Racial differences in cardiac catheterization as a function of patients' beliefs.
We examined racial differences in cardiac catheterization rates and reviewed whether patients' beliefs or other variables were associated with observed disparities. We did a prospective observational cohort study of 1045 White and African American patients at 5 Veterans Affairs (VA) medical centers whose nuclear imaging studies indicated reversible cardiac ischemia. There were few demographic differences between White and African American patients in our sample. African Americans were less likely than Whites to undergo cardiac catheterization. African Americans were more likely than Whites to indicate a strong reliance on religion and to report racial and social class discrimination and were less likely to indicate a generalized trust in people but did not differ from White patients on numerous other attitudes about health and health care. Neither sociodemographic or clinical characteristics nor patients' beliefs explained the observed disparities, but physicians' assessments of the procedure's importance and patients' likelihood of coronary disease seemed to account for differences not otherwise explained. Patients' preferences are not the likely source of racial disparities in the use of cardiac catheterization among veterans using VA care, but physicians' assessments warrant further attention.


The role of central and peripheral hormones in sexual and violent recidivism in sex offenders.
Hormonal factors are important in multifactorial theories of sexual offending. The relationship between hormones and aggression in nonhumans is well established, but the putative effect in humans is more complex, and the direction of the effect is usually unclear. In this study, a large sample (N = 771) of adult male sex offenders was assessed between 1982 and 1996. Gonadotrophic (follicle-stimulating hormone and luteinizing hormone) and androgen hormone (total and free testosterone; T) levels were assessed at Time 1, along with indicators of sex drive and hostility. Individuals were observed up to 20 years in the community, with an average time at risk of 10.9 years (SD 4.6). Gonadotrophic hormones correlated positively with self-reported hostility and were better predictors of recidivism than was T (area under the curve (AUC), 0.58-0.63). Self-reported hostility emerged as a partial mediator of this relationship between gonadotrophic hormones and recidivism. These results point to a potentially new area of investigation for hormones and sexual aggression.


TRANSPORTIN1 Promotes the Association of MicroRNA with ARGONAUTE1 in Arabidopsis.
In Arabidopsis thaliana, microRNAs (miRNAs) are mainly loaded into ARGONAUTE1 (AGO1) to posttranscriptionally regulate gene expression. We previously found that ENHANCED MiRNA ACTIVITY1 (EMA1), an importin β family protein, negatively regulates miRNA loading into AGO1. In this study, through a suppressor screening of ema1, we identified another importin β protein, TRANSPORTIN1 (TRN1), as a regulatory component in the miRNA pathway. Mutation of TRN1 did not reduce miRNA accumulation, but it impaired miRNA activity. We found that TRN1 interacted with AGO1. Mutation of the three conserved residues required for cargo recognition of TRN1 reduced its interaction with AGO1 and compromised its function in regulating miRNA activity. Intriguingly, TRN1 dysfunction did not change the cytoplasmic-nuclear distribution of miRNAs and AGO1 but reduced the amount of miRNAs associated with AGO1. These results indicate that TRN1 positively regulates miRNA activity by promoting the association of miRNAs with AGO1, and they reveal opposing roles of two importin β family proteins in miRNA loading.


The Effect of 30-Second Sprints During Prolonged Exercise on Gross Efficiency, Electromyography, and Pedaling Technique in Elite Cyclists.
Cycling competitions are often of long duration and include repeated high-intensity efforts. To investigate the effect of repeated maximal sprints during 4 hours of low-intensity cycling on gross efficiency (GE), electromyography patterns, and pedaling technique compared with work-matched low-intensity cycling in elite cyclists. Twelve elite, male cyclists performed 4 hours of cycling at 50% of maximal oxygen uptake either with 3 sets of 3 × 30-second maximal sprints (E&S) during the first 3 hours or a work-matched cycling without sprints (E) in a randomized order. Oxygen uptake, electromyography, and pedaling technique were recorded throughout the exercises. GE was reduced from start to the end of exercise in both conditions (E&S: 19.0 [0.2] vs 18.1 [0.2], E: 19.1% [0.2%] vs 18.1% [0.2%], both P = .001), with no difference in change between conditions (condition × time interaction, P = .8). Integrated electromyography increased from start to end of exercise in m. vastus lateralis and m. vastus medialis (m. vastus medialis: 9.9 [2.4], m. vastus lateralis: 8.5 [4.0] mV, main effect of time: P < .001 and P = .03, respectively) and E&S increased less than E in m. vastus medialis (mean difference -3.3 [1.5] mV, main effect of condition: P = .03, interaction, P = .06). The mechanical effectiveness only decreased in E&S (E&S: -2.2 [0.7], effect size = 0.24 vs E: -1.3 [0.8] percentage points: P = .04 and P = .8, respectively). The mean power output during each set of 3 × 30-second sprints in E&S did not differ (P = .6). GE decreases as a function of time during 4 hours of low-intensity cycling. However, the inclusion of maximal repeated sprinting does not affect the GE changes, and the ability to sprint is maintained throughout the entire session.


Survival outcomes of breast cancer patients with brain metastases: A multicenter retrospective study in Korea (KROG 16-12).
This study evaluated the influence of prognostic factors and whole brain radiotherapy (WBRT) on overall survival (OS) of breast cancer (BC) patients with brain metastases (BM). Medical records of 730 BC patients diagnosed with BM from 2000 to 2014 at 17 institutions were retrospectively reviewed. OS was calculated from BM diagnosis. Median follow-up duration was 11.9 months (range, 0.1-126.2). Median OS was 15.0 months (95% CI: 14.0-16.9). Patients with different BC-specific graded prognostic assessment (GPA) scores showed significant differences (p < 0.001) in OS. In multivariate analysis, histologic grade 3 (p = 0.014), presence of extracranial metastasis (p < 0.001), the number of BM (>4; p = 0.002), hormone receptor negativity (p = 0.005), HER2-negativity (p = 0.003), and shorter time interval (<30 months) between BC and BM diagnosis (p = 0.007) were associated with inferior OS. By summing the β-coefficients of variables that were prognostic in multivariate analyses, we developed a prognostic model that stratified patients into low-risk (≤0.673) and high-risk (>0.673) subgroups; the high-risk subgroup had poorer median OS (10.1 months, 95% CI: 7.9-11.9 vs. 21.9 months, 95% CI: 19.5-27.1, p < 0.001). Univariate and multivariate analyses of propensity score-matched patients diagnosed with BM ≥ 30 months after BC diagnosis (n = 389, "late BM") revealed that WBRT-treated patients showed superior OS compared to non-WBRT-treated patients (p = 0.070 and 0.030, respectively). Our prognostic model identified high-risk BC patients with BM who might benefit from increased surveillance; if validated, our model could guide treatment selection for such patients. Patients with late BM might benefit from WBRT as initial local treatment.


Serotonin agonists increase transferrin levels via activation of 5-HT1C receptors in choroid plexus epithelium.
Choroid plexus epithelial cells are enriched in mRNA for proteins such as the iron carrier transferrin, which acts as a trophic factor in the brain. Choroid plexus epithelial cells also have a high density of 5-HT1C receptors linked to activation of the phosphoinositide (PI) hydrolysis second messenger system. The present studies show that the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) potently increases PI hydrolysis and the levels of transferrin in primary cultures of rat choroid plexus epithelial cells. These effects are blocked by the 5-HT1C/5-HT2 receptor antagonists mesulergine and mianserin, but not by the 5-HT2 receptor-selective antagonist spiperone. Similarly, mesulergine and mianserin, but not spiperone, block the increases in transferrin levels and PI hydrolysis elicited by 5-carboxamidotryptamine (5-CT), a 5-HT1 receptor-selective agonist, and by serotonin. We conclude, therefore, that 5-HT1C receptor activation in the choroid plexus leads to an increase in the production of transferrin. By promoting transferrin synthesis in the choroid plexus, 5-HT may indirectly influence brain development and differentiation.


Argumentation in end-of-life conversations with families in Dutch intensive care units: a qualitative observational study.
In intensive care units (ICUs), decisions about the continuation or discontinuation of life-sustaining treatment (LST) are made on a daily basis. Professional guidelines recommend an open exchange of standpoints and underlying arguments between doctors and families to arrive at the most appropriate decision. Yet, it is still largely unknown how doctors and families argue in real-life conversations. This study aimed to (1) identify which arguments doctors and families use in support of standpoints to continue or discontinue LST, (2) investigate how doctors and families structure their arguments, and (3) explore how their argumentative practices unfold during conversations. A qualitative inductive thematic analysis of 101 audio-recorded conversations between doctors and families. Seventy-one doctors and the families of 36 patients from the neonatal, pediatric, and adult ICU (respectively, N-ICU, P-ICU, and A-ICU) of a large university-based hospital participated. In almost all conversations, doctors were the first to argue and families followed, thereby either countering the doctor's line of argumentation or substantiating it. Arguments put forward by doctors and families fell under one of ten main types. The types of arguments presented by families largely overlapped with those presented by doctors. A real exchange of arguments occurred in a minority of conversations and was generally quite brief in the sense that not all possible arguments were presented and then discussed together. This study offers a detailed insight in the argumentation practices of doctors and families, which can help doctors to have a sharper eye for the arguments put forward by doctors and families and to offer room for true deliberation.


Compensation for substrate elasticity in the kinematics of leaping by infant pigtailed macaques (Macaca nemestrina).
The means whereby animals adapt their locomotor behavior to variation in environmental conditions is an important and neglected problem in the area of motor control. To investigate this problem, young (3-month-old) pigtailed macaques (Macaca nemestrina) were filmed leaping a fixed distance from both rigid and elastic take-off supports. Sixteen of 17 subjects exhibited substantial invariance in the trajectories described by the major joints of the hind limb (hip, knee and ankle) during the leap. By contrast, the patterns of angular joint movement varied between performances involving the rigid and elastic supports. Maintaining invariant joint trajectories may enable the leaping animal to land safely at the target and prepare for subsequent action, and requires compensation for substrate elasticity. This compensation is effected, in part, by changing the patterns of joint flexion and extension.


