Predictive ability of host genetics and rumen microbiome for subclinical ketosis.
Subclinical metabolic disorders such as ketosis cause substantial economic losses for dairy farmers in addition to the serious welfare issues they pose for dairy cows. Major hurdles in genetic improvement against metabolic disorders such as ketosis include difficulties in large-scale phenotype recording and low heritability of traits. Milk concentrations of ketone bodies, such as acetone and β-hydroxybutyric acid (BHB), might be useful indicators to select cows for low susceptibility to ketosis. However, heritability estimates reported for milk BHB and acetone in several dairy cattle breeds were low. The rumen microbial community has been reported to play a significant role in host energy homeostasis and metabolic and physiologic adaptations. The current study aims at investigating the effects of cows' genome and rumen microbial composition on concentrations of acetone and BHB in milk, and identifying specific rumen microbial taxa associated with variation in milk acetone and BHB concentrations. We determined the concentrations of acetone and BHB in milk using nuclear magnetic resonance spectroscopy on morning milk samples collected from 277 Danish Holstein cows. Imputed high-density genotype data were available for these cows. Using genomic and microbial prediction models with a 10-fold resampling strategy, we found that rumen microbial composition explains a larger proportion of the variation in milk concentrations of acetone and BHB than do host genetics. Moreover, we identified associations between milk acetone and BHB with some specific bacterial and archaeal operational taxonomic units previously reported to have low to moderate heritability, presenting an opportunity for genetic improvement. However, higher covariation between specific microbial taxa and milk acetone and BHB concentrations might not necessarily indicate a causal relationship; therefore further validation is needed before considering implementation in selection programs.


Synthesis and Characterization of Metal-Encapsulating Si16 Cage Superatoms.
Nanoclusters, aggregates of several to hundreds of atoms, have been one of the central issues of nanomaterials sciences owing to their unique structures and properties, which could be found neither in nanoparticles with several nanometer diameters nor in organometallic complexes. Along with the chemical nature of each element, properties of nanoclusters change dramatically with size parameters, making nanoclusters strong potential candidates for future tailor-made materials; these nanoclusters are expected to have attractive properties such as redox activity, catalysis, and magnetism. Alloying of nanoclusters additionally gives designer functionality by fine control of their electronic structures in addition to size parameters. Among binary nanoclusters, binary cage superatoms (BCSs) composed of transition metal (M) encapsulating silicon cages, M@Si16, have unique cage structures of 16 silicon atoms, which have not been found in elemental silicon nanoclusters, organosilicon compounds, and silicon based clathrates. The unique composition of these BCSs originates from the simultaneous satisfaction of geometric and electronic shell-closings in terms of cage geometry and valence electron filling, where a total of 68 valence electrons occupy the superatomic orbitals of (1S)2(1P)6(1D)10(1F)14(2S)2(1G)18(2P)6(2D)10 for M = group 4 elements in neutral ground state. The most important issue for M@Si16 BCSs is fine-tuning of their characters by replacement of the central metal atoms, M, based on one-by-one adjustment of valence electron counts in the same structure framework of Si16 cage; the replacement of M yields a series of M@Si16 BCSs, based on their superatomic characteristics. So far, despite these unique features probed in the gas-phase molecular beam and predicted by quantum chemical calculations, M@Si16 have not yet been isolated. In this Account, we have focused on recent advances in synthesis and characterizations of M@Si16 BCSs (M = Ti and Ta). A series of M@Si16 BCSs (M = groups 3 to 5) was found in gas-phase molecular beam experiments by photoelectron spectroscopy and mass spectrometry: formation of halogen-, rare-gas-, and alkali-like superatoms was identified through one-by-one tuning of number of total valence electrons. Toward future functional materials in the solid state, we have developed an intensive, size-selected nanocluster source based on high-power impulse magnetron sputtering coupled with a mass spectrometer and a soft-landing apparatus. With scanning probe microscopy and photoelectron spectroscopy, the structure of surface-immobilized BCSs has been elucidated; BCSs can be dispersed in an isolated form using C60 fullerene decoration of the substrate. The intensive nanocluster source also enables the synthesis of BCSs in the 100-mg scale by coupling with a direct liquid-embedded trapping method into organic dispersants, enabling their structure characterization as a highly symmetric "metal-encapsulating tetrahedral silicon-cage" (METS) structure with Frank-Kasper geometry.


Estimating the effect of gang membership on nonviolent and violent delinquency: a counterfactual analysis.
This study reconsiders the well-known link between gang membership and criminal involvement. Recently developed analytical techniques enabled the approximation of an experimental design to determine whether gang members, after being matched with similarly situated nongang members, exhibited greater involvement in nonviolent and violent delinquency. Findings indicated that while gang membership is a function of self-selection, selection effects alone do not account for the greater involvement in delinquency exhibited by gang members. After propensity score matching was employed, gang members maintained a greater involvement in both nonviolent and violent delinquency when measured cross-sectionally, but only violent delinquency when measured longitudinally. Additional analyses using inverse probability of treatment weights reaffirmed these conclusions.


Citation analysis of orthopaedic literature; 18 major orthopaedic journals compared for Impact Factor and SCImago.
One of the disadvantages of the Impact Factor (IF) is self-citation. The SCImago Journal Rank (SJR) indicator excludes self-citations and considers the quality, rather than absolute numbers, of citations of a journal by other journals. The present study re-evaluated the influence of self-citation on the 2007 IF for 18 major orthopaedic journals and investigated the difference in ranking between IF and SJR. The journals were analysed for self-citation both overall and divided into a general group (n = 8) and a specialized group (n = 10). Self-cited and self-citing rates, as well as citation densities and IFs corrected for self-citation (cIF), were calculated. The rankings of the 18 journals by IF and by SJR were compared and the absolute difference between these rankings (DeltaR) was determined. Specialized journals had higher self-citing rates (p = 0.01, Deltamedian = 9.50, 95%CI -19.42 to 0.42), higher self-cited rates (p = 0.0004, Deltamedian = -10.50, 95%CI -15.28 to -5.72) and greater differences between IF and cIF (p = 0.003, Deltamedian = 3.50, 95%CI -6.1 to 13.1). There was no significant correlation between self-citing rate and IF for both groups (general: r = 0.46, p = 0.27; specialized: r = 0.21, p = 0.56). When the difference in ranking between IF and SJR was compared between both groups, sub-specialist journals were ranked lower compared to their general counterparts (DeltaR: p = 0.006, Deltamedian = 2.0, 95%CI -0.39 to 4.39). Citation analysis shows that specialized orthopaedic journals have specific self-citation tendencies. The correlation between self-cited rate and IF in our sample was large but, due to small sample size, not significant. The SJR excludes self-citations in its calculation and therefore enhances the underestimation in ranking of specialized journals.


Accurate identification of A-to-I RNA editing in human by transcriptome sequencing.
RNA editing enhances the diversity of gene products at the post-transcriptional level. Approaches for genome-wide identification of RNA editing face two main challenges: separating true editing sites from false discoveries and accurate estimation of editing levels. We developed an approach to analyze transcriptome sequencing data (RNA-seq) for global identification of RNA editing in cells for which whole-genome sequencing data are available. We applied the method to analyze RNA-seq data of a human glioblastoma cell line, U87MG. Around 10,000 DNA-RNA differences were identified, the majority being putative A-to-I editing sites. These predicted A-to-I events were associated with a low false-discovery rate (∼5%). Moreover, the estimated editing levels from RNA-seq correlated well with those based on traditional clonal sequencing. Our results further facilitated unbiased characterization of the sequence and evolutionary features flanking predicted A-to-I editing sites and discovery of a conserved RNA structural motif that may be functionally relevant to editing. Genes with predicted A-to-I editing were significantly enriched with those known to be involved in cancer, supporting the potential importance of cancer-specific RNA editing. A similar profile of DNA-RNA differences as in U87MG was predicted for another RNA-seq data set obtained from primary breast cancer samples. Remarkably, significant overlap exists between the putative editing sites of the two transcriptomes despite their difference in cell type, cancer type, and genomic backgrounds. Our approach enabled de novo identification of the RNA editome, which sets the stage for further mechanistic studies of this important step of post-transcriptional regulation.


A Generic Mechanism for Enhanced Cytokine Signaling via Cytokine-Neutralizing Antibodies.
Enhancement or inhibition of cytokine signaling and corresponding immune cells responses are critical factors in various disease treatments. Cytokine signaling may be inhibited by cytokine-neutralizing antibodies (CNAs), which prevents further activation of cytokine receptors. However, CNAs may result in enhanced-instead of inhibitory-cytokine signaling (an "agonistic effect") in various in vitro and in vivo experiments. This may lead to lack of efficacy or adverse events for cytokine-inhibiting based medicines. Alternatively, cytokine-antibody complexes may produce stronger signaling vs. cytokine alone, thereby increasing the efficacy of stimulating cytokine-based drugs, at equal or lower cytokine doses. In this paper, the effect of cytokine signaling enhancement by a CNA was studied in a generic mathematical model of interleukin-4 (IL-4) driven T-cell proliferation. The occurrence of the agonistic effect depends upon the antibody-to-cytokine binding affinity and initial concentrations of antibody and cytokine. Model predictions were in agreement with experimental studies. When the cytokine receptor consists of multiple subunits with substantially differing affinities (e.g., IL-4 case), the choice of the receptor chain to be blocked by the antibody is critical, for the agonistic effect to appear. We propose a generic mechanism for the effect: initially, binding of the CNA to the cytokine reduces free cytokine concentration; yet, cytokine molecules bound within the cytokine-CNA complex-and released later and over time-are "rescued" from earlier clearance via cellular internalization. Hence, although free cytokine-dependent signalling may be less potent initially, it will also be more sustained over time; and given non-linear dynamics, it will lead ultimately to larger cellular effector responses, vs. the same amount of free cytokine in the absence of CNA. We suggest that the proposed mechanism is a generic property of {cytokine, CNA, receptor} triads, both in vitro and in vivo, and can occur in a predictable fashion for a variety of cytokines of the immune system.


