Local Housing Characteristics Associated with Early Childhood Development Outcomes in Australian Disadvantaged Communities.
Disadvantaged communities tend to have poorer early childhood development outcomes. Access to safe, secure, and stable housing is a well-known social determinant of health but there is a need to examine key features of neighbourhood housing that reduce early childhood development inequities. The 2012 Australian Early Development Census (AEDC), a population-wide measure of early childhood development, and the Australian Bureau of Statistics Socio-economic Index for Areas Index of Relative Socio-economic Disadvantage were used to select fourteen disadvantaged local communities in five Australian states and territories based on those performing better (off-diagonal), or as expected (on-diagonal) on the AEDC relative to their socio-economic profile. Between 2015-2017, qualitative and quantitative housing data were collected in the local communities. In total, 87 interviews with stakeholders, 30 focus groups with local service providers and parents, and Australian Census dwelling information were analysed. A comparative case study approach was used to examine differences in housing characteristics (e.g., public housing, density, affordability, and tenure) between disadvantaged local communities performing 'better than expected' and 'as expected' on early childhood development. Perceived better housing affordability, objectively measured housing tenure (ownership) and perceived and objectively measured lower-density public housing were housing characteristics that emerged as points of difference for disadvantaged local communities where children had relatively better early childhood development outcomes. These characteristics are potential modifiable and policy sensitive housing levers for reducing early childhood development inequities.


Effects of postnatal interventions for the reduction of vertical HIV transmission on infant growth and non-HIV infections: a systematic review.
Guidelines in resource-poor settings have progressively included interventions to reduce postnatal HIV transmission through breast milk. In addition to HIV-free survival, infant growth and non-HIV infections should be considered. Determining the effect of these interventions on infant growth and non-HIV infections will inform healthcare decisions about feeding HIV-exposed infants. We synthesize findings from studies comparing breast to formula feeding, early weaning to standard-duration breastfeeding, breastfeeding with extended antiretroviral (ARV) to short-course ARV prophylaxis, and alternative preparations of infant formula to standard formula in HIV-exposed infants, focusing on infant growth and non-HIV infectious morbidity outcomes. The review objectives were to collate and appraise evidence of interventions to reduce postnatal vertical HIV transmission, and to estimate their effect on growth and non-HIV infections from birth to two years of age among HIV-exposed infants. We searched PubMed, SCOPUS, and Cochrane CENTRAL Controlled Trials Register. We included randomized trials and prospective cohort studies. Two authors independently extracted data and evaluated risk of bias. Rate ratios and mean differences were used as effect measures for dichotomous and continuous outcomes, respectively. Where pooling was possible, we used fixed-effects meta-analysis to pool results across studies. Quality of evidence was assessed using the GRADE approach. Prospective cohort studies comparing breast- versus formula-fed HIV-exposed infants found breastfeeding to be protective against diarrhoea in early life [risk ratio (RR)=0.31; 95% confidence interval (CI)=0.13 to 0.74]. The effect of breastfeeding against diarrhoea [hazard ratio (HR)=0.74; 95% CI=0.57 to 0.97] and respiratory infections (HR=0.65; 95% CI=0.41 to 1.00) was significant through two years of age. The only randomized controlled trial (RCT) available showed that breastfeeding tended to be protective against malnutrition (RR=0.63; 95% CI=0.36 to 1.12). We found no statistically significant differences in the rates of non-HIV infections or malnutrition between breast-fed infants in the extended and short-course ARV prophylaxis groups. Low to moderate quality evidence suggests breastfeeding may improve growth and non-HIV infection outcomes of HIV-exposed infants. Extended ARV prophylaxis does not appear to increase the risk for HIV-exposed infants for adverse growth or non-HIV infections compared to short-course ARV prophylaxis.


Disclosure of HIV status between parents and children in Uganda in the context of greater access to treatment.
While disclosure of HIV sero-status is encouraged in the management of the HIV and AIDS epidemic, it remains a challenge, especially among family members. This article examines the moral dilemmas and pragmatic incentives surrounding disclosure of HIV status in contemporary Uganda. Our findings are based on 12 in-depth interviews, 2 focus-group discussions, 6 key informant interviews with AIDS activists, and open-ended responses derived from 148 HIV-positive persons in a quantitative survey. The study was conducted in 2008-2009 in Kampala, Mpigi, and Soroti districts in Uganda. We found both parents and adult children facing dilemmas in disclosure, whether it was parents revealing their own HIV status to their children or the status of their perinatally infected children, or young people infected through sexual intercourse telling their parents. For both groups, there is fear of blame, stigma, discrimination, and shame and guilt related to unsafe sex, while young people also fear loss of privileges. On the other hand, there are practical imperatives for disclosure in terms of gaining access to care, treatment, and material resources. Faced with these dilemmas, HIV-positive people and their families require professional counselling to help them work through the emotional challenges encountered and identify mechanisms of support and coping.


Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants.
During the chronic lung infection of patients with cystic fibrosis (CF), Pseudomonas aeruginosa can survive for long periods due to adaptive evolution mediated by genetic variation. Hypermutability is considered to play an important role in this adaptive evolution and it has been demonstrated that mutator populations are amplified in the CF lung by hitchhiking with adaptive mutations. Two of the genes that are frequently mutated in isolates from chronic infection are mucA and lasR. Loss-of-function mutations in these genes determine the phenotypic switch to mucoidy and loss of quorum sensing, which are considered hallmarks of chronic virulence. The aims of our study were to investigate (1) the genetic background of the P. aeruginosa subpopulations with non-mutator, weak or strong mutator phenotype and their dynamics during the chronic lung infection, and (2) the time sequence in which the hypermutable, mucoid and quorum-sensing-negative phenotypes emerge during chronic lung infection. For these purposes the sequences of mutS, mutL, uvrD, mutT, mutY and mutM anti-mutator genes as well as of mucA and lasR were analysed in 70 sequential P. aeruginosa isolates obtained from the respiratory secretions of 10 CF patients (one to three isolates per time point). Analysis of the genetic background of the mutator phenotype showed that mutS was the most commonly affected gene followed by mutL in isolates with strong mutator phenotype. The mutT, mutY, mutM genes were affected in isolates with low fold-changes in the mutation frequencies compared to the reference strain PAO1. Isolates with non-mutator, weak or strong mutator phenotype were represented at all time points showing co-existence of these subpopulations, which suggests parallel evolution of the various mutators in the different focal niches of infection in the CF lung. Mutations in mucA and lasR occurred earlier than mutations in the anti-mutator genes, showing that hypermutability is not a prerequisite for the acquisition of mucoidy and loss of quorum sensing, considered hallmarks of chronic virulence. Significantly higher mutation rates and MICs of ceftazidime, meropenem and ciprofloxacin were found for isolates collected late (more than 10 years) during the chronic lung infection compared to isolates collected earlier, which suggests an amplification of the mutator subpopulation by hitchhiking with development of antibiotic resistance. Similar evolutionary pathways concordant with adaptive radiation were observed in different clonal lineages of P. aeruginosa from CF patients.


Runs of homozygosity reveal genome-wide autozygosity in Italian sheep breeds.
The availability of dense single nucleotide polymorphism (SNP) assays allows for the determination of autozygous segments based on runs of consecutive homozygous genotypes (ROH). The aim of the present study was to investigate the occurrence and distribution of ROH in 21 Italian sheep breeds using medium-density SNP genotypes in order to characterize autozygosity and identify genomic regions that frequently appeared in ROH within individuals, namely ROH islands. After filtering, the final number of animals and SNPs retained for analyses were 502 and 46 277 respectively. A total of 12 302 ROH were identified. The mean number of ROH per breed ranged from 10.58 (Comisana) to 44.54 (Valle del Belice). The average length of ROH across breeds was 4.55 Mb and ranged from 3.85 Mb (Biellese) to 5.51 Mb (Leccese). Valle del Belice showed the highest value of inbreeding on the basis of ROH (FROH = 0.099), whereas Comisana showed the lowest (FROH = 0.016), and high standard deviation values revealed high variability in autozygosity levels within each breed. Differences also existed in the length of ROH. Analysis of the distribution of ROH according to their size showed that, for all breeds, the majority of the detected ROH were <10 Mb in length, with a few long ROH >25 Mb. The levels of ROH that we estimated here reflect the inbreeding history of the investigated sheep breeds. These results also highlight that ancient and recent inbreeding have had an impact on the genome of the Italian sheep breeds and suggest that several animals have experienced recent autozygosity events. Comisana and Bergamasca appeared as the less consanguineous breeds, whereas Barbaresca, Leccese and Valle del Belice showed ROH patterns typically produced by recent inbreeding. Moreover, within the genomic regions most commonly associated with ROH, several candidate genes were detected.


Learning through a virtual patient vs. recorded lecture: a comparison of knowledge retention in a trauma case.
To compare medical students' and residents' knowledge retention of assessment, diagnosis and treatment procedures, as well as a learning experience, of patients with spinal trauma after training with either a Virtual Patient case or a video-recorded traditional lecture. A total of 170 volunteers (85 medical students and 85 residents in orthopedic surgery) were randomly allocated (stratified for student/resident and gender) to either a video-recorded standard lecture or a Virtual Patient-based training session where they interactively assessed a clinical case portraying a motorcycle accident. The knowledge retention was assessed by a test immediately following the educational intervention and repeated after a minimum of 2 months. Participants' learning experiences were evaluated with exit questionnaires. A repeated-measures analysis of variance was applied on knowledge scores. A total of 81% (n = 138) of the participants completed both tests. There was a small but significant decline in first and second test results for both groups (F(1, 135) = 18.154, p = 0.00). However, no significant differences in short-term and long-term knowledge retention were observed between the two teaching methods. The Virtual Patient group reported higher learning experience levels in engagement, stimulation, general perception, and expectations. Participants' levels engagement were reported in favor of the VP format. Similar knowledge retention was achieved through either a Virtual Patient or a recorded lecture.


