Elastic bending modulus of single-layer molybdenum disulfide (MoS2): finite thickness effect.
We derive, from an empirical interaction potential, an analytic formula for the elastic bending modulus of single-layer MoS2 (SLMoS2). By using this approach, we do not need to define or estimate a thickness value for SLMoS2, which is important due to the substantial controversy in defining this value for two-dimensional or ultrathin nanostructures such as graphene and nanotubes. The obtained elastic bending modulus of 9.61 eV in SLMoS2 is significantly higher than the bending modulus of 1.4 eV in graphene, and is found to be within the range of values that are obtained using thin shell theory with experimentally obtained values for the elastic constants of SLMoS2. This increase in bending modulus as compared to monolayer graphene is attributed, through our analytic expression, to the finite thickness of SLMoS2. Specifically, while each monolayer of S atoms contributes 1.75 eV to the bending modulus, which is similar to the 1.4 eV bending modulus of monolayer graphene, the additional pairwise and angular interactions between out of plane Mo and S atoms contribute 5.84 eV to the bending modulus of SLMoS2.


Advances in understanding the urine-concentrating mechanism.
The renal medulla produces concentrated urine through the generation of an osmotic gradient that progressively increases from the cortico-medullary boundary to the inner medullary tip. In the outer medulla, the osmolality gradient arises principally from vigorous active transport of NaCl, without accompanying water, from the thick ascending limbs of short- and long-looped nephrons. In the inner medulla, the source of the osmotic gradient has not been identified. Recently, there have been important advances in our understanding of key components of the urine-concentrating mechanism, including (a) better understanding of the regulation of water, urea, and sodium transport proteins; (b) better resolution of the anatomical relationships in the medulla; and (c) improvements in mathematical modeling of the urine-concentrating mechanism. Continued experimental investigation of signaling pathways regulating transepithelial transport, both in normal animals and in knockout mice, and incorporation of the resulting information into mathematical simulations may help to more fully elucidate the mechanism for concentrating urine in the inner medulla.


Virological investigation of four outbreaks of influenza B reassortants in the northern region of Taiwan from October 2006 to February 2007.
From October 2006 to February 2007, clinical specimens from 452 patients with symptoms related to respiratory tract infection in the northern region of Taiwan were collected. Real-time PCR and direct immunofluorescent antibody tests showed that 145 (32%) patients had influenza B virus infections. Subsequently, nucleotide sequence analyses of both hemagglutinin (HA) and neuraminidase (NA) genes of 39 isolates were performed. Isolated viruses were antigenically characterized using hemagglutinin inhibition (HI) test. Phylogenetic tree analysis showed that all the isolates belonged to the B reassortant lineage with HA gene belonged to the B/Victoria/2/87 lineage and the NA gene belonged to the B/Yamagata/16/88 lineage. In addition, a group of children aged between 6 to 8 years old resided in Yilan county were infected with a variant strain. Hemagglutinin inhibition (HI) tests confirmed that all the reassortant influenza B viruses were B/Malaysia/2506/04-like viruses. Pre- and post-immunized serum samples from 4 normal volunteers inoculated with 2007 influenza vaccine were evaluated for their HI activity on 6 reassortant B isolates including two variants that we found in the Yilan county. The results demonstrated that after vaccination, all four vaccinees had at least 4-fold increases of their HI titers. The results indicate that the 2006-2007 seasonal influenza vaccine was effective in stimulating protective immunity against the influenza B variants identified in Yilan county. Continuous surveillance of emerging influenza B variants in the northern region of Taiwan is important for the selection of proper vaccine candidate in the future.


Molecular epidemiology of group A rotaviruses in water sources and selected raw vegetables in southern Africa.
Group A rotaviruses (RVs) are the most important cause of acute viral gastroenteritis in infants and young children. In this study raw and treated drinking water supplies at plants in two geographic areas, as well as selected irrigation water and corresponding raw vegetables in three regions of southern Africa, were screened for the presence of RVs using molecular techniques. Group A RVs were detected in 11.8% of partially treated and 1.7% of finally treated drinking water samples and in 14% of irrigation water samples and 1.7% of corresponding raw vegetable samples. Type-specific reverse transcriptase-PCR and sequence analysis revealed the presence of multiple types (G1, G2, G8, and G9) in irrigation water and single types (G1 or G3) in raw and treated drinking water. Group A RVs detected in all samples consisted of mixed P types (P[4], P[6], P[8], and P[9]), with P[6] predominating. The detection of types G8, G9, and P[6] reflects the emergence of these types in clinical infections. The similarity of environmental types to those in patients with clinical RV infections confirms the value of wastewater screening as a tool for assessing RVs circulating in communities, with the benefit of detecting types that cause both clinical and subclinical infections. The results provide new information on RV types in water and related environments and identify the potential risk of waterborne transmission. In addition, the presence of RVs in drinking water underlines shortcomings in quality specifications. These data provide valuable information regarding the prevalence of RVs in environmental sources, with important implications for vaccine development.


Early Antiretroviral Therapy at High CD4 Counts Does Not Improve Arterial Elasticity: A Substudy of the Strategic Timing of AntiRetroviral Treatment (START) Trial.
Both human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) may increase cardiovascular disease (CVD) risk. Vascular function assessments can be used to study CVD pathogenesis. We compared the effect of immediate versus deferred ART initiation at CD4 counts >500 cells/mm3 on small arterial elasticity (SAE) and large artery elasticity (LAE). Radial artery blood pressure waveforms were recorded noninvasively. Small arterial elasticity and LAE were derived from analysis of the diastolic pulse waveform. Randomized treatment groups were compared with linear models at each visit and longitudinal mixed models. Study visits involved 332 participants in 8 countries: mean (standard deviation [SD]) age 35 (10), 70% male, 66% nonwhite, 30% smokers, and median CD4 count 625 cells/mm3 and 10-year Framingham risk score for CVD 1.7%. Mean (SD) SAE and LAE values at baseline were 7.3 (2.9) mL/mmHg × 100 and 16.6 (4.1) mL/mmHg × 10, respectively. Median time on ART was 47 and 12 months in the immediate and deferred ART groups, respectively. The treatment groups did not demonstrate significant within-person changes in SAE or LAE during the follow-up period, and there was no difference in mean change from baseline between treatment groups. The lack of significant differences persisted after adjustment, when restricted to early or late changes, after censoring participants in deferred group who started ART, and among subgroups defined by CVD and HIV risk factors. Among a diverse global population of HIV-positive persons with high CD4 counts, these randomized data suggest that ART treatment does not have a substantial influence on vascular function among younger HIV-positive individuals with preserved immunity.


Antenatal care in practice: an exploratory study in antenatal care clinics in the Kilombero Valley, south-eastern Tanzania.
The potential of antenatal care for reducing maternal morbidity and improving newborn survival and health is widely acknowledged. Yet there are worrying gaps in knowledge of the quality of antenatal care provided in Tanzania. In particular, determinants of health workers' performance have not yet been fully understood. This paper uses ethnographic methods to document health workers' antenatal care practices with reference to the national Focused Antenatal Care guidelines and identifies factors influencing health workers' performance. Potential implications for improving antenatal care provision in Tanzania are discussed. Combining different qualitative techniques, we studied health workers' antenatal care practices in four public antenatal care clinics in the Kilombero Valley, south-eastern Tanzania. A total of 36 antenatal care consultations were observed and compared with the Focused Antenatal Care guidelines. Participant observation, informal discussions and in-depth interviews with the staff helped to identify and explain health workers' practices and contextual factors influencing antenatal care provision. The delivery of antenatal care services to pregnant women at the selected antenatal care clinics varied widely. Some services that are recommended by the Focused Antenatal Care guidelines were given to all women while other services were not delivered at all. Factors influencing health workers' practices were poor implementation of the Focused Antenatal Care guidelines, lack of trained staff and absenteeism, supply shortages and use of working tools that are not consistent with the Focused Antenatal Care guidelines. Health workers react to difficult working conditions by developing informal practices as coping strategies or "street-level bureaucracy". Efforts to improve antenatal care should address shortages of trained staff through expanding training opportunities, including health worker cadres with little pre-service training. Attention should be paid to the identification of informal practices resulting from individual coping strategies and "street-level bureaucracy" in order to tackle problems before they become part of the organizational culture.


The Effect of Sitagliptin on Lipid Metabolism of Fatty Liver Mice and Related Mechanisms.
BACKGROUND In clinics, patients with type 2 diabetes complicated with non-alcoholic fatty liver disease (NAFLD) have been shown to receive significant improvements in blood glucose levels, lipid levels, and liver function after sitagliptin treatment, although the mechanism of drug action remains poorly understood. This study investigated the possible mechanism of sitagliptin on lipid metabolism of NAFLD mice. MATERIAL AND METHODS Male C57/BL6 mice were induced for NAFLD via 16 weeks of a high-fat diet, and were treated with 15 mg/kg/day sitagliptin for 16 consecutive weeks. Blood lipid levels were measured and samples were stained with hematoxylin and eosin (H&E) and oil red staining for liver pathology and lipid deposition. Serum levels of fibroblast growth factor (FGF)-9 and FGF-21 were quantified by enzyme-linked immunosorbent assay (ELISA). Peroxisome proliferator-activated receptor (PPAR)-α, and cAMP reactive element binding homolog (CREBH) were measured by Western blotting, while fatty acid synthase and carnitine palmitoyltransferase 1 (CPT1) mRNA levels were assayed by RT-PCR. RESULTS Compared to the control group, the NAFLD model mice had liver fatty disease, lower serum FGF-21 and FGF-19 levels, elevated serum lipid levels, depressed PPAR-α, CREBH, and CPT1 expression, and enhanced FAS expression (p<0.05). Sitagliptin treatment depressed blood lipid levels, increased serum FGF-21 and FGF-19 levels, PPAR-α, CREBH, and CPT1 expression, and suppressed FAS expression (p<0.05). CONCLUSIONS Sitagliptin can protect liver tissue and modulate lipid metabolism in NAFLD mice via elevating FGF-21 and FGF-19, upregulating liver PPAR-a and CREBH levels, and mediating expression levels of key enzymes for lipid metabolism.


