular cues in DRDSs and DRDCs, which may bias scientific or diagnostic results. Here, we use a simple mathematical model describing the relationship of digital video values and average luminance and dot contrast in the two eyes. We present an optimization algorithm that provides the set of digital video values that achieve minimal crosstalk at user-defined average luminance and dot contrast for both eyes based on photometric characteristics of a given display. We demonstrated in a psychophysical experiment with color normal participants that this solution is optimal because monocular cues were not detectable at either the calculated or the experimentally measured optima. We also explored the error by which a range of luminance and contrast combinations can be implemented. Although we used a specific monitor and red-green glasses as an example, our method can be easily applied for other filter based three-dimensional systems. This approach is useful for designing psychophysical experiments using cyclopean stimuli for a specific display.


DNA copy number amplifications in sarcomas with homogeneously staining regions and double minutes.
To identify DNA amplifications in sarcomas, comparative genomic hybridization was performed on 27 cases that were likely to display high-level DNA copy number gains. In all cases, chromosome banding analysis had revealed homogeneously staining regions or double minutes, i.e., cytogenetic signs of gene amplification. In most cases, gains predominated over losses. Low-level amplifications (ratio 1.3:1.5) were seen in 20 cases. High-level amplifications (ratio >1.5) exceeded the frequencies seen in published, unselected sarcomas of similar histotypes and were detected in 16 tumors: 4/4 osteosarcomas, 5/8 malignant fibrous histiocytomas, 3/7 leiomyosarcomas, 1/2 myosarcomas, 0/1 liposarcoma, 0/1 rhabdomyosarcoma, 1/1 pleomorphic sarcoma, 0/1 myxofibrosarcoma, 1/1 malignant mesenchymona, and 1/1 malignant schwannoma, with two to four chromosomal regions involved in nine tumors. Recurrent amplifications involved 1p33-p32, 5p15-p14, 7pter-p12, 7q21-qter, 8q21.3-qter, 11q22-q23, 16p13.2-p12, 19q12-q13.1, 20q11.2-qter, and 22q12-q13. Most of the recurrent gains/amplifications we detected have been reported in sarcomas previously. A novel gain/amplification was seen at 2q14.3-q21 in five cases of four sarcoma types. The disparate pattern of amplified sequences, the poor correspondence between the localization of low- and high-level amplifications, and the chromosomal position of homogeneously staining regions suggest the involvement of many genes in the amplifications and that the genes rarely maintain their native position in these tumors.


[Assessment of pain relief in patients receiving different variants of multimodal analgesia after major gynecological surgery].
The major gynecology surgery generally results in severe postoperative pain. Currently multimodal analgesia concept is widely used for the aim of postoperative pain relief optimization. According to this theory it is worth using the medication with different mechanism in order to increase analgesia qualify, decrease analgesic consumption and avoid adverse reaction. Unfortunately the surveys recently conducted have been pointed out the postoperative analgesia quality is still insufficient despite of using the concept mentioned above. One way to solve the problem is appearing in daily practice nefopam--centrally acting non-opioid analgesic that inhibits reuptake of serotonin, norepinephrine, and dopamine and also mitigates glutamatergic neurotransmission. In this trial we tried to assess the postoperative daily used analgesia quality and potency of preemptive multimodal analgesia model consisted of nefopam, ketoprofen, paracetamol and morphine.


[Autoradiography of protein synthesis as a method of assessment of morphofunctional changes in brain structures].
A combination of two groups of autoradiography technique (for a hole brain and individual cells) was applied with using 3H-leucine to evaluate the changes of brain functional activity on the level as anatomical structures and as different type neurons. It was found that Wistar rats with lowered motor activity induced by 3-4 weeks treatment with L-DOPA 100 mg/kg displayed the motor nuclei of the brain stem the cerebellum as highly labelled structures and the motor cortex and n. caudatus as feebly ones in comparison with control. However, a quantitative assessment of silver grains over the neurons of layers III and V of motor cortex and n. caudatus showed not only a significant increase of labelling, especially in neurons of layer V on 174%, in comparison with control but revealed unequal labelling of different type neurons. It was concluded that the applied two groups of autoradiography technique can be a useful approach to assess the brain functional activity.