GH deficiency with central precocious puberty: a new rare disorder associated with a developmental defect of the hypothalamic-pituitary area.
GH deficiency (GHD) associated with central precocious puberty (CPP) has been widely reported in cases of arachnoid cyst, septo-optic dysplasia, brain tumors, or after cerebral radiation therapy. However, idiopathic GHD associated with CPP has been reported in only one isolated case. To evaluate the occurrence and clinical features of the association of nonacquired GHD and CPP. This was a retrospective multicenter study. The study population was identified through a French nationwide multicenter network (about 3000 patients). We reviewed the medical records of all subjects diagnosed with nonacquired GHD and CPP, with or without developmental abnormalities of the hypothalamic-pituitary axis on cerebral magnetic resonance imaging (MRI), and without any known associated anomaly. We identified four patients with either isolated GHD (n=1) or multiple anterior pituitary hormone deficiencies (n=3). Clinical signs of CPP occurred at 6.4 +/- 2.3 years in boys and 7.5 +/- 0.5 years in girls, and GnRH analog therapy was started at 4.2 +/- 1.6 years after the initiation of recombinant human GH treatment. Cerebral MRI demonstrated ectopic neurohypophysis associated with anterior pituitary hypoplasia in three out of the four patients. The morphology and position of the anterior pituitary and neurohypophysis were normal in one patient who displayed a persistence of the craniopharyngeal canal. CPP is very rare in patients with nonacquired GHD and is mostly associated with developmental defects in the hypothalamic-pituitary area. Whether molecular mechanisms governing development and activation of the hypothalamic-pituitary axis share dependent factors remains to be explored.


Deprivations, futures and the wrongness of killing.
In my essay, Why abortion is immoral, I criticised discussions of the morality of abortion in which the crucial issue is whether fetuses are human beings or whether fetuses are persons. Both argument strategies are inadequate because they rely on indefensible assumptions. Why should being a human being or being a person make a moral difference? I argued that the correct account of the morality of abortion should be based upon a defensible account of why killing children and adults is wrong. I claimed that what makes killing us wrong is that our premature deaths deprive us of our futures of value, that is, the goods of life we would have experienced had we survived. This account of the wrongness of killing explains why killing is one of the worst of crimes and how killing greatly harms the victim. It coheres with the attitudes of those with cancer or HIV facing premature death. It explains why we believe it is wrong to kill infants (as personhood theories do not). It does not entail that it wrongs a human being to end her life if she is in persistent vegetative state or if her future must consist only of unbearable physical suffering and she wants to die (as sanctity of human life theories do not). This account of the wrongness of killing implies (with some defensible additional assumptions) that abortion is immoral because we were fetuses once and we know those fetuses had futures of value. Mark Brown claims that this potential future of value account is unsound because it implies that we have welfare rights to what we need to stay alive that most people would reject. I argue that Brown is incorrect in two ways: a welfare right to what we need to stay alive is not directly implied by my account and, in addition, most of us do believe that dependent human beings have substantial welfare rights to what they need to stay alive. Brown argues that depriving us of a future of value of which we have mental representations both is a better explanation of the wrongness of killing and does not imply that abortion is immoral. I reply that (a) if Brown's arguments against my view were sound, those arguments could be easily adapted to show that his view is unsound as well and (b) Brown's view is both ambiguous and unsound on any interpretation. The most popular class of pro-choice argument strategies appeals to the view that some or all fetuses lack either a mental state or function or a capacity for a mental state or function necessary for possession of the right to life. Desires, interests, sentience, various concepts, moral agency, and rationality have all been suggested as candidates for this crucial mental role. Brown's analysis is one member of this class of strategies. I believe that it is possible to show that none of these strategies is reasonable. However, there are so many of these strategies that the required argument demands something more like a book and less like a short essay. The argument of the following essay is a piece of this larger argument.


Relative influence of insulin resistance versus blood pressure on vascular changes in longstanding hypertension. ICARUS, a LIFE sub study. Insulin Carotids US Scandinavia.
Insulin resistance is associated with hypertension. The relative influences of hyperinsulinaemia and high blood pressure on vascular hypertrophy and carotid distensibility is unclear in patients with longstanding hypertension. In 88 unmedicated patients with stage II-III hypertension and left ventricular hypertrophy on electrocardiogram we measured blood pressure, minimal forearm vascular resistance (MFVR) using plethysmography, intima-media thickness (IMT) and the wall distensibility of the common carotid arteries using ultrasound, and insulin sensitivity using a 2-h isoglycaemic hyperinsulinaemic clamp. IMT was positively correlated to systolic blood pressure (r= 0.26, P < 0.05), whole body glucose uptake index (M/IG; r= 0.22, P< 0.05), age (r= 0.24, P< 0.05) and negatively correlated to body mass index (r= -0.24, P < 0.05); IMT did not correlate to fasting serum insulin (r= -0.14, NS). In men (n = 64) MFVR was positively correlated to systolic blood pressure (r = 0.30, P < 0.05), but was unrelated to M/G and serum insulin. The distensibility of the common carotid arteries was negatively correlated to systolic blood pressure (r = -0.40, P< 0.001) and in untreated patients (n = 22) positively correlated to M/IG (r = 0.47, P < 0.05). High systolic blood pressure was related to vascular hypertrophy, whereas hyperinsulinaemia and insulin resistance were not, suggesting that longstanding high blood pressure is a far more important determinant for structural vascular changes than insulin resistance at this stage of the hypertensive disease. However, hyperinsulinaemia and insulin resistance were associated with low distensibility of the common carotid arteries in the subgroup of never treated hypertensive patients.


The Politics of the Gene: Social Status and Beliefs about Genetics for Individual Outcomes.
Social scientists have predicted that individuals who occupy socially privileged positions or who have conservative political orientations are most likely to endorse the idea that genes are the root cause of differences among individuals. Drawing on a nationally representative sample of the US population, this study examines belief in the importance of genes for understanding individual differences in a series of broad domains: physical illness, serious mental illness, intelligence, personality, and success in life. We also assess whether the belief that genetics are important for these outcomes is more common among those in relatively advantaged positions or among those who are more politically conservative. Finally, we consider whether such beliefs predict attitudes toward genetics-related social policies. Our analyses suggest that belief in the importance of genetics for individual differences may well have a substantial effect on attitudes toward genetics-related policies, independent of political orientation or other measures. Our study identifies high levels of endorsement for genes as causes of health and social outcomes. We describe a cultural schema in which outcomes that are "closer to the body" are more commonly attributed to genetics. Contrary to expectations, however, we find little evidence that it is more common for whites, the socioeconomically advantaged, or political conservatives to believe that genetics are important for health and social outcomes.


Attention is spontaneously biased toward regularities.
Knowledge about regularities in the environment can be used to facilitate perception, memory, and language acquisition. Given this usefulness, we hypothesized that statistically structured sources of information receive attentional priority over noisier sources, independent of their intrinsic salience or goal relevance. We report three experiments that support this hypothesis. Experiment 1 shows that regularities bias spatial attention: Visual search was facilitated at a location containing temporal regularities, even though these regularities did not predict target location, timing, or identity. Experiments 2 and 3 show that regularities bias feature attention: Attentional capture doubled in magnitude when singletons appeared, respectively, in a color or dimension with temporal regularities among task-irrelevant stimuli. Prioritization of the locations and features of regularities is not easily accounted for in the conventional dichotomy between stimulus-driven and goal-directed attention. This prioritization may in turn promote further statistical learning, helping the mind to acquire knowledge about stable aspects of the environment.


Relative changes in the pattern of diseases presenting in dermatology outpatient clinic in the era of the COVID-19 pandemic.
As an increasing number of COVID-19 cases, there were changes in the number of patients who attended the dermatology outpatient clinics. We aimed to investigate the change profiles of dermatologic diseases in the first and second months of the COVID-19 pandemic in Turkey by comparing with the corresponding period of the previous year. The total number and diagnosis of patients, who attended a tertiary care hospital for the dermatology outpatient clinic between 1 April 2020 and 31 May 2020, were included in this study. These data were compared with the corresponding period of the previous year. The percentage of the patients with scabies, contact dermatitis, psoriasis, pityriasis rosea, urticaria, and alopecia areata were statistically significantly increased a month after the occurrence of the COVID-19 pandemic, while the percentage of patients with scabies, alopecia areata, telogen effluvium, acne vulgaris, and xerosis cutis were statistically significantly increased 2 months after the occurrence of the COVID-19 pandemic (P < 0.05). An increase in the number of certain diseases such as urticaria and pityriasis rosea may indicate the risk of asymptomatic COVID-19 carriage in these patients. Polymerase chain reaction (PCR) and/or antibody-based further studies should be performed to explore whether certain dermatologic diseases are related to asymptomatic COVID-19 cases.