Reassessing SERS enhancement factors: using thermodynamics to drive substrate design.
Over the past 40 years fundamental and application research into Surface-Enhanced Raman Scattering (SERS) has been explored by academia, industry, and government laboratories. To date however, SERS has achieved little commercial success as an analytical technique. Researchers are tackling a variety of paths to help break through the commercial barrier by addressing the reproducibility in both the SERS substrates and SERS signals as well as continuing to explore the underlying mechanisms. To this end, investigators use a variety of methodologies, typically studying strongly binding analytes such as aromatic thiols and azarenes, and report SERS enhancement factor calculations. However a drawback of the traditional SERS enhancement factor calculation is that it does not yield enough information to understand substrate reproducibility, application potential with another analyte, or the driving factors behind the molecule-metal interaction. Our work at the US Army Edgewood Chemical Biological Center has focused on these questions and we have shown that thermodynamic principles play a key role in the SERS response and are an essential factor in future designs of substrates and applications. This work will discuss the advantages and disadvantages of various experimental techniques used to report SERS enhancement with planar SERS substrates and present our alternative SERS enhancement value. We will report on three types of analysis scenarios that all yield different information concerning the effectiveness of the SERS substrate, practical application of the substrate, and finally the thermodynamic properties of the substrate. We believe that through this work a greater understanding for designing substrates will be achieved, one that is based on both thermodynamic and plasmonic properties as opposed to just plasmonic properties. This new understanding and potential change in substrate design will enable more applications for SERS based methodologies including targeting molecules that are traditionally not easily detected with SERS due to the perceived weak molecule-metal interaction of substrates.


Quantifying low birth weight, preterm birth and small-for-gestational-age effects of malaria in pregnancy: a population cohort study.
The association between malaria during pregnancy and low birth weight (LBW) is well described. This manuscript aims to quantify the relative contribution of malaria to small-for-gestational-age (SGA) infants and preterm birth (PTB) in pregnancies accurately dated by ultrasound on the Thai-Myanmar border at the Shoklo Malaria Research Unit. From 2001 to 2010 in a population cohort of prospectively followed pregnancies, we analyzed all singleton newborns who were live born, normal, weighed in the first hour of life and with a gestational age (GA) between 28+0 and 41+6 weeks. Fractional polynomial regression was used to determine the mean birthweight and standard deviation as functions of GA. Risk differences and factors of LBW and SGA were studied across the range of GA for malaria and non-malaria pregnancies. From 10,264 newborns records, population centiles were created. Women were screened for malaria by microscopy a median of 22 [range 1-38] times and it was detected and treated in 12.6% (1,292) of pregnancies. Malaria was associated with LBW, PTB, and SGA compared to those without malaria. Nearly two-thirds of PTB were classified as LBW (68% (539/789)), most of which 83% (447/539) were not SGA. After GA 39 weeks, 5% (298/5,966) of non-LBW births were identified as SGA. Low body mass index, primigravida, hypertension, smoking and female sex of the newborn were also significantly and independently associated with LBW and SGA consistent with previous publications. Treated malaria in pregnancy was associated with an increased risk for LBW, PTB, and SGA, of which the latter are most important for infant survival. Using LBW as an endpoint without adjusting for GA incorrectly estimated the effects of malaria in pregnancy. Ultrasound should be used for dating pregnancies and birth weights should be expressed as a function (or adjusted for GA) of GA in future malaria in pregnancy studies.


Ionizing radiation-induced micronucleus formation is mediated by reactive oxygen species that are produced in a manner dependent on mitochondria, Nox1, and JNK.
Ionizing radiation (IR) is known to induce genotoxic damage to DNA, chromosomes, and the nucleus. However, the damage that IR causes to the nucleus has received much less attention. Given that reactive oxygen species (ROS) are involved in IR-induced DNA breaks and chromosomal aberrations, this study examined the role of ROS in IR-induced damage to the nucleus. Human Jurkat T cells were irradiated with gamma-rays at a dose of 2.5 Gy, which resulted in a dramatic increase in both the cellular ROS levels and the number of micronuclei. This latter event was attenuated when the IR-induced ROS were eliminated through the exogenous application of an antioxidant enzyme catalase. The ability of IR to induce the accumulation of ROS and micronucleus formation was also reduced either when the cells were irradiated in the presence of rotenone, a mitochondrial respiratory chain inhibitor, or when the cellular Nox1 levels were reduced by RNA interference. These results suggest that IR stimulates both the mitochondria and Nox1 to produce ROS, and that these ROS are involved in the IR-induced formation of micronuclei. IR also activated c-Jun N-terminal kinase (JNK), which was reversed by catalase, rotenone, or Nox1 RNA interference. SP600125, a JNK-specific inhibitor, suppressed the IR-induced accumulation of ROS. This inhibitor consistently attenuated the IR-induced formation of micronuclei. Therefore, ROS and JNK appear to act in a positive mutual manner in IR-induced signaling processes. Overall, IR appears to induce the formation of micronuclei by inducing ROS through mitochondria, Nox1, and JNK.


Hierarchical mutual information for the comparison of hierarchical community structures in complex networks.
The quest for a quantitative characterization of community and modular structure of complex networks produced a variety of methods and algorithms to classify different networks. However, it is not clear if such methods provide consistent, robust, and meaningful results when considering hierarchies as a whole. Part of the problem is the lack of a similarity measure for the comparison of hierarchical community structures. In this work we give a contribution by introducing the hierarchical mutual information, which is a generalization of the traditional mutual information and makes it possible to compare hierarchical partitions and hierarchical community structures. The normalized version of the hierarchical mutual information should behave analogously to the traditional normalized mutual information. Here the correct behavior of the hierarchical mutual information is corroborated on an extensive battery of numerical experiments. The experiments are performed on artificial hierarchies and on the hierarchical community structure of artificial and empirical networks. Furthermore, the experiments illustrate some of the practical applications of the hierarchical mutual information, namely the comparison of different community detection methods and the study of the consistency, robustness, and temporal evolution of the hierarchical modular structure of networks.


Testing adhesion of direct restoratives to dental hard tissue - a review.
This articles concerns itself with the testing of adhesion between direct restoratives and dental hard tissue, ie, enamel and dentin. The aim is to survey available methods for adhesion testing and influential parameters affecting experimental outcome. The testing of adhesion to indirect restorative materials, eg, ceramics and metals, is beyond the scope of this article and shall be discussed elsewhere. The longevity and success of modern dental restorations very often relies on potent dental adhesives to provide durable bonds between the dental hard substance and the restorative composite. To predict the clinical outcome of such restorative treatment, a large variety of in vitro laboratory tests and clinical in vivo experiments have been devised, analyzed, and published. The purpose of this review is to provide a current overview of bond strength testing methods and their applicability to the characterization of dental adhesives. Regardless of the method employed, subtle variations in sample preparation may already severely impact test results, usually necessitating at least co-testing of a well-known internal reference to allow conclusive interpretation. This article attempts to list and discuss the most influential parameters, such as substrate nature, age, health status, storage, clinically relevant pre-treatment, and sample preparation. Special attention is devoted to the last aspect, as numerous publications have stressed the tremendous influence of preparatory parameters on the validity and scope of obtained data. Added to the large variety of such factors, an equally large diversity of load-applying procedures exists to actually quantify adhesion between composites and dental hard substance. This article summarizes the basics of macro and micro approaches to shear and tensile bond strength testing, as well as push- and pull-out tests. The strengths and weaknesses inherent to each method and influential test parameters are reviewed and methods for accelerated sample aging and simulation of clinical conditions presented. Alternatively to shear or tensile bond strength tests, fracture toughness is introduced together with its application to dental adhesives and an overview of its physical background.


From graphene to silicon carbide: ultrathin silicon carbide flakes.
This study presents a new ultrathin SiC structure prepared by a catalyst free carbothermal method and post-sonication process. We have found that merging ultra-light 3D graphene foam and SiO together at high temperature leads to the formation of a complex SiC structure consisting of 3D SiC foam covered with traditional 1D nanowires. Upon breaking off, the 3D SiC was confirmed to be made from 2D nanosheets. The resulting novel 2D SiC nanosheets/nanoflakes were thoroughly investigated by using optical microscope, SEM, EDS, TEM, STEM, AFM, and Raman, which verified the highly crystallised structure feature. AFM results revealed an average thickness of 2-3 nm and average size of 2 μm for the flakes. This new SiC structure could not only actualise SiC usage for nano-electronic devices but is also expected to open new applications as well.


Antitumour effects of Yangzheng Xiaoji in human osteosarcoma: the pivotal role of focal adhesion kinase signalling.
The present study examined, in vitro and in vivo, the potential antitumour effects of Yangzheng Xiaoji (YZXJ), a traditional Chinese medical formula used in cancer treatment, on osteosarcoma, a tumour type recently found to be sensitive to YZXJ. The human osteosarcoma cell line MG63 was used in cell-matrix adhesion and cell growth assays. The same cell line was used in an in vivo tumour model by establishing subcutaneous osteosarcoma xenografts. Oral and intraperitoneal routes were used to deliver the YZXJ extract. The effect of YZXJ on the activation of focal adhesion kinase (FAK) and paxillin was evaluated by immunofluorescence methods. It was found that YZXJ exhibited a significant inhibitory effect on cell-matrix adhesion as demonstrated by a cell-based assay and electric cell-substrate impedance sensing (ECIS) analysis. The effect was observed together with a reduction in phospho-FAK and phospho-paxillin in the cells when treated with YZXJ. In the in vivo tumour model, YZXJ was found to significantly inhibit the growth of osteosarcoma with a sustained effect observed when YZXJ was delivered intraperitoneally. YZXJ sensitized cells to the effect of FAK inhibitor in vitro and in vivo. It is concluded that Yangzheng Xiaoji plays a significant role in cell-matrix adhesion and tumour growth, likely by inhibiting the activation of the FAK pathway. The therapeutic role of Yangzheng Xiaoji in osteosarcoma warrants further investigation.