Characterization of sarcolemma and sarcoplasmic reticulum isolated from skeletal muscle of the freeze tolerant wood frog, Rana sylvatica: the beta(2)-adrenergic receptor and calcium transport systems in control, frozen and thawed states.
In freeze tolerant wood frog Rana sylvatica, the freeze-induced liberation of glucose plays a critical role in survival in response to sub-zero temperature exposure. We have shown that the glycaemic response is linked to selective changes in the expression of hepatic adrenergic receptors through which catecholamines act to produce their hepatic glycogenolytic effects. The purpose of the present study was to determine if skeletal muscle, another catecholamine-sensitive tissue with glycogenolytic potential, displayed similar or different changes. In order to achieve these objectives, skeletal muscle derived from Rana sylvatica was studied in control, frozen and thawed states. In isolated sarcolemmal fractions, freezing effected an 88% decrease in beta(2)-adrenergic receptor expression but was without effect on the calcium pump; while thawing resulted in a recovery of the beta(2)-adrenergic receptor to 60% of control levels and a 2.4-fold increase in calcium transport. In isolated sarcoplasmic reticular fractions, freezing effected a 52% decrease in calcium binding and a 92% decrease in oxalate-stimulated calcium uptake; while thawing elicited partial normalization to control levels to 70% with respect to calcium binding and to 47% with respect to calcium uptake. Freezing and thawing were associated with increases and decreases, receptively, in blood glucose levels but were without effect on skeletal muscle glycogen content. Thus these muscle changes in Rana sylvatica in freezing and thawing are not linked to glycogen breakdown, are different from those previously seen in liver, and may provide a role in recovery of muscle function during thawing by protecting glycogen stores for contraction and maximizing extracellular calcium for excitation-contraction coupling in the frozen state. The involvement of thyroid hormone in triggering these muscle changes is discussed.


ROptimus: a parallel general-purpose adaptive optimization engine.
Various computational biology calculations require a probabilistic optimization protocol to determine the parameters that capture the system at a desired state in the configurational space. Many existing methods excel at certain scenarios, but fail in others due, in part, to an inefficient exploration of the parameter space and easy trapping into local minima. Here, we developed a general-purpose optimization engine in R that can be plugged to any, simple or complex, modelling initiative through a few lucid interfacing functions, to perform a seamless optimization with rigorous parameter sampling. ROptimus features simulated annealing and replica exchange implementations equipped with adaptive thermoregulation to drive Monte Carlo optimization process in a flexible manner, through constrained acceptance frequency but unconstrained adaptive pseudo temperature regimens. We exemplify the applicability of our R optimizer to a diverse set of problems spanning data analyses and computational biology tasks. ROptimus is written and implemented in R, and is freely available from CRAN (http://cran.r-project.org/web/packages/ROptimus/index.html) and GitHub (http://github.com/SahakyanLab/ROptimus).


Low profile optical system for an aircraft beacon.
An optical system producing an annular cone of radiation from a point source using a low profile front lens is shown to have application as a beacon for high speed vehicles. The system comprises a high pressure short are light source with axial electrodes and integral collector, a conical reflector, and a divergent meniscus lens that has low protrusion over the surface of the vehicle. The system has minimal drag, and the radiation is distributed in directions close to the plane perpendicular to the optical axis. The influences of various parameters such as lens camber, lens aperture, source size, collector shape, collection efficiency, and beam divergence are discussed. A prototype was built at Eimae Division of Varian using a xenon short arc lamp with metal ceramic structure and integral collector.


Global regulation of erythroid gene expression by transcription factor GATA-1.
Transcription factor GATA-1 is required for erythropoiesis, yet its full actions are unknown. We performed transcriptome analysis of G1E-ER4 cells, a GATA-1-null erythroblast line that undergoes synchronous erythroid maturation when GATA-1 activity is restored. We interrogated more than 9000 transcripts at 6 time points representing the transition from late burst forming unit-erythroid (BFU-E) to basophilic erythroblast stages. Our findings illuminate several new aspects of GATA-1 function. First, the large number of genes responding quickly to restoration of GATA-1 extends the repertoire of its potential targets. Second, many transcripts were rapidly down-regulated, highlighting the importance of GATA-1 in gene repression. Third, up-regulation of some known GATA-1 targets was delayed, suggesting that auxiliary factors are required. For example, induction of the direct GATA-1 target gene beta major globin was late and, surprisingly, required new protein synthesis. In contrast, the gene encoding Fog1, which cooperates with GATA-1 in beta globin transcription, was rapidly induced independently of protein synthesis. Guided by bioinformatic analysis, we demonstrated that selected regions of the Fog1 gene exhibit enhancer activity and in vivo occupancy by GATA-1. These findings define a regulatory loop for beta globin expression and, more generally, demonstrate how transcriptome analysis can be used to generate testable hypotheses regarding transcriptional networks.


Acute Effects of Mental Activity on Response of Serum BDNF and IGF-1 Levels in Elite and Novice Chess Players.
Background and Objectives: Although the effects of physical exercise on brain functions are well studied, the influence of mental activity is unknown. The aim of this study was to assess the influence of a session of mental activity on brain neurobiological factors in chess players. Materials and Methods: Ten elite and novice chess players were recruited to participate in this study as volunteers. The subjects performed a session of standard chess matches as a mental activity. Before and after each chess match, blood samples were drawn to analyze changes in serum brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1). Results: After each chess match, both the elite and novice groups showed significant increases in serum BDNF and IGF-1 concentrations. The elite group also showed significantly greater changes in BDNF and IGF-1 levels (p ≤ 0.05) than the novice group. Conclusions: Our findings indicate that a session of standard chess matches as a mental activity is effective for elevating BDNF and IGF-1 levels, and that their elevation in elite players seems to be more pronounced than those in novice players.


Detection of Cell Surface Ligands for Human Synovial γδ T Cells.
Lack of understanding of the nature and physiological regulation of γδ T cell ligands has considerably hampered full understanding of the function of these cells. We developed an unbiased approach to identify human γδ T cells ligands by the production of a soluble TCR-γδ (sTCR-γδ) tetramer from a synovial Vδ1 γδ T cell clone from a Lyme arthritis patient. The sTCR-γδ was used in flow cytometry to initially define the spectrum of ligand expression by both human tumor cell lines and certain human primary cells. Analysis of diverse tumor cell lines revealed high ligand expression on several of epithelial or fibroblast origin, whereas those of hematopoietic origin were largely devoid of ligand. This allowed a bioinformatics-based identification of candidate ligands using RNAseq data from each tumor line. We further observed that whereas fresh monocytes and T cells expressed low to negligible levels of TCR-γδ ligands, activation of these cells resulted in upregulation of surface ligand expression. Ligand upregulation on monocytes was partly dependent upon IL-1β. The sTCR-γδ tetramer was then used to bind candidate ligands from lysates of activated monocytes and analyzed by mass spectrometry. Surface TCR-γδ ligand was eliminated by treatment with trypsin or removal of glycosaminoglycans, and also suppressed by inhibition of endoplasmic reticulum-Golgi transport. Of particular interest was that inhibition of glycolysis also blocked TCR-γδ ligand expression. These findings demonstrate the spectrum of ligand(s) expression for human synovial Vδ1 γδ T cells as well as the physiology that regulates their expression.


Breaking Down Grit: Persistency and Flexibility in the Career Plans of Military Medical Students.
The field of medicine is experiencing a crisis as high levels of physician and trainee burnout threaten the pipeline of future physicians. Grit, or passion and perseverance for long-term goals, has been studied in high-performing and elite military units and found to be predictive of successful completion of training in adverse conditions. The Uniformed Services University of the Health Sciences (USU) graduates military medical leaders who make up a significant portion of the Military Health System physician workforce. Taken together, an improved understanding of the relationships between burnout, well-being, grit, and retention among USU graduates is critical to the success of the Military Health System. The current study was approved by the Institutional Review Board at USU and explored these relations among 519 medical students across three graduating classes. These students participated in two surveys approximately one year apart from October 2018 until November 2019. Participants completed measures on grit, burnout, and likelihood of leaving the military. These data were then merged with demographic and academic data (e.g., Medical College Admission Test scores) from the USU Long Term Career Outcome Study. These variables were then analyzed simultaneously using structural equation modeling to examine the relationships among variables in a single model. Results reaffirmed the 2-factor model of grit as both passion and perseverance (or interest consistency). No significant relationships emerged between burnout and other study variables. Sustained and focused interest was predictive of less likelihood of staying in the military. This study offers important insights into the relationship among well-being factors, grit, and long-term career planning in the military. The limitations of using a single-item measure of burnout and measuring behavioral intentions in a short time frame during undergraduate medical education highlight the importance of future longitudinal studies that can examine actual behaviors across a career lifespan. However, this study offers some key insights into potential impacts on the retention of military physicians. The findings suggest that military physicians who are most likely to stay in the military tend to embrace a more fluid and flexible medical specialty path. This is critical in expectation setting for the military to train and retain military physicians across a wide range of critical wartime specialties.


Circulating long noncoding RNAs H19 and GAS5 are associated with type 2 diabetes but not with diabetic retinopathy: A preliminary study.
Recently, a wide range of biological and pathological roles of long noncoding RNAs (lncRNAs) have been discovered. However, the potential role of circulating lncRNAs H19 and GAS5 in type 2 diabetes mellitus (T2DM) and diabetic retinopathy (DR) is not clear. Here, we assessed the plasma levels of H19 and GAS5 lncRNAs in T2DM patients with/without DR and evaluated if H19 and GAS5 pre-treatment plasma levels are a predictor of early response to a single aflibercept dose in DR subgroup. Plasma lncRNA expression profiles of 119 T2DM patients (66 with DR and 53 without DR) and 110 healthy controls were determined by quantitative reverse transcription PCR. The association of lncRNA expression profiles with clinical features and aflibercept early response in DR patients was investigated. Relative H19 expression levels were significantly increased in T2DM group (including DR and non-DR subgroups) vs. controls, while GAS5 levels were decreased in T2DM group (p < 0.001). There was no significant difference in H19 and GAS5 expression levels between DR and non-DR subgroups. H19 and GAS5 expression profiles were not significantly correlated with clinical parameters or response to aflibercept therapy in DR subgroup. Our findings indicate that the circulating lncRNAs H19 and GAS5 may be associated with T2DM prevalence but may not have an important diagnostic/prognostic role in DR or early response to aflibercept intravitreal injection in DR patients. Large-scale transcriptomic studies are warranted to validate our results and investigate other lncRNA candidates in T2DM.