Glucose homeostasis in rats treated acutely and chronically with quinine.
Glucose homeostasis in normal rats was studied after chronic or acute administration of quinine. Male rats received a daily dose of 10-30 mg/kg of quinine in the drinking water for 20 weeks. The high dose caused a slight decrease in food intake and weight gain. Though basal plasma insulin levels were increased in treated rats, their plasma glucose levels were only slightly and not consistently decreased. After oral or intravenous administration of glucose, the plasma insulin levels were higher and the disappearance rate of glucose was greater in rats receiving quinine than in the controls. The insulin content of the pancreas was not affected by quinine treatment. Intraperitoneal injection of a high dose of quinine (30 mg/kg) transiently increased plasma glucose and insulin levels. The insulin response was increased during a subsequent administration of glucose but the glucose levels were not modified. This study shows that chronic administration of quinine increases plasma insulin levels, accelerates disposal of oral or intravenous glucose but does not cause hypoglycaemia in normal rats.


Cost-effectiveness of continuous positive airway pressure therapy for obstructive sleep apnea: health care system and societal perspectives.
To determine cost-effectiveness of continuous positive airway pressure (CPAP) treatment of obstructive sleep apnea (OSA) in Australia for 2017-2018 to facilitate public health decision-making. Analysis was undertaken of direct per-person costs of CPAP therapy (according to 5-year care pathways), health system and other costs of OSA and its comorbidities averted by CPAP treatment (5-year adherence rate 56.7%) and incremental benefit of therapy (in terms of disability-adjusted life years [DALYs] averted) to determine cost-effectiveness of CPAP. This was expressed as the incremental cost-effectiveness ratio (= dollars per DALY averted). Direct costs of CPAP were estimated from government reimbursements for services and advertised equipment costs. Costs averted were calculated from both the health care system perspective (health system costs only) and societal perspective (health system plus other financial costs including informal care, productivity losses, nonmedical accident costs, deadweight taxation and welfare losses). These estimates of costs (expressed in US dollars) and DALYs averted were based on our recent analyses of costs of untreated OSA. From the health care system perspective, estimated cost of CPAP therapy to treat OSA was $12 495 per DALY averted while from a societal perspective the effect was dominant (-$10 688 per DALY averted) meaning it costs more not to treat the problem than to treat it. These estimates suggest substantial community investment in measures to more systematically identify and treat OSA is justified. Apart from potential health and well-being benefits, it is financially prudent to do so.


Pathophysiology of contrast medium-induced nephropathy.
Contrast medium-induced nephropathy (CIN) is a well-known cause of acute renal failure, but the development of CIN remains poorly understood. A number of studies have been performed with the one aim, to shed some light onto the pathophysiology of CIN. These have led to manifold interpretations and sometimes contradicting conclusions. This review critically surveys mechanisms believed to mediate CIN by highlighting the complex pathophysiologic entity, including altered rheologic properties, perturbation of renal hemodynamics, regional hypoxia, auto- and paracrine factors [adenosine, endothelin, and reactive oxygen species (ROS)], and direct cytotoxic effects. Moreover, the importance of physicochemical properties of contrast media are made clear. The more recently developed iso-osmolar contrast media are dimers, not monomers as the widely used nonionic low osmolar contrast media. The dimers have physicochemical features different from other contrast media which may be of clinical importance, not only with respect to osmolality. The viscosity of the commercially available dimers is considerably higher than blood. Many experimental studies provide evidence for a greater perturbation in renal functions by dimeric contrast media in comparison to nonionic monomeric contrast media. Clinical trials have yielded conflicting results.


