RNA trafficking by acute myelogenous leukemia exosomes.
Extrinsic signaling cues in the microenvironment of acute myelogenous leukemia (AML) contribute to disease progression and therapy resistance. Yet, it remains unknown how the bone marrow niche in which AML arises is subverted to support leukemic persistence at the expense of homeostatic function. Exosomes are cell membrane-derived vesicles carrying protein and RNA cargoes that have emerged as mediators of cell-cell communication. In this study, we examined the role of exosomes in developing the AML niche of the bone marrow microenvironment, investigating their biogenesis with a focus on RNA trafficking. We found that both primary AML and AML cell lines released exosome-sized vesicles that entered bystander cells. These exosomes were enriched for several coding and noncoding RNAs relevant to AML pathogenesis. Furthermore, their uptake by bone marrow stromal cells altered their secretion of growth factors. Proof-of-concept studies provided additional evidence for the canonical functions of the transferred RNA. Taken together, our findings revealed that AML exosome trafficking alters the proliferative, angiogenic, and migratory responses of cocultured stromal and hematopoietic progenitor cell lines, helping explain how the microenvironmental niche becomes reprogrammed during invasion of the bone marrow by AML.


Neutrophil to lymphocyte ratio (NLR) improves the risk assessment of ISS staging in newly diagnosed MM patients treated upfront with novel agents.
Recent reports identify the ratio between absolute neutrophil count (ANC) and absolute lymphocyte count (ALC), called neutrophil to lymphocyte ratio (NLR), as a predictor of progression-free survival (PFS) and overall survival (OS) in various malignancies. We retrospectively examined the NLR in a cohort of 309 newly diagnosed multiple myeloma (MM) patients treated upfront with novel agents. NLR was calculated using data obtained from the complete blood count (CBC) at diagnosis and subsequently correlated with PFS and OS. The median NLR was 1.9 (range 0.4-15.9). Higher NLR was independent of international staging system (ISS) stage, plasma cell infiltration or cytogenetics. The 5-year PFS and OS estimates were, respectively, 18.2 and 36.4 % for patients with NLR ≥ 2 versus 25.5 and 66.6 % in patients with NLR < 2. Among younger patients (age <65 years, N = 179), NLR ≥ 2 had a negative prognostic impact on both PFS and OS, in all ISS stages. By combining ISS stage and NLR in a model limited to young patients, we found that 19 % of the patients were classified as very low risk, 70 % standard risk and 11 % very high risk. The 5-year estimates were 39.3, 19.4 and 10.9 % for PFS and 95.8, 50.9 and 23.6 % for OS for very low, standard-risk and very high-risk groups. We found NLR to be a predictor of PFS and OS in MM patients treated upfront with novel agents. NLR can be combined with ISS staging system to identify patients with dismal outcome. However, larger cohorts and prospective studies are needed to use NLR as additional parameter to personalise MM therapy in the era of novel agents.


Suspended Si ring resonator for mid-IR application.
In this Letter we fabricate and characterize suspended silicon (Si) waveguides and ring resonators for mid-infrared wavelength range. Both tunable laser and thermal tuning are used to cover wavelength ranges near 5.2 and 3.4 μm. The loaded quality factors are estimated at 2700 at 5.2 μm and 7900 at 3.4 μm. Heat induced spectrum distortion is observed. Absorption loss is analyzed based on the spectrum distortion, simulation, and all-optical modulation. It is shown that main loss comes from scattering at surface and should be possible to reduce by improving fabrication process.


Prevalence of papillomavirus in Brazil: a systematic review protocol.
Human papillomavirus (HPV) infection is a cause of premalignant and malignant cancer in the lower genital and digestive tracts. In Brazil, there have been no prevalence studies that included a nationwide sample, and the prevalence of HPV has not been determined in many regions. We will search the EMBASE, LILACS, MEDLINE, Web of Science and SciELO databases and previously published review articles to identify original research articles assessing HPV prevalence of the perineal (cervical, penile and anal) and oral areas. No exclusion criteria related to language or publication date will apply. 2 reviewers will independently screen for eligibility and perform data extraction. Discrepancies will be resolved through consensus; the opinion of a third reviewer will be sought as necessary. Relevant measures and data about study and population characteristics will be extracted from the included studies. Where possible, study prevalence will be pooled using a random-effects meta-analysis. The methodological quality of the studies will be assessed using an adapted version of the NIH 'Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies'. The overall quality of evidence will be assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). We expect to estimate the prevalence of perineal and oral HPV infection in the general population as well as the prevalence of HPV infection in individuals with premalignant and malignant lesions in Brazil and its 5 geographic regions. This systematic review does not require ethical approval. CRD42016032751.