Newly Described Entities in Salivary Gland Pathology.
Salivary glands may give rise to a wide spectrum of different tumors. This review concentrates on 4 salivary gland tumors that have been accepted in the recent literature as new neoplastic entities: mammary analog secretory carcinoma, cribriform adenocarcinoma of minor salivary glands (CASG), sclerosing polycystic adenosis/adenoma (SPA), and the mucinous/secretory variant of myoepithelioma. Mammary analog secretory carcinoma is a distinctive low-grade malignant salivary cancer that harbors a characteristic chromosomal translocation, t(12;15) (p13;q25), resulting in an ETV6-NTRK3 fusion. Cribriform adenocarcinoma (CASG) is a distinct tumor entity that differs from polymorphous low-grade adenocarcinoma by location (ie, most often arising on the tongue), by prominent nuclear clearing, differing alterations of the PRKD gene family, and clinical behavior with frequent metastases at the time of presentation of the primary tumor. Early nodal metastatic disease is seen in most cases of CASG; yet, they are still associated with indolent clinical behavior, making it a unique neoplasm among all low-grade salivary gland tumors. SPA is a rare sclerosing tumor of the salivary glands characterized by the combination of cystic ductal structures with variable cell lining including vacuolated, apocrine, mucinous, squamous, and foamy cells, by prominent large acinar cells with coarse eosinophilic cytoplasmic zymogen-like granules, and by closely packed ductal structures, surrounded by a peripheral myoepithelial layer and stromal fibrosis with focal inflammatory infiltrates. SPA frequently harbors intraductal epithelial dysplastic proliferations ranging from mild dysplasia to severe dysplasia/carcinoma in situ. Moreover, SPA has been proven to be a clonal process by HUMARA assay and is associated with considerable risk of recurrence. Therefore, on the basis of all these newly recognized findings, we believe that SPA is likely a neoplasm, and we suggest the name "sclerosing polycystic adenoma." The mucinous variant of myoepithelioma is a myoepithelial tumor with foci of prominent cytoplasmic clearing frequently containing intracellular mucin material and having signet-ring morphology.


Case report: heavy metal burden presenting as Bartter syndrome.
Maternal transfer of heavy metals during fetal development or lactation possibly contributed to the clinical manifestations of Bartter syndrome and developmental delay in the offspring. An 11-month-old child diagnosed with Bartter syndrome and failure to thrive was treated concurrently for elevated metal burden while he was undergoing standard medical interventions. Treatment with body-weight doses of meso-2,3-dimercaptosuccinic acid (DMSA) reduced the body burden of lead, beryllium, copper, mercury, and cadmium at the three- and sixth-month follow-up tests. During the course of the six-month treatment, the patient gained 2.4 kg (5.2 lb) and grew approximately 9.5 cm (3.75 in). His weight shifted from significantly below the 5th percentile in weight to within the 5th percentile, and from below the 5th to within the 10th percentile for length. The child's acquisition of lead, beryllium, and copper correspond to his mother's history of stained glass assembly and occurred during fetal development or lactation, since there were no other identifiable sources that could have contributed to the heavy metal burden. Tests for known genetic mutations leading to Bartter syndrome were all negative. This case report highlights the potential benefit of DMSA for treatment of heavy metal body burden in infants who present with Bartter syndrome.


Refinement of the Long-Term Conditions Questionnaire (LTCQ): patient and expert stakeholder opinion.
It is a key UK government priority to assess and improve outcomes in people with long-term conditions (LTCs). We are developing a new patient-reported outcome measure, the Long-Term Conditions Questionnaire (LTCQ), for use among people with single or multiple LTCs. This study aimed to refine candidate LTCQ items that had previously been informed through literature reviews, interviews with professional stakeholders, and interviews with people with LTCs. Cognitive interviews (n=32) with people living with LTCs and consultations with professional stakeholders (n=13) and public representatives (n=5) were conducted to assess the suitability of 23 candidate items. Items were tested for content and comprehensibility and underwent a translatability assessment. Four rounds of revisions took place, due to amendments to item structure, improvements to item clarity, item duplication, and recommendations for future translations. Twenty items were confirmed as relevant to living with LTCs and understandable to patients and professionals. This study supports the content validity of the LTCQ items among people with LTCs and professional stakeholders. The final items are suitable to enter the next stage of psychometric refinement.


Atlas of the Immune Cell Repertoire in Mouse Atherosclerosis Defined by Single-Cell RNA-Sequencing and Mass Cytometry.
Atherosclerosis is a chronic inflammatory disease that is driven by the interplay of pro- and anti-inflammatory leukocytes in the aorta. Yet, the phenotypic and transcriptional diversity of aortic leukocytes is poorly understood. We characterized leukocytes from healthy and atherosclerotic mouse aortas in-depth by single-cell RNA-sequencing and mass cytometry (cytometry by time of flight) to define an atlas of the immune cell landscape in atherosclerosis. Using single-cell RNA-sequencing of aortic leukocytes from chow diet- and Western diet-fed Apoe-/- and Ldlr-/- mice, we detected 11 principal leukocyte clusters with distinct phenotypic and spatial characteristics while the cellular repertoire in healthy aortas was less diverse. Gene set enrichment analysis on the single-cell level established that multiple pathways, such as for lipid metabolism, proliferation, and cytokine secretion, were confined to particular leukocyte clusters. Leukocyte populations were differentially regulated in atherosclerotic Apoe-/- and Ldlr-/- mice. We confirmed the phenotypic diversity of these clusters with a novel mass cytometry 35-marker panel with metal-labeled antibodies and conventional flow cytometry. Cell populations retrieved by these protein-based approaches were highly correlated to transcriptionally defined clusters. In an integrated screening strategy of single-cell RNA-sequencing, mass cytometry, and fluorescence-activated cell sorting, we detected 3 principal B-cell subsets with alterations in surface markers, functional pathways, and in vitro cytokine secretion. Leukocyte cluster gene signatures revealed leukocyte frequencies in 126 human plaques by a genetic deconvolution strategy. This approach revealed that human carotid plaques and microdissected mouse plaques were mostly populated by macrophages, T-cells, and monocytes. In addition, the frequency of genetically defined leukocyte populations in carotid plaques predicted cardiovascular events in patients. The definition of leukocyte diversity by high-dimensional analyses enables a fine-grained analysis of aortic leukocyte subsets, reveals new immunologic mechanisms and cell-type-specific pathways, and establishes a functional relevance for lesional leukocytes in human atherosclerosis.


Design of a randomized trial to evaluate the influence of mobile phone reminders on adherence to first line antiretroviral treatment in South India--the HIVIND study protocol.
Poor adherence to antiretroviral treatment has been a public health challenge associated with the treatment of HIV. Although different adherence-supporting interventions have been reported, their long term feasibility in low income settings remains uncertain. Thus, there is a need to explore sustainable contextual adherence aids in such settings, and to test these using rigorous scientific designs. The current ubiquity of mobile phones in many resource-constrained settings, make it a contextually appropriate and relatively low cost means of supporting adherence. In India, mobile phones have wide usage and acceptability and are potentially feasible tools for enhancing adherence to medications. This paper presents the study protocol for a trial, to evaluate the influence of mobile phone reminders on adherence to first-line antiretroviral treatment in South India. 600 treatment naïve patients eligible for first-line treatment as per the national antiretroviral treatment guidelines will be recruited into the trial at two clinics in South India. Patients will be randomized into control and intervention arms. The control arm will receive the standard of care; the intervention arm will receive the standard of care plus mobile phone reminders. Each reminder will take the form of an automated call and a picture message. Reminders will be delivered once a week, at a time chosen by the patient. Patients will be followed up for 24 months or till the primary outcome i.e. virological failure, is reached, whichever is earlier. Self-reported adherence is a secondary outcome. Analysis is by intention-to-treat. A cost-effectiveness study of the intervention will also be carried out. Stepping up telecommunications technology in resource-limited healthcare settings is a priority of the World Health Organization. The trial will evaluate if the use of mobile phone reminders can influence adherence to first-line antiretrovirals in an Indian context.


Nanocatalysis by the tip of a scanning tunneling microscope operating inside a reactor cell.
The platinum-rhodium tip of a scanning tunneling microscope that operates inside of an atmospheric-pressure chemical reactor cell has been used to locally rehydrogenate carbonaceous fragments deposited on the (111) surface of platinum. The carbon fragments were produced by partial dehydrogenation of propylene. The reactant gas environment inside the cell consisted of pure H(2) or a 1:9 mixture of CH(3)CHCH(2) and H(2) at 300 kelvin. The platinum-rhodium tip acted as a catalyst after activation by short voltage pulses. In this active state, the clusters in the area scanned by the tip were reacted away with very high spatial resolution.


Prevention of scopolamine-induced memory deficits by schisandrin B, an antioxidant lignan from Schisandra chinensis in mice.
The preventive effect of schisandrin B (Sch B), an antioxidant ingredient of Schisandra chinensis, was studied on scopolamine-induced dementia in mouse. Scopolamine developed oxidative stress in the brain with the decreased levels of antioxidant enzymes and increased nitrite level. At the same time, a significant impairment of learning and memory occurred when evaluated by passive avoidance task (PAT) and Morris water maze (MWM) with concomitant increase of acetylcholinesterase (AChE) activity and decreased acetylcholine levels. Pre-treatment by Sch B (10, 25, 50 mg/kg) effectively prevented scopolamine-induced oxidative stress and improved behavioural tasks. Further, the scopolamine-induced increase in AChE activity was significantly suppressed and the level of acetylcholine was maintained as normal by Sch B treatment. These results suggest that Sch B have protective function against cerebral functional defects such as dementia not only by antioxidant prevention but also exerting its potent cognitive-enhancing activity through modulation of acetylcholine level.