Effects of GABA receptor blockade on the ventilatory response to hypoxia in hypothermic newborn piglets.
Hypothermic newborn piglets have a depressed ventilatory response to hypoxia, and this may be due to an increase in CNS gamma-aminobutyric acid (GABA) levels. To evaluate the effects of GABA(A) receptor blockade on the ventilatory response to hypoxia in hypothermic piglets, 31 anesthetized paralyzed mechanically ventilated newborn piglets (2-7 d) were studied at a brain temperature of 38.5 +/- 0.5 degrees C [normothermia (NT), n = 15] or 34 +/- 0.5 degrees C [hypothermia (HT), n = 16]. The central respiratory output was evaluated by measuring burst frequency and moving time average area of phrenic nerve activity. Measurements of minute phrenic output (MPO), arterial blood pressure, heart rate, oxygen consumption, and arterial blood gases were obtained at room air and during 20 min of isocapnic hypoxia [fraction of expired oxygen (FiO2) = 0.10]. After 10 min of hypoxia, a bolus injection of 20 microL of bicuculline methiodide (BM; 10 microg) or Ringer's solution was administered into the cisterna magna over a 1-min period, and the piglets remained in hypoxia for an additional 10 min. There was an initial increase of 50 +/- 6% in MPO during the first minute of hypoxia followed by a decrease to values 24 +/- 8% above baseline at 10 min in the NT group. In contrast, in the HT group, the initial increase in MPO with hypoxia was eliminated, and, at 10 min, there was a decrease to a mean value 35 +/- 4% below baseline level (NT versus HT, p < 0.03). After administration of BM, a significant increase in MPO with hypoxia was observed in both groups compared with their placebo groups (p < 0.002 in NT-BM group, p < 0.0001 in HT-BM group). However, the magnitude of the increase in MPO during hypoxia was significantly greater in the HT group after administration of BM (NT versus HT, p < 0.0001). Changes in oxygen consumption, arterial blood pressure, heart rate, pH, partial pressure of oxygen (PaO2), and base excess with hypoxia were not different between NT and HT groups before and after the administration of BM. The cardiorespiratory response to hypoxia was not modified after administration of Ringer's solution to NT and HT placebo groups. These data suggest that the depression in hypoxic ventilatory response produced by HT is in part modulated by an increased CNS GABA concentration.


STK33 Promotes Growth and Progression of Pancreatic Cancer as a Critical Downstream Mediator of HIF1α.
The serine/threonine kinase STK33 has been implicated in cancer cell proliferation. Here, we provide evidence of a critical role for STK33 in the pathogenesis and metastatic progression of pancreatic ductal adenocarcinoma (PDAC). STK33 expression in PDAC was regulated by the hypoxia-inducible transcription factor HIF1α. In human PDAC specimens, STK33 was overexpressed and associated with poor prognosis. Enforced STK33 expression promoted PDAC proliferation, migration, invasion, and tumor growth, whereas STK33 depletion exerted opposing effects. Mechanistic investigations showed that HIF1α regulated STK33 via direct binding to a hypoxia response element in its promoter. In showing that dysregulated HIF1α/STK33 signaling promotes PDAC growth and progression, our results suggest STK33 as a candidate therapeutic target to improve PDAC treatment. Cancer Res; 77(24); 6851-62. ©2017 AACR.


Measurement of subvisible particulates in lyophilised Erwinia chrysanthemi L-asparaginase and relationship with clinical experience.
In order to generate further characterisation data for the lyophilised product Erwinia chrysanthemi L-asparaginase, reconstituted drug product (DP; marketed as Erwinase or Erwinaze) was analysed for subvisible (2-10 μm) particulate content using both the light obscuration (LO) method and the newer flow-imaging microscopy (FIM) technique. No correlation of subvisible particulate counts exists between FIM and LO nor do the counts correlate with activity at both release and on stability. The subvisible particulate content of lyophilised Erwinia L-asparaginase appears to be consistent and stable over time and in line with other parenteral biopharmaceutical products. The majority (ca. 75%) of subvisible particulates in L-asparaginase DP were at the low end of the measurement range by FIM (2-4 μm). In this size range, FIM was unable to definitively classify the particulates as either protein or non-protein. More sensitive measurement techniques would be needed to classify the particulates in lyophilised L-asparaginase into type (protein and non-protein), so the LO technique has been chosen for on-going DP analyses. E. chrysanthemi L-asparaginase has a lower rate of hypersensitivity compared with native Escherichia coli preparations, but a subset of patients develop hypersensitivity to the Erwinia enzyme. A DP lot that had subvisible particulate counts on the upper end of the measurement range by both LO and FIM had the same incidence of allergic hypersensitivity in clinical experience as lots at all levels of observed subvisible particulate content, suggesting that the presence of L-asparaginase subvisible particulates is not important with respect to allergic response.