The future burden of obesity-related diseases in the 53 WHO European-Region countries and the impact of effective interventions: a modelling study.
Non-communicable diseases (NCDs) are the biggest cause of death in Europe putting an unsustainable burden on already struggling health systems. Increases in obesity are a major cause of NCDs. This paper projects the future burden of coronary heart disease (CHD), stroke, type 2 diabetes and seven cancers by 2030 in 53 WHO European Region countries based on current and past body mass index (BMI) trends. It also tests the impact of obesity interventions on the future disease burden. Secondary data analysis of country-specific epidemiological data using a microsimulation modelling process. The effect of three hypothetical scenarios on the future burden of disease in 2030 was tested: baseline scenario, BMI trends go unchecked; intervention 1, population BMI decreases by 1%; intervention 2, BMI decreases by 5%. Quantifying the future burden of major NCDs and the impact of interventions on this future disease burden. By 2030 in the whole of the European region, the prevalence of diabetes, CHD and stroke and cancers was projected to reach an average of 3990, 4672 and 2046 cases/100 000, respectively. The highest prevalence of diabetes was predicted in Slovakia (10 870), CHD and stroke-in Greece (11 292) and cancers-in Finland (5615 cases/100 000). A 5% fall in population BMI was projected to significantly reduce cumulative incidence of diseases. The largest reduction in diabetes and CHD and stroke was observed in Slovakia (3054 and 3369 cases/100 000, respectively), and in cancers was predicted in Germany (331/100 000). Modelling future disease trends is a useful tool for policymakers so that they can allocate resources effectively and implement policies to prevent NCDs. Future research will allow real policy interventions to be tested; however, better surveillance data on NCDs and their risk factors are essential for research and policy.


A Survey of Midwives' Attitudes Toward Men in Midwifery.
The midwifery profession in the United States demonstrates a significant lack of diversity. The critical need to address the lack of racial and ethnic diversity in the midwifery workforce is well recognized; little attention, however, has been given to gender diversity. This study focused on gender diversity within midwifery, specifically with regard to men who are midwives. Nearly 99% of midwives in the United States are women. No research has previously explored the attitudes of the predominantly female midwifery workforce toward its male members. An invitation to an internet survey was sent to the American College of Nurse-Midwives (ACNM) membership. Quantitative and open-ended questions assessed attitudes toward and experiences with male midwives, whether members thought men belong in the profession, whether gender impacts quality of care, if ACNM should facilitate gender diversification, and whether exposure to male midwives impacts attitudes toward gender diversification. Data analysis of qualitative responses used a qualitative description methodology to identify common themes. Six thousand, nine hundred sixty-five surveys were distributed, and 864 participants completed the survey. Respondents reported beliefs that men belong in midwifery (71.4%), that gender does not affect quality of care (74%), and that ACNM should support gender diversity (72%). Respondents' perspectives revealed 3 dichotomous themes pertaining to the core nature of midwifery and how men fit within the profession: 1) inclusion versus exclusion, 2) empowerment versus protection, and 3) sharing with versus taking from. Often, the same respondent expressed both aspects of the dichotomy simultaneously. This study contributes new information about midwives' attitudes and beliefs toward gender diversity in midwifery in the United States. The values of professionalism, tradition, feminism, protection, and diversification inform participant responses. Findings support efforts toward gender diversification and have implications for implementation in education and practice.


Elective delivery before 39 weeks: the risk of infant admission to the neonatal intensive care unit.
Despite American College of Obstetricians and Gynecologists guidelines suggesting that non-urgent planned deliveries be scheduled at/after 39 weeks; elective delivery before 39 weeks occurs often in the United States. The objective of this study is to estimate the elective delivery rate between 36(0/7) and 38(6/7) weeks gestation and compare NICU admission rates between elective and non-elective deliveries. We conducted a retrospective cohort (n = 1,577) study. Charts were reviewed for all singleton deliveries (2006-2007) between 36(0/7) and 38(6/7) weeks gestation taking place at one hospital in NYS to determine delivery status. We computed adjusted relative risks (RR) with 95% confidence intervals (CI) for elective delivery in relation to NICU admission using robust Poisson regression. 32.8% of all births were elective: 20.7% of vaginal and 55.7% of cesarean births. Elective delivery increased with increasing gestational age. After controlling for potential confounders, infants born via a vaginal elective delivery (RR = 1.40, CI: 1.00, 1.94), an elective cesarean (RR = 2.05, CI: 1.53, 2.76), or a non-elective cesarean (RR = 2.00, CI: 1.50, 2.66) are at significantly increased risk of NICU admission compared to infants born via a non-elective vaginal delivery. Elective delivery before 39 weeks is common and increases the risk of infant NICU admission.


Regulated Activation of the PAR Polarity Network Ensures a Timely and Specific Response to Spatial Cues.
How do cells polarize at the correct time and in response to the correct cues? In the C. elegans zygote, the timing and geometry of polarization rely on a single dominant cue-the sperm centrosome-that matures at the end of meiosis and specifies the nascent posterior. Polarization requires that the conserved PAR proteins, which specify polarity in the zygote, be poised to respond to the centrosome. Yet, how and when PAR proteins achieve this unpolarized, but responsive, state is unknown. We show that oocyte maturation initiates a fertilization-independent PAR activation program. PAR proteins are initially not competent to polarize but gradually acquire this ability following oocyte maturation. Surprisingly, this program allows symmetry breaking even in unfertilized oocytes lacking centrosomes. Thus, if PAR proteins can respond to multiple polarizing cues, how is specificity for the centrosome achieved? Specificity is enforced by Polo-like and Aurora kinases (PLK-1 and AIR-1 in C. elegans), which impose a delay in the activation of the PAR network so that it coincides with maturation of the centrosome cue. This delay suppresses polarization by non-centrosomal cues, which can otherwise trigger premature polarization and multiple or reversed polarity domains. Taken together, these findings identify a regulatory program that enforces proper polarization by synchronizing PAR network activation with cell cycle progression, thereby ensuring that PAR proteins respond specifically to the correct cue. Temporal control of polarity network activity is likely to be a common strategy to ensure robust, dynamic, and specific polarization in response to developmentally deployed cues.