Insights into early vasculogenesis revealed by expression of the ETS-domain transcription factor Fli-1 in wild-type and mutant zebrafish embryos.
Fli-1 is an ETS-domain transcription factor whose locus is disrupted in Ewing's Sarcoma and F-MuLV induced erythroleukaemia. To gain a better understanding of its normal function, we have isolated the zebrafish homologue. Similarities with other vertebrates, in the amino acid sequence and DNA binding properties of Fli-1 from zebrafish, suggest that its function has been conserved during vertebrate evolution. The initial expression of zebrafish fli-1 in the posterior lateral mesoderm overlaps with that of gata2 in a potential haemangioblast population which likely contains precursors of blood and endothelium. Subsequently, fli-1 and gata2 expression patterns diverge, with separate fli-1 and gata2 expression domains arising in the developing vasculature and in sites of blood formation respectively. Elsewhere in the embryo, fli-1 is expressed in sites of vasculogenesis. The expression of fli-1 was investigated in a number of zebrafish mutants, which affect the circulatory system. In cloche, endothelium is absent and blood is drastically reduced. In contrast to the blood and endothelial markers that have been studied previously, fli-1 expression was initiated normally in cloche embryos, indicating that induction of fli-1 is one of the earliest indicators of haemangioblast formation. Furthermore, although fli-1 expression in the trunk was not maintained, the normal expression pattern in the anterior half of the embryo was retained. These anterior cells did not, however, condense to form blood vessels. These data indicate that cloche has previously unsuspected roles at multiple stages in the formation of the vasculature. Analysis of fli-1 expression in midline patterning mutants floating head and squint, confirms a requirement for the notochord in the formation of the dorsal-aorta. The formation of endothelium in one-eyed pinhead, cyclops and squint embryos indicates a novel role for the endoderm in the formation of the axial vein. The phenotype of sonic-you mutants implies a likely role for Sonic Hedgehog in mediating these processes.


Changes in food and nutrient intake of 6- to 17-year-old Germans between the 1980s and 2006.
To compare the food consumption and nutrient intakes of German children and adolescents in the 1980s with present dietary habits. Two cross-sectional representative surveys, the German National Food Consumption Study (Nationale Verzehrsstudie, NVS) from 1985-8 and the nutrition module 'EsKiMo' of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) from 2006, were analysed for differences in food and nutrient intakes stratified by age and sex groups. Secondary analyses of data from representative observational studies. Children and adolescents aged 6-17 years living in Germany in the 1980s (n 2265) and in 2006 (n 2506). Food consumption was characterised by higher amounts of vegetables/pulses, fruits/nuts and beverages and less meat products/sausages, butter, fats/oils, potatoes/potato products and bread/pastries in 2006 than in 1985-8. The overall changes in food intake were reflected in improvements of macronutrient composition, increased water intake and lower energy density of the diet. Intake of most vitamins and minerals increased in relation to energy intake, but the nutrient density of the diet for vitamins B12 and D decreased. The most critical nutrients observed in NVS and EsKiMo were folate, vitamin D, vitamin A, vitamin E, Ca and Fe. In addition, dietary fibre intake was relatively low and fatty acid and carbohydrate compositions were not favourable. Further efforts will be necessary to improve dietary habits among children and adolescents.


Migration of monocytes across endothelium and passage through extracellular matrix involve separate molecular domains of PECAM-1.
During the inflammatory response, the adhesion molecule PECAM plays a crucial role in transendothelial migration, the passage of leukocytes across endothelium. We report here an additional role for PECAM in the subsequent migration of monocytes through the subendothelial extracellular matrix. PECAM has six immunoglobulin (Ig) superfamily domains. Monoclonal antibodies whose epitopes map to domains 1 and/or 2 selectively block monocyte migration through the endothelial junction, whereas those that map to domain 6 block only the migration through the extracellular matrix, trapping the monocyte between the endothelium and its basal lamina. Therefore, transendothelial migration (diapedesis) and passage through extracellular matrix (interstitial migration) are distinct and separable phases of monocyte emigration. Furthermore, distinct and separate Ig domains of PECAM are involved in mediating these two steps.


E-cadherin is involved in the intrahepatic metastasis of hepatocellular carcinoma.
In human hepatocellular carcinoma (HCC), the liver is the major target organ of metastasis, which is known as intrahepatic metastasis. To analyze the mechanism of this metastasis, we established two sublines from the human HCC cell line Li7. Subline Li7HM produced multiple liver metastasis, whereas subline Li7NM never did so after intrasplenic injection into nude mice. Two-dimensional gel electrophoresis and immunoblot analysis showed that only Li7NM expressed vimentin and lacked E-cadherin expression, indicating that this clone had undergone epithelial-mesenchymal transition. We then transfected mouse E-cadherin complementary DNA into Li7NM cells and found that the transfectant cells (EM16.21B.3) formed liver metastasis (8/16 mice) after intrasplenic injection and liver tumors (11/13 mice) after intrahepatic injection, whereas the control cell line formed no tumors. These results suggest that E-cadherin plays an important role in the process of intrahepatic metastasis of HCC.


A morphological study of retinal changes in unilateral amblyopia using optical coherence tomography image segmentation.
The purpose of this study was to evaluate the possible structural changes of the macula in patients with unilateral amblyopia using optical coherence tomography (OCT) image segmentation. 38 consecutive patients (16 male; mean age 32.4±17.6 years; range 6-67 years) with unilateral amblyopia were involved in this study. OCT examinations were performed with a time-domain OCT device, and a custom-built OCT image analysis software (OCTRIMA) was used for OCT image segmentation. The axial length (AL) was measured by a LenStar LS 900 device. Macular layer thickness, AL and manifest spherical equivalent refraction (MRSE) of the amblyopic eye were compared to that of the fellow eye. We studied if the type of amblyopia (strabismus without anisometropia, anisometropia without strabismus, strabismus with anisometropia) had any influence on macular layer thickness values. There was significant difference between the amblyopic and fellow eyes in MRSE and AL in all subgroups. Comparing the amblyopic and fellow eyes, we found a statistically significant difference only in the thickness of the outer nuclear layer in the central region using linear mixed model analysis keeping AL and age under control (p = 0.032). There was no significant difference in interocular difference in the thickness of any macular layers between the subgroups with one-way between-groups ANCOVA while statistically controlling for interocular difference in AL and age. According to our results there are subtle changes in amblyopic eyes affecting the outer nuclear layer of the fovea suggesting the possible involvement of the photoreceptors. However, further studies are warranted to support this hypothesis.


Objectively Monitoring Amyotrophic Lateral Sclerosis Patient Symptoms During Clinical Trials With Sensors: Observational Study.
Objective symptom monitoring of patients with Amyotrophic Lateral Sclerosis (ALS) has the potential to provide an important source of information to evaluate the impact of the disease on aspects of real-world functional capacity and activities of daily living in the home setting, providing useful objective outcome measures for clinical trials. This study aimed to investigate the feasibility of a novel digital platform for remote data collection of multiple symptoms-physical activity, heart rate variability (HRV), and digital speech characteristics-in 25 patients with ALS in an observational clinical trial setting to explore the impact of the devices on patients' everyday life and to record tolerability related to the devices and study procedures over 48 weeks. In this exploratory, noncontrolled, nondrug study, patients attended a clinical site visit every 3 months to perform activity reference tasks while wearing a sensor, to conduct digital speech tests and for conventional ALS monitoring. In addition, patients wore the sensor in their daily life for approximately 3 days every month for the duration of the study. The amount and quality of digital speech data captured at the clinical sites were as intended, and there were no significant issues. All the home monitoring sensor data available were propagated through the system and were received as expected. However, the amount and quality of physical activity home monitoring data were lower than anticipated. A total of 3 or more days (or partial days) of data were recorded for 65% of protocol time points, with no data collected for 24% of time points. At baseline, 24 of 25 patients provided data, reduced to 13 of 18 patients at Week 48. Lower-than-expected quality HRV data were obtained, likely because of poor contact between the sensor and the skin. In total, 6 of 25 patients had mild or moderate adverse events (AEs) in the skin and subcutaneous tissue disorders category because of skin irritation caused by the electrode patch. There were no reports of serious AEs or deaths. Most patients found the sensor comfortable, with no or minimal impact on daily activities. The platform can measure physical activity in patients with ALS in their home environment; patients used the equipment successfully, and it was generally well tolerated. The quantity of home monitoring physical activity data was lower than expected, although it was sufficient to allow investigation of novel physical activity end points. Good-quality in-clinic speech data were successfully captured for analysis. Future studies using objective patient monitoring approaches, combined with the most current technological advances, may be useful to elucidate novel digital biomarkers of disease progression.


Influence of molecular scattering models on aerosol optical properties measured by high spectral resolution lidar.
The influence of molecular scattering models on aerosol optical properties measured by high spectral resolution lidar (HSRL) is experimentally investigated and theoretically evaluated. The measurements analyzed in this study were made during three field campaigns by the German Aerospace Center airborne HSRL. The influence of the respective theoretical model on spaceborne HSRL retrievals is also estimated. Generally, the influence on aerosol extinction coefficient can be neglected for both airborne and spaceborne HSRLs. However, the influence on aerosol backscatter coefficient depends on aerosol concentration and is larger than 3% (6%) at ground level for airborne (spaceborne) HSRLs, which is considerable for the spaceborne HSRL, especially when the aerosol concentration is low. A comparison of the HSRL measurements and coordinated ground-based sunphotometer measurements shows that the influence of the model is observable and comparable to the measurement error of the lidar system.


Assessing the validity and reliability of family factors on physical activity: A case study in Turkey.
Childhood obesity rates have been rising rapidly in developing countries. A better understanding of the risk factors and social context is necessary to inform public health interventions and policies. This paper describes the validation of several measurement scales for use in Turkey, which relate to child and parent perceptions of physical activity (PA) and enablers and barriers of physical activity in the home environment. The aim of this study was to assess the validity and reliability of several measurement scales in Turkey using a population sample across three socio-economic strata in the Turkish capital, Ankara. Surveys were conducted in Grade 4 children (mean age = 9.7 years for boys; 9.9 years for girls), and their parents, across 6 randomly selected schools, stratified by SES (n = 641 students, 483 parents). Construct validity of the scales was evaluated through exploratory and confirmatory factor analysis. Internal consistency of scales and test-retest reliability were assessed by Cronbach's alpha and intra-class correlation. The scales as a whole were found to have acceptable-to-good model fit statistics (PA Barriers: RMSEA = 0.076, SRMR = 0.0577, AGFI = 0.901; PA Outcome Expectancies: RMSEA = 0.054, SRMR = 0.0545, AGFI = 0.916, and PA Home Environment: RMSEA = 0.038, SRMR = 0.0233, AGFI = 0.976). The PA Barriers subscales showed good internal consistency and poor to fair test-retest reliability (personal α = 0.79, ICC = 0.29, environmental α = 0.73, ICC = 0.59). The PA Outcome Expectancies subscales showed good internal consistency and test-retest reliability (negative α = 0.77, ICC = 0.56; positive α = 0.74, ICC = 0.49). Only the PA Home Environment subscale on support for PA was validated in the final confirmatory model; it showed moderate internal consistency and test-retest reliability (α = 0.61, ICC = 0.48). This study is the first to validate measures of perceptions of physical activity and the physical activity home environment in Turkey. Our results support the originally hypothesized two-factor structures for Physical Activity Barriers and Physical Activity Outcome Expectancies. However, we found the one-factor rather than two-factor structure for Physical Activity Home Environment had the best model fit. This study provides general support for the use of these scales in Turkey in terms of validity, but test-retest reliability warrants further research.