The effect of various factors on variability of retinal nerve fiber layer thickness measurements using optical coherence tomography.
To evaluate the effects of various factors on the variability of retinal nerve fiber layer (RNFL) thickness measurements using the Stratus optical coherence tomography (OCT) in normal and glaucomatous eyes. Four hundred seventy-four subjects (103 normal eyes and 371 glaucomatous eyes) were scanned to determine the RNFL thickness measurements using the Stratus OCT. Measurements were obtained twice during the same day. The standard deviation (SD) was used to compare the variability in RNFL thickness measurements of the normal subjects to that of the glaucomatous patients. Multivariate regression analysis was used to evaluate which covariates were independent predictors of SD in overall mean RNFL thickness. The mean SD of all RNFL thickness measurements was larger in the glaucoma group except in one sector. In the multivariate regression analysis, the average signal strength (SS) and the relative SS change (difference in SS between initial and repeat scans, divided by initial SS) were independent predictors of the SD in the RNFL thickness measurements (partial R(2) = 0.018, 0.013; p = 0.016, 0.040, respectively). Glaucomatous eyes tend to be more variable than normal eyes in RNFL thickness measurement using the Straus OCT. The average SS and the relative SS changes appear to correlate with the variability in RNFL thickness measurement. Therefore, the results of the RNFL analysis should not be interpreted independently of these factors.


Automatic Calcium Scoring in Low-Dose Chest CT Using Deep Neural Networks With Dilated Convolutions.
Heavy smokers undergoing screening with low-dose chest CT are affected by cardiovascular disease as much as by lung cancer. Low-dose chest CT scans acquired in screening enable quantification of atherosclerotic calcifications and thus enable identification of subjects at increased cardiovascular risk. This paper presents a method for automatic detection of coronary artery, thoracic aorta, and cardiac valve calcifications in low-dose chest CT using two consecutive convolutional neural networks. The first network identifies and labels potential calcifications according to their anatomical location and the second network identifies true calcifications among the detected candidates. This method was trained and evaluated on a set of 1744 CT scans from the National Lung Screening Trial. To determine whether any reconstruction or only images reconstructed with soft tissue filters can be used for calcification detection, we evaluated the method on soft and medium/sharp filter reconstructions separately. On soft filter reconstructions, the method achieved F1 scores of 0.89, 0.89, 0.67, and 0.55 for coronary artery, thoracic aorta, aortic valve, and mitral valve calcifications, respectively. On sharp filter reconstructions, the F1 scores were 0.84, 0.81, 0.64, and 0.66, respectively. Linearly weighted kappa coefficients for risk category assignment based on per subject coronary artery calcium were 0.91 and 0.90 for soft and sharp filter reconstructions, respectively. These results demonstrate that the presented method enables reliable automatic cardiovascular risk assessment in all low-dose chest CT scans acquired for lung cancer screening.


Simultaneous Remote Observations of Intense Reconnection Effects by DMSP and MMS Spacecraft During a Storm Time Substorm.
During a magnetic storm on 23 June 2015, several very intense substorms took place, with signatures observed by multiple spacecraft including DMSP and Magnetospheric Multiscale (MMS). At the time of interest, DMSP F18 crossed inbound through a poleward expanding auroral bulge boundary at 23.5 h magnetic local time (MLT), while MMS was located duskward of 22 h MLT during an inward crossing of the expanding plasma sheet boundary. The two spacecraft observed a consistent set of signatures as they simultaneously crossed the reconnection separatrix layer during this very intense reconnection event. These include (1) energy dispersion of the energetic ions and electrons traveling earthward, accompanied with high electron energies in the vicinity of the separatrix; (2) energy dispersion of polar rain electrons, with a high-energy cutoff; and (3) intense inward convection of the magnetic field lines at the MMS location. The high temporal resolution measurements by MMS provide unprecedented observations of the outermost electron boundary layer. We discuss the relevance of the energy dispersion of the electrons, and their pitch angle distribution, to the spatial and temporal evolution of the boundary layer. The results indicate that the underlying magnetotail magnetic reconnection process was an intrinsically impulsive and the active X-line was located relatively close to the Earth, approximately at 16-18 RE.


Deconstructing sub-clinical psychosis into latent-state and trait variables over a 30-year time span.
Our aim was to deconstruct the variance underlying the expression of sub-clinical psychosis symptoms into portions associated with latent time-dependent states and time-invariant traits. We analyzed data of 335 subjects from the general population of Zurich, Switzerland, who had been repeatedly measured between 1979 (age 20/21) and 2008 (age 49/50). We applied two measures of sub-clinical psychosis derived from the SCL-90-R, namely schizotypal signs (STS) and schizophrenia nuclear symptoms (SNS). Variance was decomposed with latent state-trait analysis and associations with covariates were examined with generalized linear models. At ages 19/20 and 49/50, the latent states underlying STS accounted for 48% and 51% of variance, whereas for SNS those estimates were 62% and 50%. Between those age classes, however, expression of sub-clinical psychosis was strongly associated with stable traits (75% and 89% of total variance in STS and SNS, respectively, at age 27/28). Latent states underlying variance in STS and SNS were particularly related to partnership problems over almost the entire observation period. STS was additionally related to employment problems, whereas drug-use was a strong predictor of states underlying both syndromes at age 19/20. The latent trait underlying expression of STS and SNS was particularly related to low sense of mastery and self-esteem and to high depressiveness. Although most psychosis symptoms are transient and episodic in nature, the variability in their expression is predominantly caused by stable traits. Those time-invariant and rather consistent effects are particularly influential around age 30, whereas the occasion-specific states appear to be particularly influential at ages 20 and 50.


Task shifting interventions for cardiovascular risk reduction in low-income and middle-income countries: a systematic review of randomised controlled trials.
To evaluate evidence from published randomised controlled trials (RCTs) for the use of task-shifting strategies for cardiovascular disease (CVD) risk reduction in low-income and middle-income countries (LMICs). Systematic review of RCTs that utilised a task-shifting strategy in the management of CVD in LMICs. We searched the following databases for relevant RCTs: PubMed from the 1940s, EMBASE from 1974, Global Health from 1910, Ovid Health Star from 1966, Web of Knowledge from 1900, Scopus from 1823, CINAHL from 1937 and RCTs from ClinicalTrials.gov. We focused on RCTs published in English, but without publication year. We included RCTs in which the intervention used task shifting (non-physician healthcare workers involved in prescribing of medications, treatment and/or medical testing) and non-physician healthcare providers in the management of CV risk factors and diseases (hypertension, diabetes, hyperlipidaemia, stroke, coronary artery disease or heart failure), as well as RCTs that were conducted in LMICs. We excluded studies that are not RCTs. Of the 2771 articles identified, only three met the predefined criteria. All three trials were conducted in practice-based settings among patients with hypertension (2 studies) and diabetes (1 study), with one study also incorporating home visits. The duration of the studies ranged from 3 to 12 months, and the task-shifting strategies included provision of medication prescriptions by nurses, community health workers and pharmacists and telephone follow-up posthospital discharge. Both hypertension studies reported a significant mean blood pressure reduction (2/1 mm Hg and 30/15 mm Hg), and the diabetes trial reported a reduction in the glycated haemoglobin levels of 1.87%. There is a dearth of evidence on the implementation of task-shifting strategies to reduce the burden of CVD in LMICs. Effective task-shifting interventions targeted at reducing the global CVD epidemic in LMICs are urgently needed.


Contrast Media Extravasation in CT and MRI - A Literature Review and Strategies for Therapy.
Contrast extravasation events in daily radiological routine may lead to serious complications, especially during CT examinations. The resulting symptoms may vary from local pain up to skin ulcers, necrosis or even acute compartment syndrome.There are no uniformly accepted radiological guidelines or recommendations regarding detection and treatment of extravasation events and immanent complications in a timely manner. Systematic literature research considering the last 35 years via PubMed using search terms "contrast medium extravasation/paravasation". In the literature, there are conservative management approaches of contrast media extravasation without major evidence base, such as unguent dressings, cooling or splinting. This therapy is mostly symptomatic. Additionally, various invasive techniques are described. We discuss these techniques in the context of contemporary literature, such as the hyaluronidase Injection into the site of extravasation, suction/aspiration technique including flushing of the affected tissue areas and the squeezing technique. However, most citations lack scientific evidence: many articles include anecdotal enumerations, case studies or cite publications from the era, when ionic high osmolar contrast media was state-of-the-art. Besides, many authors derive their extravasation management from studies, where agents other than contrast media were investigated. After detailed literature review, we suggest early (plastic) surgical consultation when non-ionic, low-osmolar contrast medium extravasation is about 150 cc or more. In case of extravasation less than 150 cc but in presence of additional symptoms such as impaired perfusion or altered sensibility, the (plastic) surgeon should also be consulted instantly. We do not recommend any invasive first line therapy when contrast media extravasation is less than 150 cc and the patient presents no additional symptoms, besides swelling and local pain. Nevertheless continuous monitoring and accurate conservative management such as active cooling and elevation, splinting of the affected extremity are mandatory as early detection of critical symptoms helps to initiate prompt surgical intervention and avoid sequelae. · Morbidity after contrast media extravasation is extremely rare.. · Predicting sequelae after contrast extravasation is difficult at first sight.. · Treatments such as hyaluronidase injection, suction/aspiration, squeeze technique have been described.. · Surgical consultation is recommended for extravasation > 150 cc or when additional symptoms occur.. · Mandlik V, Prantl L, Schreyer AG. Contrast Media Extravasation in CT and MRI - A Literature Review and Strategies for Therapy. Fortschr Röntgenstr 2019; 191: 25 - 32.