Assessment of the role of common genetic variation in the transient neonatal diabetes mellitus (TNDM) region in type 2 diabetes: a comparative genomic and tagging single nucleotide polymorphism approach.
Recent evidence supports the strong overlap between genes implicated in monogenic diabetes and susceptibility to type 2 diabetes. Transient neonatal diabetes mellitus (TNDM) is a rare disorder associated with overexpression of genes at a paternally expressed imprinted locus on chromosome 6q24. There are two overlapping genes in this region: the transcription factor zinc finger protein associated with cell cycle control and apoptosis (ZAC also known as PLAGL1) and HYMA1, which encodes an untranslated mRNA. Several type 2 diabetes linkage studies have reported linkage to chromosome 6q22-25. We hypothesized that common genetic variation at this TNDM region influences type 2 diabetes susceptibility. In addition to the coding regions, we used comparative genomic analysis to identify conserved noncoding regions, which were resequenced for single nucleotide polymorphism (SNP) discovery in 47 individuals. Twenty-six SNPs were identified. Fifteen tag SNPs (tSNPs) were successfully genotyped in a large case-control (n = 3,594) and family-based (n = 1,654) study. We did not find any evidence of association or overtransmission of any tSNP to affected offspring or of a parent-of-origin effect. Using a study sufficiently powered to detect odds ratios of <1.2, we conclude that common variation in the TNDM region does not play an important role in the genetic susceptibility to type 2 diabetes.


The prognostic value of CXCR4 in acute myeloid leukemia.
CXC chemokine receptor (CXCR4) has been shown to be expressed in a subset of acute myeloid leukemia (AML) patients and is correlated with a poor prognosis. CXCR4 expression appears to be an independent prognostic factor for survival in a heterogeneous group of AML patients. To better assess its significance, we analyzed CXCR4 expression in a group of AML patients. The prognostic value of CXCR4 expression in 53 patients with AML presenting between 2003 and 2008 was analyzed. Formalin-fixed, paraffin-embedded bone marrow biopsy or clot sections were stained using immunohistochemical methods. CXCR4 was expressed in 26 patients (49.1%). A patient age of less than 60 years (P=0.023), achievement of complete remission after induction therapy (P<0.001), and no CXCR4 expression (P=0.010) were all associated with better progression-free survival (PFS). Among mutations of NPM1, CEBPA, FLT3 ITD, and FLT3 D835 and expression of CXCR4, only CXCR4 expression was associated with PFS (P=0.010; by log-rank test). By multivariate analysis, CXCR4 expression was an independent prognostic factor (P=0.001 for PFS and P=0.001 for overall survival). CXCR4 expression in patients with a normal karyotype was detected in 15 of 22 patients (68.2%, relative ratio 4.46, P=0.035). Expression of CXCR4 in normal-karyotype AML showed inferior PFS (median 2.0 vs. 10.7 mo, P=0.026) and had a trend toward inferior overall survival (median 10.8 vs. 14.0 mo, P=0.058). These results suggest that CXCR4 expression is associated with poor prognosis in patients with AML. Specifically, CXCR4 expression is common in normal-karyotype AML and is a marker of more aggressive disease in this population. CXCR4 expression could be incorporated into the risk assessment of patients with AML.


Diminished response of Werner's syndrome fibroblasts to growth factors PDGF and FGF.
Patients with Werner's syndrome, an autosomal recessive disorder, undergo an accelerated aging process that leads to premature death. Fibroblasts from such patients typically grow poorly in culture. Here it is shown that fibroblasts from a patient with Werner's syndrome have a markedly attenuated mitogenic response to platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF). In contrast, they have a full mitogenic response to fetal bovine serum. Both PDGF binding and receptor numbers per cell are unaltered. The Werner's syndrome cells express high constitutive levels of collagenase in vitro. Although PDGF enhances collagenase expression through increased levels of hybridizable collagenase messenger RNA in normal skin fibroblasts, no induction of collagenase occurs in the Werner's syndrome fibroblasts. Moreover, the failure to respond to this agonist effect of PDGF is not restored by fetal bovine serum. The data suggest that failure of one or more PDGF-mediated pathways in Werner's syndrome cells may contribute to the phenotypic expression of the disorder.


Measurement invariance of a neuropsychological battery across urban and rural older adults in Costa Rica.
This study evaluated the measurement invariance of a neuropsychological battery across rural and urban older adults from Costa Rica. Rural and urban older adults (N = 295) from the Epidemiology and Development of Alzheimer's Disease (EDAD) study in Costa Rica were assessed. The baseline factor model for the EDAD neuropsychological measures was identified with nine neuropsychological measures and three cognitive constructs: Verbal Memory, Spatial Reasoning, and Cognitive Flexibility. Measurement and structural invariance were established, and, then, group comparisons of the latent cognitive factors were conducted to explore regional disparities. The findings showed that most of the neuropsychological tests in EDAD can be directly compared across the groups, allowing for cognitive constructs comparisons. The rural sample showed a disadvantage in the Spatial Reasoning and Cognitive Flexibility abilities. When age and education were included in the models, differences between the regions disappeared. Having more years of education was associated with higher cognitive abilities, with a larger effect for the rural group. Norms for Costa Rican older adults should consider age and education adjustments. This study contributes to the growing area of measurement invariance in neuropsychological assessment as it highlights the importance of examining the comparability of assessment measures across different cultural groups.