Enhancement of optical processes in coupled plasmonic nanocavities [Invited].
We present detailed experimental and numerical investigations of resonances in deep nanogroove gratings in metallic substrates. These plasmonic nanocavity gratings feature enhanced fields within the grooves that enable a large enhancement of linear and nonlinear optical processes. This enhancement relies on both localized and propagating surface plasmons on the nanopatterned surface. We show that the efficiency of optical processes such as Raman scattering and four-wave mixing is dramatically enhanced by plasmonic nanocavity gratings.


Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases.
The gut microbiota modulate host biology in numerous ways, but little is known about the molecular mediators of these interactions. Previously, we found a widely distributed family of nonribosomal peptide synthetase gene clusters in gut bacteria. Here, by expressing a subset of these clusters in Escherichia coli or Bacillus subtilis, we show that they encode pyrazinones and dihydropyrazinones. At least one of the 47 clusters is present in 88% of the National Institutes of Health Human Microbiome Project (NIH HMP) stool samples, and they are transcribed under conditions of host colonization. We present evidence that the active form of these molecules is the initially released peptide aldehyde, which bears potent protease inhibitory activity and selectively targets a subset of cathepsins in human cell proteomes. Our findings show that an approach combining bioinformatics, synthetic biology, and heterologous gene cluster expression can rapidly expand our knowledge of the metabolic potential of the microbiota while avoiding the challenges of cultivating fastidious commensals.


The East-West blood trade : How the German Democratic Republic obtained foreign currency with blood products (1983-1990).
Using the East-West blood trade of the German Democratic Republic (GDR) in the 1980s as an example, this study aims to show what kind of problems arise when trade agreements are made with authoritarian regimes, where transparency is lacking and the general public is not informed about the trading conditions. Files from the Ministry of Health and the Foreign Trade Ministry show the extent, aims, and scope of the blood exports to the West. Within the East-West trade, blood was regarded solely as a commercial good; ethical concerns played no part. The blood trade was the most important income source of unscheduled foreign currency for the GDR health sector. People were asked to donate for the wellbeing of society and without receiving remuneration. They were unaware that their blood was an object of commercial trade. Most of the revenue was put into secret accounts of the GDR Foreign Trade Ministry or went to Western intermediaries. The regulations for blood deliveries often challenged the blood donation institutes; they lacked donors, modern techniques/equipment, and personal. Buyers in the West repeatedly complained about the quality of the blood products. The Western intermediaries sold the goods to bulk-buyers, predominantly in German-speaking countries.


Acute mastoiditis in children: susceptibility factors and management.
The objective was to review our experience with clinical course, diagnostic and therapeutic profile of children treated for acute mastoiditis, and to investigate for possible susceptibility factors. Study was designed as retrospective review of pediatric patients presenting with acute mastoiditis secondary to acute otitis media over the last 6 years, from 2000 to 2006. The study involved children aged from 1 to 16 years treated for acute mastoiditis and subsequent intratemporal and intracranial complications in Clinic for otorhinolaryngology, Clinic Center Banja Luka. Selected clinical parameters, mastoid coalescence and risk factors for necessity of surgical intervention were analyzed. Medical history review of a total of 13 patients with acute mastoiditis was analyzed. Acute coalescent mastoiditis occurred 11 patients (84%) while noncoalescent form of acute mastoiditis occurred in 2 cases (16%). Intracranial complication occurred in 3 patients (2 meningitis and 1 peridural intracranial abscess), while 2 patients had intratemporal complication (subperiostal abscess) associated to coalescent mastoiditis. We observed clinical profile of acute mastoiditis in regard to pathology found on the tympanic membrane, middle ear mucosa and destructions on the bony wall of the middle ear and mastoid. The main signs of progressive infection were tympanic membrane perforation, pulsatile suppurative secretion from the mucosa, and intratemporal abscess. All patients with coalescent mastoiditis required mastoidectomy, while noncoalescent mastoiditis was treated conservatively with broad-spectrum intravenous antibiotics and myringotomy. In conclusion acute mastoiditis is uncommon but serious complication of acute otitis media in children associated with significant morbidity. Coalescent mastoiditis concomitant with subperiostal abscess, intracranial complications and mastoiditis not responsive after 48 hours to intravenous antibiotics should urge clinician to timely mastoid surgery.


Applying Mathematical Optimization Methods to an ACT-R Instance-Based Learning Model.
Computational models of cognition provide an interface to connect advanced mathematical tools and methods to empirically supported theories of behavior in psychology, cognitive science, and neuroscience. In this article, we consider a computational model of instance-based learning, implemented in the ACT-R cognitive architecture. We propose an approach for obtaining mathematical reformulations of such cognitive models that improve their computational tractability. For the well-established Sugar Factory dynamic decision making task, we conduct a simulation study to analyze central model parameters. We show how mathematical optimization techniques can be applied to efficiently identify optimal parameter values with respect to different optimization goals. Beyond these methodological contributions, our analysis reveals the sensitivity of this particular task with respect to initial settings and yields new insights into how average human performance deviates from potential optimal performance. We conclude by discussing possible extensions of our approach as well as future steps towards applying more powerful derivative-based optimization methods.


Undergraduate clinical neurosciences programme development: a consumer-based evaluation.
Intern responses to a questionnaire were used to evaluate an undergraduate clinical neurosciences programme. The data obtained were judged an authentic measure of instructional efficacy. Most interns rated themselves competent in performing the neurological examination but ill-equipped to interpret their findings and to manage effectively common problems, especially emergencies. Neurological diseases and the non-biomedical aspects of patient care were identified relatively infrequently as matters needing greater emphasis. Explanations for these findings may include a curriculum of traditional format, differences in teaching and assessing theoretical and practical competence, and the typical responsibilities of interns in an academic hospital. Intern evaluation of undergraduate clinical programmes can provide data useful to their development.


Plant productivity and environment.
An analysis of major U.S. crops shows that there is a large genetic potential for yield that is unrealized because of the need for better adaptation of the plants to the environments in which they are grown. Evidence from native populations suggests that high productivity can occur in these environments and that opportunities for improving production in unfavorable environments are substantial. Genotypic selection for adaptation to such environments has already played an important role in agriculture, but the fundamental mechanisms are poorly understood. Recent scientific advances make exploration of these mechanisms more feasible and could result in large gains in productivity.


Distribution, Characteristics, and Regulatory Potential of Long Noncoding RNAs in Brown-Rot Fungi.
Long noncoding RNAs have been thoroughly studied in plants, animals, and yeasts, where they play important roles as regulators of transcription. Nevertheless, almost nothing is known about their presence and characteristics in filamentous fungi, especially in basidiomycetes. In the present study, we have carried out an exhaustive annotation and characterization of lncRNAs in two lignin degrader basidiomycetes, Coniophora puteana and Serpula lacrymans. We identified 2,712 putative lncRNAs in the former and 2,242 in the latter, mainly originating from intergenic locations of transposon-sparse genomic regions. The lncRNA length, GC content, expression levels, and stability of the secondary structure differ from coding transcripts but are similar in these two species and resemble that of other eukaryotes. Nevertheless, they lack sequence conservation. Also, we found that lncRNAs are transcriptionally regulated in the same proportion as genes when the fungus actively decomposes soil organic matter. Finally, up to 7% of the upstream gene regions of Coniophora puteana and Serpula lacrymans are transcribed and produce lncRNAs. The study of expression trends in these gene-lncRNA pairs uncovered groups with similar and opposite transcriptional profiles which may be the result of cis-transcriptional regulation.


Providing web-based feedback and social norms information to reduce student alcohol intake: a multisite investigation.
Unhealthy alcohol use among university students is cause for concern, yet the level of help seeking behavior for alcohol use is low within the student population. Electronic brief interventions delivered via the Internet present an alternative to traditional treatments and could enable the delivery of interventions on a population basis. Further evidence is needed of the effectiveness of Internet-delivered interventions and of their generalizability across educational institutions. Our objective was to evaluate the effectiveness across 4 UK universities of a Web-based intervention for student alcohol use. In total, 1112 participants took part. Participants were stratified by educational institution, gender, age group, year of study, and self-reported weekly consumption of alcohol and randomly assigned to either the control arm or to the immediate or delayed intervention arms. Intervention participants gained access to the intervention between weeks 1 to 7 or weeks 8 to 15, respectively. The intervention provided electronic personalized feedback and social norms information on drinking behavior accessed by logging on to a website. Participants registered interest by completing a brief screening questionnaire and were then asked to complete 4 further assessments across the 24 weeks of the study. Assessments included a retrospective weekly drinking diary, the Alcohol Use Disorders Identification Test (AUDIT), and a readiness-to-change algorithm. The outcome variable was the number of units of alcohol consumed in the last week. The effect of treatment arm and time on units consumed last week and average units consumed per drinking occasion were investigated using repeated measures multivariate analysis of covariance (MANCOVA). In addition, the data were modeled using a longitudinal regression with time points clustered within students. MANCOVA revealed a main effect of time on units of alcohol consumed over the last week. A longitudinal regression model showed an effect of assessment across time predicting that participants who completed at least 2 assessments reduced their drinking. The model predicted an additional effect of being assigned to an intervention arm, an effect that increased across time. Regression analysis predicted that being male or being assigned to an intervention arm increased the odds of not completing all assessments. The number of units of alcohol consumed over the last week at registration, age, university educational institution, and readiness to change were not predictive of completion. Delivering an electronic personalized feedback intervention to students via the Internet can be effective in reducing weekly alcohol consumption. The effect does not appear to differ by educational institution. Our model suggested that monitoring alone is likely to reduce weekly consumption over 24 weeks but that consumption could be further reduced by providing access to a Web-based intervention. Further research is needed to understand the apparent therapeutic effect of monitoring and how this can be utilized to enhance the effectiveness of brief Web-based interventions.