The waveform fluctuation and the clinical factors of the initial and sustained erythropoietic response to continuous erythropoietin receptor activator in hemodialysis patients.
Erythropoiesis-stimulating agents (ESA) are the main treatment for anemia in hemodialysis (HD) patients. We evaluated factors determining the response after treatment of a new ESA (continuous erythropoietin erythropoietin receptor activator (CERA)). 61 HD patients were classified by their response at two different timings. First, patients whose hematocrit (Hct) increased 1.5% in the first week were defined as initial responders (IR, n = 16). We compared several parameters between IR and the rest of the study subjects (non-IR, n = 45). Second, patients whose Hct increased 2% in the 4th week were defined as sustained responders (SR, n = 12), and we did a similar comparison. The Hct showed a waveform fluctuation. Compared with the rest, IR had significantly lower platelet counts and higher levels of ferritin, total protein, total bilirubin, and serum sodium, while SR had significantly lower levels of C-reactive protein and low-density lipoprotein (All P < 0.05). In comparison with the rest, higher Hct persisted for 10 weeks in SR but only for two separate weeks (the 1st and 7th week) in IR. The initial and sustained erythropoietic responses are independent from each other and are associated with different factors. Treatment focusing on these factors may improve the response.


Role of endothelial nitric oxide synthase in aggravation of indomethacin-induced gastric damage in adjuvant arthritic rats.
The role of nitric oxide synthase (NOS) isozymes in the aggravation of indomethacin-induced gastric damage in adjuvant arthritic rats was investigated. Two weeks after injection of Freund's complete adjuvant, the animals were given indomethacin, and the stomach was examined for damage 4 h later. Indomethacin caused hemorrhagic lesions in the normal rat stomach, and these lesions were markedly aggravated in arthritic rats. Pretreatment with L-NAME (a nonselective inhibitor of NOS) and aminoguanidine (a relative selective inhibitor of iNOS) did not affect the ulcerogenic response in normal rats but dose-dependently prevented the aggravation of lesions in arthritic rats, but the effect of aminoguanidine was apparently less than that of L-NAME. The increased ulcerogenic response in arthritic rats was significantly suppressed by 1400 W (a selective inhibitor of iNOS) and L-NIO (a selective inhibitor of eNOS) but not by L-NPA (a selective inhibitor of nNOS). The concurrent administration of 1400 W and L-NIO almost totally abolished the aggravation of damage in arthritic rats. The expressions of eNOS and iNOS but not nNOS in the gastric mucosa were clearly enhanced in arthritic rats. Mucosal levels of non-protein sulfhydryls were significantly lower in arthritic rats than those in normal rats. The aggravation of damage in arthritic rats was significantly prevented by glutathione. These results suggest that the increased ulcerogenic response to indomethacin in arthritic rat stomachs is mediated by NO derived from eNOS in addition to iNOS. It is assumed that eNOS/NO may act harmfully on the gastric mucosa of arthritic rats with mucosal SH deficiency.


Effect of Puumala hantavirus infection on human umbilical vein endothelial cell hemostatic function: platelet interactions, increased tissue factor expression and fibrinolysis regulator release.
Puumala virus (PUUV) infection causes over 5000 cases of hemorrhagic fever in Europe annually and can influence the hemostatic balance extensively. Infection might lead to hemorrhage, while a recent study showed an increased risk of myocardial infarction during or shortly after PUUV infection. The mechanism by which this hantavirus influences the coagulation system remains unknown. Therefore we aimed to elucidate mechanisms explaining alterations seen in primary and secondary hemostasis during PUUV infection. By using low passage PUUV isolates to infect primary human umbilical vein endothelial cells (HUVECs) we were able to show alterations in the regulation of primary- and secondary hemostasis and in the release of fibrinolysis regulators. Our main finding was an activation of secondary hemostasis due to increased tissue factor (TF) expression leading to increased thrombin generation in a functional assay. Furthermore, we showed that during infection platelets adhered to HUVEC and subsequently specifically to PUUV virus particles. Infection of HUVEC with PUUV did not result in increased von Willebrand factor while they produced more plasminogen activator inhibitor type-1 (PAI-1) compared to controls. The PAI-1 produced in this model formed complexes with vitronectin. This is the first report that reveals a potential mechanism behind the pro-coagulant changes in PUUV patients, which could be the result of increased thrombin generation due to an increased TF expression on endothelial cells during infection. Furthermore, we provide insight into the contribution of endothelial cell responses regarding hemostasis in PUUV pathogenesis.


Antipsychotic prescription and mortality in hospitalized older persons.
Recent scientific reports have shown that older persons treated with antipsychotics for dementia-related behavioural symptoms have increased mortality. However, the impact of these drugs prescribed during hospitalization has rarely been assessed. We aimed to investigate whether antipsychotics are associated with an increased risk of mortality during hospitalization and at 3-month follow-up in elderly inpatients. We analyzed data gathered during two waves (2010 and 2012) by the REPOSI (Registro Politerapie Società Italiana Medicina Interna). All new prescriptions of antipsychotic drugs during hospitalization, whether maintained or discontinued at discharge, were collected, and logistic regression models were used to analyze their association with in-hospital and 3-month mortality. Covariates were age, sex, the Short Blessed Test (SBT) score, and the Cumulative Illness Rating Scale. Among 2703 patients included in the study, 135 (5%) received new prescriptions for antipsychotic drugs. The most frequently prescribed antipsychotic during hospitalization and eventually maintained at discharge was haloperidol (38% and 36% of cases, respectively). Patients newly prescribed with antipsychotics were older and had a higher Cumulative Illness Rating Scale comorbidity index both at admission and at discharge compared to those who did not receive a prescription. Of those prescribed antipsychotics, 71% had an SBT score ≥10 (indicative of dementia), 12% had an SBT score of 5-9 (indicative of questionable dementia); and 17% had an SBT score <5 (indicative of normal cognition). In-hospital mortality was slightly higher in patients prescribed antipsychotic drugs (14.3% vs 9.4%; P = 0.109), but in multivariate analysis only male sex, older age, and higher SBT scores were significantly related to mortality during hospitalization. At 3-month follow-up, only male sex, older age, and higher SBT scores were associated with mortality. We found that the prescription of antipsychotic drugs during hospitalization was not associated with in-hospital or follow-up mortality. Short-term antipsychotic prescriptions (for acutely ill patients) may have a different effect than long-term, repeated prescriptions.


Malignant transformation in chronic osteomyelitis: recognition and principles of management.
Malignant transformation as a result of chronic osteomyelitis represents a relatively rare and late complication with a declining incidence in the modern world. For most patients, the interval between the occurrence of the original bacterial infection and the transformation to malignant degeneration is several years. The diagnosis of malignant transformation in a chronic discharging sinus requires a high index of clinical suspicion. Wound biopsies should be obtained early, especially with the onset of new clinical signs such as increased pain, a foul smell, and changes in wound drainage. Squamous cell carcinoma is the most common presenting malignancy. Definitive treatment is amputation proximal to the tumor or wide local excision, combined with adjuvant chemotherapy and radiation therapy in selected patients. Early diagnosis may sometimes allow for treatment consisting of en bloc excision and limb salvage techniques. However, the most effective treatment is prevention with definitive treatment of the osteomyelitis, including adequate débridement, wide excision of the affected area, and early reconstruction.


N-acetyl-6-hydroxytryptophan oxidase, a developmentally controlled phenol oxidase from Aspergillus nidulans.
We have purified a specific phenol oxidase which is produced during conidiophore development in the fungus Aspergillus nidulans. Two active forms (A and B) have molecular masses of 50 and 48 kDa respectively; they have identical N-termini (24 residues). We have analysed the metal ion content of the B form; it is unusual in consisting of one zinc and two copper atoms per molecule. A temperature-sensitive mutant (ivoB192) produces a thermolabile enzyme, implying that ivoB is the structural locus. The natural substrate of the enzyme is N-acetyl-6-hydroxytryptophan, but it can be assayed colorimetrically or polarographically using hydroquinone monomethyl ether (HME) as substrate. It will also oxidize p-cresol, but not tyrosine, 3,4-dihydroxyphenylalanine or o-methoxyphenol. Colour development with HME substrate is strongly enhanced by high ammonium ion concentrations. Activity against HME is inhibited by 2,3-dihydroxynaphthalene, phenylhydrazine, diethyl dithiocarbamate and 8-hydroxyquinolene.


Abdominal obesity, gender and the risk of rheumatoid arthritis - a nested case-control study.
The risk of development of rheumatoid arthritis (RA) could be affected by immune activation in obesity. Our objective was to evaluate the association between obesity in general, and abdominal obesity, and the risk for subsequent development of RA. In two large population-based, prospective cohorts, 557 cases (mean age at RA symptom onset 58, SD 10 years, 68% women) who subsequently developed RA and 1671 matched controls were identified. From a health examination antedating symptom onset (median 5.5 years), collected data on body mass index (BMI; kg/m2), smoking habits, and educational level was used in conditional logistical regression models. Corresponding regression models were used to analyse the association between waist circumference measurements (cm) and RA development in a subset of the population. BMI and waist circumference were associated with the risk of RA development, adjusted odds ratio (OR) (95% CI), 1.13 (1.00, 1.28) per 5 kg/m2, and 1.02 (1.01, 1.04) per cm, respectively. An association was also observed for obesity (BMI ≥30) OR 1.45 (1.07, 1.95), compared with BMI <25. After stratification for sex the associations were enhanced in men, and attenuated in women. Among men with BMI above normal a 3-5 times increased risk for RA disease development at 50 years of age or earlier was observed. Abdominal obesity with waist circumference >102 cm was associated with a 2-3 times increased risk of RA, but not abdominal obesity (>88 cm) in women. Obesity or abdominal obesity, respectively, was independently associated with a modest increase of the risk for subsequent development of RA. This appeared to be relevant mainly for early RA disease onset among men.