Nickel-silver alloy electrocatalysts for hydrogen evolution and oxidation in an alkaline electrolyte.
The development of improved catalysts for the hydrogen evolution reaction (HER) and hydrogen oxidation reaction (HOR) in basic electrolytes remains a major technical obstacle to improved fuel cells, water electrolyzers, and other devices for electrochemical energy storage and conversion. Based on the free energy of adsorbed hydrogen intermediates, theory predicts that alloys of nickel and silver are active for these reactions. In this work, we synthesize binary nickel-silver bulk alloys across a range of compositions and show that nickel-silver alloys are indeed more active than pure nickel for hydrogen evolution and, possibly, hydrogen oxidation. To overcome the mutual insolubility of silver and nickel, we employ electron-beam physical vapor codeposition, a low-temperature synthetic route to metastable alloys. This method also produces flat and uniform films that facilitate the measurement of intrinsic catalytic activity with minimal variations in the surface area, ohmic contact, and pore transport. Rotating-disk-electrode measurements demonstrate that the hydrogen evolution activity per geometric area of the most active catalyst in this study, Ni0.75Ag0.25, is approximately twice that of pure nickel and has comparable stability and hydrogen oxidation activity. Our experimental results are supported by density functional theory calculations, which show that bulk alloying of Ni and Ag creates a variety of adsorption sites, some of which have near-optimal hydrogen binding energy.


Photoreceptor organization and rhythmic phagocytosis in the nile rat Arvicanthis ansorgei: a novel diurnal rodent model for the study of cone pathophysiology.
To characterize rod and cone distribution, organization, and phagocytosis in the diurnal mouse-like rodent Arvicanthis ansorgei. Retinas of adult A. ansorgei were processed for histology, electron microscopy and immunohistochemistry using rod- and mouse cone-specific antibodies. For phagocytosis studies, retinas were sampled every 3 hours under a 12-hour light-dark cycle and processed for double-label immunohistochemistry. The number of phagosomes in the retinal pigmented epithelium were quantified with a morphometric system. A. ansorgei retinas were composed of 33% cones and 67% rods, approximately 10 times more cones than mice and rats. Cones were arranged in two cell layers at the scleral surface, distributed uniformly across the entire retina. Cone arrestin was distributed throughout the dark-adapted cones, from outer segments to synapses, whereas short- and mid-wavelength cone opsins were restricted to outer segments. Short-wavelength cone density was mapped in wholemounted retinas, in a significantly higher number in the central region. Rhodopsin immunopositive (rod) phagosomes showed a small peak late in the dark phase, then a large burst 1 to 2 hours after light onset, after decreasing to low baseline levels by 12 AM. Mid-wavelength cone opsin immunopositive (cone) phagosomes were 10 times less numerous than rods, and demonstrated a broad peak 1 to 2 hours after light onset. The diurnal rodent A. ansorgei possesses a large number of cones, organized in a strict anatomic array. Rod and cone outer segment phagocytosis and shedding can be monitored simultaneously and show similar profiles but different amplitudes. This species may constitute a valuable novel animal model for investigating cone pathophysiology.


Technical Note: Anatomic identification of isolated modern human molars: testing Procrustes aligned outlines as a standardization procedure for elliptic fourier analysis.
The determination of the precise position of permanent first and second modern human molars, following standard tooth identification criteria, is often difficult because of their morphological similarities. Here, we proposed to evaluate the suitability of two-dimensional crown contour shape analysis in achieving this objective. The method was tested separately on 180 first and second maxillary molars (UM) and 180 first and second mandibular molars (LM) securely identified (in anatomical position in their sockets). Generalized Procrustes superimposition is used to normalize the outlines prior to applying elliptic Fourier analyses ("EFAproc" method). Reliability and effectiveness of this morphometric procedure was evaluated by comparing the results obtained for the same dataset with four other morphometric methods of contour analysis. Cross-validated ("leave one individual out") percentages of misclassification yielded by linear discriminant analyses were used for determining the anatomic position of modern human molars. The percentages of misclassifications obtained from every method of contour analysis were low (1.67% to 3.33% for the UM, 5.56% to 6.67% for the LM) indicating the high suitability of crown contour analyses in correctly identifying molars. A reliable protocol, based on predictive linear discriminant analyses, was then proposed for identification of isolated molars. In addition, our results confirmed that the EFAproc method is suitable for normalizing outlines prior to undertaking elliptic Fourier analyses, especially in the case of nearly circular outlines: it obtained better classification than the classic method of normalization of Fourier descriptors for UM and provided also some advantages over the three landmarks-based methods tested here.


Thresholds for Resuscitation of Extremely Preterm Infants in the UK, Sweden, and Netherlands.
It is widely acceptable to involve parents in decision-making about the resuscitation of extremely preterm infants (EPIs) in the gray zone. However, there are different views about where the boundaries of the gray zone should lie. Our aim in this study was to compare the resuscitation thresholds for EPIs between neonatologists in the United Kingdom, Sweden, and the Netherlands. We distributed an online survey to consultant neonatologists and neonatal registrars and fellows that included clinical scenarios in which parents requested resuscitation or nonresuscitation. Respondents were asked about the lowest gestational age and/or the worst prognosis at which they would provide resuscitation and the highest gestational age and/or the best prognosis at which they would withhold resuscitation. In additional scenarios, influence of the condition at birth or consideration of available health care resources was assessed. The survey was completed by 162 neonatologists (30% response rate). There was a significant difference between countries; the gray zone for most UK respondents was 23 + 0/7 to 23 + 6/7 or 24 weeks' gestation, compared with 22 + 0/7 to 22 + 6/7 or 23 weeks' gestation in Sweden and 24 + 0/7 to 25 + 6/7 or 26 weeks' gestation in the Netherlands. Resuscitation thresholds were higher if an infant was born in poor condition. There was wide variation in the prognosis that warranted resuscitation or nonresuscitation. Consideration of resource scarcity did not alter responses. In this survey, we found significant differences in approach to the resuscitation of EPIs, with a spectrum from most proactive (Sweden) to least proactive (Netherlands). Most survey respondents indicated shifts in decision-making that were associated with particular weeks' gestation. Despite the different approaches to decision-making in the 3 countries, there was relatively little difference between countries in neonatologists' prognostic thresholds for resuscitation.


Pharmacogenomic characterization of US FDA-approved cytotoxic drugs.
Individualization of cancer chemotherapy based on the patient's genetic makeup holds promise for reducing side effects and improving efficacy. However, the relative contribution of genetics to drug response is unknown. In this study, we investigated the cytotoxic effect of 29 commonly prescribed chemotherapeutic agents from diverse drug classes on 125 lymphoblastoid cell lines derived from 14 extended families. The results of this systematic study highlight the variable role that genetics plays in response to cytotoxic drugs, ranging from a heritability of <0.15 for gemcitabine to >0.60 for epirubicin. Putative quantitative trait loci for cytotoxic response were identified, as well as drug class-specific signatures, which could indicate possible shared genetic mechanisms. In addition to the identification of putative quantitative trait locis, the results of this study inform the prioritization of chemotherapeutic drugs with a sizable genetic response component for future investigation.


Effects of music on memory for text.
Previous research has suggested that the use of song can facilitate recall of text. This study examined the effect of repetition of a melody across verses, familiarity with the melody, rhythm, and other structural processing hypotheses to explain this phenomenon. Two experiments were conducted, each with 100 participants recruited from undergraduate Psychology programs (44 men, 156 women, M age = 28.5 yr., SD = 9.4). In Exp. 1, participants learned a four-verse ballad in one of five encoding conditions (familiar melody, unfamiliar melody, unknown rhythm, known rhythm, and spoken). Exp. 2 assessed the effect of familiarity in rhythm-only conditions and of pre-exposure with a previously unfamiliar melody. Measures taken were number of verbatim words recalled and number of lines produced with correct syllabic structure. Analysis indicated that rhythm, with or without musical accompaniment, can facilitate recall of text, suggesting that rhythm may provide a schematic frame to which text can be attached. Similarly, familiarity with the rhythm or melody facilitated recall. Findings are discussed in terms of integration and dual-processing theories.


p53 protein expression and genetic mutation in two primary cell types in pulmonary sclerosing haemangioma.
To investigate the significance of p53 protein expression and genetic mutations in two primary cell types in pulmonary sclerosing haemangioma (PSH). p53 protein expression in polygonal cells and cuboidal cells in 19 patients with PSH was detected using immunohistochemistry. The two major cell types were captured using laser capture microdissection technology. Mutations in the p53 gene (exons 5-8) were examined using single-stranded conformation polymorphism and DNA sequencing analysis. p53 protein expression and gene mutations were observed in 15.8% (3/19) of cases. In these cases, p53 protein was expressed in the nucleus of both cell types, with higher expression levels and mutation rates in polygonal cells than in surface cuboidal cells. Two cases showed mutation only in the polygonal cells, while one case showed double (separate) mutations in both the polygonal and cuboidal cells. p53 mutation was exhibited in PSH. The mutation rate in polygonal cells was higher than that in surface cuboidal cells.


The influence of fenofibrate on lipid profile, endothelial dysfunction, and inflammatory markers in type 2 diabetes mellitus patients with typical and mixed dyslipidemia.
Type 2 diabetes is associated with early development of endothelial dysfunction. Patients present with typical dyslipidemia (predominantly high levels of triglycerides [TG] and low levels of high-density lipoprotein cholesterol [HDL-C]) or mixed hypercholesterolemia (high levels of low-density lipoprotein cholesterol [LDL-C] and TG with low HDL-C). Normal levels include LDL-C < 100 mg/dL, TG < 135 mg/dL, and HDL-C > 40 mg/dL for men and >50 mg/dL for women. To determine the effects of 8 weeks' administration of fenofibrate on inflammatory markers, metabolic parameters, and endothelial dysfunction. We administered micronized fenofibrate (Laboratories Fourneir S.A Dijon, France) daily for 8 weeks to 40 dyslipidemic, type 2 diabetes patients with equal numbers in each arm of the typical or mixed dyslipidemia groups. Noninvasive endothelial function assessments were performed and serum inflammatory markers obtained before and after treatment. The typical group demonstrated significantly greater TG reduction and HDL-C increment, ie, 56% vs, 21.3% (P < .005) and 21% vs. 7.6% (P = .001), respectively, compared with the mixed group. There was greater LDL-C reduction within the mixed group compared with the typical group 21.0% vs. 2.2% (P < .05). Endothelial dysfunction was present in both groups at baseline. After treatment, the typical group demonstrated significant improvement in resting brachial diameter (3.9 mm [interquartile range {IQR} 3.3-4.7] to 4.2 mm [IQR 3.4-4.8], P = .001) compared with no change within the mixed group (3.6 mm [IQR 3.1-5.4] to 3.7 mm [IQR 3.1-5.3], P = .26). Flow-mediated diameter improved significantly in both groups. The mixed group had significantly greater levels of hs-CRP at baseline but no changes throughout the study. The mixed group demonstrated an increase in vascular adhesion molecule-1 from 706 ng/mL (IQR 566-1195) to 845 ng/mL (637-1653; P = .01), a reduction of tumor necrosis factor-α from 7.0 pg/mL (IQR 1.0-43.5) to 2.5 pg/mL (IQR 1.5-13.5; P = .04) throughout the study. We effectively compared 8 weeks of fenofibrate therapy in type 2 diabetics with contrasting lipid abnormalities. The typical dyslipidemia group showed significantly greater lipid improvements compared with the mixed dyslipidemia group. Both groups had improvements in endothelial functions that were independent of the lipid levels. We concluded that fibrate therapy in type 2 diabetics is beneficial, especially those with typical dyslipidemia and extends beyond its lipid lowering properties.