Bridging the gap: Using Veerman and Van Yperen's (2007) framework to conceptualise and develop evidence informed practice in an Irish youth work organisation.
While there is considerable support among the policy, practice and academic communities for the idea that practice in youth work should be based on evidence, Veerman and Van Yperen (2007) highlight the fact that little practice in the area of youth care is actually evidence based due to the paucity of experimental studies in the field and the difficulties associated with evaluation of non-standardised interventions such as youth work. They propose a model consisting of levels of evidence, the aim of which is to 'bridge the gap between evidence based and evidence informed practice' (p. 218). In order to address the dearth of examples in the international literature of how organisations have dealt with these complexities in practice, this article provides a case study of how a large Irish youth organisation, Foróige, has endeavoured to adopt an inclusive approach to evidence, working towards both evidence based and evidence informed practice. Drawing on Veerman and Van Yperen's (2007) framework, the case study shows that Foróige committed itself to gathering different types of evidence, including logic models and theoretical understandings at the foundation level and experimental design studies of key programmes at the advanced level. The case study focuses in detail on the intermediate level, whereby practitioners were trained to evaluate aspects of their own work, with a view to embedding evaluation and reflection in day to day practice. The process is described and key lessons emerging are discussed.


Modern technologies and algorithms for scaffolding assembled genomes.
The computational reconstruction of genome sequences from shotgun sequencing data has been greatly simplified by the advent of sequencing technologies that generate long reads. In the case of relatively small genomes (e.g., bacterial or viral), complete genome sequences can frequently be reconstructed computationally without the need for further experiments. However, large and complex genomes, such as those of most animals and plants, continue to pose significant challenges. In such genomes, assembly software produces incomplete and fragmented reconstructions that require additional experimentally derived information and manual intervention in order to reconstruct individual chromosome arms. Recent technologies originally designed to capture chromatin structure have been shown to effectively complement sequencing data, leading to much more contiguous reconstructions of genomes than previously possible. Here, we survey these technologies and the algorithms used to assemble and analyze large eukaryotic genomes, placed within the historical context of genome scaffolding technologies that have been in existence since the dawn of the genomic era.


Biomedical progress rates as new parameters for models of economic growth in developed countries.
While the doubling of life expectancy in developed countries during the 20th century can be attributed mostly to decreases in child mortality, the trillions of dollars spent on biomedical research by governments, foundations and corporations over the past sixty years are also yielding longevity dividends in both working and retired population. Biomedical progress will likely increase the healthy productive lifespan and the number of years of government support in the old age. In this paper we introduce several new parameters that can be applied to established models of economic growth: the biomedical progress rate, the rate of clinical adoption and the rate of change in retirement age. The biomedical progress rate is comprised of the rejuvenation rate (extending the productive lifespan) and the non-rejuvenating rate (extending the lifespan beyond the age at which the net contribution to the economy becomes negative). While staying within the neoclassical economics framework and extending the overlapping generations (OLG) growth model and assumptions from the life cycle theory of saving behavior, we provide an example of the relations between these new parameters in the context of demographics, labor, households and the firm.


Predictors of change differ for moderate and vigorous intensity physical activity and for weekdays and weekends: a longitudinal analysis.
Predictors of physical activity (PA) change are rarely investigated separately for different PA intensities and for weekdays/weekends. We investigated whether individual-level predictors of one-year change in objectively-measured physical activity differ for moderate PA (MPA) and vigorous PA (VPA) and for weekends and weekdays. Accelerometer-assessed PA (mins) was obtained at baseline and +1 year (n = 875, 41.5% male, Mean ± SD baseline age: 9.8 ± 0.4 years-old). Potential predictors (n = 38) were assessed at baseline from psychological (e.g., self-efficacy), socio-cultural (e.g., parent support) and environmental domains (e.g., land use). Associations between predictors and change in MPA (2000-3999 counts/minute (cpm)) and VPA (≥4000 cpm) separately for weekdays and weekends were studied using multi-level linear regression. Analyses were adjusted for school clustering, sex and baseline PA. Weekend PA declined (MPA decline 4.6 ± 21.8 mins/day; VPA decline: 2.1 ± 20.1 mins/day; both p < 0.001) whereas weekday PA did not significantly change. Higher baseline PA and being a girl were associated with greater PA declines in all four outcomes; remaining predictors differed for MPA and VPA and/or weekdays and weekends. Family logistic support was associated with less of a decline in weekend MPA (CI 95%) 0.15 (0.05, 0.25) and VPA 0.19 (0.09, 0.29), and peer support with less of a decline in weekday MPA 0.18 (0.02, 0.34) and VPA 0.22 (0.06, 0.38). Results highlight the relevance of investigating predictors of PA change separately for different PA intensities and for weekdays/weekends. In addition to continued focus on school PA promotion, more effort to target interventions during weekends, such as in the family and community appears important. Encouraging peer support to increase weekday PA and targeting parent support for weekend PA may be health promotion priorities.


Plasma cortisol levels of dogs at a county animal shelter.
Plasmacortisol levels were examined to assess the stress of dogs in a county animal shelter. Groups of dogs confined in the shelter for their 1st, 2nd, or 3rd day had higher cortisol levels than did a group maintained in the shelter for more than 9 days. Dogs in the shelter for an intermediate period (Day 4-9) had intermediate levels of cortisol. The cortisol concentrations of dogs during their first day in the shelter were greater than either those of the same dogs on Day 4/5 in the shelter or those of a group of pet dogs sampled in their own homes. There was no overall effect of 20 min of social interaction with a human (e.g., petting) on the plasma cortisol levels of dogs in the shelter on Day 1-3. However, the gender of the petter did affect cortisol levels. Those dogs interacting with a female had lower cortisol concentrations at the end of the session than did dogs interacting with a male. The results suggest that confinement in a public animal shelter produces a prolonged activation of the hypothalamic-pituitary-adrenal axis. Further, it appears that some subtle aspect of interaction with a human may be capable of moderating this response. Possible implications for the welfare of confined dogs, and for the development of behavior problems in dogs obtained from shelters, are discussed.


A self-assembling lanthanide molecular nanoparticle for optical imaging.
Chromophores that incorporate f-block elements have considerable potential for use in bioimaging applications because of their advantageous photophysical properties compared to organic dye, which are currently widely used. We are developing new classes of lanthanide-based self-assembling molecular nanoparticles as reporters for imaging and as multi-functional nanoprobes or nanosensors for use with biological samples. One class of these materials, which we call lanthanide "nano-drums", are homogeneous 4d-4f clusters approximately 25 to 30 Å in diameter. These are capable of emitting from the visible to near-infrared wavelengths. Here, we present the synthesis, crystal structure, photophysical properties and comparative cytotoxicity data for a 32 metal Eu-Cd nano-drum [Eu(8)Cd(24)L(12)(OAc)(48)] (1). We also explored the imaging capabilities of this nano-drum using epifluorescence, TIRF, and two-photon microscopy platforms.


The association between automatic thoughts about eating, the actual-ideal weight discrepancies, and eating disorders symptoms: a longitudinal study in late adolescence.
This study tested the reciprocal relationships between automatic thoughts about eating and the actual-ideal weight discrepancies, and their role in the formation and maintenance of eating disorders (ED) symptoms in a non-clinical sample of adolescents. In particular, we investigated whether thoughts about eating mediated the effects of weight discrepancies on ED formation and whether weight discrepancies mediated the effects of thoughts about eating on ED formation were investigated. Data were collected three times, with a 2-month interval between Time 1 (T1) and Time 2 (T2), and a 9-month interval between T2 and Time 3 (T3). Adolescents (N = 55) aged 15-18 filled out the SCOFF Questionnaire, assessing eating disorders symptoms, and the Eating Disorder Thoughts Questionnaire, evaluating automatic thoughts. To assess weight discrepancies questions about actual (subjectively reported) and ideal body weight were asked followed by objective measurement of height and weight. Negative thoughts about eating (T2) mediated the relation between weight discrepancies (T1) and symptoms of anorexia and bulimia (T3). In addition, the association between negative thoughts (T1) and eating disorders symptoms (T3) was mediated by weight discrepancies (T2). The negative thoughts and the actual (both subjectively reported and objectively measured)-ideal weight discrepancies constitute a vicious cycle, related to higher ED symptoms. Prevention of eating disorders should be directed to adolescents who manifest large weight discrepancies or high levels of negative thoughts about eating, as they are at risk for developing eating disorder symptoms.