I. EXECUTIVE CONTROL IN EARLY CHILDHOOD.
Executive control (EC) is a central construct in developmental science, although measurement limitations have hindered understanding of its nature and development in young children, relation to social risk, and prediction of important outcomes. Disentangling EC from the foundational cognitive abilities it regulates and that are inherently required for successful executive task completion (e.g., language, visual/spatial perception, and motor abilities) is particularly challenging at preschool age, when these foundational abilities are still developing and consequently differ substantially among children. A novel latent bifactor modeling approach delineated respective EC and foundational cognitive abilities components that undergird executive task performance in a socio demographically stratified sample of 388 preschoolers in a longitudinal, cohort-sequential study. The bifactor model revealed a developmental shift, where both EC and foundational cognitive abilities contributed uniquely to executive task performance at ages 4.5 and 5.25 years, but were not separable at ages 3 and 3.75. Contrary to the view that EC is vulnerable to socio-familial risk, the contributions of household financial and learning resources to executive task performance were not specific to EC but were via their relation to foundational cognitive abilities. EC, though, showed a unique, discriminant relation with hyperactive symptoms late in the preschool period, whereas foundational cognitive abilities did not predict specific dimensions of dysregulated behavior. These findings form the basis for a new, integrated approach to the measurement and conceptualization of EC, which includes dual consideration of the contributions of EC and foundational cognitive abilities to executive task performance, particularly in the developmental context of preschool.


Actual position of interleukin(IL)-33 in atherosclerosis and heart failure: Great Expectations or En attendant Godot?
Atherosclerosis has been recognized as an inflammatory/autoimmune disease. The long-standing low-grade inflammation which fuels its development is primarily focused on the components of the vessel wall. Originally, inflammation in atherogenesis was supposed to be driven by the pro-inflammatory Th1 cellular and cytokine immune response. On the basis of accumulating evidence, this view has been re-evaluated to include the Th17/Th1 axis which is shared by most diseases of sterile inflammation. The anti-inflammatory Th2 cellular and cytokine immune response is initiated concomitantly with the former two, the latter dampening their harmful reactions which culminate in full-blown atherosclerosis. Interleukin-33, a novel member of the IL-1 cytokine superfamily, was suggested to take part in the anti-atherogenic response by mediating the Th1-to-Th2 switch of the immune reactions. However, IL-33 is a multifaceted mediator with both pro- and anti-inflammatory activities, also called a "dual factor" or a "Janus face" interleukin. IL-33 occurs both in an extracellular (cytokine-like) and in a nuclear-bound (transcription factor-like) form, each of them performing distinct activities of their own. This review article presents the latest data relevant to IL-33's role in atherosclerosis and cardiac diseases as perceived by a cardiologist and a cardiac surgeon.


68Ga-Chelation and comparative evaluation of N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) conjugated NGR and RGD peptides as tumor targeted molecular imaging probes.
Peptides containing RGD and NGR motifs display high affinity towards tumor vasculature molecular markers, integrin αvβ3 and CD13 receptors, respectively. In the present study, RGD and NGR peptides were conjugated with the novel acyclic chelator N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) for radiolabeling with 68Ga. The radiotracers [68Ga-HBED-CC-c(NGR)] and [68Ga-HBED-CC-c(RGD)] were quite hydrophilic with respective log P values being -2.8 ± 0.14 and -2.1 ± 0.17. 68Ga-HBED-CC-c(RGD) displayed a significantly higher (p < 0.05) uptake in murine melanoma B16F10 tumors as compared to 68Ga-HBED-CC-c(NGR) indicating its higher specificity towards integrin αvβ3-positive tumors. The two radiotracers showed similar uptake in CD13-positive human fibrosarcoma HT-1080 tumor xenografts (∼1.5 ± 0.2% ID g-1). The tumor uptake of the two radiotracers was significantly reduced (p < 0.05) in both animal models during blocking studies. The tumor-to-blood ratio was observed to be ∼2-2.5 for the two radiotracers, whereas the tumor-to-muscle ratio was significantly higher (p < 0.005) for 68Ga-HBED-CC-c(RGD) in the two animal models. The two radiotracers 68Ga-HBED-CC-c(NGR) and 68Ga-HBED-CC-c(RGD) exhibited renal excretion with rapid clearance from blood and other non-target organs. Thus, 68Ga-chelated HBED-CC conjugated NGR and RGD peptides expressed features conducive towards development as tumor targeted molecular imaging probes. This study further opens avenues for the successful conjugation of different peptides with the acyclic chelator HBED-CC and expansion of 68Ga-based radiopharmaceuticals.


Quantitative test of the barrier nucleosome model for statistical positioning of nucleosomes up- and downstream of transcription start sites.
The positions of nucleosomes in eukaryotic genomes determine which parts of the DNA sequence are readily accessible for regulatory proteins and which are not. Genome-wide maps of nucleosome positions have revealed a salient pattern around transcription start sites, involving a nucleosome-free region (NFR) flanked by a pronounced periodic pattern in the average nucleosome density. While the periodic pattern clearly reflects well-positioned nucleosomes, the positioning mechanism is less clear. A recent experimental study by Mavrich et al. argued that the pattern observed in Saccharomyces cerevisiae is qualitatively consistent with a "barrier nucleosome model," in which the oscillatory pattern is created by the statistical positioning mechanism of Kornberg and Stryer. On the other hand, there is clear evidence for intrinsic sequence preferences of nucleosomes, and it is unclear to what extent these sequence preferences affect the observed pattern. To test the barrier nucleosome model, we quantitatively analyze yeast nucleosome positioning data both up- and downstream from NFRs. Our analysis is based on the Tonks model of statistical physics which quantifies the interplay between the excluded-volume interaction of nucleosomes and their positional entropy. We find that although the typical patterns on the two sides of the NFR are different, they are both quantitatively described by the same physical model with the same parameters, but different boundary conditions. The inferred boundary conditions suggest that the first nucleosome downstream from the NFR (the +1 nucleosome) is typically directly positioned while the first nucleosome upstream is statistically positioned via a nucleosome-repelling DNA region. These boundary conditions, which can be locally encoded into the genome sequence, significantly shape the statistical distribution of nucleosomes over a range of up to approximately 1,000 bp to each side.


Automated 3D-printed unibody immunoarray for chemiluminescence detection of cancer biomarker proteins.
A low cost three-dimensional (3D) printed clear plastic microfluidic device was fabricated for fast, low cost automated protein detection. The unibody device features three reagent reservoirs, an efficient 3D network for passive mixing, and an optically transparent detection chamber housing a glass capture antibody array for measuring chemiluminescence output with a CCD camera. Sandwich type assays were built onto the glass arrays using a multi-labeled detection antibody-polyHRP (HRP = horseradish peroxidase). Total assay time was ∼30 min in a complete automated assay employing a programmable syringe pump so that the protocol required minimal operator intervention. The device was used for multiplexed detection of prostate cancer biomarker proteins prostate specific antigen (PSA) and platelet factor 4 (PF-4). Detection limits of 0.5 pg mL-1 were achieved for these proteins in diluted serum with log dynamic ranges of four orders of magnitude. Good accuracy vs. ELISA was validated by analyzing human serum samples. This prototype device holds good promise for further development as a point-of-care cancer diagnostics tool.


Does sentinel lymph node biopsy have a role in node-positive head and neck squamous carcinoma?
The objective of the study was to determine whether sentinel lymph node biopsy (SLNB) can be used to reduce clinical overstaging of cervical nodes in head and neck squamous cell carcinoma (SCC) in a developing world setting. Sentinel and echelon lymph nodes were identified by means of a combination of lymphoscintigraphy, gamma probe and blue dye identification. They were analysed histologically and their pathological status was compared with the rest of the neck dissection specimen to determine diagnostic accuracy in patients with T1-4 N0-3 SCC of the oral cavity or oropharynx undergoing primary surgical resection and neck dissection. Thirty-three patients were included in the study, 13 in the node-negative (N0) and 20 in the node-positive (N+) group. In the clinically N0 group the sensitivity of SLNB was 100% and the negative predictive value (NPV) 100%. In the clinically N+ group the sensitivity was 71% and the NPV 60% for staging the nodal status of the neck. CONCLUSIONS; The accuracy of SLNB in the clinically N+ neck is too low for SLNB to be a means of avoiding comprehensive neck dissection. 2B.


Exposure to butadiene and lymphatic and hematopoietic cancer.
Several follow-up studies have assessed lymphatic and hematopoietic cancer (LHC) among workers with potential exposure to 1,3-butadiene. These investigations of the styrene-butadiene rubber and butadiene manufacturing industries include 17,448 subjects with an average of 22 years of follow-up. When the results of the studies are combined, the total number of observed leukemia deaths is 36, compared with 34.2 expected. The standardized mortality ratio is 1.05, with a 95% confidence interval of 0.74-1.46. These null data are compatible with, at most, a weak positive association of butadiene with leukemia. There is little evidence of an association with other forms of LHC among styrene-butadiene rubber workers (55 observed/50.1 expected deaths). Only one study has evaluated directly the relation between estimates of butadiene exposure and leukemia, and this investigation reports a positive association. The result, however, cannot be interpreted as causal, because there is no satisfactory explanation for the marked discrepancy between this case-control study and a null follow-up study based on the same subjects. Overall, the epidemiologic evidence does not provide persuasive evidence that butadiene exposure causes LHC.


Genetic mutations and somatic anomalies in association with 46,XY gonadal dysgenesis.
To assess genetic mutations and associated somatic anomalies in a series of patients with 46,XY gonadal dysgenesis (GD). Single center retrospective study. University pediatric hospital. Fourteen patients with 46,XY GD. None. Genotype-phenotype relationship. The presenting symptom was disorders of sex development (6 patients), primary amenorrhea (2 patients), discordance between 46,XY karyotype and female external genitalia (3 patients), discovery of Müllerian structures at surgery (2 patients), or diagnosed in the evaluation of a gonadal tumor (1 patient). Müllerian structures were shown by ultrasound evaluation in 7 of 13 patients, genitography in 3 of 6 patients and/or surgery in 8 of 10 patients (3 not seen at imaging), or only by histologic examination (1 patient). Three patients had gonadoblastoma and/or seminoma. A mutation was found in 7 patients of whom 2 had family history of reproductive problems and 5 had associated somatic anomalies. The mutations were FOG2/ZFPM2 (1 patient), SRY (2 patients), WT1 (1 patient), or deletions of distal chromosome 9p (3 patients). Among the three other patients with associated anomalies and no mutation, two had ectodermal dysplasia and one had leukemia. Mutations were observed in half of the patients with 46,XY GD with Müllerian structures. We also describe for the first time the association between GD and ectodermal dysplasia. Müllerian structures can be found in some cases only by histologic examination, which should be coupled to preventive gonadectomy because of the risk of tumor formation.