Synthesis of cholesterol imprinted polymeric particles.
The aim of this study is to prepare cholesterol-imprinted polymeric particles. N-Methacryloyl-(L)-tyrosinemethylester (MAT) was chosen as the complexing monomer. In the first step, functional monomer MAT was synthesized by the reaction of L-tyrosine methylester and methacryloyl chloride and characterized by FTIR and NMR. Then, cholesterol was complexed with MAT in different mol ratios and the cholesterol-imprinted poly(2-hydroxyethyl methacrylate-N-methacryloyl-(L)-tyrosine methylester) [MIP] particles were synthesized by bulk polymerization. After that, the template molecules (i.e., cholesterol) were removed using chloroform. MIP particles were characterized by elemental analysis, FTIR, SEM, swelling tests and surface area measurements. Cholesterol adsorption experiments were performed in a batch experimental set-up. Adsorption medium was methanol or intestinal mimicking solution. Stigmasterol and estradiol were used as competing molecules in selectivity tests. Obtained results were as follows: swelling ratio of MIP and non-imprinted (NIP) particles were 60.8% and 44.1% in water. With the increase in the amount of MAT in the polymerization medium, incorporation of MAT was increased (16.6-78.0 micromol/g). SEM photographs showed the surface roughness and porosity. Specific surface area of NIP and MIP particles were found as 19.2 and 31.5 m(2)/g, respectively. Template molecules (i.e., cholesterol) were removed from the polymer structure in the ratio of 76-84% of the initial concentration. Cholesterol adsorption increased with the increase in cholesterol concentration up to 1.5 mg/mL. MIP particles prepared using higher amounts of cholesterol exhibit significantly higher capacity to the NIP particles (i.e., control polymer). MIP particles were 3.09 and 3.60 times selective with respect to the stigmasterol and estradiol, respectively. Reusability of MIP particles was also investigated. MIP particles showed negligible loss in the cholesterol adsorption capacity after five adsorption-desorption cycles with the same adsorbent.


Diuretics and beta-blockers do not have adverse effects at 1 year on plasma lipid and lipoprotein profiles in men with hypertension. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.
Concern based on the reported short-term adverse effects of antihypertensive agents on plasma lipid and lipoprotein profiles (PLPPs) has complicated the therapy for hypertension. To compare the long-term (1-year) effects of 6 different antihypertensive drugs and placebo on PLPPs in a multicenter, randomized, double-blind, parallel-group clinical trial in 15 US Veterans Affairs medical centers. A total of 1292 ambulatory men, 21 years or older, with diastolic blood pressures (DBPs) ranging from 95 to 109 mm Hg taking placebo were randomized to receive placebo or 1 of 6 antihypertensive drugs: hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, or prazosin. After drug titration, patients with a DBP of less than 90 mm Hg were followed up for 1 year. Plasma lipids and lipoprotein profiles were determined at baseline, after initial titration, and at 1 year. After 8 weeks on a regimen of hydrochlorothiazide, increases of 3.3 mg/dL (0.09 mmol/L) in total cholesterol and 2.7 mg/dL in apolipoprotein B were significantly different (P< or =.05) from decreases of 9.3 mg/dL in total cholesterol and 5.4 mg/dL in ApoB levels while receiving prazosin but not from placebo. Patients achieving positive DBP control using hydrochlorothiazide (responders) showed no adverse changes in PLPPs, whereas nonresponders exhibited increases in triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels. Plasma lipids and lipoprotein profiles did not change significantly among treatment groups after 1 year except for minor decreases in high-density lipoprotein 2 levels using hydrochlorothiazide, clonidine, and atenolol. None of these 6 antihypertensive drugs has any long-term adverse effects on PLPPs and, therefore, may be safely prescribed. Previously reported short-term adverse effects from using hydrochlorothiazide are limited to nonresponders.


Effect of extracellular polymeric substances on the mechanical properties of Rhodococcus.
The mechanical properties of Rhodococcus RC291 were measured using force spectroscopy equipped with a bacterial cell probe. Rhodococcal cells in the late growth stage of development were found to have greater adhesion to a silicon oxide surface than those in the early growth stage. This is because there are more extracellular polymeric substances (EPS) that contain nonspecific binding sites available on the cells of late growth stage. It is found that EPS in the late exponential phase are less densely bound but consist of chains able to extend further into their local environment, while the denser EPS at the late stationary phase act more to sheath the cell. Contraction and extension of the EPS could change the density of the binding sites, and therefore affect the magnitude of the adhesion force between the EPS and the silicon oxide surface. By treating rhodococcal EPS as a surface-grafted polyelectrolyte layer and using scaling theory, the interaction between EPS and a solid substrate was modelled for the cell approaching the surface which revealed that EPS possess a large capacity to store charge. Changing the pH of the surrounding medium acts to change the conformation of EPS chains.


Metagenomic analyses of bacteria on human hairs: a qualitative assessment for applications in forensic science.
Mammalian hairs are one of the most ubiquitous types of trace evidence collected in the course of forensic investigations. However, hairs that are naturally shed or that lack roots are problematic substrates for DNA profiling; these hair types often contain insufficient nuclear DNA to yield short tandem repeat (STR) profiles. Whilst there have been a number of initial investigations evaluating the value of metagenomics analyses for forensic applications (e.g. examination of computer keyboards), there have been no metagenomic evaluations of human hairs-a substrate commonly encountered during forensic practice. This present study attempts to address this forensic capability gap, by conducting a qualitative assessment into the applicability of metagenomic analyses of human scalp and pubic hair. Forty-two DNA extracts obtained from human scalp and pubic hairs generated a total of 79,766 reads, yielding 39,814 reads post control and abundance filtering. The results revealed the presence of unique combinations of microbial taxa that can enable discrimination between individuals and signature taxa indigenous to female pubic hairs. Microbial data from a single co-habiting couple added an extra dimension to the study by suggesting that metagenomic analyses might be of evidentiary value in sexual assault cases when other associative evidence is not present. Of all the data generated in this study, the next-generation sequencing (NGS) data generated from pubic hair held the most potential for forensic applications. Metagenomic analyses of human hairs may provide independent data to augment other forensic results and possibly provide association between victims of sexual assault and offender when other associative evidence is absent. Based on results garnered in the present study, we believe that with further development, bacterial profiling of hair will become a valuable addition to the forensic toolkit.