Dissociation between sustained single-neuron spiking and transient β-LFP oscillations in primate motor cortex.
Determining the relationship between single-neuron spiking and transient (20 Hz) β-local field potential (β-LFP) oscillations is an important step for understanding the role of these oscillations in motor cortex. We show that whereas motor cortex firing rates and beta spiking rhythmicity remain sustained during steady-state movement preparation periods, β-LFP oscillations emerge, in contrast, as short transient events. Single-neuron mean firing rates within and outside transient β-LFP events showed no differences, and no consistent correlation was found between the beta oscillation amplitude and firing rates, as was the case for movement- and visual cue-related β-LFP suppression. Importantly, well-isolated single units featuring beta-rhythmic spiking (43%, 125/292) showed no apparent or only weak phase coupling with the transient β-LFP oscillations. Similar results were obtained for the population spiking. These findings were common in triple microelectrode array recordings from primary motor (M1), ventral (PMv), and dorsal premotor (PMd) cortices in nonhuman primates during movement preparation. Although beta spiking rhythmicity indicates strong membrane potential fluctuations in the beta band, it does not imply strong phase coupling with β-LFP oscillations. The observed dissociation points to two different sources of variation in motor cortex β-LFPs: one that impacts single-neuron spiking dynamics and another related to the generation of mesoscopic β-LFP signals. Furthermore, our findings indicate that rhythmic spiking and diverse neuronal firing rates, which encode planned actions during movement preparation, may naturally limit the ability of different neuronal populations to strongly phase-couple to a single dominant oscillation frequency, leading to the observed spiking and β-LFP dissociation.NEW & NOTEWORTHY We show that whereas motor cortex spiking rates and beta (~20 Hz) spiking rhythmicity remain sustained during steady-state movement preparation periods, β-local field potential (β-LFP) oscillations emerge, in contrast, as transient events. Furthermore, the β-LFP phase at which neurons spike drifts: phase coupling is typically weak or absent. This dissociation points to two sources of variation in the level of motor cortex beta: one that impacts single-neuron spiking and another related to the generation of measured mesoscopic β-LFPs.


Health, growth and reproductive success of mice exposed to environmentally relevant levels of Ra-226 via drinking water over multiple generations.
To assess health, growth and reproductive success of mammals exposed for multiple generations to levels of radium-226 known to occur in environments surrounding uranium mines and mills in Canada. The study consisted of a control group and four treatment groups each containing 40 mice (20 males and 20 females) of the CBA/CaJ strain that were continuously exposed to a range of radium-226 levels via drinking water. Breeding was at 8-10 weeks of age and the study was concluded after three breeding cycles. When compared to control mice, constant consumption of drinking water containing 0.012, 0.076, 0.78 and 8.0 Bq/l of radium-226 over four generations of mice did not demonstrably affect physical condition, weight, pregnancy rate, number of pups per litter, sex ratio and bodyweight gain of pups. Between generations, the observed differences in pregnancy rates that were noted in all groups, including controls, seemed to directly correlate with the weight and age of the females at breeding. Based on the endpoints measured on four generations of mice, there is no indication that the consumption of radium-226 via drinking water (at activity concentrations up to 8.0 Bq/l) affects health, growth and reproductive fitness.


Identification of intravascular tumor microenvironment features predicting the recurrence of pathological stage I lung adenocarcinoma.
Histological vascular invasion (VI) by tumors is reportedly a risk factor influencing recurrence or survival after surgical treatment; however, few studies have evaluated which VI features affect recurrence or survival. The objective of this study was to evaluate how VI features affect recurrence in lung adenocarcinoma patients. We selected 106 patients with pathological stage I lung adenocarcinoma who showed VI and examined the properties of intravascular tumors associated with recurrence. First we investigated the relationship between the frequency of VI in a histological cross-section and the incidence of recurrence; however, a significant impact was not observed. Microscopic examination revealed the intravascular tumors were composed of not only cancer cells but also non-cancerous cells. To examine whether the characteristics of intravascular cancer cells and/or non-cancerous cells have prognostic value, we examined the expression levels of epithelial-mesenchymal transition-related markers in cancer cells and the numbers of infiltrating non-cancerous cells, including macrophages, endothelial cells, and fibroblasts. High levels of E-cadherin expression in the intravascular cancer cells were significant predictors of recurrence (P = 0.004), whereas the expressions of CD44, CD44 variant 6, and vimentin were not. Large numbers of intravascular CD204(+) macrophages (P = 0.016), CD34(+) microvessels (P = 0.007), and α-smooth muscle actin (+) fibroblasts (P = 0.033) were also significant predictors of recurrence. Our results indicated VI with abundant stromal cell infiltrates might be a predictor of recurrence and suggested the tumor microenvironment created by cancer cells and stromal cells within the blood vessel may play an important role during the metastatic process.


Economic evaluation of a pharmacogenomic multi-gene panel test to optimize anti-hypertension therapy: simulation study.
Hypertension is the strongest modifiable risk factor for cardiovascular disease, affecting 80 million individuals in the US and responsible for ∼360,000 deaths, at total annual costs of $93.5 billion. Antihypertension therapies guided by single genotypes are clinically more effective and may avert more adverse events than the standard of care of layering anti-hypertensive drug therapies, thus potentially decreasing costs. This study aimed to determine the economic benefits of the implementation of multi-gene panel guided therapies for hypertension from the payer perspective within a 3-year time horizon. A simulation analysis was conducted for a panel of 10 million insured patients categorized clinically as untreated, treated but uncontrolled, and treated and controlled over a 3-year treatment period. Inputs included research data; empirical data from a 11-gene panel with known functional, heart, blood vessel, and kidney genotypes; and therapy efficacy and safety estimates from literature. Cost estimates were categorized as related to genetic testing, evaluation and management, medication, or adverse events. Multi-gene panel guided therapy yielding savings of $6,256,607,500 for evaluation and management, $908,160,000 for medications, and $37,467,508,716 for adverse events, after accounting for incremental genetic testing costs of $2,355,540,000. This represents total 3-year savings of $42,276,736,216, or a 47% reduction, and 3-year savings of $4,228 and annual savings of $1,409 per covered patient. A precision medicine approach to genetically guided therapy for hypertension patients using a multi-gene panel reduced total 3-year costs by 47%, yielding savings exceeding $42.3 billion in an insured panel of 10 million patients. Importantly, 89% of these savings are generated by averting specific adverse events and, thus, optimizing choice of therapy in function of both safety and efficacy.


From Theory to Practice: Implementation of a Resource Allocation Model in Health Departments.
To develop a resource allocation model to optimize health departments' Centers for Disease Control and Prevention (CDC)-funded HIV prevention budgets to prevent the most new cases of HIV infection and to evaluate the model's implementation in 4 health departments. We developed a linear programming model combined with a Bernoulli process model that allocated a fixed budget among HIV prevention interventions and risk subpopulations to maximize the number of new infections prevented. The model, which required epidemiologic, behavioral, budgetary, and programmatic data, was implemented in health departments in Philadelphia, Chicago, Alabama, and Nebraska. The optimal allocation of funds, the site-specific cost per case of HIV infection prevented rankings by intervention, and the expected number of HIV cases prevented. The model suggested allocating funds to HIV testing and continuum-of-care interventions in all 4 health departments. The most cost-effective intervention for all sites was HIV testing in nonclinical settings for men who have sex with men, and the least cost-effective interventions were behavioral interventions for HIV-negative persons. The pilot sites required 3 to 4 months of technical assistance to develop data inputs and generate and interpret the results. Although the sites found the model easy to use in providing quantitative evidence for allocating HIV prevention resources, they criticized the exclusion of structural interventions and the use of the model to allocate only CDC funds. Resource allocation models have the potential to improve the allocation of limited HIV prevention resources and can be used as a decision-making guide for state and local health departments. Using such models may require substantial staff time and technical assistance. These model results emphasize the allocation of CDC funds toward testing and continuum-of-care interventions and populations at highest risk of HIV transmission.


Discordance between morphological and molecular species boundaries among Caribbean species of the reef sponge Callyspongia.
Sponges are among the most species-rich and ecologically important taxa on coral reefs, yet documenting their diversity is difficult due to the simplicity and plasticity of their morphological characters. Genetic attempts to identify species are hampered by the slow rate of mitochondrial sequence evolution characteristic of sponges and some other basal metazoans. Here we determine species boundaries of the Caribbean coral reef sponge genus Callyspongia using a multilocus, model-based approach. Based on sequence data from one mitochondrial (COI), one ribosomal (28S), and two single-copy nuclear protein-coding genes, we found evolutionarily distinct lineages were not concordant with current species designations in Callyspongia. While C. fallax,C. tenerrima, and C. plicifera were reciprocally monophyletic, four taxa with different morphologies (C. armigera,C. longissima,C. eschrichtii, and C. vaginalis) formed a monophyletic group and genetic distances among these taxa overlapped distances within them. A model-based method of species delimitation supported collapsing these four into a single evolutionary lineage. Variation in spicule size among these four taxa was partitioned geographically, not by current species designations, indicating that in Callyspongia, these key taxonomic characters are poor indicators of genetic differentiation. Taken together, our results suggest a complex relationship between morphology and species boundaries in sponges.


Electrically contractile polymers augment right ventricular output in the heart.
Research into the development of artificial heart muscle has been limited to assembly of stem cell-derived cardiomyocytes seeded around a matrix, while nonbiological approaches to tissue engineering have rarely been explored. The aim of the study was to apply electrically contractile polymer-based actuators as cardiomyoplasty for positive inotropic support of the right ventricle. Complex trilayer polypyrrole (PPy) bending polymers for high-speed applications were generated. Bending motion occurred directly as a result of electrochemically driven charging and discharging of the PPy layers. In a rat model (n = 5), strips of polymers (3 × 20 mm) were attached and wrapped around the right ventricle (RV). RV pressure was continuously monitored invasively by direct RV cannulation. Electrical activation occurred simultaneously with either diastole (in order to evaluate the polymer's stand-alone contraction capacity; group 1) or systole (group 2). In group 1, the pressure generation capacity of the polymers was measured by determining the area under the pressure curve (area under curve, AUC). In group 2, the RV pressure AUC was measured in complexes directly preceding those with polymer contraction and compared to RV pressure complexes with simultaneous polymer contraction. In group 1, the AUC generated by polymer contraction was 2768 ± 875 U. In group 2, concomitant polymer contraction significantly increased AUC compared with complexes without polymer support (5987 ± 1334 U vs. 4318 ± 691 U, P ≤ 0.01). Electrically contractile polymers are able to significantly augment right ventricular contraction. This approach may open new perspectives for myocardial tissue engineering, possibly in combination with fetal or embryonic stem cell-derived cardiomyocytes.