Involvement of multiple chromosome 17p loci in medulloblastoma tumorigenesis.
Loss of heterozygosity for sequences located on chromosome 17p in several tumor types is often associated with mutations in the tumor suppressor gene p53. We previously showed consistent deletion of chromosome 17p12-13.1 in medulloblastoma, a common childhood brain tumor. Using denaturing gradient gel electrophoresis and direct sequencing, we have detected p53 mutations in only two of 20 medulloblastoma specimens. Moreover, additional RFLP studies of these 20 specimens showed loss of heterozygosity at a more distal and distinct site, 17p13.3. Deletion of 17p almost invariably signified a negative prognosis. Our results suggest that p53 mutations may contribute to the pathogenesis of medulloblastoma in relatively few cases. The consistent deletion of other discrete loci on 17p suggests that additional or alternative tumor suppressor genes may contribute to the tumor's phenotype.


Recursive Partitioning vs Computerized Adaptive Testing to Reduce the Burden of Health Assessments in Cleft Lip and/or Palate: Comparative Simulation Study.
Computerized adaptive testing (CAT) has been shown to deliver short, accurate, and personalized versions of the CLEFT-Q patient-reported outcome measure for children and young adults born with a cleft lip and/or palate. Decision trees may integrate clinician-reported data (eg, age, gender, cleft type, and planned treatments) to make these assessments even shorter and more accurate. We aimed to create decision tree models incorporating clinician-reported data into adaptive CLEFT-Q assessments and compare their accuracy to traditional CAT models. We used relevant clinician-reported data and patient-reported item responses from the CLEFT-Q field test to train and test decision tree models using recursive partitioning. We compared the prediction accuracy of decision trees to CAT assessments of similar length. Participant scores from the full-length questionnaire were used as ground truth. Accuracy was assessed through Pearson's correlation coefficient of predicted and ground truth scores, mean absolute error, root mean squared error, and a two-tailed Wilcoxon signed-rank test comparing squared error. Decision trees demonstrated poorer accuracy than CAT comparators and generally made data splits based on item responses rather than clinician-reported data. When predicting CLEFT-Q scores, individual item responses are generally more informative than clinician-reported data. Decision trees that make binary splits are at risk of underfitting polytomous patient-reported outcome measure data and demonstrated poorer performance than CATs in this study.


Analysis of "early" thymidine/inosine protection as an adjunct to methotrexate therapy.
The feasibility of "early" thymidine and inosine protection of methotrexate (MTX) toxicity is evaluated in this paper. This approach is based on the proposition that the most vulnerable period for susceptible host cells to MTX toxicity is an interval following a pulse of MTX when the MTX monoglutamate level is high. In contrast, tumor cells that accumulate active MTX polyglutamyl derivatives are exposed to the cytotoxic effects of MTX, not only when the monoglutamate levels are high, but also over the much longer interval during which polyglutamyl derivatives are retained within these cells. The protecting agents employed, thymidine and inosine, circumvent the antipurine and antipyrimidine effects of MTX, but neither agent inhibits the transport or the polyglutamylation of MTX. Nucleoside protection given over 6 hours after MTX markedly decreased toxicity to normal BDF1 mice at MTX doses up to 150 mg/kg/day for 3 consecutive days. The LD10 for unprotected mice was 14 mg/kg/day, while the LD10 for the protected mice was 114 mg/kg/day, a greater than eightfold increase in the drug dose delivered. MTX with early nucleoside protection produced a 50% increase in median life span in tumor-bearing mice at doses of drug that were toxic to unprotected mice. Flow cytometric analyses indicated that consecutive daily pulses of MTX with early nucleoside protection alter the cell cycle distribution. By 24 hours after the last of three daily pulses of MTX, the G1 component was maximal (80% of the cell population), with less than 2% of the cells in G2M and 17% of the cells in S phase. This distribution persisted for 24 hours, after which a normal pattern emerged, a process that was accelerated by neither thymidine/inosine nor leucovorin. These studies support the concept that toxicity to the host is initiated largely in the interval shortly after MTX administration. The data indicate that early nucleoside protection permits the repetitive administration of much higher doses of MTX than can be given with MTX alone. This approach may be useful not only in the treatment of human neoplasms but in the treatment of other disorders, such as rheumatoid arthritis, psoriatic arthritis, or psoriasis. Finally, this paper considers the potential advantages of early thymidine/inosine protection in comparison to leucovorin rescue with the administration of low or moderate doses of MTX.


Ethanol-sensitive sites on the human dopamine transporter.
Previous studies have shown that ethanol enhanced [(3)H]dopamine uptake in Xenopus oocytes expressing the dopamine transporter (DAT). This increase in DAT activity was mirrored by an increase in the number of transporters expressed at the cell surface. In the present study, ethanol potentiated the function of DAT expressed in HeLa cells but inhibited the function of the related norepinephrine transporter (NET). Chimeras generated between DAT and NET were examined for ethanol sensitivity and demonstrated that a 76-amino acid region spanning transmembrane domains (TMD) 2 and 3 was essential for ethanol potentiation of DAT function. The second intracellular loop between TMD 2 and 3 of DAT, which differs from that of NET by four amino acids, was explored for possible sites of ethanol action. Site-directed mutagenesis was used to replace each of these residues in DAT with the corresponding residue in NET, and the resulting cRNA were expressed in Xenopus oocytes. We found that mutations G130T or I137F abolished ethanol potentiation of DAT function, whereas the mutations F123Y and L138F had no significant effect. These results identify novel sites in the second intracellular loop that are important for ethanol modulation of DAT activity.


Breastfeeding questions to medicines call centres from the Australian public and health professionals.
There is considerable uncertainty regarding medication use during breastfeeding. This study compared lactation-related questions about medicines from consumers and health professionals to identify knowledge gaps. A retrospective, mixed-methods study of lactation-related call data extracted from two Australian medicines call centre databases: National Prescribing Service (NPS) Medicines Line (ML) for the general public and Therapeutic Advice and Information Service (TAIS) for health professionals, was conducted. Of the 5662 lactation-related calls by consumers to ML, most were from women enquiring about themselves (95%). The 2219 lactation-related calls from health professionals to TAIS were largely from GPs (46%), community pharmacists (35%) and nurses (12%). Consumers commonly enquired about medicines freely accessible or over-the-counter, including non-steroidal anti-inflammatory products (9.3%), paracetamol (6.9%), ibuprofen (4.8%) and codeine (4.2%). Health professionals' questions involved prescription medicines such as antidepressants (16.9%), with queries on sertraline (3.7%), levonorgestrel (2.7%) and domperidone (2.4%) most common. Question themes were similar for both cohorts, focusing mainly around medication safety, risk minimisation and milk supply. Understanding the compelling and common themes driving medicines help-seeking related to breastfeeding is key to addressing information gaps and improving overall medication use during breastfeeding.


Identification of 8 Novel Mutations in Nephrogenesis-Related Genes in Chinese Han Patients with Unilateral Renal Agenesis.
Few genetic studies have focused on unilateral renal agenesis (URA), which is a disorder with insidious clinical manifestations and a tendency to result in renal failure. We aimed to detect pathogenic mutations in nephrogenesis-related genes, which were identified by a literature review conducted among a large cohort of Chinese Han patients with URA. Totally, 86 unrelated URA patients were included. All URA patients were diagnosed by employing radiological methods. Patients with a solitary kidney owing to nephrectomy or renal atrophy due to secondary factors were excluded. Nine (10.5%) patients had a family history of abnormal nephrogenesis. Fifteen (17.4%) had other malformations in the urogenital system. All coding exons and adjacent intron regions of 25 genes were analyzed using next-generation sequencing and validated by Sanger sequencing and 100 ethnically matched healthy controls. Ten conserved mutations (9 missense mutations and 1 deletion mutation) were identified in SALL1, EYA1, RET, HNF1B, DSTYK, WNT4, and SIX5. All mutations were novel or rare (frequency <0.1%) in the public databases and absent from the 100 healthy controls. Nine patients carried mutations in candidate genes. Most of the patients carried one single heterozygous mutation, except for 2, who respectively carried compound heterozygous mutations and 2 single heterozygous mutations. In addition, 2 patients shared the same mutation in DSTYK. A total of 10.5% of our URA cases could be explained by mutations in our candidate genes. The mutations in nephrogenesis-related genes in the Chinese Han patients with URA had a decentralized distribution without any hotspot mutations.