Simulated disparity and peripheral blur interact during binocular fusion.
We have developed a low-cost, practical gaze-contingent display in which natural images are presented to the observer with dioptric blur and stereoscopic disparity that are dependent on the three-dimensional structure of natural scenes. Our system simulates a distribution of retinal blur and depth similar to that experienced in real-world viewing conditions by emmetropic observers. We implemented the system using light-field photographs taken with a plenoptic camera which supports digital refocusing anywhere in the images. We coupled this capability with an eye-tracking system and stereoscopic rendering. With this display, we examine how the time course of binocular fusion depends on depth cues from blur and stereoscopic disparity in naturalistic images. Our results show that disparity and peripheral blur interact to modify eye-movement behavior and facilitate binocular fusion, and the greatest benefit was gained by observers who struggled most to achieve fusion. Even though plenoptic images do not replicate an individual's aberrations, the results demonstrate that a naturalistic distribution of depth-dependent blur may improve 3-D virtual reality, and that interruptions of this pattern (e.g., with intraocular lenses) which flatten the distribution of retinal blur may adversely affect binocular fusion.


Atrial fibrillation in patients undergoing coronary artery surgery is associated with adverse outcome.
The aim was to determine the association between atrial fibrillation (AF) and outcome in patients undergoing coronary artery bypass grafting (CABG). All patients undergoing CABG between January 2010 and June 2013 were identified in the Swedish Heart Surgery Registry. Outcomes studied were all-cause mortality, cardiovascular mortality, myocardial infarction, congestive heart failure, ischemic stroke, and recurrent AF. Patients with history of AF prior to surgery (preoperative AF) and patients without history of AF but with AF episodes post-surgery (postoperative AF) were compared to patients with no AF using adjusted Cox regression models. Among 9,107 identified patients, 8.1% (n = 737) had preoperative AF, and 25.1% (n = 2,290) had postoperative AF. Median follow-up was 2.2 years. Compared to no AF, preoperative AF was associated with higher risk of all-cause mortality, adjusted hazard ratio with 95% confidence interval (HR) 1.76 (1.33-2.33); cardiovascular mortality, HR 2.43 (1.68-3.50); and congestive heart failure, HR 2.21 (1.72-2.84). Postoperative AF was associated with risk of all-cause mortality, HR 1.27 (1.01-1.60); cardiovascular mortality, HR 1.52 (1.10-2.11); congestive heart failure, HR 1.47 (1.18-1.83); and recurrent AF, HR 4.38 (2.46-7.78). No significant association was observed between pre- or postoperative AF and risk for myocardial infarction and ischemic stroke. Approximately 1 in 3 patients undergoing CABG had pre- or postoperative AF. Patients with pre- or postoperative AF were at higher risk of all-cause mortality, cardiovascular mortality, and congestive heart failure, but not of myocardial infarction or ischemic stroke. Postoperative AF was associated with higher risk of recurrent AF.


Information content of household-stratified epidemics.
Household structure is a key driver of many infectious diseases, as well as a natural target for interventions such as vaccination programs. Many theoretical and conceptual advances on household-stratified epidemic models are relatively recent, but have successfully managed to increase the applicability of such models to practical problems. To be of maximum realism and hence benefit, they require parameterisation from epidemiological data, and while household-stratified final size data has been the traditional source, increasingly time-series infection data from households are becoming available. This paper is concerned with the design of studies aimed at collecting time-series epidemic data in order to maximize the amount of information available to calibrate household models. A design decision involves a trade-off between the number of households to enrol and the sampling frequency. Two commonly used epidemiological study designs are considered: cross-sectional, where different households are sampled at every time point, and cohort, where the same households are followed over the course of the study period. The search for an optimal design uses Bayesian computationally intensive methods to explore the joint parameter-design space combined with the Shannon entropy of the posteriors to estimate the amount of information in each design. For the cross-sectional design, the amount of information increases with the sampling intensity, i.e., the designs with the highest number of time points have the most information. On the other hand, the cohort design often exhibits a trade-off between the number of households sampled and the intensity of follow-up. Our results broadly support the choices made in existing epidemiological data collection studies. Prospective problem-specific use of our computational methods can bring significant benefits in guiding future study designs.


Methylene blue sensitized dichromated gelatin holograms: a new electron donor for their improved photosensitivity.
Tetramethylguanidine (TMG) used as the electron donor in conjunction with methylene blue sensitized dichromated gelatin (MBDCG) can produce bright reflection holograms recorded at 633 nm at an exposure level of 50 mJ/cm(2). Thus DCG hologram recording and some independence from suppliers of proprietary holographic recording materials is now open to all those with low power He-Ne lasers. The high alkalinity of the system allows the unexposed coated material to have an effective lifetime at room temperature of weeks rather than days. Its low dichromate content has an environmental advantage over the usual DCG formulations. Replacement of methylene blue by eosin can produce similar photosensitivity to 514 nm. The superiority of TMG over previously reported electron donors used with MBDCG is discussed.