CPR skills retention of lay basic rescuers.
In 1979-1980, 950 telephone company personnel were trained and tested at the basic rescuer level on recording manikins. In October 1981, a random group of 40 were retested without warning on the recording manikin. Skills retention was measured by comparing the tapes from training and retesting. Sixteen (40%) of those retested were able to perform effective ventilations and compressions of the manikin with 60% to 70% average retention compared to their training scores. The remaining 24 (60%) had ineffective ventilations or compressions or both. The two groups did not differ in the performance level achieved during training, or in the time interval between training and retesting. Eleven individuals retested at 13 to 14 months did not perform better than those retested later, suggesting the maximum skills deterioration had occurred within the first year. However, the effective performance group on the average were younger, and the majority had first aid training in addition to their CPR training. Only one had CPR retraining. This study supports the following recommendations: 1) lay basic rescuers should be retrained within the first year; 2) further studies of the factors influencing retention are advisable; 3) the younger age groups should be the first priority for citizen CPR training; and 4) because first aid training appears to improve CPR retention, training in both should be encouraged.


Homeopathic Oscillococcinum® for preventing and treating influenza and influenza-like illness.
Influenza is a highly infectious viral disease that is particularly common in the winter months. Oscillococcinum® is a patented homeopathic medicine that is made from a 1% solution of wild duck heart and liver extract, which is then serially diluted 200 times with water and alcohol. To determine whether homeopathic Oscillococcinum® is more effective than placebo in the prevention and/or treatment of influenza and influenza-like illness in adults or children. We searched CENTRAL (2014, Issue 8), MEDLINE (1966 to August week 4, 2014), MEDLINE In-Process & Other Non-Indexed Citations (4 September 2014), AMED (2006 to September 2014), Web of Science (1985 to September 2014), LILACS (1985 to September 2014) and EMBASE (1980 to September 2014). We contacted the manufacturers of Oscillococcinum® for information on further trials. Randomised, placebo-controlled trials of Oscillococcinum® in the prevention and/or treatment of influenza and influenza-like illness in adults or children. Three review authors independently extracted data and assessed risk of bias in the eligible trials. No new trials were included in this 2014 update. We included six studies: two prophylaxis trials (327 young to middle-aged adults in Russia) and four treatment trials (1196 teenagers and adults in France and Germany). The overall standard of trial reporting was poor and hence many important methodological aspects of the trials had unclear risk of bias. There was no statistically significant difference between the effects of Oscillococcinum® and placebo in the prevention of influenza-like illness: risk ratio (RR) 0.48, 95% confidence interval (CI) 0.17 to 1.34, P value = 0.16. Two treatment trials (judged as 'low quality') reported sufficient information to allow full data extraction: 48 hours after commencing treatment, there was an absolute risk reduction of 7.7% in the frequency of symptom relief with Oscillococcinum® compared with that of placebo (risk difference (RD) 0.077, 95% CI 0.03 to 0.12); the RR was 1.86 (95% CI 1.27 to 2.73; P value = 0.001). A significant but lesser effect was observed at three days (RR 1.27, 95% CI 1.03 to 1.56; P value = 0.03), and no significant difference between the groups was noted at four days (RR 1.11, 95% CI 0.98 to 1.27; P value = 0.10) or at five days (RR 1.06, 95% CI 0.96 to 1.16; P value = 0.25). One of the six studies reported one patient who suffered an adverse effect (headache) from taking Oscillococcinum®. There is insufficient good evidence to enable robust conclusions to be made about Oscillococcinum® in the prevention or treatment of influenza and influenza-like illness. Our findings do not rule out the possibility that Oscillococcinum® could have a clinically useful treatment effect but, given the low quality of the eligible studies, the evidence is not compelling. There was no evidence of clinically important harms due to Oscillococcinum®.


Predictive models for carcinogenicity and mutagenicity: frameworks, state-of-the-art, and perspectives.
Mutagenicity and carcinogenicity are endpoints of major environmental and regulatory concern. These endpoints are also important targets for development of alternative methods for screening and prediction due to the large number of chemicals of potential concern and the tremendous cost (in time, money, animals) of rodent carcinogenicity bioassays. Both mutagenicity and carcinogenicity involve complex, cellular processes that are only partially understood. Advances in technologies and generation of new data will permit a much deeper understanding. In silico methods for predicting mutagenicity and rodent carcinogenicity based on chemical structural features, along with current mutagenicity and carcinogenicity data sets, have performed well for local prediction (i.e., within specific chemical classes), but are less successful for global prediction (i.e., for a broad range of chemicals). The predictivity of in silico methods can be improved by improving the quality of the data base and endpoints used for modelling. In particular, in vitro assays for clastogenicity need to be improved to reduce false positives (relative to rodent carcinogenicity) and to detect compounds that do not interact directly with DNA or have epigenetic activities. New assays emerging to complement or replace some of the standard assays include Vitotox, GreenScreenGC, and RadarScreen. The needs of industry and regulators to assess thousands of compounds necessitate the development of high-throughput assays combined with innovative data-mining and in silico methods. Various initiatives in this regard have begun, including CAESAR, OSIRIS, CHEMOMENTUM, CHEMPREDICT, OpenTox, EPAA, and ToxCast. In silico methods can be used for priority setting, mechanistic studies, and to estimate potency. Ultimately, such efforts should lead to improvements in application of in silico methods for predicting carcinogenicity to assist industry and regulators and to enhance protection of public health.


The mental health of visitors of web-based support forums for bereaved by suicide.
Persons bereaved by suicide are reluctant to ask for social support when they experience feelings of guilt and blame. A web-based peer forum may provide a safe and anonymous place for mutual support. This study examined the mental health changes of visitors of two online support forums for persons bereaved by suicide and their experiences with the forum over 1 year. Visitors of two forums completed self-report measures at baseline and at 6 and 12 months' follow-up. Repeated measures analyses were used to study changes in well-being, depressive symptoms, and complicated grief. Additionally, participants were interviewed about their experiences with the forum. The 270 participants were mostly female, low in well-being, with high levels of depressive symptoms and complicated grief. Suicidal risk was high for 5.9%. At 12 months, there were small to medium-sized significant improvements in well-being and depressive symptoms (p < .001) and nearly as much for grief (p = .08). About two thirds reported benefit from visiting the forum. Because of the pre-post design we cannot determine whether a causal relationship exists between the form and changes in mental health. After 1 year some positive changes but a large group was still struggling with their mental health. Interviews indicate that the forum was valued for finding recognition.


Analysis of Myc bound loci identified by CpG island arrays shows that Max is essential for Myc-dependent repression.
The c-myc proto-oncogene encodes a transcription factor, c-Myc, which is deregulated and/or overexpressed in many human cancers. Despite c-Myc's importance, the identity of Myc-regulated genes and the mechanism by which Myc regulates these genes remain unclear. By combining chromatin immunoprecipitation with CpG island arrays, we identified 177 human genomic loci that are bound by Myc in vivo. Analyzing a cohort of known and novel Myc target genes showed that Myc-associated protein X, Max, also bound to these regulatory regions. Indeed, Max is bound to these loci in the presence or absence of Myc. The Myc:Max interaction is essential for Myc-dependent transcriptional activation; however, we show that Max bound targets also include Myc-repressed genes. Moreover, we show that the interaction between Myc and Max is essential for gene repression to occur. Taken together, the identification and analysis of Myc bound target genes supports a model whereby Max plays an essential and universal role in the mechanism of Myc-dependent transcriptional regulation.


White and green teas (Camellia sinensis var. sinensis): variation in phenolic, methylxanthine, and antioxidant profiles.
Recent investigations have associated white teas with anti-carcinogenic, immune-boosting, and antioxidative properties that may impact human health in a manner comparable to green teas. An in-depth chemical analysis of white tea types was conducted to quantify polyphenols and antioxidant potential of 8 commercially available white teas, and compare them to green tea. Extraction and HPLC protocols were optimized and validated for the quantification of 9 phenolic and 3 methylxanthine compounds to examine inter- and intra-variation in white and green tea types and subtypes. A sampling strategy was devised to assess various subtypes procured from different commercial sources. Variation in antioxidant activity and total phenolic content (TPC) of both tea types was further assessed by the 1-1-diphenyl-2-picrylhydrazyl (DPPH) and Folin-Ciocalteau (F-C) assays, respectively. Total catechin content (TCC) for white teas ranged widely from 14.40 to 369.60 mg/g of dry plant material for water extracts and 47.16 to 163.94 mg/g for methanol extracts. TCC for green teas also ranged more than 10-fold, from 21.38 to 228.20 mg/g of dry plant material for water extracts and 32.23 to 141.24 mg/g for methanol extracts. These findings indicate that statements suggesting a hierarchical order of catechin content among tea types are inconclusive and should be made with attention to a sampling strategy that specifies the tea subtype and its source. Certain white teas have comparable quantities of total catechins to some green teas, but lesser antioxidant capacity, suggesting that white teas have fewer non-catechin antioxidants present. Practical Application: In this investigation white and green teas were extracted in ways that mimic common tea preparation practices, and their chemical profiles were determined using validated analytical chemistry methods. The results suggest certain green and white tea types have comparable levels of catechins with potential health promoting qualities. Specifically, the polyphenolic content of green teas was found to be similar to certain white tea varieties, which makes the latter tea type a potential substitute for people interested in consuming polyphenols for health reasons. Moreover, this study is among the first to demonstrate the effect subtype sampling, source of procurement, cultivation, and processing practices have on the final white tea product, as such analysis has previously been mostly carried out on green teas.