Asymmetric syntheses of (-)-3-epi-Fagomine, (2R,3S,4R)-dihydroxypipecolic acid, and several polyhydroxylated homopipecolic acids.
A range of enantiopure polyhydroxylated piperidines, including (2R,3S,4R)-dihydroxypipecolic acid, (-)-3-epi-fagomine, (2S,3S,4R)-dihydroxyhomopipecolic acid, (2S,3R,4R)-dihydroxyhomopipecolic acid, and two trihydroxy-substituted homopipecolic acids, have been prepared using diastereoselective olefinic oxidations of a range of enantiopure tetrahydropyridines as the key step. The requisite substrates were readily prepared from tert-butyl sorbate using our diastereoselective hydroamination or aminohydroxylation protocols followed by ring-closing metathesis. After diastereoselective olefinic oxidation of the resultant enantiopure tetrahydropyridines and deprotection, enantiopure polyhydroxylated piperidines were isolated as single diastereoisomers (>99:1 dr) in good overall yield.


5-HT1B receptor knockout mice show a compensatory reduction in 5-HT2C receptor function.
Although null mutant ('knockout') mice have provided valuable animal models to complement traditional approaches to psychopharmacology, such animals may also show complex adaptations to the induced mutation. Here we demonstrate that serotonin1B (5-HT1B) receptor knockout (KO) mice show adaptations in serotonin2C (5-HT2C) receptor-mediated functions. They show smaller reductions in food intake and locomotor activity in response to administration of 5-HT2C receptor agonists that are not accounted for by altered drug disposition. These effects are not mimicked by pretreatment of wildtype (WT) mice with a 5-HT1B receptor antagonist showing that they result from a longer term adaptation to the loss of 5-HT1B receptor function and not from a short-term interaction between 5-HT1B- and 5-HT2C-mediated functions. In addition, we show that 5-HT1B receptor KO mice have a lowered hypothalamic c-fos response to the administration of 5-HT2C receptor agonists. These results demonstrate that compensatory adaptations to the constitutive loss of 5-HT1B receptors may be an important determinant of the altered response of 5-HT1B KO mice to a variety of pharmacological challenges.


Malrotation: Age-Related Differences in Reoperation Rate.
Intestinal malrotation classically presents in the neonatal period with bilious vomiting. However, population studies suggest that up to two-thirds of these patients are diagnosed later in childhood or in adulthood. Increased morbidity in the adult population has been reported. Local experience suggested that surgery was technically more difficult in older children and led to the hypothesis that it would be associated with increased morbidity. A retrospective case note analysis was performed on all children presenting with intestinal malrotation to a tertiary referral center between January 2002 and November 2014. Case notes and operation records were reviewed and those who underwent laparotomy for confirmed malrotation were included. Children were grouped as infants (< 1 year) and older (> 1 year). The primary outcome was total emergency reoperation rate. Secondary outcomes were requirement for a bypass at reoperation and mortality. A total of 131 children with malrotation were identified (104 infants, 27 older children; 78 males; age range, 0-16 years). Overall, 13 patients had emergency reoperation following initial Ladd procedure (6 infants and 7 older children). Risk for reoperation was significantly higher in older children (p = 0.005) and additionally a bypass procedure was more often required in older children than infants (4 children, 2 infants, p = 0.016). Adhesiolysis was required on four occasions and redo Ladd procedure in two; these were evenly distributed between both groups. One child was found to have distal bowel obstruction at reoperation. There were three deaths (2.3%), all in the infant group. One was directly associated with malrotation with extensive bowel necrosis. The other two died of unrelated sepsis several months later. Malrotation surgery in older children is associated with a significantly higher emergency reoperation rate. The primary duodenal bypass procedure should always be considered with longstanding chronic intermittent obstruction associated with malrotation if the simple Ladd procedure is deemed inadequate.


The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults.
Helicobacter pylori infection is increasingly difficult to treat. The purpose of these consensus statements is to provide a review of the literature and specific, updated recommendations for eradication therapy in adults. A systematic literature search identified studies on H pylori treatment. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an online platform, finalized, and voted on by an international working group of specialists chosen by the Canadian Association of Gastroenterology. Because of increasing failure of therapy, the consensus group strongly recommends that all H pylori eradication regimens now be given for 14 days. Recommended first-line strategies include concomitant nonbismuth quadruple therapy (proton pump inhibitor [PPI] + amoxicillin + metronidazole + clarithromycin [PAMC]) and traditional bismuth quadruple therapy (PPI + bismuth + metronidazole + tetracycline [PBMT]). PPI triple therapy (PPI + clarithromycin + either amoxicillin or metronidazole) is restricted to areas with known low clarithromycin resistance or high eradication success with these regimens. Recommended rescue therapies include PBMT and levofloxacin-containing therapy (PPI + amoxicillin + levofloxacin). Rifabutin regimens should be restricted to patients who have failed to respond to at least 3 prior options. Optimal treatment of H pylori infection requires careful attention to local antibiotic resistance and eradication patterns. The quadruple therapies PAMC or PBMT should play a more prominent role in eradication of H pylori infection, and all treatments should be given for 14 days.


Imaging diagnosis--spinal cord hemangioma in two dogs.
Intramedullary masses are a dilemma due to the limited access for a nonsurgical biopsy, thus, accurate imaging characterization is crucial. Magnetic resonance imaging findings of two confirmed canine thoracic intramedullary hemangiomas are described. A capillary hemangioma was of mixed intensity but predominantly T2-hyperintense and mildly T1-hyperintense to spinal cord with strong contrast enhancement. A cavernous hemangioma had a target-like appearance in both T1-weighted (T1w) and T2-weighted (T2w) images. In T2w images there was a small isointense center surrounded by a relatively large hyperintense area. In T1w images, there was a large isointense centre with a relatively small hyperintense periphery. Such characteristics should prioritize hemangioma as a consideration in a progressive myelopathy due to an intramedullary mass.


Structure activity characterization of Bordetella petrii lipid A, from environment to human isolates.
Bordetella petrii, a facultative anaerobic species, is the only known member of the Bordetella genus with environmental origin. However it was also recently isolated from humans. The structures of the B. petrii lipid A moieties of the endotoxins were characterized here for the first time for an environmental strain and compared to that of human isolates. Characterization was achieved using chemical analyses, gas chromatography-mass spectrometry, and Matrix Assisted Laser Desorption Ionisation mass spectrometry. The analyses revealed that the different lipid A structures contain a common bisphosphorylated β-(1→6)-linked d-glucosamine disaccharide with hydroxytetradecanoic acid in amide as well at the C-3' in ester linkages. Similar to Bordetella pertussis and Bordetella bronchiseptica lipids A, the hydroxytetradecanoic acid at the C-2' position was substituted by tetradecanoic acid. Unlike B. pertussis, the hydroxytetradecanoic acid at the C-2 position was substituted with either 12:0 or 14:0 and/or their 2-OH forms. Depending on the environmental or human origin the structures differed in the length and degree of fatty acid acylation and impacted the IL-6 and TNF-α inflammatory responses tested. In one isolate we showed the presence at the C-3 position of the short-chain 10:0(3-OH), which according to our previous analyses is more characteristic of the human pathogens in the genus like B. pertussis and Bordetella parapertussis.


Italian consensus conference on management of uterine sarcomas on behalf of S.I.G.O. (Societa' italiana di Ginecologia E Ostetricia).
Uterine sarcomas are very rare tumours with different histotypes, molecular features and clinical outcomes; therefore, it is difficult to carry out prospective clinical trials, and this often results in heterogeneous management of patients in the clinical practice. We planned to set up an Italian consensus conference on these diseases in order to provide recommendations on treatments and quality of care in our country. Early-stage uterine sarcomas are managed by hysterectomy + bilateral salpingo-oophorectomy according to menopausal status and histology; lymphadenectomy is not indicated in patients without bulky nodes, and morcellation must be avoided. The postoperative management is represented by observation, even though chemotherapy can be considered in some high-risk patients. In early-stage low-grade endometrial stromal sarcoma and adenosarcomas without sarcomatous overgrowth, hormonal adjuvant treatment can be offered based on hormone receptor expression. In selected cases, external beam radiotherapy ± brachytherapy can be considered to increase local control only. Patients with advanced disease involving the abdomen can be offered primary chemotherapy (or hormonal therapy in the case of low-grade endometrial stromal sarcoma and adenosarcoma without sarcomatous overgrowth), even if potentially resectable in the absence of residual disease in order to test the chemosensitivity (or hormonosensitivity); debulking surgery can be considered in patients with clinical and radiological response. Chemotherapy is based on anthracyclines ± ifosfamide or dacarbazine. Palliative radiotherapy can be offered for symptom control, and stereotactic radiotherapy can be used for up to five isolated metastatic lesions. Treatment of uterine sarcoma should be centralised at referral centres and managed in a multidisciplinary setting.


Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice.
Chronic venous disease and venous hypertension are common consequences of valve insufficiency, yet the molecular mechanisms regulating the formation and maintenance of venous valves have not been studied. Here, we provide what we believe to be the first description of venous valve morphogenesis and identify signaling pathways required for the process. The initial stages of valve development were found to involve induction of ephrin-B2, a key marker of arterial identity, by venous endothelial cells. Intriguingly, developing and mature venous valves also expressed a repertoire of proteins, including prospero-related homeobox 1 (Prox1), Vegfr3, and integrin-α9, previously characterized as specific and critical regulators of lymphangiogenesis. Using global and venous valve-selective knockout mice, we further demonstrate the requirement of ephrin-B2 and integrin-α9 signaling for the development and maintenance of venous valves. Our findings therefore identified molecular regulators of venous valve development and maintenance and highlighted the involvement of common morphogenetic processes and signaling pathways in controlling valve formation in veins and lymphatic vessels. Unexpectedly, we found that venous valve endothelial cells closely resemble lymphatic (valve) endothelia at the molecular level, suggesting plasticity in the ability of a terminally differentiated endothelial cell to take on a different phenotypic identity.