Depth of the biologically active zone in upland habitats at the Hanford Site, Washington: Implications for remediation and ecological risk management.
Soil invertebrates, mammals, and plants penetrate and exploit the surface soil layer (i.e., the biologically active zone) to varying depths. As the US Department of Energy remediates radioactive and hazardous wastes in soil at the Hanford Site, a site-specific definition of the biologically active zone is needed to identify the depth to which remedial actions should be taken to protect the environment and avoid excessive cleanup expenditures. This definition may then be considered in developing a point of compliance for remediation in accordance with existing regulations. Under the State of Washington Model Toxic Control Act (MTCA), the standard point of compliance for soil cleanup levels with unrestricted land use is 457 cm (15 ft) below ground surface. When institutional controls are required to control excavations to protect people, MTCA allows a conditional point of compliance to protect biological resources based on the depth of the biologically active zone. This study was undertaken to identify and bound the biologically active zone based on ecological resources present at the Hanford Site. Primary data were identified describing the depths to which ants, mammals, and plants may exploit the surface soil column at the Hanford Site and other comparable locations. The maximum depth observed for harvester ants (Pogonomyrmex spp.) was 270 cm (8.9 ft), with only trivial excavation below 244 cm (8 ft). Badgers (Taxidea taxus) are the deepest burrowing mammal at the Hanford Site, with maximum burrow depths of 230 cm (7.6 ft); all other mammals did not burrow below 122 cm (4 ft). Shrubs are the deepest rooting plants with rooting depths to 300 cm (9.8 ft) for antelope bitterbrush (Purshia tridentata). The 2 most abundant shrub species did not have roots deeper than 250 cm (8.2 ft). The deepest rooted forb had a maximum root depth of 240 cm (7.9 ft). All other forbs and grasses had rooting depths of 200 cm (6.6 ft) or less. These data indicate that the biologically active soil zone in the Hanford Central Plateau does not exceed 300 cm (9.8 ft), the maximum rooting depth for the deepest rooting plant. The maximum depth at which most other plant and animal species occur is substantially shallower. Spatial distribution and density of burrows and roots over depths were also evaluated. Although maximum excavation by harvester ants is 270 cm (8.9 ft), trivial volume of soil is excavated below 150 cm (∼5 ft). Maximum rooting depths for all grasses, forbs, and the most abundant and deepest rooting shrubs are 300 cm (9.8 ft) or less. Most root biomass (>50-80%) is concentrated in the top 100 cm (3.3 ft), whereas at the maximum depth (9.8 ft), only trace root biomass is present. Available data suggest a limited likelihood for significant transport of contaminants to the surface by plants at or below 244 cm (8 ft), and suggest that virtually all plants or animal species occurring on the Central Plateau have a negligible likelihood for transporting soil contaminants to the surface from depths at or below 305 cm (10 ft).


Diffusion and interfacial transport of water in Nafion.
Water absorption, membrane swelling, and self-diffusivity of water in 1100 equivalent weight Nafion were measured as functions of temperature and water activity. Free volume per water at 80 °C, determined from water uptake and volume expansion data, decreases with water content in the membrane from 12 cm(3)/mol at λ = 0.5 H(2)O/SO(3) to 1.5 cm(3)/mol at λ = 4. The change in free volume with water content displays a transition at λ = 4. Limiting water self-diffusivity in Nafion was determined by pulsed gradient spin echo NMR at long delay times. The limiting self-diffusivity increases exponentially with water activity; the rate of increase of diffusivity with water content shows a transition at λ = 4. The tortuosity of the hydrophilic domains in Nafion decreased from 20 at low membrane water activity to 3 at λ = 4. It suggested a change in the connectivity of the hydrophilic domains absorbed water occurs at λ ∼ 4. The diffusivity results were employed to separate the contributions of diffusional and interfacial resistance for water transport across Nafion membranes, which enabled the determination of the interfacial mass transport coefficients. A diffusion model was developed which incorporated activity-dependent diffusivity, volume expansion, and the interfacial resistance, and was used to resolve the water activity profiles in the membrane.


Screening for late-onset congenital adrenal hyperplasia in hirsutism or amenorrhea.
Late-onset congenital adrenal hyperplasia is a mild genetic defect in steroidogenesis that presents with hirsutism and menstrual irregularities and responds to specific treatment with dexamethasone sodium phosphate. Its incidence as a significant cause of hirsutism or amenorrhea is controversial because it cannot be distinguished clinically from other causes. However, it is readily diagnosed by a marked increase in 17 alpha-hydroxyprogesterone levels after adrenocorticotropic hormone stimulation. Seventy-seven randomly selected women with hirsutism or amenorrhea were tested, and eight women (10.4%) were found to have late-onset congenital adrenal hyperplasia. Plasma levels of other hormones were similar in patients with and without late-onset congenital adrenal hyperplasia and were of no benefit in making the diagnosis. It is concluded that the adrenocorticotropic hormone stimulation test should be more widely utilized in patients presenting with hirsutism or menstrual dysfunction.


An analysis of the anatomic variations of the paranasal sinuses and ethmoid roof using computed tomography.
To determine the Keros classification and asymmetrical distribution rates of the ethmoid roof and the frequency of anatomic variations of the paranasal sinuses. Paranasal sinus scans of 500 patients obtained using computed tomography were evaluated retrospectively. Measurements were performed using a coronal plan with right-left comparison and with distance measurement techniques. The depth of the lateral lamella was calculated by subtracting the depth of the cribriform plate from the depth of the medial ethmoid roof. The results were classified according to their Keros classification. Any asymmetries in the ethmoid roof depth and fovea ethmoidalis configuration were examined. The anatomic variations frequently encountered in paranasal sinuses (pneumatized middle concha, paradoxical middle concha, agger nasi cells, Haller cells, Onodi cells, etc.) were defined. The mean height of the lateral lamella cribriform plate (LLCP) was 4.92±1.70 mm. The cases were classified as 13.4% Keros Type I, 76.1% Keros Type II, and 10.5% Keros Type III. There was asymmetry in the LLCP depths of 80% of the cases, and a configuration asymmetry in the fovea in 35% of the cases. In 32% of the cases with fovea configuration asymmetry, there was also asymmetry in the height of the right and left LLCP. The most frequent variations were nasal septum deviation (81.8%), agger nasi cells (63.8%), intralamellar air cells (45%), and concha bullosa (30%). Using the Keros classification for LLCP height, higher rates of Keros Type I were found in other studies than in our study. The most frequent classification was Keros Type II. The paranasal sinus variations in each patient should be carefully evaluated. The data obtained from these evaluations can prevent probable complications by informing rhinologists performing endoscopic sinus surgery about preoperative and intraoperative processes.


Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer.
The presence of the TMPRSS2-ERG fusion gene in prostate tumors has recently been associated with an aggressive phenotype, as well as recurrence and death from prostate cancer. These associations suggest the hypothesis that the gene fusion may be used as a prognostic indicator for prostate cancer. In this study, fluorescent in situ hybridization (FISH) assays were used to assess TMPRSS2-ERG fusion status in a group of 214 prostate cancer cases from two population-based studies. The FISH assays were designed to detect both fusion type (deletion vs. translocation) and the number of fusion copies (single vs. multiple). Genotyping of four ERG and one TMPRSS2 SNPs using germline DNA was also performed in a sample of the cases (n = 127). Of the 214 tumors scored for the TMPRSS2-ERG fusion, 64.5% were negative and 35.5% were positive for the fusion. Cases with the TMPRSS2-ERG fusion did not exhibit reduced prostate cancer survival (HR = 0.92, 95% CI = 0.22-3.93), nor was there a significant difference in cause-specific survival when stratifying by translocation or deletion (HR = 0.84, 95% CI = 0.23-3.12) or by the number of retained fusion copies (HR = 1.22, 95% CI = 0.45-3.34). However, evidence for reduced prostate cancer-specific survival was apparent in those cases whose tumor had multiple copies of the fusion. The variant T allele of the TMPRSS2 SNP, rs12329760, was positively associated with TMPRSS2-ERG fusion by translocation (p = 0.05) and with multiple copies of the gene fusion (p = 0.03). If replicated, the results presented here may provide insight into the mechanism by which the TMPRSS2-ERG gene fusion arises and also contribute to diagnostic evaluations for determining the subset of men who will go on to develop metastatic prostate cancer.


Study on the Mechanism of the Danggui-Chuanxiong Herb Pair on Treating Thrombus through Network Pharmacology and Zebrafish Models.
Danggui-Chuanxiong (DC) is a commonly used nourishing and activating blood medicine pair in many gynecological prescriptions and modern Chinese medicine. However, its activating blood mechanism has not been clearly elucidated. Our research aimed at investigating the activating blood mechanisms of DC using network pharmacology and zebrafish experiments. Network pharmacology was used to excavate the potential targets and mechanisms of DC in treating thrombus. The antithrombotic, anti-inflammatory, antioxidant, and vasculogenesis activities of DC and the main components of DC, ferulic acid (DC2), ligustilide (DC7), and levistilide A (DC17), were evaluated by zebrafish models in vivo. A total of 24 compounds were selected as the active ingredients with favorable pharmacological parameters for this herb pair. A total of 89 targets and 18 pathways related to the thrombus process were gathered for active compounds. The genes, TNF, CXCR4, IL2, ESR1, FGF2, HIF1A, CXCL8, AR, FOS, MMP2, MMP9, STAT3, and RHOA, might be the main targets for this herb pair to exert cardiovascular activity from the analysis of protein-protein interaction and KEGG pathway results, which were mainly related to inflammation, vasculogenesis, immunity, hormones, and so forth. The zebrafish experiment results showed that DC had antithrombotic, anti-inflammatory, antioxidant, and vasculogenesis activities. The main compounds had different effects of zebrafish activities. Especially, the antithrombotic activity of the DC17H group, anti-inflammatory activities of DCH and DC2H groups, antioxidant activities of DCM, DCH, DC2, DC7, and DC17 groups, and vasculogenesis activities of DCM, DCH, and DC2 groups were stronger than those of the positive group. The integrated method coupled zebrafish models with network pharmacology provided the insights into the mechanisms of DC in treating thrombus.


Stromal fibroblasts induce metastatic tumor cell clusters via epithelial-mesenchymal plasticity.
Emerging evidence supports the hypothesis that multicellular tumor clusters invade and seed metastasis. However, whether tumor-associated stroma induces epithelial-mesenchymal plasticity in tumor cell clusters, to promote invasion and metastasis, remains unknown. We demonstrate herein that carcinoma-associated fibroblasts (CAFs) frequently present in tumor stroma drive the formation of tumor cell clusters composed of two distinct cancer cell populations, one in a highly epithelial (E-cadherinhiZEB1lo/neg: Ehi) state and another in a hybrid epithelial/mesenchymal (E-cadherinloZEB1hi: E/M) state. The Ehi cells highly express oncogenic cell-cell adhesion molecules, such as carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and CEACAM6 that associate with E-cadherin, resulting in increased tumor cell cluster formation and metastatic seeding. The E/M cells also retain associations with Ehi cells, which follow the E/M cells leading to collective invasion. CAF-produced stromal cell-derived factor 1 and transforming growth factor-β confer the Ehi and E/M states as well as invasive and metastatic traits via Src activation in apposed human breast tumor cells. Taken together, these findings indicate that invasive and metastatic tumor cell clusters are induced by CAFs via epithelial-mesenchymal plasticity.