Angiopoietin-1 induces migration of monocytes in a tie-2 and integrin-independent manner.
Angiopoietin-1 (Ang-1) is an angiogenic growth factor that activates Tie-2 and integrins to promote vessel wall remodeling. The recent finding of the potential proatherogenic effects of Ang-1 prompted us to investigate whether Ang-1 promotes monocyte chemotaxis, endothelial binding, and transendothelial migration, key events in the progression of atherosclerosis. Here, we show that Ang-1 induces chemotaxis of monocytes in a manner that is independent of Tie-2 and integrin binding but dependent on phosphoinositide 3-kinase and heparin. In addition, Ang-1 promoted phosphoinositide 3-kinase-dependent binding of monocytes to endothelial monolayers and stimulated transendothelial migration. Fluorescence-activated cell sorting analysis showed that exogenous Ang-1 adheres directly to monocytes as well as to human umbilical endothelial cells, but neither Tie-2 mRNA nor protein were expressed by primary monocytes. Although Ang-1 binding to human umbilical endothelial cells was partially Tie-2 and integrin dependent, Ang-1 binding to monocytes was independent of these factors. Finally, preincubation of monocytes with soluble heparin abrogated Ang-1 binding to monocytes and migration, and partially prevented Ang-1 binding to human umbilical endothelial cells. In summary, Ang-1 induces chemotaxis of monocytes by a mechanism that is dependent on phosphoinositide 3-kinase and heparin but independent of Tie-2 and integrins. The ability of Ang-1 to recruit monocytes suggests it may play a role in inflammatory angiogenesis and may promote atherosclerosis.


Accelerated Microstructure Imaging via Convex Optimization (AMICO) from diffusion MRI data.
Microstructure imaging from diffusion magnetic resonance (MR) data represents an invaluable tool to study non-invasively the morphology of tissues and to provide a biological insight into their microstructural organization. In recent years, a variety of biophysical models have been proposed to associate particular patterns observed in the measured signal with specific microstructural properties of the neuronal tissue, such as axon diameter and fiber density. Despite very appealing results showing that the estimated microstructure indices agree very well with histological examinations, existing techniques require computationally very expensive non-linear procedures to fit the models to the data which, in practice, demand the use of powerful computer clusters for large-scale applications. In this work, we present a general framework for Accelerated Microstructure Imaging via Convex Optimization (AMICO) and show how to re-formulate this class of techniques as convenient linear systems which, then, can be efficiently solved using very fast algorithms. We demonstrate this linearization of the fitting problem for two specific models, i.e. ActiveAx and NODDI, providing a very attractive alternative for parameter estimation in those techniques; however, the AMICO framework is general and flexible enough to work also for the wider space of microstructure imaging methods. Results demonstrate that AMICO represents an effective means to accelerate the fit of existing techniques drastically (up to four orders of magnitude faster) while preserving accuracy and precision in the estimated model parameters (correlation above 0.9). We believe that the availability of such ultrafast algorithms will help to accelerate the spread of microstructure imaging to larger cohorts of patients and to study a wider spectrum of neurological disorders.


NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues.
The CCN family of genes presently consists of six distinct members encoding proteins that participate in fundamental biological processes such as cell proliferation, attachment, migration, differentiation, wound healing, angiogenesis, and several pathologies including fibrosis and tumorigenesis. Whereas CYR61 and CTGF were reported to act as positive regulators of cell growth, NOV (nephroblastoma overexpressed) provided the first example of a CCN protein with negative regulatory properties and the first example of aberrant expression being associated with tumour development. The subsequent discovery of the ELM1, rCOP1, and WISP proteins has broadened the variety of functions attributed to the CCN proteins and has extended previous observations to other biological systems. This review discusses fundamental questions regarding the regulation of CCN gene expression in normal and pathological conditions, and the structural basis for their specific biological activity. After discussing the role of nov and other CCN proteins in the development of a variety of different tissues such as kidney, nervous system, muscle, cartilage, and bone, the altered expression of the CCN proteins in various pathologies is discussed, with an emphasis on the altered expression of nov in many different tumour types such as Wilms's tumour, renal cell carcinomas, prostate carcinomas, osteosarcomas, chondrosarcomas, adrenocortical carcinomas, and neuroblastomas. The possible use of nov as a tool for molecular medicine is also discussed. The variety of biological functions attributed to the CCN proteins has led to the proposal of a model in which physical interactions between the amino and carboxy portions of the CCN proteins modulate their biological activity and ensure a proper balance of positive and negative signals through interactions with other partners. In this model, disruption of the secondary structure of the CCN proteins induced by deletions of either terminus is expected to confer on the truncated polypeptide constitutive positive or negative activities.


Galectin-1 in early acute myocardial infarction.
Myocardial infarction (MI) is the most serious manifestation of coronary artery disease and the cause of significant mortality and morbidity worldwide. Galectin-1(GAL-1), a divalent 14.5-kDa protein, is present both inside and outside cells, and has both intracellular and extracellular functions. Hypoxia inducible factor-1 alpha (HIF-1α) is a transcription factor mediating early and late responses to myocardial ischemia. Identification of the pattern of expression of GAL-1 and HIF-1α in the heart during the first 24 hours following acute MI will help in understanding early molecular changes in this event and may provide methods to overcome serious complications. Mouse model of MI was used and heart samples were processed for immunohistochemical and immunofluorescent labeling and Enzyme linked immunosorbent assay to identify GAL-1 and HIF 1α levels in the heart during the first 24 hours following MI. There was significant increase in left ventricular GAL-1 at 20 (p = 0.001) and 30 minutes (p = 0.004) following MI. There was also a significant increase in plasma GAL-1 at 4 hours (p = 0.012) and 24 hours (p = 0.001) following MI. A significant increase in left ventricular HIF-1 α was seen at 20 minutes (p = 0.047) following MI. In conclusion, we show for the first time that GAL-1 level in the left ventricle is increased in early ischemic period. We also report for the first time that HIF-1 α is significantly increased at 20 minutes following MI. In addition we report for the first time that mouse plasma GAL-1 level is significantly raised as early as 4 hours following MI.


Patient Perspectives to Inform a Health Literacy Educational Program: A Systematic Review and Thematic Synthesis of Qualitative Studies.
Patient-centred care is tailored to the needs of patients and is necessary for better health outcomes, especially for individuals with limited health literacy (LHL). However, its implementation remains challenging. The key to effectively address patient-centred care is to include perspectives of patients with LHL within the curricula of (future) healthcare providers (HCP). This systematic review aimed to explore and synthesize evidence on the needs, experiences and preferences of patients with LHL and to inform an existing educational framework. We searched three databases: PsychInfo, Medline and Cinahl, and extracted 798 articles. One-hundred and three articles met the inclusion criteria. After data extraction and thematic synthesis, key themes were identified. Patients with LHL and chronic diseases encounter multiple problems in the care process, which are often related to a lack of person-centeredness. Patient perspectives were categorized into four key themes: (1) Support system; (2) Patient self-management; (3) Capacities of HCPs; (4) Barriers in healthcare systems. "Cultural sensitivity" and "eHealth" were identified as recurring themes. A set of learning outcomes for (future) HCPs was developed based on our findings. The perspectives of patients with LHL provided valuable input for a comprehensive and person-centred educational framework that can enhance the relevance and quality of education for (future) HCPs, and contribute to better person-centred care for patients with LHL.


Tailoring single chain polymer nanoparticle thermo-mechanical behavior by cross-link density.
Single chain polymer nanoparticles (SCPNs) are formed from intrachain cross-linking of a single polymer chain, making SCPN distinct from other polymer nanoparticles for which the shape is predefined before polymerization. The degree of cross-linking in large part determines the internal architecture of the SCPNs and therefore their mechanical and thermomechanical properties. Here, we use molecular dynamics (MD) simulations to study thermomechanical behavior of individual SCPNs with different underlying structures by varying the ratio of cross-linking and the degree of polymerization. We characterize the particles in terms of shape, structure, glass transition temperature, mobility, and stress response to compressive loading. The results indicate that the constituent monomers of SCPNs become less mobile as the degree of cross-linking is increased corresponding to lower diffusivity and higher stress at a given temperature.


Randomised controlled trials in overweight children: practicalities and realities.
To highlight and discuss the practical aspects of conducting high quality, randomised controlled trials (RCTs) with overweight and obese children and their families. Realistic considerations and suggestions for researchers arising from the experiences of three Australian interventions in overweight/obese children are highlighted. The practical implications of key issues arising during this type of RCT include study design, obtaining ethical approval, choice of outcome measures, recruitment, working with families, impact and process evaluation, retention strategies, managing multi-site trials and data management. Interventions for overweight children and their families are challenging. Although there were some differences in the design and outcome measures among the three studies, there were many similarities. Multi-site trials, although more expensive than single-site trials, are advantageous in increasing sample size and external validity. Collectively we have developed strategies to address key problems in conducting RCTs, including the common challenges of recruitment, retention and working with families.


Noise-free normalized fringe patterns and local pixel transforms for strain extraction.
Noise reduction is one of the most exciting problems in automatic fringe processing. We propose a two-dimensional (2-D) envelope transform for normalization of fringe patterns, coupled with spin filtering, to construct so-called noise-free normalized fringe patterns. The 2-D envelope transform uses correct fringe intensity envelopes for normalization of fringe patterns, i.e., for making the fringe background and amplitude constant over the whole field. Spin filtering is applied to fringe patterns for removal of random noise taking into account fringe flow. With spin filtering and the 2-D envelope transform, a noise-free normalized fringe pattern is constructed for postprocessing. Based on this improved fringe pattern, two local pixel transforms for strain extraction from a single moiré pattern are developed, in which the digital pure secondary moiré method is improved and the strain-field image method with division is developed.