A cytonuclear incompatibility causes anther sterility in Mimulus hybrids.
Multilocus interactions (also known as Dobzhansky-Muller incompatibilities) are thought to be the major source of hybrid inviability and sterility. Because cytoplasmic and nuclear genomes have conflicting evolutionary interests and are often highly coevolved, cytonuclear incompatibilities may be among the first to develop in incipient species. Here, we report the discovery of cytoplasm-dependent anther sterility in hybrids between closely related Mimulus species, outcrossing M. guttatus and selfing M. nasutus. A novel pollenless anther phenotype was observed in F2 hybrids with the M. guttatus cytoplasm (F2G) but not in the reciprocal F2N hybrids, F1 hybrids or parental genotypes. The pattern of phenotypic segregation in the F2G hybrids and two backcross populations fit a Mendelian single-locus recessive model, allowing us to map the underlying nuclear locus to a small region on LG7 of the Mimulus linkage map. Anther sterility was associated with a 20% reduction in flower size in backcross hybrids and we mapped a major cytoplasm-dependent corolla width QTL with its peak at the anther sterility locus. We argue that the cytonuclear anther sterility seen in hybrids reflects the presence of a cryptic cytoplasmic male sterility (CMS) and restorer system within the hermaphroditic M. guttatus population and therefore name the anther sterility locus restorer-of-male-fertility (RMF). The genetic mapping of RMF is a first step toward testing hypotheses about the molecular basis, individual fitness consequences, and ecological context of CMS and restoration in a system without stable CMS-restorer polymorphism (i.e., gynodioecy). The discovery of cryptic CMS in a hermaphroditic wildflower further suggests that selfish cytoplasmic evolution may play an important, but often undetected, role in shaping patterns of hybrid incompatibility and interspecific introgression in plants.


Effects of Frozen Storage on Phospholipid Content in Atlantic Cod Fillets and the Influence on Diet-Induced Obesity in Mice.
A large fraction of the n-3 polyunsaturated fatty acids (PUFAs) in cod fillet is present in the form of phospholipids (PLs). Freezing initiates hydrolysis of the PLs present in the fillet. Here, we compared the effects of Western diets based on frozen cod, fresh cod or pork with a diet based on casein in male C57BL/6J mice fed for 12 weeks at thermoneutrality. Diets based on fresh cod contained more PL-bound n-3 PUFAs (3.12 mg/g diet) than diets based on frozen cod (1.9 mg/g diet). Mice fed diets containing pork and fresh cod, but not frozen cod, gained more body and fat mass than casein-fed mice. Additionally, the bioavailability of n-3 PUFAs present in the cod fillets was not influenced by storage conditions. In a second experiment, diets with pork as the protein source were supplemented with n-3 PUFAs in the form of PL or triacylglycerol (TAG) to match the levels of the diet containing fresh cod. Adding PL-bound, but not TAG-bound, n-3 PUFAs, to the pork-based diet increased body and fat mass gain. Thus, supplementation with PL-bound n-3 PUFAs did not protect against, but rather promoted, obesity development in mice fed a pork-based diet.


Monitoring of Optimal Cerebral Perfusion Pressure in Traumatic Brain Injured Patients Using a Multi-Window Weighting Algorithm.
Methods to identify an autoregulation guided "optimal" cerebral perfusion pressure (CPPopt) for traumatic brain injury patients (TBI) have been reported through several studies. An important drawback of existing methodology is that CPPopt can be calculated only in ∼50-60% of the monitoring time. In this study, we hypothesized that the CPPopt yield and the continuity can be improved significantly through application of a multi-window and weighting calculation algorithm, without adversely affecting preservation of its prognostic value. Data of 526 severe TBI patients admitted between 2003 and 2015 were studied. The multi-window CPPopt calculation was based on automated curve fitting in pressure reactivity index (PRx)-CPP plots using data from 36 increasing length time windows (2-8 h). The resulting matrix of CPPopts was then averaged in a weighted manner. The yield, continuity, and stability of CPPopt were studied. The difference between patients' actual CPP and CPPopt (ΔCPP) was calculated and the association with outcome was analyzed. Overall, the multi-window method demonstrated more continuous and stable presentation of CPPopt in this cohort. The new method resulted in a mean (±SE) CPPopt yield of 94% ± 2.1%, as opposed to the previous single-window-based CPPopt yield of 51% ± 0.94%. The stability of CPPopt across the whole monitoring period was significantly improved by using the new algorithm (p < 0.001). The relationship between ΔCPP according to the multi-window algorithm and outcome was similar to that for CPPopt calculated on the basis of a single window. In conclusion, this study validates the use of a new multi-window and weighting algorithm for significant improvement of CPPopt yield in TBI patients. This methodological improvement is essential for its clinical application in future CPPopt trials.


Specific encapsidation of fragments of TMV RNA.
The in vitro reconstitution of tobacco mosaic virus (TMV) is initiated by the binding of a disk of TMV protein to the 'disk recognition site', a region of the RNA chain at or near the 5'-terminus for which the disk has special affinity. In order to gain insight into the recognition process, we have studied the ability of disks to encapsidate short RNA fragments produced by partial pancreatic or T1 RNase digestion of TMV RNA. The disk is capable of dicriminating among such fragments, encapsidating only a few of the many present in the digest. The products of encapsidation are short nucleoprotein rods of the same diameter as TMV and of length proportional to that of the encapsidated RNA fragment. The particles differ from TMV, however, in one significant aspect (apart from their length): they possess rings of RNA-free protein at one or both extremities of the rod. In the case of T1 RNase digestion the principal encapsidated fragments were fragments T1 (105 nucleotides) and a family of smaller fragments containing elements of the same sequence. Partial digestion with pancreatic RNase generated only one major fragment (fragment P1; 150 nucleotides) with affinity for the disk. Fragment T1 has been sequenced and shown to represent a portion of the coat protein cistron. Fragment P1 has been partially sequenced but its function is not yet known. Several lines of evidence indicate that fragment T1 is not the disk recognition site. The portion of the TMV RNA chain from which fragment P1 is derived, on the other hand, is encapsidated early in the reconstitution process; thus fragment P1 may contain the disk recognition site. Fragment T1 and fragment P1 both have purine-rich and cytosine-poor sequences near their termini. In addition, fragment T1, and possibly fragment P1, possess a periodicity of order three in purine residues. It seems likely that one or both of the aforesaid properties are largely responsible for the affinity of these fragments for the disk.


Cell Signaling and Stress Responses.
Stress-signaling pathways are evolutionarily conserved and play an important role in the maintenance of homeostasis. These pathways are also critical for adaptation to new cellular environments. The endoplasmic reticulum (ER) unfolded protein response (UPR) is activated by biosynthetic stress and leads to a compensatory increase in ER function. The JNK and p38 MAPK signaling pathways control adaptive responses to intracellular and extracellular stresses, including environmental changes such as UV light, heat, and hyperosmotic conditions, and exposure to inflammatory cytokines. Metabolic stress caused by a high-fat diet represents an example of a stimulus that coordinately activates both the UPR and JNK/p38 signaling pathways. Chronic activation of these stress-response pathways ultimately causes metabolic changes associated with obesity and altered insulin sensitivity. Stress-signaling pathways, therefore, represent potential targets for therapeutic intervention in the metabolic stress response and other disease processes.


Dissolution of three insensitive munitions formulations.
The US military fires live munitions during training. To save soldiers lives both during training and war, the military is developing insensitive munitions (IM) that minimize unintentional detonations. Some of the compounds in the IM formulation are, however, very soluble in water, raising environmental concerns about their fate and transport. We measured the dissolution of three of these IM formulations, IMX101, IMX104 and PAX21 using laboratory drip tests and studied the accompanying changes in particle structure using micro computed tomography. Our laboratory drip tests mimic conditions on training ranges, where spatially isolated particles of explosives scattered by partial detonations are dissolved by rainfall. We found that the constituents of these IM formulations dissolve sequentially and in the order predicted by their aqueous solubility. The order of magnitude differences in solubility among their constituents produce water solutions whose compositions and concentrations vary with time. For IMX101 and IMX104, that contain 3-nitro-1,2,4-triazol-5-one (NTO), the solutions also vary in pH. The good mass balances measured for the drip tests indicate that the formulations are not being photo-or bio-transformed under laboratory conditions.


Parental depressive symptoms and adolescent adjustment: a prospective test of an explanatory model for the role of marital conflict.
Despite calls for process-oriented models for child maladjustment due to heightened marital conflict in the context of parental depressive symptoms, few longitudinal tests of the mechanisms underlying these relations have been conducted. Addressing this gap, the present study examined multiple factors longitudinally that link parental depressive symptoms to adolescent adjustment problems, building on a conceptual model informed by emotional security theory (EST). Participants were from 320 families (158 boys, 162 girls), including mothers and fathers, who took part when their children were in kindergarten (T1), second (T2), seventh (T3), eighth (T4) and ninth (T5) grades. Parental depressive symptoms (T1) were related to changes in adolescents' externalizing and internalizing symptoms (T5), as mediated by parents' negative emotional expressiveness (T2), marital conflict (T3), and emotional insecurity (T4). Evidence was thus advanced for emotional insecurity as an explanatory process in the context of parental depressive symptoms.


Multiple biomarkers in molecular oncology. II. Molecular diagnostics applications in breast cancer management.
In recent years, the application of genomic and proteomic technologies to the problem of breast cancer prognosis and the prediction of therapy response have begun to yield encouraging results. Independent studies employing transcriptional profiling of primary breast cancer specimens using DNA microarrays have identified gene expression profiles that correlate with clinical outcome in primary breast biopsy specimens. Recent advances in microarray technology have demonstrated reproducibility, making clinical applications more achievable. In this regard, one such DNA microarray device based upon a 70-gene expression signature was recently cleared by the US FDA for application to breast cancer prognosis. These DNA microarrays often employ at least 70 gene targets for transcriptional profiling and prognostic assessment in breast cancer. The use of PCR-based methods utilizing a small subset of genes has recently demonstrated the ability to predict the clinical outcome in early-stage breast cancer. Furthermore, protein-based immunohistochemistry methods have progressed from using gene clusters and gene expression profiling to smaller subsets of expressed proteins to predict prognosis in early-stage breast cancer. Beyond prognostic applications, DNA microarray-based transcriptional profiling has demonstrated the ability to predict response to chemotherapy in early-stage breast cancer patients. In this review, recent advances in the use of multiple markers for prognosis of disease recurrence in early-stage breast cancer and the prediction of therapy response will be discussed.