Reconstructing Forearm Free Flap Donor Sites Using Full-Thickness Skin Grafts Harvested from the Ipsilateral Arm.
To compare morbidity and aesthetic outcomes of full-thickness skin grafts (FTSGs) and split-thickness skin grafts (STSGs) in the reconstruction of the forearm free flap donor site. Case series, retrospective chart review. Institutional microvascular database. Subjects who underwent forearm free flaps and FTSGs for donor site reconstruction from April 2016 to November 2017 were included. FTSGs were obtained from the donor forearm with a proximal S-shaped incision, thereby avoiding additional wound creation. Morbidity outcomes were compared to 68 consecutive patients with STSG reconstruction from January 2009 to May 2010. Complications, including tendon exposure, subjective functional impairment, complete graft loss, partial graft loss, infection, paresthesias, and hematoma/seroma, were evaluated, as were aesthetic outcomes. Sixty-eight patients underwent FTSG reconstruction. No significant differences between FTSGs and STSGs were demonstrated in terms of graft loss ≥40% (4% vs 4%, P = 1.000), partial graft loss (<40%) (29% vs 40%, P = .207), tendon exposure (9% vs 12%, P = .573), infection (15% vs 13%, P = .805), paresthesias (12% vs 7%, P = .382), subjective functional impairment (0% vs 2%, P = .316), or hematoma/seroma (2% vs 0%, P = .316). Aesthetic outcomes were better in the FTSG group compared to the STSG group, as determined by both patients (P = .004) and surgeon (P < .001). Our results advocate for the consideration of FTSGs in the reconstruction of the forearm free flap donor site given superior aesthetic results without additional donor site morbidity or additional wound creation when compared to STSGs.


In silico insight into two rice chromosomal regions associated with submergence tolerance and resistance to bacterial leaf blight and gall midge.
Plants respond to both biotic and abiotic stresses through a common signaling system to provide defense and protection against many adverse environments. Many genes/QTLs governing resistance to both biotic and abiotic stresses have been studied and mapped in rice. Sub1, a major QTL for submergence tolerance is collocated with a gene Gm1 for gall midge resistance on chromosome 9 (Region 1). Likewise a bigger region on chromosome 5 (Region 2) has a minor QTL for submergence tolerance collocated with genes for bacterial blight resistance. Utilizing the rice sequence and annotation data (TIGR) and rice genome annotation project database (RAP-DB), we wanted to know the kinds of genes underlying these two chromosomal regions where genes/QTL governing tolerance to both biotic and abiotic stresses are collocated. We also analyzed the pattern of distribution of these genes across the BAC/PAC clones spanning the region so that candidate genes can be short listed for a functional analysis. Genes known to have a role in submergence tolerance were present in both the regions. Region 1, had a unique transcription factor like trithorax protein, which is a positional candidate gene for submergence tolerance. Pyruvate decarboxylase (PDC) gene for alcohol fermentation and cation transporting ATPase c-terminal domain are likely candidates for submergence QTL in Region 2. Genes such as SKP1 and elicitor induced cytochrome p450 associated with tissue necrosis and insect resistance were found in region 1. Multiple copies of ORFs for signal transduction proteins, transcription factors, genes for systemic acquired resistance, Ubiquitin proteins and pathogen elicitor identification and degrading proteins were located as a cluster in Region 2, where bacterial blight resistance genes mapped. Validation of the data obtained from TIGR with other databases (RAP and KOME) confirmed our findings. The functional role of some of the significant candidate genes needs to be established. Allele/gene specific markers can then be designed for use in MAS thus enhancing durable tolerance/resistance faster.


Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm.
Deterministic lateral displacement (DLD) pillar arrays are an efficient technology to sort, separate and enrich micrometre-scale particles, which include parasites, bacteria, blood cells and circulating tumour cells in blood. However, this technology has not been translated to the true nanoscale, where it could function on biocolloids, such as exosomes. Exosomes, a key target of 'liquid biopsies', are secreted by cells and contain nucleic acid and protein information about their originating tissue. One challenge in the study of exosome biology is to sort exosomes by size and surface markers. We use manufacturable silicon processes to produce nanoscale DLD (nano-DLD) arrays of uniform gap sizes ranging from 25 to 235 nm. We show that at low Péclet (Pe) numbers, at which diffusion and deterministic displacement compete, nano-DLD arrays separate particles between 20 to 110 nm based on size with sharp resolution. Further, we demonstrate the size-based displacement of exosomes, and so open up the potential for on-chip sorting and quantification of these important biocolloids.


Dread and the disvalue of future pain.
Standard theories of decision-making involving delayed outcomes predict that people should defer a punishment, whilst advancing a reward. In some cases, such as pain, people seem to prefer to expedite punishment, implying that its anticipation carries a cost, often conceptualized as 'dread'. Despite empirical support for the existence of dread, whether and how it depends on prospective delay is unknown. Furthermore, it is unclear whether dread represents a stable component of value, or is modulated by biases such as framing effects. Here, we examine choices made between different numbers of painful shocks to be delivered faithfully at different time points up to 15 minutes in the future, as well as choices between hypothetical painful dental appointments at time points of up to approximately eight months in the future, to test alternative models for how future pain is disvalued. We show that future pain initially becomes increasingly aversive with increasing delay, but does so at a decreasing rate. This is consistent with a value model in which moment-by-moment dread increases up to the time of expected pain, such that dread becomes equivalent to the discounted expectation of pain. For a minority of individuals pain has maximum negative value at intermediate delay, suggesting that the dread function may itself be prospectively discounted in time. Framing an outcome as relief reduces the overall preference to expedite pain, which can be parameterized by reducing the rate of the dread-discounting function. Our data support an account of disvaluation for primary punishments such as pain, which differs fundamentally from existing models applied to financial punishments, in which dread exerts a powerful but time-dependent influence over choice.


Assessing Trends in Hospital System Structures From 2008 to 2015.
The Affordable Care Act introduced a major systematic change aimed to promote coordination across the care continuum. Yet, it remains unknown the extent to which hospital system structures have changed following the Affordable Care Act. The structure of hospital systems has important implications for the cost, quality, and accessibility of health services. To assess trends in the structures of hospital systems. We aggregated data from the American Hospital Association (AHA) Annual Survey to the system level. Using a panel of hospital systems from 2008 to 2015, we assessed trends in the number of hospital systems, their size, ownership characteristics, geospatial arrangements, and integration with outpatient services. In the period 2008-2015, there was an increasing percentage of hospitals that were system affiliated as well as growth in the number of hospital systems. A greater percentage of hospital systems that were organized as moderately centralized systems transitioned to centralized systems than to decentralized systems (19.8% vs. 4.7%; P<0.001). In terms of geospatial arrangement, a greater percentage of hub-and-spoke systems moved to a regional design than to national systems (20.0% vs. 8.2%; P<0.05). An increasing trend over time toward greater integration with outpatient services was found in a measure of total system level integration with outpatient services. Our findings suggest that hospital systems may be moving toward more regional designs. In addition, the trend of increasing integration offered across hospital systems overall, and as portion of total integration, suggests that systems may be increasing their services along the continuum of care.


Analysis of the influence of O(2) A-band absorption on atmospheric correction of ocean-color imagery.
Two satellite-borne ocean-color sensors scheduled for launch in the mid 1990's each have a spectral band (nominally 745-785 nm) that completely encompasses the O(2) A band at 762 nm. These spectral bands are to be used in atmospheric correction of the color imagery by assessment of the aerosol contribution to the total radiance at the sensor. The effect of the O(2) band on the radiance measured at the satellite is studied with a line-by-line backward Monte Carlo radiative transfer code. As expected, if the O(2) absorption is ignored, unacceptably large errors in the atmospheric correction result. The effects of the absorption depend on the vertical profile of the aerosol. By assuming an aerosol profile-the base profile-we show that it is possible to remove most of the O(2)-absorption effects from atmospheric correction in a simple manner. We also investigate the sensitivity of the results to the details of the assumed base profile and find that, with the exception of situations in which there are significant quantities of aerosol in the stratosphere, e.g., following volcanic eruptions or in the presence of thin cirrus clouds, the quality of the atmospheric correction depends only weakly on the base profile. Situations with high concentrations of stratospheric aerosol require additional information regarding vertical structure for this spectral band to be used in atmospheric correction; however, it should be possible to infer the presence of such aerosol by a failure of the atmospheric correction to produce acceptable water-leaving radiance in the red. An important feature of our method for removal of the O(2)-absorption effects is that it permits the use of lookup tables that can be prepared in the absence of O(2) absorption by the use of more efficient radiative transfer codes.


Archaeological Central American maize genomes suggest ancient gene flow from South America.
Maize (Zea mays ssp. mays) domestication began in southwestern Mexico ∼9,000 calendar years before present (cal. BP) and humans dispersed this important grain to South America by at least 7,000 cal. BP as a partial domesticate. South America served as a secondary improvement center where the domestication syndrome became fixed and new lineages emerged in parallel with similar processes in Mesoamerica. Later, Indigenous cultivators carried a second major wave of maize southward from Mesoamerica, but it has been unclear until now whether the deeply divergent maize lineages underwent any subsequent gene flow between these regions. Here we report ancient maize genomes (2,300-1,900 cal. BP) from El Gigante rock shelter, Honduras, that are closely related to ancient and modern maize from South America. Our findings suggest that the second wave of maize brought into South America hybridized with long-established landraces from the first wave, and that some of the resulting newly admixed lineages were then reintroduced to Central America. Direct radiocarbon dates and cob morphological data from the rock shelter suggest that more productive maize varieties developed between 4,300 and 2,500 cal. BP. We hypothesize that the influx of maize from South America into Central America may have been an important source of genetic diversity as maize was becoming a staple grain in Central and Mesoamerica.