Motor cortical activity during drawing movements: population representation during spiral tracing.
Monkeys traced spirals on a planar surface as unitary activity was recorded from either premotor or primary motor cortex. Using the population vector algorithm, the hand's trajectory could be accurately visualized with the cortical activity throughout the task. The time interval between this prediction and the corresponding movement varied linearly with the instantaneous radius of curvature; the prediction interval was longer when the path of the finger was more curved (smaller radius). The intervals in the premotor cortex fell into two groups, whereas those in the primary motor cortex formed a single group. This suggests that the change in prediction interval is a property of a single population in primary motor cortex, with the possibility that this outcome is due to the different properties generated by the simultaneous action of separate subpopulations in premotor cortex. Electromyographic (EMG) activity and joint kinematics were also measured in this task. These parameters varied harmonically throughout the task with many of the same characteristics as those of single cortical cells. Neither the lags between joint-angular velocities and hand velocity nor the lags between EMG and hand velocity could explain the changes in prediction interval between cortical activity and hand velocity. The simple spatial and temporal relationship between cortical activity and finger trajectory suggests that the figural aspects of this task are major components of cortical activity.


[Frontal, or generalized, epilepsy].
The author studied the results of surgical treatment of 28 epileptic patients where the localization of the epileptogenic focus was on the medial surface of the hemisphere in the area of the frontal pole or on the lateral surface. Taking into consideration the theoretical premises, an analysis of literary data and the results of a comprehensive clinical study of patients the author comes to the conclusion that for a localization of the epileptogenic focus in the area of the pole and medio-basal parts of the frontal lobes primary generalized epileptic seizures and distant synchronous bioelectrical activity in the EEG without distinct focal changes are most characteristic.


The effect of methylene blue on the hepatocellular redox state and liver lipid content during chronic ethanol feeding in the rat.
Feeding of ethanol in a liquid diet to male Wistar rats caused decreases in the hepatic cytosolic and mitochondrial [NAD+]/[NADH] ratios. This redox-state change was attenuated after 16 days of feeding ethanol as 36% of the total energy intake. Supplementation of the ethanol-containing liquid diet with Methylene Blue largely prevented the ethanol-induced redox state changes, but did not significantly decrease the severity of the hepatic lipid accumulation that resulted from ethanol ingestion. Methylene Blue did not affect body-weight gain, ethanol intake or serum ethanol concentrations in ethanol-fed rats, nor did the compound influence the hepatic redox state or liver lipid content of appropriate pair-fed control animals. These findings suggest that the altered hepatic redox state that results from ethanol oxidation is not primarily responsible for the production of fatty liver after long-term ethanol feeding in the rat.


Prevalence of caffeine consumers, daily caffeine consumption, and factors associated with caffeine use among active duty United States military personnel.
Although representative data on caffeine intake in Americans are available, these data do not include US service members (SMs). The few previous investigations in military personnel largely involve convenience samples. This cross-sectional study examined prevalence of caffeine consumers, daily caffeine consumption, and factors associated with caffeine use among United States active duty military service members (SMs). A stratified random sample of SMs were asked to complete an on-line questionnaire on their personal characteristics and consumption of caffeinated products (exclusive of dietary supplements). Eighteen percent (n = 26,680) of successfully contacted SMs (n = 146,365) completed the questionnaire. Overall, 87% reported consuming caffeinated products ≥1 time/week. Mean ± standard error per-capita consumption (all participants) was 218 ± 2 and 167 ± 3 mg/day for men and women, respectively. Caffeine consumers ingested 243 ± 2 mg/day (251 ± 2 mg/day men, 195 ± 3 mg/day women). On a body-weight basis, men and women consumed respectively similar caffeine amounts (2.93 vs 2.85 mg/day/kg; p = 0.12). Among individual caffeinated products, coffee had the highest use (68%), followed by sodas (42%), teas (29%), energy drinks (29%) and gums/candy/medications (4%). In multivariable logistic regression, characteristics independently associated with caffeine use (≥1 time/week) included female gender, older age, white race/ethnicity, higher body mass index, tobacco use or former use, greater alcohol intake, and higher enlisted or officer rank. Compared to National Health and Nutrition Examination Survey data, daily caffeine consumption (mg/day) by SMs was higher, perhaps reflecting higher mental and physical occupational demands on SMs.