Tracking Performance Changes With Running-Stride Variability When Athletes Are Functionally Overreached.
Stride-to-stride fluctuations in running-stride interval display long-range correlations that break down in the presence of fatigue accumulated during an exhaustive run. The purpose of the study was to investigate whether long-range correlations in running-stride interval were reduced by fatigue accumulated during prolonged exposure to a high training load (functional overreaching) and were associated with decrements in performance caused by functional overreaching. Ten trained male runners completed 7 d of light training (LT7), 14 d of heavy training (HT14) designed to induce a state of functional overreaching, and 10 d of light training (LT10) in a fixed order. Running-stride intervals and 5-km time-trial (5TT) performance were assessed after each training phase. The strength of long-range correlations in running-stride interval was assessed at 3 speeds (8, 10.5, and 13 km/h) using detrended fluctuation analysis. Relative to performance post-LT7, time to complete the 5TT was increased after HT14 (+18 s; P < .05) and decreased after LT10 (-20 s; P = .03), but stride-interval long-range correlations remained unchanged at HT14 and LT10 (P > .50). Changes in stride-interval long-range correlations measured at a 10.5-km/h running speed were negatively associated with changes in 5TT performance (r -.46; P = .03). Runners who were most affected by the prolonged exposure to high training load (as evidenced by greater reductions in 5TT performance) experienced the greatest reductions in stride-interval long-range correlations. Measurement of stride-interval long-range correlations may be useful for monitoring the effect of high training loads on athlete performance.


Salivary glucose levels in diabetes mellitus patients: A case-control study.
The aim of the present study was undertaken to correlate the glucose levels in saliva and blood of diabetic and healthy nondiabetic individuals and to determine the efficacy of saliva as a diagnostic tool. This was a case-control study. Forty-five patients previously diagnosed with diabetes mellitus and 45 healthy controls were included in the study. The patients and controls were asked to come to the clinic in the morning, after 8-10 h fasting. At that time, 5 ml of venous blood and unstimulated saliva was collected from both the groups, and 2 h after meal, again, venous blood and unstimulated saliva were collected. The saliva and sera from blood samples were subjected to glucose estimation. Saliva was collected in sterilized vials, and blood was collected in test tubes. Glucose estimation was done by oxidase-peroxidase method. Pearson's correlation coefficient, Student's t-test and paired t-test were used for statistical analysis. Correlation coefficient values show that there is a significant positive correlation between fasting blood and fasting salivary glucose levels and postprandial blood and postprandial salivary glucose levels. Salivary glucose level estimation can be used as a potential indicator in screening, diagnosis and monitoring of diabetes mellitus. Furthermore, it is an easy and noninvasive method.


Targeting cyclin-dependent kinase 1 (CDK1) but not CDK4/6 or CDK2 is selectively lethal to MYC-dependent human breast cancer cells.
Although MYC is an attractive therapeutic target for breast cancer treatment, it has proven challenging to inhibit MYC directly, and clinically effective pharmaceutical agents targeting MYC are not yet available. An alternative approach is to identify genes that are synthetically lethal in MYC-dependent cancer. Recent studies have identified several cell cycle kinases as MYC synthetic-lethal genes. We therefore investigated the therapeutic potential of specific cyclin-dependent kinase (CDK) inhibition in MYC-driven breast cancer. Using small interfering RNA (siRNA), MYC expression was depleted in 26 human breast cancer cell lines and cell proliferation evaluated by BrdU incorporation. MYC-dependent and MYC-independent cell lines were classified based on their sensitivity to siRNA-mediated MYC knockdown. We then inhibited CDKs including CDK4/6, CDK2 and CDK1 individually using either RNAi or small molecule inhibitors, and compared sensitivity to CDK inhibition with MYC dependence in breast cancer cells. Breast cancer cells displayed a wide range of sensitivity to siRNA-mediated MYC knockdown. The sensitivity was correlated with MYC protein expression and MYC phosphorylation level. Sensitivity to siRNA-mediated MYC knockdown did not parallel sensitivity to the CDK4/6 inhibitor PD0332991; instead MYC-independent cell lines were generally sensitive to PD0332991. Cell cycle arrest induced by MYC knockdown was accompanied by a decrease in CDK2 activity, but inactivation of CDK2 did not selectively affect the viability of MYC-dependent breast cancer cells. In contrast, CDK1 inactivation significantly induced apoptosis and reduced viability of MYC-dependent cells but not MYC- independent cells. This selective induction of apoptosis by CDK1 inhibitors was associated with up-regulation of the pro-apoptotic molecule BIM and was p53-independent. Overall, these results suggest that further investigation of CDK1 inhibition as a potential therapy for MYC-dependent breast cancer is warranted.


Two single-headed myosin V motors bound to a tetrameric adapter protein form a processive complex.
Myo4p, one of two class V myosins in budding yeast, continuously transports messenger RNA (mRNA) cargo in the cell but is nonprocessive when characterized in vitro. The adapter protein She3p tightly binds to the Myo4p rod, forming a single-headed motor complex. In this paper, we show that two Myo4p-She3p motors are recruited by the tetrameric mRNA-binding protein She2p to form a processive double-headed complex. The binding site for She3p was mapped to a single α helix that protrudes at right angles from She2p. Processive runs of several micrometers on yeast actin-tropomyosin filaments were observed only in the presence of She2p, and, thus, motor activity is regulated by cargo binding. While moving processively, each head steps ~72 nm in a hand-over-hand motion. Coupling two high-duty cycle monomeric motors via a common cargo-binding adapter protein creates a complex with transport properties comparable with a single dimeric processive motor such as vertebrate myosin Va.