Development of an ex vivo retention model simulating bioadhesion in the oral cavity using human saliva and physiologically relevant irrigation media.
In recent years, there has been a particular interest in bioadhesive formulations for oromucosal drug delivery as this may promote prolonged local therapy and enhanced systemic effect. Saliva plays a vital role in oromucosal drug absorption by dissolving the drug and presenting it to the mucosal surface. However, the rheological, chemical, and interfacial properties of this complex biological fluid may strongly affect the adhesion of bioadhesive formulations. There is a need for well characterized in vitro models to assess the bioadhesive properties of oral dosage forms for administration in the oral cavity. Thus we aimed at developing an advanced ex vivo buccal retention model, with focus on choosing a physiologically relevant irrigation media closely resembling human saliva. Spray dried chitosan microparticles containing metformin hydrochloride as an example of a small hydrophilic drug, were employed as bioadhesive formulations. Chewing-stimulated human whole saliva was collected and characterized for use in retention studies in comparison with four artificial irrigation media; phosphate buffer, Saliva Orthana(®), porcine gastric mucin base media (PGM3), and xanthan gum based media (XG2). Retention of metformin, applied as spray dried microparticles on porcine buccal mucosa, greatly depended on the characteristics of the irrigation media. When rheology of the irrigation media was examined, changes in retention profiles could be interpreted, as irrigation media containing mucin and xanthan gum possessed a higher viscosity than phosphate buffer, which led to longer retention of the drug due to better hydration of the mucosa and the spray dried microparticles. Metformin retention profiles were comparable when human saliva, Saliva Orthana(®), or PGM3 were used as irrigation media. Moreover, PGM3 displayed physico-chemical properties closest to those of human saliva with regard to pH, protein content and surface tension. Saliva Orthana(®) and PGM3 are therefore considered as suitable irrigation media for further retention studies.


Escherichia coli cAMP receptor protein-DNA complexes. 1. Energetic contributions of half-sites and flanking sequences in DNA recognition.
In Escherichia coli, the cyclic AMP receptor protein (CRP) serves as a sensor of the intracellular level of cyclic AMP. At increasing concentrations of cyclic AMP, CRP becomes activated upon binding a cyclic AMP molecule. The activated CRP is capable of regulating the expression of more than 20 genes by binding to specific DNA sites. The specific DNA sequences recognized by CRP consist of two-half-sites of the consensus sequence TGTGA......XCAXA. At present, the relative contributions of the two half-site and flanking sequences in the energetics of CRP recognition have not been quantitatively defined. A series of 20 DNA sequences was designed to dissect the contributions of individual half-sites and flanking sequences using the natural gal P1 and lac P1 sequences as the initial targets. The binding of CRP to these DNA sequences was monitored by fluorescence anisotropy. None of the individual half-sites or flanking sequences contributes more to the binding energetics than a random sequence. In the lac P1 sequence, the combination of both half-sites leads to a >100-fold increase in affinity compared to that of an individual half-site in CRP-DNA complex formation. The flanking sequence of lac P1 exhibits a 10- and 0-fold enhancement in affinity for CRP compared to that of a random sequence in the presence and absence of the two half-sites, respectively. The observations of the gal P1 sequence differ from those of the lac P1 sequence. The combination of both half-sites exhibits no significant increase in affinity, but the flanking sequence exhibits a 100-fold enhancement in the presence of the two half-sites. However, there is a disproportionate contribution from the flanking sequence proximal to the conserved TGTGA motif. The total energetics of the gal-CRP complex formation is essentially due to the presence of the conserved half-site and its adjacent flanking sequence. Thus, the relative contributions of the half-site and flanking sequences to the energetics of DNA recognition are operon specific.


Low vitamin D levels are associated with atopic dermatitis, but not allergic rhinitis, asthma, or IgE sensitization, in the adult Korean population.
The effect of vitamin D on allergic conditions is unclear. In particular, large-scale, population-based studies examining this relationship in adult Asian populations are lacking. To evaluate the association between serum vitamin D levels and allergic conditions in the general adult Korean population. A cross-sectional study was performed by using data collected from 15,212 individuals 19 years or older who participated in the Korean National Health and Nutrition Examination Survey from 2008 to 2010. The confounder-adjusted mean serum 25-hydroxyvitamin D (25[OH]D) levels of participants with and without allergic conditions (including atopic dermatitis, asthma, allergic rhinitis, and increased total and allergen-specific serum IgE) were compared by using multiple linear regression analyses. Multiple logistic regression analyses with confounder adjustment estimated the odds ratios (ORs) for developing each condition according to adequate, inadequate, or deficient serum 25(OH)D levels. After adjusting for potential confounders, mean serum 25(OH)D levels were significantly lower in participants diagnosed with atopic dermatitis than in those without this diagnosis (mean ± SE, 18.58 ± 0.29 ng/mL vs 19.20 ± 0.15 ng/mL; P = .02). Compared with participants with adequate vitamin D levels (≥20 ng/mL), confounder-adjusted ORs of atopic dermatitis were significantly higher in those with inadequate (12-19.99 ng/mL) or deficient (<12 ng/mL) levels (OR [95% CI], 1.50 [1.10-2.06] and 1.48 [1.04-2.12], respectively; P = .02). This relationship was not observed in participants with the other allergic conditions. Vitamin D-insufficient adult individuals within the general Korean population have an increased likelihood of atopic dermatitis, but not asthma, allergic rhinitis, or IgE sensitization.


Through the eyes of children: perceptions of environmental change in tropical forests.
This study seeks to understand children's perceptions of their present and future environments in the highly biodiverse and rapidly changing landscapes of Kalimantan, Indonesian Borneo. We analyzed drawings by children (target age 10-15 years) from 22 villages, which show how children perceive the present conditions of forests and wildlife surrounding their villages and how they expect conditions to change over the next 15 years. Analyses of picture elements and their relationships to current landscape variables indicate that children have a sophisticated understanding of their environment and how different environmental factors interact, either positively or negatively. Children appear to have landscape-dependent environmental perceptions, showing awareness of past environmental conditions and many aspects of recent trends, and translating these into predictions for future environmental conditions. The further removed their present landscape is from the originally forested one, the more environmental change they expect in the future, particularly declines in forest cover, rivers, animal diversity and increases in temperature and natural disasters. This suggests that loss of past perceptions and associated "shifting environmental baselines" do not feature strongly among children on Borneo, at least not for the perceptions we investigated here. Our findings that children have negative expectations of their future environmental conditions have important political implications. More than other generations, children have a stake in ensuring that future environmental conditions support their long-term well-being. Understanding what drives environmental views among children, and how they consider trade-offs between economic development and social and environmental change, should inform optimal policies on land use. Our study illuminates part of the complex interplay between perceptions of land cover and land use change. Capturing the views of children through artistic expressions provides a potentially powerful tool to influence public and political opinions, as well as a valuable approach for developing localized education and nature conservation programs.


Transitions in care for older adults with and without dementia.
To describe transitions in care of persons with dementia with attention to nursing facility transitions. Prospective cohort. Public health system. Four thousand one hundred ninety-seven community-dwelling older adults. Participants' electronic medical records were merged with Medicare claims, Medicaid claims, the Minimum Data Set (MDS), and the Outcome and Assessment Information Set (OASIS) from 2001 to 2008 with a mean follow-up of 5.2 years from the time of enrollment. Older adults with prevalent (n = 524) or incident (n = 999) dementia had greater Medicare (44.7% vs 44.8% vs 11.4%, P < .001) and Medicaid (21.0% vs 16.8% vs 1.4%, P < .001) nursing facility use, greater hospital (76.2% vs 86.0% vs 51.2%, P < .001) and home health (55.7% vs 65.2% vs 27.3%, P < .001) use, more transitions in care per person-year of follow-up (2.6 vs 2.7 vs 1.4, P < .001), and more mean total transitions (11.2 vs 9.2 vs 3.8, P < .001) than those who were never diagnosed (n = 2,674). For the 1,523 participants with dementia, 74.5% of transitions to nursing facilities were transfers from hospitals. For transitions from nursing facilities, the conditional probability was 41.0% for a return home without home health care, 10.7% for home health care, and 39.8% for a hospital transfer. Of participants with dementia with a rehospitalization within 30 days, 45% had been discharged to nursing facilities from the index hospitalization. At time of death, 46% of participants with dementia were at home, 35% were in the hospital, and 19% were in a nursing facility. Individuals with dementia live and frequently die in community settings. Nursing facilities are part of a dynamic network of care characterized by frequent transitions.


Chromatin structure, not DNA sequence specificity, is the primary determinant of topoisomerase II sites of action in vivo.
In the studies reported here we have used topoisomerase II as a model system for analyzing the factors that determine the sites of action for DNA-binding proteins in vivo. To localize topoisomerase II sites in vivo we used an inhibitor of the purified enzyme, the antitumor drug VM-26. This drug stabilizes an intermediate in the catalytic cycle, the cleavable complex, and substantially stimulates DNA cleavage by topoisomerase II. We show that lysis of VM-26 treated tissue culture cells with sodium dodecyl sulfate induces highly specific double-strand breaks in genomic DNA, and we present evidence indicating that these double-strand breaks are generated by topoisomerase II. Using indirect end labeling to map the cleavage products, we have examined the in vivo sites of action of topoisomerase II in the 87A7 heat shock locus, the histone repeat, and a tRNA gene cluster at 90BC. Our analysis reveals that chromatin structure, not sequence specificity, is the primary determinant in topoisomerase II site selection in vivo. We suggest that chromatin organization may provide a general mechanism for generating specificity in a wide range of DNA-protein interactions in vivo.