Cardiac contractility and sarcolemmal calcium binding in several cardiac muscle preparations.
Striking correlations are found between cardiac contractility and Ca2+ binding to isolated cardiac sarcolemma in rabbit, neonatal rat, and frog ventricular tissue. Deviations from this correlation are seen in the adult rat ventricle and rabbit atrium. The observation of this correlation in the three former tissues and under various ionic conditions suggests that this correlation is not coincidental and that Ca2+ bound to the cardiac sarcolemma is of major importance in the control of myocardial contractility. The data are consistent with a functional Ca2+-induced Ca2+ release system in the sarcoplasmic reticulum (SR) of all the tissues (which is controlled by Ca2+ entry from sarcolemmal sites), with the adult rat ventricular and rabbit atrial SR Ca2+ release being much more sensitive to CA2+. It is suggested that the frog, neonatal rat, and rabbit ventricles depend more directly on the entry of Ca2+ from sarcolemmal sites for the control of tension development, whereas the adult rat ventricle and rabbit atrium depend to a greater extent on CA2+ released from the SR.


Action of nitro- and halophenols upon oxygen consumption and phosphorylation by a cell-free particulate system from arbacia eggs.
1. The ability of 4,6-dinitrocresol and eight other substituted phenols to stimulate oxygen uptake and inhibit phosphorylation by a cell-free particulate system from unfertilized Arbacia eggs has been determined. Five of those agents can produce both stimulation of oxygen consumption and inhibition of phosphorylation; one inhibits both oxygen consumption and phosphorylation; and two have no effect on either oxygen consumption or phosphorylation. In every case the effects of these substituted phenols upon the cell-free particulate systems parallel those upon oxygen consumption and cleavage in the intact fertilized Arbacia eggs. 2. The data suggest that energy for cleavage of the Arbacia egg is provided at least in part by oxidative phosphorylation and that substituted phenols may block cleavage by interfering with generation and transfer of high-energy phosphate groups.


CFU-S(11) activity does not localize solely with the aorta in the aorta-gonad-mesonephros region.
The aorta-gonad-mesonephros (AGM) region is a potent hematopoietic site in the midgestation mouse conceptus and first contains colony-forming units-spleen day 11 (CFU-S(11)) at embryonic day 10 (E10). Because CFU-S(11) activity is present in the AGM region before the onset of hematopoietic stem cell (HSC) activity, CFU-S(11) activity in the complex developing vascular and urogenital regions of the AGM was localized. From E10 onward, CFU-S(11) activity is associated with the aortic vasculature, and is found also in the urogenital ridges (UGRs). Together with data obtained from organ explant cultures, in which up to a 16-fold increase in CFU-S(11) activity was observed, it was determined that CFU-S(11) can be increased autonomously both in vascular sites and in UGRs. Furthermore, CFU-S(11) activity is present in vitelline and umbilical vessels. This, together with the presence of CFU-S(11) in the UGRs 2 days before HSC activity, suggests both temporally and spatially distinct emergent sources of CFU-S(11). (Blood. 2000;96:2902-2904)


Oral immunization with a replication-deficient recombinant vaccinia virus protects mice against influenza.
Mice immunized with two intragastrically administered doses of a replication-deficient recombinant vaccinia virus containing the hemagglutinin and nucleoprotein genes from H1N1 influenza virus developed serum anti-H1 immunoglobulin G (IgG) antibody that completely protected the lungs from challenge with H1N1. Almost all of the mice given two intragastric doses also developed mucosal anti-H1 IgA antibody, and those with high anti-H1 IgA titers had completely protected noses. Intramuscular injection of the vaccine protected the lungs but not the noses from challenge. We also found that the vaccine enhanced recovery from infection caused by a shifted (H3N2) influenza virus, probably through the induction of nucleoprotein-specific cytotoxic T-lymphocyte activity. A replication-deficient, orally administered, enteric-coated, vaccinia virus-vectored vaccine might safely protect humans against influenza.