Evolution of responses to (un)fairness.
The human sense of fairness is an evolutionary puzzle. To study this, we can look to other species, in which this can be translated empirically into responses to reward distribution. Passive and active protest against receiving less than a partner for the same task is widespread in species that cooperate outside kinship and mating bonds. There is less evidence that nonhuman species seek to equalize outcomes to their own detriment, yet the latter has been documented in our closest relatives, the apes. This reaction probably reflects an attempt to forestall partner dissatisfaction with obtained outcomes and its negative impact on future cooperation. We hypothesize that it is the evolution of this response that allowed the development of a complete sense of fairness in humans, which aims not at equality for its own sake but for the sake of continued cooperation.


Orthonormal aberration polynomials for anamorphic optical imaging systems with rectangular pupils.
The classical aberrations of an anamorphic optical imaging system, representing the terms of a power-series expansion of its aberration function, are separable in the Cartesian coordinates of a point on its pupil. We discuss the balancing of a classical aberration of a certain order with one or more such aberrations of lower order to minimize its variance across a rectangular pupil of such a system. We show that the balanced aberrations are the products of two Legendre polynomials, one for each of the two Cartesian coordinates of the pupil point. The compound Legendre polynomials are orthogonal across a rectangular pupil and, like the classical aberrations, are inherently separable in the Cartesian coordinates of the pupil point. They are different from the balanced aberrations and the corresponding orthogonal polynomials for a system with rotational symmetry but a rectangular pupil.


MicroRNA-570-3p regulates HuR and cytokine expression in airway epithelial cells.
Asthma is a chronic lung disease that affects people of all ages and is characterized by high morbidity. The mechanisms of asthma pathogenesis are unclear, and there is a need for development of diagnostic biomarkers and greater understanding of regulation of inflammatory responses in the lung. Post-transcriptional regulation of cytokines, chemokines, and growth factors by the action of microRNAs and RNA-binding proteins on stability or translation of mature transcripts is emerging as a central means of regulating the inflammatory response. In this study, we demonstrate that miR-570-3p expression is increased with TNFα stimuli in normal human bronchial epithelial cells (2.6 ± 0.6, p = 0.01) and the human airway epithelial cell line A549 (4.6 ± 1.4, p = 0.0068), and evaluate the functional effects of its overexpression on predicted mRNA target genes in transfected A549 cells. MiR-570-3p upregulated numerous cytokines and chemokines (CCL4, CCL5, TNFα, and IL-6) and also enhanced their induction by TNFα. For other cytokines (CCL2 and IL-8), the microRNA exhibited an inhibitory effect to repress their upregulation by TNFα. These effects were mediated by a complex pattern of both direct and indirect regulation of downstream targets by miR-570-3p. We also show that the RNA-binding protein HuR is a direct target of miR-570-3p, which has implications for expression of numerous other inflammatory mediators that HuR is known regulate post-transcriptionally. Finally, expression of endogenous miR-570-3p was examined in both serum and exhaled breath condensate (EBC) from asthmatic and healthy patients, and was found to be significantly lower in EBC of asthmatics and inversely correlated to their lung function. These studies implicate miR-570-3p as a potential regulator of asthmatic inflammation with potential as both a diagnostic and therapeutic target in asthma.


Intubation Setting, Aspiration, and Ventilator-Associated Conditions.
Patients experience endotracheal intubation in various settings with wide-ranging risks for postintubation complications such as aspiration and ventilator-associated conditions. To evaluate associations between intubation setting, presence of aspiration biomarkers, and clinical outcomes. This study is a subanalysis of data from the NO-ASPIRATE single-blinded randomized clinical trial. Data were prospectively collected for 513 adult patients intubated within 24 hours of enrollment. Patients with documented aspiration events at intubation were excluded. In the NO-ASPIRATE trial, intervention patients received enhanced oropharyngeal suctioning every 4 hours and control patients received sham suctioning. Tracheal specimens for α-amylase and pepsin tests were collected upon enrollment. Primary outcomes were ventilator hours, lengths of stay, and rates of ventilator-associated conditions. Of the baseline tracheal specimens, 76.4% were positive for α-amylase and 33.1% were positive for pepsin. Proportions of positive tracheal α-amylase and pepsin tests did not differ significantly between intubation locations (study hospital, transfer from other hospital, or field intubation). No differences were found for ventilator hours or lengths of stay. Patients intubated at another hospital and transferred had significantly higher ventilator-associated condition rates than did those intubated at the study hospital (P = .02). Ventilator-associated condition rates did not differ significantly between patients intubated in the field and patients in other groups. Higher ventilator-associated condition rates associated with interhospital transfer may be related to movement from bed, vehicle loading and unloading, and transport vehicle vibrations. Airway assessment and care may also be suboptimal in the transport environment.


Protein secondary-shell interactions enhance the photoinduced hydrogen production of cobalt protoporphyrin IX.
Hydrogen is an attractive fuel with potential for production scalability, provided that inexpensive, efficient molecular catalysts utilizing base metals can be developed for hydrogen production. Here we show for the first time that cobalt myoglobin (CoMyo) catalyzes hydrogen production in mild aerobic conditions with turnover number of 520 over 8 hours. Compared to free Co-protoporphyrin IX, incorporation into the myoglobin scaffold results in a 4-fold increase in photoinduced hydrogen production activity. Engineered variants in which specific histidine resides in proximity of the active site were mutated to alanine result in modulation of the catalytic activity, with the H64A/H97A mutant displaying activity 2.5-fold higher than wild type. Our results demonstrate that protein scaffolds can augment and modulate the intrinsic catalytic activity of molecular hydrogen production catalysts.


Understanding perpetrators of nonphysical sexual coercion: characteristics of those who cross the line.
Sexual coercion is defined here as a form of male sexual misconduct in which nonphysical tactics (e.g., verbal pressure) are utilized to gain sexual contact with an unwilling female partner. This study compares the risk characteristics of sexually coercive (n=81) and nonoffending college males (n=223) across several domains. Results revealed that sexual coercers differed from nonoffenders in that they more often subscribed to rape myths, viewed interpersonal violence as more acceptable, reported greater hostility toward females, and perceived male-female relationships as more inherently adversarial. In addition, compared to nonoffenders, sexually coercive males showed stronger indicators of promiscuity and delinquency, reported more psychopathic personality traits, had more empathic deficits, and were more likely to have experienced certain forms of childhood abuse. In most respects, coercers did not differ from those who reported engaging in more severe forms of sexual assault involving the use of physical force. These results suggest important differences between nonoffending males and those who "cross the line" by engaging in sexually coercive acts. In addition, consistent parallels can be drawn between the predictors of sexual coercion identified in this study and those documented in the sexual aggression (e.g., forcible rape) literature.


The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2012 on the long-term treatment of bipolar disorder.
These guidelines are based on a first edition that was published in 2004, and have been edited and updated with the available scientific evidence up to October 2012. Their purpose is to supply a systematic overview of all scientific evidence pertaining to the long-term treatment of bipolar disorder in adults. Material used for these guidelines are based on a systematic literature search using various data bases. Their scientific rigor was categorised into six levels of evidence (A-F) and different grades of recommendation to ensure practicability were assigned. Maintenance trial designs are complex and changed fundamentally over time; thus, it is not possible to give an overall recommendation for long-term treatment. Different scenarios have to be examined separately: Prevention of mania, depression, or an episode of any polarity, both in acute responders and in patients treated de novo. Treatment might differ in Bipolar II patients or Rapid cyclers, as well as in special subpopulations. We identified several medications preventive against new manic episodes, whereas the current state of research into the prevention of new depressive episodes is less satisfactory. Lithium continues to be the substance with the broadest base of evidence across treatment scenarios. Although major advances have been made since the first edition of this guideline in 2004, there are still areas of uncertainty, especially the prevention of depressive episodes and optimal long-term treatment of Bipolar II patients.


3.6 million neonatal deaths--what is progressing and what is not?
Each year 3.6 million infants are estimated to die in the first 4 weeks of life (neonatal period)--but the majority continue to die at home, uncounted. This article reviews progress for newborn health globally, with a focus on the countries in which most deaths occur--what data do we have to guide accelerated efforts? All regions are advancing, but the level of decrease in neonatal mortality differs by region, country, and within countries. Progress also differs by the main causes of neonatal death. Three major causes of neonatal deaths (infections, complications of preterm birth, and intrapartum-related neonatal deaths or "birth asphyxia") account for more than 80% of all neonatal deaths globally. The most rapid reductions have been made in reducing neonatal tetanus, and there has been apparent progress towards reducing neonatal infections. Limited, if any, reduction has been made in reducing global deaths from preterm birth and for intrapartum-related neonatal deaths. High-impact, feasible interventions to address these 3 causes are summarized in this article, along with estimates of potential for lives saved. A major gap is reaching mothers and babies at birth and in the early postnatal period. There are promising community-based service delivery models that have been tested mainly in research studies in Asia that are now being adapted and evaluated at scale and also being tested through a network of African implementation research trials. To meet Millennium Development Goal 4, more can and must be done to address neonatal deaths. A critical step is improving the quantity, quality and use of data to select and implement the most effective interventions and strengthen existing programs, especially at district level.


Estimation of Caffeine Regimens: A Machine Learning Approach for Enhanced Clinical Decision Making at a Neonatal Intensive Care Unit (NICU).
The decision-making process for estimating the optimal dosage is critical in clinical settings. In the neonatal intensive care unit (NICU), preterm neonates suffering from apnea of prematurity, optimum drug dosage can make a difference between life and death. To improve clinical decision making in the NICU, we have developed prediction models using machine learning algorithms. We have used optimized Support Vector Machine (SVM), decision trees with ensembles created using Bagging, Boosting, Random Forest, optimized Multi Layer Perceptron (MLP) and Deep Learning to predict adequacy of caffeine, a methylxanthine used to prevent the development of recurrent apneas, to reduce the need for mechanical ventilation. The respective models developed were evaluated using 100 clinical caffeine cases collected from the Neonatal Intensive Care Unit (NICU) of Kasturba Medical College, Manipal. Our results indicate that a deep belief network (DBN) having an area under curve (AUC) of 0.91, followed by an optimized MLP with the Score for Neonatal Acute Physiology I (SNAP I) as an input feature, outperform other models for assessing the drug effectiveness. Furthermore, the optimized MLP followed by a DBN, with SNAP I as an input feature is a more accurate model for predicting the therapeutic concentration of caffeine. These results suggest that the proposed SNAP I (illness severity score) acts as a critical input variable to enhance the performance of the prediction model. The machine learning approach is very useful for building decision support systems in the NICU in general, and it provides specific solutions to optimize the administration of lifesaving drugs to neonates who are very sensitive to dosages. Using our method, physicians can assess the adequacy and efficacy of caffeine on the study population in a NICU before administering it to neonates.