Integrated genomic profiling and modelling for risk stratification in patients with advanced oesophagogastric adenocarcinoma.
Prognosis of patients with advanced oesophagogastric adenocarcinoma (mEGAC) is poor and molecular determinants of shorter or longer overall survivors are lacking. Our objective was to identify molecular features and develop a prognostic model by profiling the genomic features of patients with mEGAC with widely varying outcomes. We profiled 40 untreated mEGACs (20 shorter survivors <13 months and 20 longer survivors >36 months) with whole-exome sequencing (WES) and RNA sequencing and performed an integrated analysis of exome, transcriptome, immune profile and pathological phenotypes to identify the molecular determinants, developing an integrated model for prognosis and comparison with The Cancer Genome Atlas (TCGA) cohorts. KMT2C alterations were exclusively observed in shorter survivors together with high level of intratumour heterogeneity and complex clonal architectures, whereas the APOBEC mutational signatures were significantly enriched in longer survivors. Notably, the loss of heterozygosity in chromosome 4 (Chr4) was associated with shorter survival and 'cold' immune phenotype characterised by decreased B, CD8, natural killer cells and interferon-gamma responses. Unsupervised transcriptomic clustering revealed a shorter survivor subtype with distinct expression features (eg, upregulated druggable targets JAK2, MAP3K13 and MECOM). An integrated model was then built based on clinical variables and the identified molecular determinants, which significantly segregated shorter and longer survivors. All the above features and the integrated model have been validated independently in multiple TCGA cohorts. This study discovered novel molecular features prognosticating overall survival in patients with mEGAC and identified potential novel targets in shorter survivors.


Enhancers, enhancers - from their discovery to today's universe of transcription enhancers.
Transcriptional enhancers are short (200-1500 base pairs) DNA segments that are able to dramatically boost transcription from the promoter of a target gene. Originally discovered in simian virus 40 (SV40), a small DNA virus, transcription enhancers were soon also found in immunoglobulin genes and other cellular genes as key determinants of cell-type-specific gene expression. Enhancers can exert their effect over long distances of thousands, even hundreds of thousands of base pairs, either from upstream, downstream, or from within a transcription unit. The number of enhancers in eukaryotic genomes correlates with the complexity of the organism; a typical mammalian gene is likely controlled by several enhancers to fine-tune its expression at different developmental stages, in different cell types and in response to different signaling cues. Here, I provide a personal account of how enhancers were discovered more than 30 years ago, and also address the amazing development of the field since then.


Economic impact of stable flies (Diptera: Muscidae) on dairy and beef cattle production.
Stable flies, Stomoxys calcitrans (L.), are among the most damaging arthropod pests of cattle worldwide. The last estimate of their economic impact on United States cattle production was published 20 yr ago and placed losses at $608 million. Subsequently, several studies of effects of stable flies on beef cattle weight gain and feed efficiency have been published, and stable flies have become increasingly recognized as pests of cattle on pasture and range. We analyzed published studies and developed yield-loss functions to relate stable fly infestation levels to cattle productivity, and then estimated the economic impact of stable flies on cattle production in the United States. Four industry sectors were considered: dairy, cow-calf, pastured stockers, and feeder cattle. In studies reporting stable fly infestation levels of individual herds, median annual per animal production losses were estimated to be 139 kg of milk for dairy cows, and 6, 26, and 9 kg body weight for preweanling calves, pastured stockers, and feeder cattle, respectively. The 200,000 stable flies emerging from an average sized winter hay feeding site reduce annual milk production of 50 dairy cows by an estimated 890 kg and weight gain of 50 preweanling calves, stockers, or feeder cattle by 58, 680, or 84 kg. In 2009 dollars, the value of these losses would be $254, $132, $1,279, or $154, respectively. Using cattle inventories and average prices for 2005-2009, and median monthly infestation levels, national losses are estimated to be $360 million for dairy cattle, $358 million for cow-calf herds, $1,268 million for pastured cattle, and $226 million for cattle on feed, for a total impact to U.S. cattle industries of $2,211 million per year. Excluded from these estimates are effects of stable flies on feed conversion efficiency, animal breeding success, and effects of infested cattle on pasture and water quality. Additional research on the effects of stable flies on high-production dairy cows and nursing beef calves is needed to increase the reliability of the estimates.


Suicide among patients with amyotrophic lateral sclerosis.
Studies on the suicide risk among patients with amyotrophic lateral sclerosis (ALS) in countries without legalized euthanasia or assisted suicide are important additions to data on the wish to die of these patients. We conducted a population-based cohort study in Sweden between 1965 and 2004, which comprised of 6,642 patients with incident ALS identified from the Swedish Inpatient Register. We calculated the standardized mortality ratios (SMRs) of suicide among the patients using the suicide rates of the general Swedish population as a reference. In total, 21 patients committed suicide during follow-up, compared to the predicted 3.6 suicides. Thus, we noted an almost 6-fold increased risk for suicide among ALS patients [SMR 5.8, 95% confidence interval (CI) 3.6-8.8]. Patients who committed suicide were, on average, around 7 years younger at the time of their first period of hospitalization than patients who did not commit suicide. The highest relative risk for suicide was observed within the first year after the patient's first period of hospitalization (SMR 11.2, 95% CI 5.8-19.6). After that, the relative risks decreased with time after hospitalization (P-value for trend = 0.006), but remained elevated 3 years later. The relative risks of suicide among ALS patients did not show a clear trend over time in contrast to the decreasing trend of relative risks for suicide among patients with cancer during the same period. Patients with ALS are at excess risk of suicide in Sweden and the relative risk is higher during the earlier stage of the disease.


Meta-analysis of crowdsourced data compendia suggests pan-disease transcriptional signatures of autoimmunity.
Background: The proliferation of publicly accessible large-scale biological data together with increasing availability of bioinformatics tools have the potential to transform biomedical research. Here we report a crowdsourcing Jamboree that explored whether a team of volunteer biologists without formal bioinformatics training could use OMiCC, a crowdsourcing web platform that facilitates the reuse and (meta-) analysis of public gene expression data, to compile and annotate gene expression data, and design comparisons between disease and control sample groups. Methods: The Jamboree focused on several common human autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), type I diabetes (DM1), and rheumatoid arthritis (RA), and the corresponding mouse models. Meta-analyses were performed in OMiCC using comparisons constructed by the participants to identify 1) gene expression signatures for each disease (disease versus healthy controls at the gene expression and biological pathway levels), 2) conserved signatures across all diseases within each species (pan-disease signatures), and 3) conserved signatures between species for each disease and across all diseases (cross-species signatures). Results: A large number of differentially expressed genes were identified for each disease based on meta-analysis, with observed overlap among diseases both within and across species. Gene set/pathway enrichment of upregulated genes suggested conserved signatures (e.g., interferon) across all human and mouse conditions. Conclusions: Our Jamboree exercise provides evidence that when enabled by appropriate tools, a "crowd" of biologists can work together to accelerate the pace by which the increasingly large amounts of public data can be reused and meta-analyzed for generating and testing hypotheses. Our encouraging experience suggests that a similar crowdsourcing approach can be used to explore other biological questions.


Genetic basis for expression of the major globotetraose-containing lipopolysaccharide from H. influenzae strain Rd (RM118).
A genetic basis for the biosynthetic assembly of the globotetraose containing lipopolysaccharide (LPS) of Haemophilus influenzae strain RM118 (Rd) was determined by structural analysis of LPS derived from mutant strains. We have previously shown that the parent strain RM118 elaborates a population of LPS molecules made up of a series of related glycoforms differing in the degree of oligosaccharide chain extension from the distal heptose residue of a conserved phosphorylated inner-core element, L-alpha-D-Hepp-(1-->2)-L-alpha-D-Hepp-(1-->3)-[beta-D-Glcp-(1-->4)-]-L-alpha-D-Hepp-(1-->5)-alpha-Kdo. The fully extended LPS glycoform expresses the globotetraose structure, beta-D-GalpNAc-(1-->3)-alpha-D-Galp-(1-->4)-beta-D-Galp-(1-->4)-beta-D-Glcp. A fingerprinting strategy was employed to establish the structure of LPS from strains mutated in putative glycosyltransferase genes compared to the parent strain. This involved glycose and linkage analysis on intact LPS samples and analysis of O-deacylated LPS samples by electrospray ionization mass spectrometry and 1D (1)H-nuclear magnetic resonance spectroscopy. Four genes, lpsA, lic2A, lgtC, and lgtD, were required for sequential addition of the glycoses to the terminal inner-core heptose to give the globotetraose structure. lgtC and lgtD were shown to encode glycosyltransferases by enzymatic assays with synthetic acceptor molecules. This is the first genetic blueprint determined for H. influenzae LPS oligosaccharide biosynthesis, identifying genes involved in the addition of each glycose residue.


Health Promotion in Practice-District Nurses׳ Experiences of Working with Health Promotion and Lifestyle Interventions Among Patients at Risk of Developing Cardiovascular Disease.
Health Promotion Practice (HPP) has the objective to promote a healthier lifestyle and reduce the risk of disease. The aim of this study was to examine district nurses׳ experiences of working with health preventive actions among patients with risk factors for cardiovascular disease (CVD), and to identify facilitators and obstacles in HPP. The study was carried out with a qualitative approach where individual semistructured interviews were performed with a total of 12 district nurses in primary care. Data transcripts were analyzed with a manifest content analysis. Five categories were identified. Firstly, informants regarded HPP as the core essence of their work. Secondly, counseling and coaching were reported as crucial elements in working with HPP. Thirdly, informants identified tools such as motivational interviewing (MI) to facilitate HPP. In the fourth category facilitators and barriers of HPP appeared, consisting of both positive and negative attitudes and presence as well as lack of organizational culture and structure. Finally, some informants were dissatisfied with HPP and viewed it as compulsory or as a burden, while others were satisfied and experienced it as a stimulating challenge. This study identified that HPP is the core of the district nurses׳ work to promote a healthier lifestyle in individuals with CVD. Organizational structures and culture need to be improved in order to support district nurses to successfully work with HPP. To optimize health promotion and strengthen patients׳ self-care, it is recommended that HPP include holistic elements of care.