Cartilage integration: evaluation of the reasons for failure of integration during cartilage repair. A review.
Articular cartilage is a challenging tissue to reconstruct or replace principally because of its avascular nature; large chondral lesions in the tissue do not spontaneously heal. Where lesions do penetrate the bony subchondral plate, formation of hematomas and the migration of mesenchymal stem cells provide an inferior and transient fibrocartilagenous replacement for hyaline cartilage. To circumvent the poor intrinsic reparative response of articular cartilage several surgical techniques based on tissue transplantation have emerged. One characteristic shared by intrinsic reparative processes and the new surgical therapies is an apparent lack of lateral integration of repair or graft tissue with the host cartilage that can lead to poor prognosis. Many factors have been cited as impeding cartilage:cartilage integration including; chondrocyte cell death, chondrocyte dedifferentiation, the nature of the collagenous and proteoglycan networks that constitute the extracellular matrix, the type of biomaterial scaffold employed in repair and the origin of the cells used to repopulate the defect or lesion. This review addresses the principal intrinsic and extrinsic factors that impede integration and describe how manipulation of these factors using a host of strategies can positively influence cartilage integration.


Characterization of the gene for the mouse prostaglandin E receptor subtype EP2: tissue-specific initiation of transcription in the macrophage and the uterus.
Genomic DNA clones for the mouse prostaglandin (PG) E receptor subtype EP2 were isolated and characterized. The mouse EP2 gene is composed of 2 exons and 1 intron, and spans 16 kb. The intron which is approx. 12 kb in length is located at the end of the sixth transmembrane domain, as with other prostanoid receptor genes. Based on this structure, transcripts were analysed in endotoxin-treated macrophages and pseudopregnant uteri, in which abundant expression of EP2 mRNA was observed. Sequence analysis of cDNA clones from these origins and Northern hybridization of these RNAs revealed that the uterine EP2 mRNA (U-type) has a longer 5'-untranslated region than the macrophage EP2 transcript (M-type). The major transcription initiation sites for M-type and U-type EP2 are located 124 and 769 bp upstream of the translation start site, respectively. The M-type was expressed in various tissues, whereas the U-type was found only in the uterus. The 2 kb segment containing the immediate 5'-flanking and 5'-noncoding regions contain three consensus sequences for the NF-IL6 binding site, one consensus sequence for the NF-kappaB binding site, four AP-2 consensus sequences, one AP-4 consensus sequence, one potential cAMP response element, and one potential progesterone response element. These results suggest that EP2 gene expression in the macrophage and uterus is under the control of distinct mechanisms involving alternative promoters.


Meta-analysis of intracranial hemorrhage in acute coronary syndromes: incidence, predictors, and clinical outcomes.
Little is known about the incidence, predictors, or outcomes of intracranial hemorrhage (ICH) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). We aimed to determine the incidence and timing of ICH, characterize the location of ICH, and identify independent baseline predictors of ICH in NSTE ACS patients. We pooled patient-level data from 4 contemporary antithrombotic therapy trials. Multivariable modeling identified independent predictors of ICH. ICHs were adjudicated by a clinical events committee. Of 37 815 patients, 135 (0.4%) had an ICH. The median (25th, 75th percentiles) follow-up was 332 (184, 434) days but differed across trials. Locations of ICH were intracerebral (50%), subdural (31%), subarachnoid (18.5%), and intraventricular (11%). Independent predictors of ICH were older age (HR per 10 years, 1.61; 95% CI, 1.35 to 1.91); prior stroke/transient ischemic attack; HR, 1.95; 95% CI, 1.14 to 3.35), higher systolic blood pressure; HR per 10 mm Hg increase, 1.09; 95% CI, 1.01 to 1.18), and larger number of antithrombotic agents (HR per each additional agent, 2.06; 95% CI, 1.49 to 2.84). Of all ICHs, 45 (33%) were fatal. In patients with NSTE ACS enrolled in recent clinical trials of antithrombotic therapies, ICH was uncommon. Patients with older age, prior transient ischemic attack/stroke, higher systolic blood pressure, or larger number of antithrombotic agents were at increased risk. One-third of patients with ICH died. These data may be useful to trialists and data and safety monitoring committees for trial conduct and monitoring. URL: https://www.clinicaltrials.gov/. Unique identifiers: TRACER: NCT00527943, PLATO: NCT00391872, APPRAISE-2: NCT00831441, TRILOGY ACS: NCT00699998.