The human heavy chain Ig V region gene repertoire is biased at all stages of B cell ontogeny, including early pre-B cells.
The expressed human Ig repertoire is not an equal representation of all V(H) segments present in genomic DNA. Studies have shown that a restricted set of V(H) gene segments are over-represented in Ab repertoires of fetal/neonatal and adult B cells. Additionally, this restricted set of V(H) genes is frequently expressed by autoimmune and tumor B cells. To investigate at which developmental stage a bias in the repertoire begins, we compared the V(H)3 and V(H)4 family repertoires of pre-B and immature B cells from bone marrow and mature B cells from peripheral blood of two adults. We found that the V4-34 and V4-59 gene segments of the V(H)4 family and the V3-23 gene segment of the V(H)3 family dominate the repertoires of the surface Ig-negative early pre-B as well as immature and mature B cells. Furthermore, the pattern of utilization of other V(H)3 family members suggests that certain genes that are frequently rearranged during early stages of B cell development are subsequently disfavored during later stages of B cell maturation. We conclude that the over-representation of certain V genes could arise from sequential mechanisms operating at both early and later stages of B cell development. These V(H)-mediated mechanisms might include preferential rearrangement and/or efficiency of pairing with the surrogate light chain at the surface Ig-negative, early pre-B cell stage and ligand selection at more mature, surface Ig-positive, B cell stages.


Stability and Wash Resistance of Local Made Mosquito Bednets and Detergents Treated with Pyrethroids against Susceptible Strain of Malaria Vector Anopheles stephensi.
We aimed to evaluate different fibres of bednets impregnated with various pyrethroids. The stability of insecticide on the bednet was measured using different methods of washings as well as local made detergents. The entire test was carried out according to the WHO-recommended methods. In addition, the impact of the numbers of washes on the stability of the insecticides was determined. Permethrin 10% (EC), deltamethrin 10% (SC), lambdacyhalothrin 2.5% (CS) and cyfluthrin 5% (EW) were used at the recommended dosages. Three different local detergents were used. Two kinds of washing methods (shaking, no shaking) were used and in each method four kinds of washings, i.e. no wash, one wash, two washes and three washes was done. The main malaria vectors, Anopheles stephensi, which is susceptible to all insecticides (BEECH strain), was tested with impregnated bednets in 3 minutes exposure time and the mortality was measured after 24 hours recovery period. Knock-down was measured as well using appropriate statistical methods. Lambdacyhalothrin has saved its insecticidal impact after being washed, whereas, deltamethrin has lost its activity faster than other insecticides. Tow other insecticides had moderate effect. Golnar soap detergent has least effect on the durability of insecticides, but the Shoma had the most. Whit increasing the times of washing, insecticidal effects was decreased, but shaking had no influence on the decreasing of the quality of insecticidal impact. Results will be useful for local people who wish to use pyrethroid-impregnated bednets with their own local made detergent and bednets.


Plasmonic nanolaser using epitaxially grown silver film.
A nanolaser is a key component for on-chip optical communications and computing systems. Here, we report on the low-threshold, continuous-wave operation of a subdiffraction nanolaser based on surface plasmon amplification by stimulated emission of radiation. The plasmonic nanocavity is formed between an atomically smooth epitaxial silver film and a single optically pumped nanorod consisting of an epitaxial gallium nitride shell and an indium gallium nitride core acting as gain medium. The atomic smoothness of the metallic film is crucial for reducing the modal volume and plasmonic losses. Bimodal lasing with similar pumping thresholds was experimentally observed, and polarization properties of the two modes were used to unambiguously identify them with theoretically predicted modes. The all-epitaxial approach opens a scalable platform for low-loss, active nanoplasmonics.


Practice Patterns of Pneumocystis Pneumonia Prophylaxis in Connective Tissue Diseases: A Survey of Infectious Disease Physicians.
Immunosuppressive therapy for connective tissue diseases (CTDs) increases risk for opportunistic infections including Pneumocystis pneumonia (PCP). High mortality rates are reported in CTD patients with PCP, which suggests a potential need for prophylaxis, but indications remain poorly defined. Wide variations in the use of PCP prophylaxis among rheumatologists have been documented. This study evaluated PCP prophylaxis patterns for CTD patients among infectious disease (ID) physicians. An electronic survey was emailed to 1264 adult ID physicians who are members of the Infectious Diseases Society of America Emerging Infections Network. Six hundred thirty-one physicians responded to the survey. Respondents to the survey were more likely to work in academics (P = .02) and be early (<5 years) or late (≥25 years) in their careers (P = .0002). Forty-three percent (n = 269) made no recommendations for PCP prophylaxis in non-HIV patients. Of the 362 respondents who did make such recommendations, the greatest consensus for disease-based prophylaxis was for granulomatosis with polyangiitis (53%). For therapy-based prophylaxis, corticosteroids ≥20 mg/d was the most frequently cited indication (87%). Surrogate laboratory markers to aid in decisions about prophylaxis were not routinely used (21%). Although the majority recommended discontinuation of PCP prophylaxis with tapering of corticosteroids (65%), there was variability in the specific dose. Eighty-nine percent of respondents felt that guidelines about PCP prophylaxis would be helpful. There is little consensus about PCP prophylaxis in CTDs among ID physicians. Guidelines for PCP prophylaxis would be helpful when caring for these complex patients.


Paraoxonase cluster polymorphisms are associated with sporadic ALS.
Paraoxonases (PONs) are involved in the detoxification of organophosphate pesticides and chemical nerve agents. Due to a reported possible twofold increased risk of ALS in Gulf War veterans and the associations of PON1 polymorphisms with the neurologic symptom complex of the Gulf War syndrome, the authors investigated the association between sporadic ALS (SALS) and PON gene cluster variants in a large North American Caucasian family-based and case-control cohort (N = 1,891). Clinically definite and probable ALS was diagnosed according to the revised El Escorial criteria, exclusion of family history of ALS, and SOD1 mutation analysis. Single nucleotide polymorphism (SNP) genotyping was done using TaqMan assays on ABI7900HT. Data were analyzed using SPSS, Haploview, FBAT, and THESIAS. A haploblock of high linkage disequilibrium (LD) spanning PON2 and PON3 was associated with SALS. The SNPs rs10487132 and rs11981433 were in strong LD and associated with SALS in the trio (parents-affected child triad) model. The association of rs10487132 was replicated in 450 nuclear pedigrees comprising trios and discordant sibpairs. No association was found in case-control models, and their haplostructure was different from that of the trios with overall reduced LD. Resequencing identified an intronic variant (rs17876088) that differentiated between detrimental and protective SALS haplotypes. This study demonstrates evidence of significant association of variants in the Paraoxonase gene cluster with sporadic ALS and is compatible with the hypothesis that environmental toxicity in a susceptible host may precipitate ALS.


Ion mobility-mass spectrometry reveals the influence of subunit packing and charge on the dissociation of multiprotein complexes.
The composition, stoichiometry, and organization of protein complexes can be determined by collision-induced dissociation (CID) coupled to tandem mass spectrometry (MS/MS). The increased use of this approach in structural biology prompts a better understanding of the dissociation mechanism(s). Here we report a detailed investigation of the CID of two dodecameric, heat-stable and toroidally shaped complexes: heat shock protein 16.9 (HSP16.9) and stable protein 1 (SP-1). While HSP16.9 dissociates by sequential loss of unfolded monomers, SP-1 ejects not only monomers, but also its building blocks (dimers), and multiples thereof (tetramers and hexamers). Unexpectedly, the dissociation of SP-1 is strongly charge-dependent: loss of the building blocks increases with higher charge states of this complex. By combining MS/MS with ion mobility (IM-MS/MS), we have monitored the unfolding and dissociation events for these complexes in the gas phase. For HSP16.9 unfolding occurs at lower energies than the ejection of subunits, whereas for SP-1 unfolding and dissociation take place simultaneously. We consider these results in the light of the structural organization of HSP16.9 and SP-1 and hypothesize that SP-1 is unable to unfold extensively due to its particular quaternary structure and unusually high charge density. This investigation increases our understanding of the factors governing the CID of protein complexes and moves us closer to the goal of obtaining structural information on subunit interactions and packing from gas-phase experiments.


Exploring healthcare assistants' role and experience in pain assessment and management for people with advanced dementia towards the end of life: a qualitative study.
Pain assessment and management are key aspects in the care of people with dementia approaching the end of life but become challenging when patient self-report is impaired or unavailable. Best practice recommends the use of observational pain assessments for these patients; however, difficulties have been documented with health professionals' use of these tools in the absence of additional collateral patient knowledge. No studies have explored the role, perspectives and experiences of healthcare assistants in pain assessment and management in dementia; this study provides insight into this important area. A qualitative approach was adopted, using key informant interviews with healthcare assistants caring for people with advanced dementia approaching the end of life in hospice, nursing home and acute care settings. Thematic analysis was the analytic approach taken to interpretation of interview data. Data were collected between June 2014 and September 2015. Fourteen participants took part in the study. Participants' average length of caring experience was 15.4 years and most were female. Three key themes emerged: recognising pain, reporting pain, and upskilling. Participants were often the first to notice obvious causes of pain and to detect changes in patient norms which signified hidden causes of pain. Comprehensive knowledge of resident norms enabled participants to observe for behavioural and nonverbal indicators of pain and distinguish these from non-pain related behaviours. Pain reporting was heavily impacted by relationships with professional staff and the extent to which participants felt valued in their role. Positive relationships resulted in comprehensive pain reports; negative relationships led to perfunctory or ambiguous reporting. Participants emphasised a desire for further training and upskilling, including in the use and reporting of basic pain tools. Healthcare assistants are frontline staff who have a key role in direct patient care, spending a considerable amount of time with patients in comparison to other health professionals. These staff are often first to notice changes in patients that may signify pain and to alert professional staff. However, to ensure the quality of these reports, further efforts must be made in reversing stigma attached to this role and in upskilling these members of the healthcare team.