Providing health insurance in rural china: from research to policy.
The focus of this case study is utilizing research to influence policy in a large developing country. Our experiences involve the lack of health insurance for China's rural populations and how our research helped shape China's recent policy attention and efforts on this issue. More than 80 percent of China's 700 million rural residents have no health insurance. This has been the case for the past thirty years, since the collapse of the once-successful Rural Cooperative Medical System after the economic reforms of the early 1980s. In 2002, the Chinese government announced a new rural health financing policy to provide health insurance for its rural populations, financed by a matching fund with contributions from central and local governments, as well as from individual households. This article documents the authors' experiences in addressing several critical questions for converting research results into policy actions, including the following: How are researchers to address policy relevant questions? How are they to acquire the attention of top policy makers to a specific problem? When is the issue at hand serious but not yet critical? And lastly, how are researchers to develop policy recommendations that stand a good chance of being accepted and enacted? Major lessons learned include the need to better understand the mandates and institutional constraints of the policy makers, the appropriateness of timing of both research result and policy efforts, how to use a country's cultural context to garner support of the government, how to enhance the policy's impact by combining formal and informal channels of communication for research dissemination, and the importance of following the policy process through the implementation phase to ensure the original objectives are achieved.


Structural properties of cationic surfactant-fatty alcohol bilayers: insights from dissipative particle dynamics.
Bilayers, self-assembled by cationic surfactants and fatty alcohols in water, are the basic units of lamellar gel networks - creamy formulations extensively used in cosmetics and pharmaceutics. Mesoscopic modelling and study of the bilayers formed by single- or double-tail cationic surfactants (CTAC or DHDAC), and fatty alcohols (FAs) in the lamellar fluid and gel phases were employed. Fatty alcohols with alkyl tail equal to or greater than the surfactant alkyl tail, i.e., C16FA or C18FA and C22FA, were considered. A model formulation was explored with the FA concentration greater than that of the surfactant and the structure of the fluid and gel bilayers in tensionless state characterised via the density profiles across the bilayers, orientational order parameters of the surfactant and FA chains, intrinsic analysis of the bilayer interfaces, and bending rigidity. The intrinsic analysis allows identification and quantification of the coexistence of the interdigitated and non-interdigitated phases present within the gel bilayers. The FA chains were found to conform the primary scaffolding of the bilayers while the surfactant chains tessellate bilayer monolayers from their water-hydrophobic interface. Further, the overlap of the FA chains from the apposed monolayers of the fluid bilayers rises with increasing FA length. Finally, the prevalence of the non-interdigitated phase over the interdigitated phase within the gel bilayers becomes enhanced upon the FA length increase with a preference of the surfactant chains to reside in the non-interdigitated phase rather than the interdigitated phase.


Fruits and vegetables and ovarian cancer risk in a pooled analysis of 12 cohort studies.
Because fruits and vegetables are rich in bioactive compounds with potential cancer-preventive actions, increased consumption may reduce the risk of ovarian cancer. Evidence on the association between fruit and vegetable intake and ovarian cancer risk has not been consistent. We analyzed and pooled the primary data from 12 prospective studies in North America and Europe. Fruit and vegetable intake was measured at baseline in each study using a validated food-frequency questionnaire. To summarize the association between fruit and vegetable intake and ovarian cancer, study-specific relative risks (RR) were estimated using the Cox proportional hazards model, and then combined using a random-effects model. Among 560,441 women, 2,130 cases of invasive epithelial ovarian cancer occurred during a maximum follow-up of 7 to 22 years across studies. Total fruit intake was not associated with ovarian cancer risk-the pooled multivariate RR for the highest versus the lowest quartile of intake was 1.06 [95% confidence interval (95% CI), 0.92-1.21; P value, test for trend = 0.73; P value, test for between-studies heterogeneity = 0.74]. Similarly, results for total vegetable intake indicated no significant association (pooled multivariate RR, 0.90; 95% CI, 0.78-1.04, for the highest versus the lowest quartile; P value, test for trend = 0.06; P value, test for between-studies heterogeneity = 0.31). Intakes of botanically defined fruit and vegetable groups and individual fruits and vegetables were also not associated with ovarian cancer risk. Associations for total fruits and vegetables were similar for different histologic types. These results suggest that fruit and vegetable consumption in adulthood has no important association with the risk of ovarian cancer.


Dopamine release in the basal ganglia.
Dopamine (DA) is a key transmitter in the basal ganglia, yet DA transmission does not conform to several aspects of the classic synaptic doctrine. Axonal DA release occurs through vesicular exocytosis and is action potential- and Ca²⁺-dependent. However, in addition to axonal release, DA neurons in midbrain exhibit somatodendritic release by an incompletely understood, but apparently exocytotic, mechanism. Even in striatum, axonal release sites are controversial, with evidence for DA varicosities that lack postsynaptic specialization, and largely extrasynaptic DA receptors and transporters. Moreover, DA release is often assumed to reflect a global response to a population of activities in midbrain DA neurons, whether tonic or phasic, with precise timing and specificity of action governed by other basal ganglia circuits. This view has been reinforced by anatomical evidence showing dense axonal DA arbors throughout striatum, and a lattice network formed by DA axons and glutamatergic input from cortex and thalamus. Nonetheless, localized DA transients are seen in vivo using voltammetric methods with high spatial and temporal resolution. Mechanistic studies using similar methods in vitro have revealed local regulation of DA release by other transmitters and modulators, as well as by proteins known to be disrupted in Parkinson's disease and other movement disorders. Notably, the actions of most other striatal transmitters on DA release also do not conform to the synaptic doctrine, with the absence of direct synaptic contacts for glutamate, GABA, and acetylcholine (ACh) on striatal DA axons. Overall, the findings reviewed here indicate that DA signaling in the basal ganglia is sculpted by cooperation between the timing and pattern of DA input and those of local regulatory factors.


Laser acupuncture for treating musculoskeletal pain: a systematic review with meta-analysis.
Laser acupuncture has been studied extensively over several decades to establish evidence-based clinical practice. This systematic review aims to evaluate the effects of laser acupuncture on pain and functional outcomes when it is used to treat musculoskeletal disorders and to update existing evidence with data from recent randomized controlled trials (RCTs). A computer-based literature search of the databases MEDLINE, AMED, EMBASE, CINAHL, SPORTSDiscus, Cochrane Library, PubMed, Current Contents Connect, Web of Science, and SCOPUS was used to identify RCTs comparing between laser acupuncture and control interventions. A meta-analysis was performed by calculating the standardized mean differences and 95% confidence intervals, to evaluate the effect of laser acupuncture on pain and functional outcomes. Included studies were assessed in terms of their methodological quality and appropriateness of laser parameters. Forty-nine RCTs met the inclusion criteria. Two-thirds (31/49) of these studies reported positive effects, were of high methodological quality, and reported the dosage adequately. Negative or inconclusive studies commonly failed to demonstrate these features. For all diagnostic subgroups, positive effects for both pain and functional outcomes were more consistently seen at long-term follow-up rather than immediately after treatment. Moderate-quality evidence supports the effectiveness of laser acupuncture in managing musculoskeletal pain when applied in an appropriate treatment dosage; however, the positive effects are seen only at long-term follow-up and not immediately after the cessation of treatment.


Nutrient deficiencies as a risk factor in Taiwanese patients with postherpetic neuralgia.
Postherpetic neuralgia (PHN) is the most common complication of herpes zoster (HZ). The aim of the present study was to compare the nutritional status of PHN patients with that of healthy controls, and then to identify risk factors for PHN using multivariate multiple logistic regressions. In the present cross-sectional study, we prospectively enrolled fifty PHN patients for at least 3 months and fifty healthy controls. We selected nine circulating nutrients including ionised Ca, Zn, retinol, folic acid, vitamin B12, vitamin C, α-tocopherol, γ-tocopherol and lycopene associated with both immunity and the modulation of neuropathic pain, and measured their concentrations in plasma/serum. Concentrations of ionised Ca, Zn, vitamin C and vitamin B12 were significantly lower in PHN patients than in controls after excluding those patients receiving supplements since the outbreak of HZ. The prevalence of either mild/marginal or severe deficiencies for any of the nine selected circulating nutrients in PHN patients (92 %) was much higher than that in controls (46 %) (P < 0·001). Lower concentrations of vitamin C ( ≤ 45·0 μmol/l), ionised Ca ( ≤ 1·05 mmol/l) and Zn ( ≤ 0·91 g/l) were found to increase independently the risk of PHN using binary variable (dichotomy) analyses with both PHN patients and controls in a multivariate logistic regression analysis. No significant correlations existed between the risks of PHN and the concentrations of retinol, folic acid, vitamin B12, lycopene or α:γ-tocopherol ratios. Thus, lower concentrations of circulating nutrients, namely vitamin C, ionised Ca or Zn, are probably a risk factor in Taiwanese patients with PHN.


Impulsivity and pathological gambling: Is it a state or a trait problem?
This study tested 37 Chinese male pathological gamblers and 40 controls to understand the relationship between pathological gambling and impulsivity as a long-term trait or a short-term state in the cognitive and affective domain. Trait impulsivity was measured by the Barratt Impulsiveness Scale-11. State impulsivity in the cognitive and affective domains were measured by the Stroop Color Word Test and the Emotional Conflict Task, respectively. The pathological gamblers scored significantly higher than the controls on the Barratt Impulsiveness Scale-11. However, there were no significant group differences in performance on the Stroop Color Word Test or the Emotional Conflict Task. Findings clearly show that pathological gambling is associated with trait but not state impulsivity. In other words, pathological gambling is associated with an impulsivity stemming from enduring personality characteristics that lead gamblers to focus on short-term gains (trait impulsivity) rather than momentary cognitive or affective disinhibition (state impulsivity). Interventions should aim to change pathological gamblers' habitual functioning style by cultivating healthy reflection habits and focusing on long-term rewards.