Constructing noise-invariant representations of sound in the auditory pathway.
Identifying behaviorally relevant sounds in the presence of background noise is one of the most important and poorly understood challenges faced by the auditory system. An elegant solution to this problem would be for the auditory system to represent sounds in a noise-invariant fashion. Since a major effect of background noise is to alter the statistics of the sounds reaching the ear, noise-invariant representations could be promoted by neurons adapting to stimulus statistics. Here we investigated the extent of neuronal adaptation to the mean and contrast of auditory stimulation as one ascends the auditory pathway. We measured these forms of adaptation by presenting complex synthetic and natural sounds, recording neuronal responses in the inferior colliculus and primary fields of the auditory cortex of anaesthetized ferrets, and comparing these responses with a sophisticated model of the auditory nerve. We find that the strength of both forms of adaptation increases as one ascends the auditory pathway. To investigate whether this adaptation to stimulus statistics contributes to the construction of noise-invariant sound representations, we also presented complex, natural sounds embedded in stationary noise, and used a decoding approach to assess the noise tolerance of the neuronal population code. We find that the code for complex sounds in the periphery is affected more by the addition of noise than the cortical code. We also find that noise tolerance is correlated with adaptation to stimulus statistics, so that populations that show the strongest adaptation to stimulus statistics are also the most noise-tolerant. This suggests that the increase in adaptation to sound statistics from auditory nerve to midbrain to cortex is an important stage in the construction of noise-invariant sound representations in the higher auditory brain.


The course of life of patients with childhood atopic dermatitis.
Atopic dermatitis mainly covers the period of infancy to adulthood, an important period in the development of an individual. The impairment of quality of life and the psychological wellbeing of children with atopic dermatitis have been well documented but so far no data exist about the impact of atopic dermatitis in childhood on fulfilling age-specific developmental tasks and achieving developmental milestones during this period, referred to as the course of life. The aims of this study were to: (i) assess the course of life and define the disease-related consequences in young adult patients with childhood atopic dermatitis and (ii) determine whether the severity of atopic dermatitis is predictive for the course of life, the disease-related consequences and quality of life later in life. Adult patients who grew up with atopic dermatitis were asked to complete a medical history questionnaire, the Skindex-29, the "course of life" questionnaire and a subjective disease-specific questionnaire. Patients with severe atopic dermatitis in childhood showed a significant delayed social development in their course of life. The results of the disease-specific questionnaire demonstrated remarkable high percentages of psycho-social consequences and physical discomfort caused by atopic dermatitis in childhood. Patients showed a severely negative impact of atopic dermatitis on their current quality of life. This is the first study that applied the "course of life" questionnaire in atopic dermatitis. More insight in the course of life, disease-specific consequences and quality of life of atopic dermatitis is of high importance, especially in case of severe atopic dermatitis.


Ultraminiaturized photovoltaic and radio frequency powered optoelectronic systems for wireless optogenetics.
Wireless control and power harvesting systems that operate injectable, cellular-scale optoelectronic components provide important demonstrated capabilities in neuromodulatory techniques such as optogenetics. Here, we report a radio frequency (RF) control/harvesting device that offers dramatically reduced size, decreased weight and improved efficiency compared to previously reported technologies. Combined use of this platform with ultrathin, multijunction, high efficiency solar cells allows for hundred-fold reduction of transmitted RF power, which greatly enhances the wireless coverage. Fabrication involves separate construction of the harvester and the injectable µ-ILEDs. To test whether the presence of the implantable device alters behavior, we implanted one group of wild type mice and compared sociability behavior to unaltered controls. Social interaction experiments followed protocols defined by Silverman et al. with minor modifications. The results presented here demonstrate that miniaturized RF harvesters, and RF control strategies with photovoltaic harvesters can, when combined with injectable µ-ILEDs, offer versatile capabilities in optogenetics. Experimental and modeling studies establish a range of effective operating conditions for these two approaches. Optogenetics studies with social groups of mice demonstrate the utility of these systems. The addition of miniaturized, high performance photovoltaic cells significantly expands the operating range and reduces the required RF power. The platform can offer capabilities to modulate signaling path in the brain region of freely-behaving animals. These suggest its potential for widespread use in neuroscience.


Using hyperbolic Lagrangian coherent structures to investigate vortices in bioinspired fluid flows.
We use direct Lyapunov exponents to identify Lagrangian coherent structures (LCSs) in a bioinspired fluid flow: the wakes of rigid pitching panels with a trapezoidal planform geometry chosen to model idealized fish caudal fins. When compared with commonly used Eulerian criteria, the Lagrangian method has previously exhibited the ability to define structure boundaries without relying on a preselected threshold. In addition, qualitative changes in the LCS have previously been shown to correspond to physical changes in the vortex structure. For this paper, digital particle image velocimetry experiments were performed to obtain the time-resolved velocity fields for Strouhal numbers of 0.17 and 0.27. A classic reverse von Karman vortex street pattern was observed along the midspan of the near wake at low Strouhal number, but at higher Strouhal number the complexity of the wake increased downstream of the trailing edge. The spanwise vortices spread transversely across the wake and lose coherence, and this event was shown to correspond to a qualitative change in the LCS at the same time and location.