Multiloculated Hydrocephalus: Open Craniotomy or Endoscopy?
Multiloculated hydrocephalus (MLH) is a condition in which patients have multiple, separate abnormal cerebrospinal fluid collections with no communication between them. Despite technical advancements in pediatric neurosurgery, neurological outcomes are poor in these patients and the approach to this pathology remains problematic especially given individual anatomic complexity and cerebrospinal fluid (CSF) hydrodynamics. A uniform surgical strategy has not yet been developed. Current treatment options for MLH are microsurgical fenestration of separate compartments by open craniotomy or endoscopy, shunt surgery in which multiple catheters are placed in the compartments, and combinations of these modalities. Craniotomy for fenestration allows better visualization of the compartments and membranes, and it can offer easy fenestration or excision of membranes and wide communication of cystic compartments. Hemostasis is more easily achieved. However, because of profound loss of CSF during surgery, open craniotomy is associated with an increased chance of subdural hygroma and/or hematoma collection and shunt malfunction. Endoscopy has advantages such as minimal invasiveness, avoidance of brain retraction, less blood loss, faster operation time, and shorter hospital stay. Disadvantages are also similar to those of open craniotomy. Intraoperative bleeding can usually be easily managed by irrigation or coagulation. However, handling of significant intraoperative bleeding is not as easy. Currently, endoscopic fenestration tends to be performed more often as initial treatment and open craniotomy may be useful in patients requiring repeated endoscopic procedures.


Outcomes of early language delay: I. Predicting persistent and transient language difficulties at 3 and 4 years.
Parent-based assessments of vocabulary, grammar, nonverbal ability, and use of language to refer to post and future (displaced reference) were obtained for 8,386 twin children at 2 years of age. Children with 2 year vocabulary scores below the 10th centile were designated the early language delay (ELD) group, and their outcomes at 3 and 4 years were contrasted with the remainder of the sample, the typical language (TL) group. At 3 and 4 years old, children were designated as language impaired if their scores fell below the 15th centile on at least 2 of the 3 parent-provided language measures: vocabulary, grammar, and use of abstract language. At 3 years, 44.1% of the ELD group (as compared to 7.2% of the TL group) met criteria for persistent language difficulties, decreasing slightly to 40.2% at 4 years (as compared to 8.5% of the TL group), consistent with previous reports of frequent spontaneous resolution of delayed language in preschoolers. Although relations between language and nonverbal abilities at 2 years and outcome at 3 and 4 years within the ELD group were highly statistically significant, effect sizes were small, and classification of outcome on the basis of data on 2-year-olds was far too inaccurate to be clinically useful. Children whose language difficulties persisted were not necessarily those with the most severe initial difficulties. Furthermore, measures of parental education and the child's history of ear infections failed to substantially improve the prediction.


Structural basis for differential insertion kinetics of dNMPs opposite a difluorotoluene nucleotide residue.
We have recently challenged the widely held view that 2,4-difluorotoluene (dF) is a nonpolar isosteric analogue of the nucleotide dT, incapable of forming hydrogen bonds (HBs). To gain a further understanding for the kinetic preference that favors dAMP insertion opposite a templating dF, a result that mirrors the base selectivity that favors dAMP insertion opposite dT by RB69 DNA polymerase (RB69pol), we determined presteady-state kinetic parameters for incorporation of four dNMPs opposite dF by RB69pol and solved the structures of corresponding ternary complexes. We observed that both the F2 and F4 substituent of dF in these structures serve as HB acceptors forming HBs either directly with dTTP and dGTP or indirectly with dATP and dCTP via ordered water molecules. We have defined the shape and chemical features of each dF/dNTP pair in the RB69pol active site without the corresponding phosphodiester-linkage constraints of dF/dNs when they are embedded in isolated DNA duplexes. These features can explain the kinetic preferences exhibited by the templating dF when the nucleotide incorporation is catalyzed by wild type RB69pol or its mutants. We further show that the shapes of the dNTP/dF nascent base pair differ markedly from the corresponding dNTP/dT in the pol active site and that these differences have a profound effect on their incorporation efficiencies.


Test-re-test reliability and inter-rater reliability of a digital pelvic inclinometer in young, healthy males and females.
Objective. The purpose of this study was to investigate the reliability of a digital pelvic inclinometer (DPI) for measuring sagittal plane pelvic tilt in 18 young, healthy males and females. Method. The inter-rater reliability and test-re-test reliabilities of the DPI for measuring pelvic tilt in standing on both the right and left sides of the pelvis were measured by two raters carrying out two rating sessions of the same subjects, three weeks apart. Results. For measuring pelvic tilt, inter-rater reliability was designated as good on both sides (ICC = 0.81-0.88), test-re-test reliability within a single rating session was designated as good on both sides (ICC = 0.88-0.95), and test-re-test reliability between two rating sessions was designated as moderate on the left side (ICC = 0.65) and good on the right side (ICC = 0.85). Conclusion. Inter-rater reliability and test-re-test reliability within a single rating session of the DPI in measuring pelvic tilt were both good, while test-re-test reliability between rating sessions was moderate-to-good. Caution is required regarding the interpretation of the test-re-test reliability within a single rating session, as the raters were not blinded. Further research is required to establish validity.


Clinical chemistry score versus high-sensitivity cardiac troponin I and T tests alone to identify patients at low or high risk for myocardial infarction or death at presentation to the emergency department.
Testing for high-sensitivity cardiac troponin (hs-cTn) may assist triage and clinical decision-making in patients presenting to the emergency department with symptoms of acute coronary syndrome; however, this could result in the misclassification of risk because of analytical variation or laboratory error. We sought to evaluate a new laboratory-based risk-stratification tool that incorporates tests for hs-cTn, glucose level and estimated glomerular filtration rate to identify patients at risk of myocardial infarction or death when presenting to the emergency department. We constructed the clinical chemistry score (CCS) (range 0-5 points) and validated it as a predictor of 30-day myocardial infarction (MI) or death using data from 4 cohort studies involving patients who presented to the emergency department with symptoms suggestive of acute coronary syndrome. We calculated diagnostic parameters for the CCS score separately using high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT). For the combined cohorts (n = 4245), 17.1% of participants had an MI or died within 30 days. A CCS score of 0 points best identified low-risk participants: the hs-cTnI CCS had a sensitivity of 100% (95% confidence interval [CI] 99.5%-100%), with 8.9% (95% CI 8.1%-9.8%) of the population classified as being at low risk of MI or death within 30 days; the hs-cTnT CCS had a sensitivity of 99.9% (95% CI 99.2%-100%), with 10.5% (95% CI 9.6%-11.4%) of the population classified as being at low risk. The CCS had better sensitivity than hs-cTn alone (hs-cTnI < 5 ng/L: 96.6%, 95% CI 95.0%-97.8%; hs-cTnT < 6 ng/L: 98.2%, 95% CI 97.0%-99.0%). A CCS score of 5 points best identified patients at high risk (hs-cTnI CCS: specificity 96.6%, 95% CI 96.0%-97.2%; 11.2% [95% CI 10.3%-12.2%] of the population classified as being at high risk; hs-cTnT CCS: specificity 94.0%, 95% CI 93.1%-94.7%; 13.1% [95% CI 12.1%-14.1%] of the population classified as being at high risk) compared with using the overall 99th percentiles for the hs-cTn assays (specificity of hs-cTnI 93.2%, 95% CI 92.3-94.0; specificity of hs-cTnT 73.8%, 95% CI 72.3-75.2). The CCS score at the chosen cut-offs was more sensitive and specific than hs-cTn alone for risk stratification of patients presenting to the emergency department with suspected acute coronary syndrome. Study registration: ClinicalTrials.gov, nos. NCT01994577; NCT02355457.


Candidate markers for the detection of hepatocellular carcinoma in low-molecular weight fraction of serum.
Hepatocellular carcinoma (HCC) represents an important public health problem in Egypt where up to 90% of HCC cases are attributable to hepatitis C viral (HCV) infection. Serum alpha-fetoprotein is elevated in only approximately 60% of HCC patients. The development of effective markers for the detection of HCC could have an impact on cancer mortality and significant public health implications worldwide. The objective of our study was to assess six candidate markers for detection of HCC identified by mass spectrometric analysis of enriched serum. The study examined 78 HCC cases and 72 age- and gender-matched cancer-free controls recruited from the Egyptian population. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometric analysis of enriched low-molecular weight fraction of serum was used for identification of the candidate markers. Our analyses show that all six candidate markers are associated with HCC after adjustment for important covariates including HCV and hepatitis B viral infections. The marker candidates are independently predictive of HCC with areas under the receiver operating characteristic (AuROC) curve ranging from 63-93%. A combination of the six markers improves prediction accuracy to 100% sensitivity, 91% specificity and 98% AuROC curve in an independent test set of 50 patients. Two of the candidate markers were identified by sequencing as fragments of complement C3 and C4. In conclusion, a set of six peptides distinguished with high prediction accuracy HCC from controls in an Egyptian population with a high rate of chronic HCV infection. Further evaluation of these marker candidates for the diagnosis of HCC is needed.


Gathering up meiotic telomeres: a novel function of the microtubule-organizing center.
During meiosis, telomeres cluster and promote homologous chromosome pairing. Telomere clustering depends on conserved SUN and KASH domain nuclear membrane proteins, which form a complex called the linker of nucleoskeleton and cytoskeleton (LINC) and connect telomeres with the cytoskeleton. It has been thought that LINC-mediated cytoskeletal forces induce telomere clustering. However, how cytoskeletal forces induce telomere clustering is not fully understood. Recent study of fission yeast has shown that the LINC complex forms the microtubule-organizing center (MTOC) at the telomere, which has been designated as the "telocentrosome", and that microtubule motors gather telomeres via telocentrosome-nucleated microtubules. This MTOC-dependent telomere clustering might be conserved in other eukaryotes. Furthermore, the MTOC-dependent clustering mechanism appears to function in various other biological events. This review presents an overview of the current understanding of the mechanism of meiotic telomere clustering and discusses the universality of the MTOC-dependent clustering mechanism.