Modular, multi-input transcriptional logic gating with orthogonal LacI/GalR family chimeras.
In prokaryotes, the construction of synthetic, multi-input promoters is constrained by the number of transcription factors that can simultaneously regulate a single promoter. This fundamental engineering constraint is an obstacle to synthetic biologists because it limits the computational capacity of engineered gene circuits. Here, we demonstrate that complex multi-input transcriptional logic gating can be achieved through the use of ligand-inducible chimeric transcription factors assembled from the LacI/GalR family. These modular chimeras each contain a ligand-binding domain and a DNA-binding domain, both of which are chosen from a library of possibilities. When two or more chimeras have the same DNA-binding domain, they independently and simultaneously regulate any promoter containing the appropriate operator site. In this manner, simple transcriptional AND gating is possible through the combination of two chimeras, and multiple-input AND gating is possible with the simultaneous use of three or even four chimeras. Furthermore, we demonstrate that orthogonal DNA-binding domains and their cognate operators allow the coexpression of multiple, orthogonal AND gates. Altogether, this work provides synthetic biologists with novel, ligand-inducible logic gates and greatly expands the possibilities for engineering complex synthetic gene circuits.


Psychiatric factors associated with dangerous misidentification delusions.
The delusional misidentification syndromes are characterized by misidentification delusions of others or of the self. Aggressive ideas or behaviors often accompany these delusions. The relationship between delusional misidentification and dangerousness remains for the most part poorly understood. In the present article, we compare a group of dangerous individuals suffering from dangerous misidentification delusions with a group of dangerous individuals suffering from other types of delusions. Individuals with dangerous misidentification delusions were more likely to experience grandiose ideation, thought disorder, generalized hostility, excitement, general psychopathology, and a previous history of violence than dangerous delusional individuals with no delusional misidentification. The group with dangerous delusional misidentification syndromes was less likely to attack others with weapons than were the dangerous delusional group with no delusional misidentification.


Dangerous delusions? Misidentification syndromes and professional negligence.
A number of case histories have reported an association between the presence of misidentification syndromes and violent behavior. If patients with such delusions are truly more likely to perpetrate violent acts, treating mental health professionals could potentially be considered liable for not warning or protecting potential victims. However, the purported association between violence and misidentification can be adequately explained by biased case ascertainment and reporting. The current literature on misidentification syndromes is used as a means of demonstrating possible sources of error and bias that must be considered whenever mental health professionals are asked to reach conclusions about the relationship of rare events.


The interleukin 23 receptor gene does not confer risk to systemic sclerosis and is not associated with systemic sclerosis disease phenotype.
Multiple studies indicate the role of the interleukin (IL)-17/IL-23 axis in autoimmune diseases, including systemic sclerosis (SSc). The aim of the current study was to investigate the possible implication of the IL23R gene in SSc susceptibility and/or clinical phenotype. An initial case-control study in 143 Dutch patients with SSc and geographically matched healthy individuals (n = 246) was carried out and followed by a replication study in a cohort of 365 Spanish patients with SSc and 515 healthy individuals. Seven single nucleotide polymorphisms (SNPs) spanning the IL23R gene were selected and genotyped using a Taqman assay. Using a Dutch cohort of patients with SSc and controls we observed an association between two (rs11209032, rs1495965) of the seven tested SNPs and disease susceptibility (allelic p values: p = 0.02 and p = 0.01 respectively). However, a replication study in an independent Spanish cohort did not confirm these findings and reveal no association of any of the IL23R-tested SNP with disease susceptibility or clinical phenotype. Similarly, a meta-analysis considering both populations did not reveal any significant association. In addition, no association was observed between IL23R genetic variants and SSc clinical phenotypes. Our results suggest that the IL23R gene is not associated with SSc susceptibility or clinical phenotype.


Determining utility values in patients with anterior cruciate ligament tears using clinical scoring systems.
Several instruments and clinical scoring systems have been established to evaluate patients with ligamentous knee injuries. A comparison of individual articles in the literature is challenging, not only because of heterogeneity in methodology, but also due to the variety of the scoring systems used to document clinical outcomes. There is limited information about the correlation between used scores and quality of life with no information being available on the impact of each score on the utility values. The aim of this study was to compare the most commonly used scores for evaluating patients with anterior cruciate ligament (ACL) injuries, and to establish corresponding utility values. These values will be used for the interpretation and comparison of outcome results in the currently available literature for different treatment options. Four hypothetical vignettes were defined, based on different levels of activities after rupture of the ACL to simulate typical situations seen in daily practice. A questionnaire, including the Health Utility Index (HUI) for utility values, the IKDC subjective score, the Lysholm and the Tegner score, was created and 25 orthopedic surgeons were asked to fill the questionnaire for each hypothetical patient as proxies for all patients they had treated and who would fit in that hypothetical vignette. The utility value as an indicator for quality of life increased with the level of activity. Having discomforts already during normal activities of daily living was rated with a mean utility value of 0.37 ± 0.19, half of that of a situation where mild sport activity was possible without discomfort (0.78 ± 0.11). All investigated scores were able to distinguish clearly (p < 0.05) between the hypothetical vignettes. However, the utility values correlated best with the IKDC subjective score (r = 0.86, p < 0.001) followed by the Lysholm score (r = 0.77, p < 0.001) and the Tegner score (r = 0.77, p < 0.001). Here we report the correlation between the most commonly used scores for the assessment of patients with a ruptured ACL and utility values as an indicator of quality of life. Assumptions were based on expert opinions to provide a possible transformation algorithm. The IKDC subjective knee score showed the highest correlation to the quality of life (i.e. HUI) in patients with a ruptured ACL. Confirmation of our results is needed by systematic inclusion of a measurement instrument for utility values in future clinical studies beside the already used clinical knee scoring systems.


Association between sociodemographic, dietary, and substance use factors and accelerometer-measured 24-hour movement behaviours in Brazilian adolescents.
Sociodemographic factors and lifestyle behaviours were evidenced as correlates of self-reported 24-hour movement behaviours in high-income settings. However, it is unclear how these relations occur in a middle-income country setting, with unique cultural and social characteristics. This study aimed to examine the association between sociodemographic, dietary, and substance use factors with accelerometer-measured 24-hour movement behaviours in Brazilian adolescents. Information on sex, age, socioeconomic status (SES), family structure, dietary behaviours, and history of substance use were collected by a questionnaire. Sleep duration, sedentary behaviour, and light- and moderate-to-vigorous physical activity (LPA and MVPA) were measured using wrist-worn accelerometers. On average, females slept more (β = 21.09, 95%CI 13.18; 28.98), engaged in more LPA (β = 17.60, 95%CI 8.50; 27.13), and engaged in less sedentary behaviour (β = -16.82, 95%CI -30.01; -4.30) and MVPA (β = -4.76, 95%CI -7.48; -1.96) than males. Age and sedentary behaviour were positively associated (β = 8.60, 95%CI 2.53; 14.64). Unprocessed foods were positively related to LPA (β = 2.21, 95%CI 0.55; 3.92), whereas processed foods were positively related to sedentary behaviour (β = 3.73, 95%CI 0.03; 7.38) and inversely related to MVPA (β = -0.89, 95%CI -1.68; -0.10). Family structure, SES, and substance use factors were not significantly associated with any 24-hour movement behaviour.Conclusions: Sex, age, and dietary behaviours, unlike SES or substance use, were associated with 24-hour movement behaviours in this sample of Brazilian adolescents and are important factors to consider in interventions, policies, and practice. What is Known: • The 24-hour movement behaviours are composed of sleep, sedentary behaviour, and physical activity and are important determinants of health. • Most adolescents do not engage in adequate levels of physical activity, sedentary behaviour, and sleep, and there is a need to better understand factors related to these behaviours. What is New: • Sex, age, and dietary behaviours were associated with the 24-hour movement behaviours. • No associations were found between socioeconomic status and substance use with the 24-hour movement behaviours.


A Computational Statistics Approach to Evaluate Blood Biomarkers for Breast Cancer Risk Stratification.
Breast cancer is the second leading cause of cancer mortality among women. Mammography and tumor biopsy followed by histopathological analysis are the current methods to diagnose breast cancer. Mammography does not detect all breast tumor subtypes, especially those that arise in younger women or women with dense breast tissue, and are more aggressive. There is an urgent need to find circulating prognostic molecules and liquid biopsy methods for breast cancer diagnosis and reducing the mortality rate. In this study, we systematically evaluated metabolites and proteins in blood to develop a pipeline to identify potential circulating biomarkers for breast cancer risk. Our aim is to identify a group of molecules to be used in the design of portable and low-cost biomarker detection devices. We obtained plasma samples from women who are cancer free (healthy) and women who were cancer free at the time of blood collection but developed breast cancer later (susceptible). We extracted potential prognostic biomarkers for breast cancer risk from plasma metabolomics and proteomics data using statistical and discriminative power analyses. We pre-processed the data to ensure the quality of subsequent analyses, and used two main feature selection methods to determine the importance of each molecule. After further feature elimination based on pairwise dependencies, we measured the performance of logistic regression classifier on the remaining molecules and compared their biological relevance. We identified six signatures that predicted breast cancer risk with different specificity and selectivity. The best performing signature had 13 factors. We validated the difference in level of one of the biomarkers, SCF/KITLG, in plasma from healthy and susceptible individuals. These biomarkers will be used to develop low-cost liquid biopsy methods toward early identification of breast cancer risk and hence decreased mortality. Our findings provide the knowledge basis needed to proceed in this direction.


Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.
Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.


Mechanisms of moving the mind's eye: planning and execution of spatial shifts of attention.
The usefulness of attentional orienting, both in the real world and in the laboratory, depends not only on the ability to attend to objects or other inputs but also on the ability to shift attention between them. Although understanding the basic characteristics of these shifts is a critical step toward understanding the brain mechanisms that produce them, the literature remains unresolved on a very basic and potentially revealing characteristic of these shifts-namely, whether attention takes longer to shift a farther distance across the visual field. We addressed this question using a series of behavioral tasks involving the voluntary orienting of attention to locations in the visual field. The findings support a model in which attentional shifts include separate "planning" and "execution" stages and in which only the planning stage requires more time for shifts of a greater distance. These results offer resolution to the longstanding debate concerning the effect of attentional shift distance on shift time and provide insight into the fundamental mechanisms of attentional shifting.