Real-time prediction of influenza outbreaks in Belgium.
Seasonal influenza is a worldwide public health concern. Forecasting its dynamics can improve the management of public health regulations, resources and infrastructure, and eventually reduce mortality and the costs induced by influenza-related absenteism. In Belgium, a network of Sentinel General Practitioners (SGPs) is in place for the early detection of the seasonal influenza epidemic. This surveillance network reports the weekly incidence of influenza-like illness (ILI) cases, which makes it possible to detect the epidemic onset, as well as other characteristics of the epidemic season. In this paper, we present an approach for predicting the weekly ILI incidence in real-time by resorting to a dynamically calibrated compartmental model, which furthermore takes into account the dynamics of other influenza seasons. In order to validate the proposed approach, we used data collected by the Belgian SGPs for the influenza seasons 2010-2016. In spite of the great variability among different epidemic seasons, providing weekly predictions makes it possible to capture variations in the ILI incidence. The confidence region becomes more representative of the epidemic behavior as ILI data from more seasons become available. Since the SIR model is then calibrated dynamically every week, the predicted ILI curve gets rapidly tuned to the dynamics of the ongoing season. The results show that the proposed method can be used to characterize the overall behavior of an epidemic.


Fluorescein fluorescence use in the management of intracranial neoplastic and vascular lesions: a review and report of a new technique.
The use of fluorescent technologies in neurosurgery has a substantial history with applications to vascular and tumor surgery dating back to the 1940s. This review focuses on the applications of fluorescence imaging to intracranial vascular and neoplastic lesions using sodium fluorescein. The authors performed a literature search for articles about the use of sodium fluorescein in neurosurgery. Fifty-five articles were initially retrieved, and 37 of these were appropriate for this review. The subcategorization of these articles revealed 2 describing the properties of fluorescein, 19 articles relating to applications of fluorescein to tumor, 11 relating to vascular applications, and 5 reporting side effects associated with fluorescein use. Articles related to use of this agent in evaluation of CSF leak were excluded. Sodium fluorescein has been reported to be a useful surgical adjunct in resection of neoplastic lesions based on differential fluorescence between normal and neoplastic tissue. There are many reports on the utility of fluorescein in vascular imaging relating to arteriovenous malformations, aneurysms, and vessel anastomosis; however, these reports do not examine primary outcomes. Sodium fluorescein has been judged as generally safe with few reports of severe complications. Sodium fluorescein has demonstrated promise as a useful surgical adjunct in neurosurgery for vascular and neoplastic lesions. It is well tolerated, but further study is required to determine its full utility. Finally, we will introduce a new practical technology that could potentially improve intraoperative application of sodium fluorescein by improving its fluorescence visualization while using substantially lower doses of this dye.


Viscous flow circulation of the solar wind behind venus.
A latitudinal circulation model of solar wind flow in the near wake of Venus is presented. It is shown that solar wind fluxes entering through the polar terminator can be viscously forced to lower latitudes. The resulting motion produces a downstream elongation of the nightside polar ionosphere out to the downstream extension of the middle- and low-latitude ionopause. The geometry suggested by this flow circulation model provides a simple explanation of the ionospheric bulge inferred from the Pioneer Venus observations.


Genetic risk assessment in hookah smokers.
The genotoxic effect of hookah smoke was investigated on somatic chromosomes of 35 occupationally nonexposed male hookah smokers. These were compared with an equal number of nonsmokers matched with respect to age, sex, drug intake, if any, and socio-economic status. The mitotic index (MI), chromosomal aberrations (CA), sister chromatid exchanges (SCE) and satellite associations (SA) were analysed. All the parameters showed a significant increase (p < 0.01) in the smokers compared with control individuals, viz MI, 3.88-5.41; CA, 0.94-2.22; SCE, 3.59-5.66; and SA, 5.2-8.65. A distinct time and dose effect relationship was observed. Hookah smoke is thus, both clastogenic and genotoxic for human beings.