The Omani Arabic version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).
The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Omani Arabic language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the 3 Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 57 JIA patients (22.8% systemic, 28.1% oligoarticular, 35.1% RF negative polyarthritis, 14.0% other categories) and 85 healthy children, were enrolled in two centres. Notably, none of the enrolled JIA patients is affected with enthesitis-related arthritis or undifferentiated arthritis. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed satisfactory psychometric performances. In conclusion, the Omani Arabic version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.


Targeted small-molecule inhibitors of protein kinase B as anticancer agents.
Protein kinase B (PKB or Akt) is a central component of the PI3K - PKB - mTOR signalling cascade and is firmly established as an attractive target for pharmacological intervention in cancer. A number of small molecule inhibitors with well-defined, direct molecular interactions with PKB are now known, covering a range of mechanisms from ATP- or substrate-competitive inhibition, through allosteric modulation of the kinase activity, to inhibition of the phosphatidylinositol-dependent activation process. The development of small molecule inhibitors of PKB has benefited greatly from the application of structural biology techniques, particularly for lead generation and the optimisation of compound potency and selectivity. The development of the major chemical series of PKB inhibitors will be outlined, with an emphasis on the application of structure-based design and the strategies used to optimise compound pharmacodynamics, efficacy and therapeutic window. The development of small molecules targeting PKB for anticancer therapy has reached an exciting stage, with the first selective inhibitors entering clinical trials, and several additional chemotypes demonstrating efficacy in preclinical models.


Wheat flour fortification with iron and other micronutrients for reducing anaemia and improving iron status in populations.
Anaemia is a condition where the number of red blood cells (and consequently their oxygen-carrying capacity) is insufficient to meet the body's physiological needs. Fortification of wheat flour is deemed a useful strategy to reduce anaemia in populations. To determine the benefits and harms of wheat flour fortification with iron alone or with other vitamins and minerals on anaemia, iron status and health-related outcomes in populations over two years of age. We searched CENTRAL, MEDLINE, Embase, CINAHL, 21 other databases and two trials registers up to 21 July 2020, together with contacting key organisations to identify additional studies. We included cluster- or individually-randomised controlled trials (RCTs) carried out among the general population from any country, aged two years and above. The interventions were fortification of wheat flour with iron alone or in combination with other micronutrients. We included trials comparing any type of food item prepared from flour fortified with iron of any variety of wheat DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results and assessed the eligibility of studies for inclusion, extracted data from included studies and assessed risks of bias. We followed Cochrane methods in this review. Our search identified 3538 records, after removing duplicates. We included 10 trials, involving 3319 participants, carried out in Bangladesh, Brazil, India, Kuwait, Philippines, South Africa and Sri Lanka. We identified two ongoing studies and one study is awaiting classification. The duration of interventions varied from 3 to 24 months. One study was carried out among adult women and one trial among both children and nonpregnant women. Most of the included trials were assessed as low or unclear risk of bias for key elements of selection, performance or reporting bias. Three trials used 41 mg to 60 mg iron/kg flour, three trials used less than 40 mg iron/kg and three trials used more than 60 mg iron/kg flour. One trial used various iron levels based on type of iron used: 80 mg/kg for electrolytic and reduced iron and 40 mg/kg for ferrous fumarate. All included studies contributed data for the meta-analyses. Iron-fortified wheat flour with or without other micronutrients added versus wheat flour (no added iron) with the same other micronutrients added Iron-fortified wheat flour with or without other micronutrients added versus wheat flour (no added iron) with the same other micronutrients added may reduce by 27% the risk of anaemia in populations (risk ratio (RR) 0.73, 95% confidence interval (CI) 0.55 to 0.97; 5 studies, 2315 participants; low-certainty evidence). It is uncertain whether iron-fortified wheat flour with or without other micronutrients reduces iron deficiency (RR 0.46, 95% CI 0.20 to 1.04; 3 studies, 748 participants; very low-certainty evidence) or increases haemoglobin concentrations (in g/L) (mean difference MD 2.75, 95% CI 0.71 to 4.80; 8 studies, 2831 participants; very low-certainty evidence). No trials reported data on adverse effects in children (including constipation, nausea, vomiting, heartburn or diarrhoea), except for risk of infection or inflammation at the individual level. The intervention probably makes little or no difference to the risk of Infection or inflammation at individual level as measured by C-reactive protein (CRP) (mean difference (MD) 0.04, 95% CI -0.02 to 0.11; 2 studies, 558 participants; moderate-certainty evidence). Iron-fortified wheat flour with other micronutrients added versus unfortified wheat flour (nil micronutrients added) It is unclear whether wheat flour fortified with iron, in combination with other micronutrients decreases anaemia (RR 0.77, 95% CI 0.41 to 1.46; 2 studies, 317 participants; very low-certainty evidence). The intervention probably reduces the risk of iron deficiency (RR 0.73, 95% CI 0.54 to 0.99; 3 studies, 382 participants; moderate-certainty evidence) and it is unclear whether it increases average haemoglobin concentrations (MD 2.53, 95% CI -0.39 to 5.45; 4 studies, 532 participants; very low-certainty evidence). No trials reported data on adverse effects in children. Nine out of 10 trials reported sources of funding, with most having multiple sources. Funding source does not appear to have distorted the results in any of the assessed trials. Fortification of wheat flour with iron (in comparison to unfortified flour, or where both groups received the same other micronutrients) may reduce anaemia in the general population above two years of age, but its effects on other outcomes are uncertain. Iron-fortified wheat flour in combination with other micronutrients, in comparison with unfortified flour, probably reduces iron deficiency, but its effects on other outcomes are uncertain. None of the included trials reported data on adverse side effects except for risk of infection or inflammation at the individual level. The effects of this intervention on other health outcomes are unclear. Future studies at low risk of bias should aim to measure all important outcomes, and to further investigate which variants of fortification, including the role of other micronutrients as well as types of iron fortification, are more effective, and for whom.


MR of disc protrusion engendered by infectious spondylitis.
The purpose of this study was to determine if infection-related disc protrusion formed a component of the perispinous/epidural mass in patients with intervertebral disc infection. A retrospective review was undertaken of 16 consecutive patients with intervertebral disc space infection who were referred for gadolinium-enhanced MRI. Possible correlation was sought between disc infection and the presence of associated posterior disc protrusion as determined by MRI. Of the 16 infected discs, 10 cases were in the lumbosacral spine, 3 in the thoracic spine, and 3 in the cervical spine. Four cases had isolated posteriorly directed disc protrusion, and 12 showed both posterior and anterior disc protrusions. The infection in patients with disc protrusion was related to Staphylococcus aureus in 14 patients, Salmonella enteritidis in 1, and Streptococcus pneumoniae in 1. This study showed that disc protrusion occurred in combination with disc space infections. Local factors such as the secretion by hyaluronidase from Staphylococcus aureus may play an important role in causing focal disc protrusion. The clinical importance of this finding is in the recognition that a significant part of the compromise of the spinal canal in cases of disc infection can be related to disc fragments engendered by the infectious process.


Effect of Slug-Mediated Down-Regulation of E-Cadherin on Invasiveness and Metastasis of Anaplastic Thyroid Cancer Cells.
BACKGROUND Slug has been found to promote migration and invasion of many cancer cells, including anaplastic thyroid cancer (ATC). Thus, targeting Slug expression could provide new approaches for the treatment of patients with ATC. MATERIAL AND METHODS Small interfering RNA (siRNA) targeting Slug (Slug siRNA) was used to construct clonal derivatives in the metastatic ATC SW1736 cells. Slug cDNA transfection was used to restore the Slug expression in the Slug siRNA-transfected SW1736 cells (Slug siRNA/SW1736). E-cadherin siRNA was used to inhibit E-cadherin expression in the Slug siRNA/SW1736 cells. The SW1736 cell migration, invasion, and signaling pathway was analyzed in vitro. Furthermore, the stable Slug siRNA-transfected SW1736 clones were used for the lung metastasis assay in an in vivo mouse model. RESULTS Targeting Slug expression in SW1736 cells showed a 45% decrease in migration and an 85% decrease in invasiveness in vitro. Knockdown of E-cadherin by E-cadherin siRNA transfection or Slug overexpression by Slug cDNA transfection restored the invasive and migrative ability in SW1736 cells. In addition, we found an 80% decrease in the number of macroscopic lung metastases nodes of mice by in vivo analysis. Western blot assay showed that Slug expression was inhibited and E-cadherin expression was increased in the Slug siRNA-transfected tumors. CONCLUSIONS Targeting Slug signaling pathway is effective in preventing lung metastasis in ATC.


Characterizing microplastic size and morphology of photodegraded polymers placed in simulated moving water conditions.
Aquatic plastic debris experiences environmental stressors that lead to breakdown into smaller micro-sized plastic particles. This work quantified microplastic formation with the environmental stressors of UV irradiation followed by mechanical strain induced by movement of water with an emphasis on connecting our results to changes in the materials chemical/physical properties. Polypropylene, polyethylene, and polyethylene terephthalate thin films and polypropylene injection-molded sheets were irradiated with 254 nm UV light, placed into aquatic microcosms, collected through sieving, and counted under a microscope. Results showed increasingly more particles in smaller size classes, the smallest being 74-177 μm. Mechanical strain from the turbulent water caused 2.3-3× more microplastics to be formed for the thinnest (∼25 μm) film and 1.4-2× more for thicker films and sheets. The most common morphology of microplastics was fibers, particularly in thicker polypropylene samples, which was attributed to absorbance of the photons and the changes observed in the crystallinity and glass transition as measured with differential scanning calorimetry (DSC). When irradiated for 24, 48, or 72 h, longer irradiation resulted in more microplastics formed by polypropylene films, which correlated with changes in the glass transition temperature as measured by DSC and the extent of oxidation as measured with FTIR. Irradiation at 300 nm produced fewer microplastics due to slower kinetics of phototransformations. Overall, this work evaluates the impact of combined photodegradation and water motion toward microplastic particles formed. It provides quantitative evidence that mechanical strain of water movement exacerbates photo-induced formation of microplastics and shows that the existence of fibers in natural systems can be the result of photodegradation.


SU-E-J-03: Positioning Errors of Metal Localization Devices with Motion Artifacts on KV and MV Cone Beam CT.
To investigate motion artifacts of kV CBCT and MV CBCT images on metal localization devices for image guided radiation therapy. 8 MU pelvis CBCT template for Siemens Artiste MVision and Pelvis template for Varian IX on-board Exact Arms kV were used to acquire CBCT images in this study. Images from both CBCT modalities were compared in CNRs, metal landmark absolute positions, and image volume distortion on three different planes of view. The images were taken on a breathing-simulated thoracic phantom in which several typical metal localization devices were implanted, including clips and wires for breast patients, gold seeds for prostate patients, and BBs as skin marks. To magnify the artifacts, a 4cm diameter metal ball was also implanted in the thoracic phantom to mimic the metal artifacts. The amplitude of the sinusoidal breathing was 1cm, and the period varies from 2sec, 4sec to 8sec. For MV CBCT, the CNR at 4sec breathing cycle with 1cm breathing amplitude was 5.0, 3.4 and 4.6 for clips, gold seeds and BBs, respectively while it was 1.5, 2.0 and 1.6 for kV CBCT. On the images, kV CBCT showed symmetric streaking artifacts both in the transverse and longitudinal directions relative to the motion direction. kV CBCT images predicted 89% of the expected volume, while MV CBCT images predicted 95% of the expected volume. Simulated soft tissue observed in MVCT cannot be detected in kVCT. MV CBCT images showed better volume prediction, less streaking effects and better CNRs of a moving metal target, i.e. clips, BBs, gold seeds and metal balls than kV CBCT images. MV CBCT was more advantageous compared to kV CBCT with less motion artifacts for metal localization devices.


Vulnerability of dynamic genetic conservation units of forest trees in Europe to climate change.
A transnational network of genetic conservation units for forest trees was recently documented in Europe aiming at the conservation of evolutionary processes and the adaptive potential of natural or man-made tree populations. In this study, we quantified the vulnerability of individual conservation units and the whole network to climate change using climate favourability models and the estimated velocity of climate change. Compared to the overall climate niche of the analysed target species populations at the warm and dry end of the species niche are underrepresented in the network. However, by 2100, target species in 33-65 % of conservation units, mostly located in southern Europe, will be at the limit or outside the species' current climatic niche as demonstrated by favourabilities below required model sensitivities of 95%. The highest average decrease in favourabilities throughout the network can be expected for coniferous trees although they are mainly occurring within units in mountainous landscapes for which we estimated lower velocities of change. Generally, the species-specific estimates of favourabilities showed only low correlations to the velocity of climate change in individual units, indicating that both vulnerability measures should be considered for climate risk analysis. The variation in favourabilities among target species within the same conservation units is expected to increase with climate change and will likely require a prioritization among co-occurring species. The present results suggest that there is a strong need to intensify monitoring efforts and to develop additional conservation measures for populations in the most vulnerable units. Also, our results call for continued transnational actions for genetic conservation of European forest trees, including the establishment of dynamic conservation populations outside the current species distribution ranges within European assisted migration schemes.


On the activity and fidelity of chromatin-associated hepatic DNA polymerase-beta in aging murine species of different life spans.
Activity and accuracy of chromatin-directed DNA replication have been compared in young and aged Mus musculus and Peromyscus leucopus, two murine species with contrasting maximum lifespans. Chromatin isolated from livers of mature adults of both species copied efficiently exogenous DNA templates using predominantly DNA polymerase-beta. The DNA synthetic activity of liver chromatin remained constant in both species throughout their lifetimes. The fidelity of chromatin-directed poly [d(A-T)] synthesis was similar for the comparatively short-lived M. musculus and the relatively long-lived P. leucopus and remained unaltered in old animals. The fidelity of poly [d(A-T)] copying catalyzed by DNA polymerase-beta-dissociated from liver chromatin was comparable to that of the chromatin-directed synthesis. The dissociation enzymes did not exhibit diminished fidelity of poly [d(A-T)] synthesis with age. In all ages of both species examined, the murine liver DNA polymerase-beta, both chromatin-associated and solubilized, exhibited high error frequencies; approximately one dGMP was incorporated for every 500-1,000 complementary nucleotides polymerized. The relationship of these results to the accuracy of DNA replication and repair as a determinant of aging is considered.


Factors influencing hospital high length of stay outliers.
The study of length of stay (LOS) outliers is important for the management and financing of hospitals. Our aim was to study variables associated with high LOS outliers and their evolution over time. We used hospital administrative data from inpatient episodes in public acute care hospitals in the Portuguese National Health Service (NHS), with discharges between years 2000 and 2009, together with some hospital characteristics. The dependent variable, LOS outliers, was calculated for each diagnosis related group (DRG) using a trim point defined for each year by the geometric mean plus two standard deviations. Hospitals were classified on the basis of administrative, economic and teaching characteristics. We also studied the influence of comorbidities and readmissions. Logistic regression models, including a multivariable logistic regression, were used in the analysis. All the logistic regressions were fitted using generalized estimating equations (GEE). In near nine million inpatient episodes analysed we found a proportion of 3.9% high LOS outliers, accounting for 19.2% of total inpatient days. The number of hospital patient discharges increased between years 2000 and 2005 and slightly decreased after that. The proportion of outliers ranged between the lowest value of 3.6% (in years 2001 and 2002) and the highest value of 4.3% in 2009. Teaching hospitals with over 1,000 beds have significantly more outliers than other hospitals, even after adjustment to readmissions and several patient characteristics. In the last years both average LOS and high LOS outliers are increasing in Portuguese NHS hospitals. As high LOS outliers represent an important proportion in the total inpatient days, this should be seen as an important alert for the management of hospitals and for national health policies. As expected, age, type of admission, and hospital type were significantly associated with high LOS outliers. The proportion of high outliers does not seem to be related to their financial coverage; they should be studied in order to highlight areas for further investigation. The increasing complexity of both hospitals and patients may be the single most important determinant of high LOS outliers and must therefore be taken into account by health managers when considering hospital costs.


Evaluating the process of online health information searching: a qualitative approach to exploring consumer perspectives.
The Internet is a common resource that patients and consumers use to access health-related information. Multiple practical, cultural, and socioeconomic factors influence why, when, and how people utilize this tool. Improving the delivery of health-related information necessitates a thorough understanding of users' searching-related needs, preferences, and experiences. Although a wide body of quantitative research examining search behavior exists, qualitative approaches have been under-utilized and provide unique perspectives that may prove useful in improving the delivery of health information over the Internet. We conducted this study to gain a deeper understanding of online health-searching behavior in order to inform future developments of personalizing information searching and content delivery. We completed three focus groups with adult residents of Olmsted County, Minnesota, which explored perceptions of online health information searching. Participants were recruited through flyers and classifieds advertisements posted throughout the community. We audio-recorded and transcribed all focus groups, and analyzed data using standard qualitative methods. Almost all participants reported using the Internet to gather health information. They described a common experience of searching, filtering, and comparing results in order to obtain information relevant to their intended search target. Information saturation and fatigue were cited as main reasons for terminating searching. This information was often used as a resource to enhance their interactions with health care providers. Many participants viewed the Internet as a valuable tool for finding health information in order to support their existing health care resources. Although the Internet is a preferred source of health information, challenges persist in streamlining the search process. Content providers should continue to develop new strategies and technologies aimed at accommodating diverse populations, vocabularies, and health information needs.


Effects of indole-3-carbinol on the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in smokers.
Indole-3-carbinol (I3C) is a component of the human diet, occurring as a conjugate in certain cruciferous vegetables. I3C protects against carcinogenesis in a variety of animal models by modifying carcinogen metabolism. In mice, I3C decreases lung tumor formation by the tobacco-specific nitrosamine 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by enhancing its hepatic clearance (M. A. Morse et al., Cancer Res., 50: 2613-2617, 1990). In this study, our goal was to determine whether I3C would have similar effects on NNK metabolism in smokers as it did in mice. Thirteen women took 400 mg of I3C on 5 consecutive days and maintained constant smoking habits during this period. Their urine was analyzed before and after the I3C treatment period for two metabolites of NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide (NNAL-Gluc). I3C treatment resulted in decreased levels of urinary NNAL, NNAL-Gluc, and NNAL plus NNAL-Gluc, and increased NNAL-Gluc:NNAL ratio in 10 of the 13 women. The mean decreases in NNAL (-0.27 +/- 0.09 pmol/mg creatinine, -23.4%) and NNAL plus NNAL-Gluc (-0.43 +/- 0.16 pmol/mg creatinine, -10.9%) were statistically significant as was the increase in NNAL-Gluc:NNAL ratio (1.1 +/- 0.5, 39.9%). These changes in urinary metabolites of NNK were consistent with those seen in mice treated with I3C and NNK; they suggest that I3C increased hepatic metabolism of NNK in our smokers. This is the first study to examine the effects of I3C on metabolism of an exogenous carcinogen in humans.


Decarbonylative ether dissection by iridium pincer complexes.
A unique chain-rupturing transformation that converts an ether functionality into two hydrocarbyl units and carbon monoxide is reported, mediated by iridium(i) complexes supported by aminophenylphosphinite (NCOP) pincer ligands. The decarbonylation, which involves the cleavage of one C-C bond, one C-O bond, and two C-H bonds, along with formation of two new C-H bonds, was serendipitously discovered upon dehydrochlorination of an iridium(iii) complex containing an aza-18-crown-6 ether macrocycle. Intramolecular cleavage of macrocyclic and acyclic ethers was also found in analogous complexes featuring aza-15-crown-5 ether or bis(2-methoxyethyl)amino groups. Intermolecular decarbonylation of cyclic and linear ethers was observed when diethylaminophenylphosphinite iridium(i) dinitrogen or norbornene complexes were employed. Mechanistic studies reveal the nature of key intermediates along a pathway involving initial iridium(i)-mediated double C-H bond activation.