Lymphoplasmacytic sclerosing pancreatitis: inflammatory mimic of pancreatic carcinoma.
Lymphoplasmacytic sclerosing pancreatitis (LP) is a rare cause of benign mass lesions of the pancreas that can resemble adenocarcinoma. This study evaluates and classifies a series of patients with LP. Patients with benign pancreatic disease were identified from a prospective pancreatic database, and these cases were reviewed to identify patients with LP. Patients were subdivided into two groups: (1) classic LP, which included those patients who had all four of the characteristic histologic features of LP, including lymphoplasmacytic infiltration of the pancreas, interstitial fibrosis, periductal inflammation, and periphlebitis; and (2) intermediate LP, which included patients with at least two of these histologic findings. Patient demographics, pathologic and clinical features, and outcome were analyzed. From 1985 to 2001, a total of 1287 pancreatic resections were performed at our institution, of which 159 were for benign disease. Of these, 31 had pathologic features consistent with LP, and all of these patients had a presumed preoperative diagnosis of pancreatic carcinoma. Most of these patients presented with jaundice (n = 21) or abdominal pain (n = 7). In 29 of 31 patients, curative resection was possible. Of these, 28% (8/29) developed recurrence after resection: seven with jaundice and one with recurrent pancreatitis (median time to recurrence, 11 months; median follow up, 38 months). All patients with recurrent jaundice appeared to have biliary strictures at the time of direct cholangiography and no patient had malignancy. A review of the pathology reports identified 19 patients with classic LP and 12 patients with intermediate LP, and there was no difference between these two groups. LP is a rare cause of pancreatitis that is difficult to differentiate from carcinoma preoperatively. Patients with classic and intermediate LP appear to demonstrate a similar clinical behavior. Nearly one third of patients have a progressive course after resection, with 25% developing recurrent jaundice; thus close follow-up is mandatory for all patients.


The influence of alcohol content variation in UK packaged beers on the uncertainty of calculations using the Widmark equation.
It is common for forensic practitioners to calculate an individual's likely blood alcohol concentration following the consumption of alcoholic beverage(s) for legal purposes, such as in driving under the influence (DUI) cases. It is important in these cases to be able to give the uncertainty of measurement on any calculated result, for this reason uncertainty data for the variables used for any calculation are required. In order to determine the uncertainty associated with the alcohol concentration of beer in the UK the alcohol concentration (%v/v) of 218 packaged beers (112 with an alcohol concentration of ≤5.5%v/v and 106 with an alcohol concentration of >5.5%v/v) were tested using an industry standard near infra-red (NIR) analyser. The range of labelled beer alcohol by volume (ABV's) tested was 3.4%v/v - 14%v/v. The beers were obtained from a range of outlets throughout the UK over a period of 12 months. The root mean square error (RMSE) was found to be ±0.43%v/v (beers with declared %ABV of ≤5.5%v/v) and ±0.53%v/v (beers with declared %ABV of >5.5%v/v) the RMSE for all beers was ±0.48%v/v. The standard deviation from the declared %ABV is larger than those previously utilised for uncertainty calculations and illustrates the importance of appropriate experimental data for use in the determination of uncertainty in forensic calculations.


Integrating the Water Planetary Boundary With Water Management From Local to Global Scales.
The planetary boundaries framework defines the "safe operating space for humanity" represented by nine global processes that can destabilize the Earth System if perturbed. The water planetary boundary attempts to provide a global limit to anthropogenic water cycle modifications, but it has been challenging to translate and apply it to the regional and local scales at which water problems and management typically occur. We develop a cross-scale approach by which the water planetary boundary could guide sustainable water management and governance at subglobal contexts defined by physical features (e.g., watershed or aquifer), political borders (e.g., city, nation, or group of nations), or commercial entities (e.g., corporation, trade group, or financial institution). The application of the water planetary boundary at these subglobal contexts occurs via two approaches: (i) calculating fair shares, in which local water cycle modifications are compared to that context's allocation of the global safe operating space, taking into account biophysical, socioeconomic, and ethical considerations; and (ii) defining a local safe operating space, in which interactions between water stores and Earth System components are used to define local boundaries required for sustaining the local water system in stable conditions, which we demonstrate with a case study of the Cienaga Grande de Santa Marta wetlands in Colombia. By harmonizing these two approaches, the water planetary boundary can ensure that water cycle modifications remain within both local and global boundaries and complement existing water management and governance approaches.


Critical time course of right frontoparietal involvement in mental number space.
Neuropsychological, neurophysiological, and neuroimaging studies suggest that right frontoparietal circuits may be necessary for the processing of mental number space, also known as the mental number line (MNL). Here we sought to specify the critical time course of three nodes that have previously been related to MNL processing: right posterior parietal cortex (rPPC), right FEF (rFEF), and right inferior frontal gyrus (rIFG). The effects of single-pulse TMS delivered at 120% distance-adjusted individual motor threshold were investigated in 21 participants, within a window of 0-400 msec (sampling interval = 33 msec) from the onset of a central digit (1-9, 5 excluded). Pulses were delivered in a random order and with equal probability at each time point, intermixed with noTMS trials. To analyze whether and when TMS interfered with MNL processing, we fitted bimodal Gaussian functions to the observed data and measured effects on changes in the Spatial-Numerical Association of Response Codes (SNARC) effect (i.e., an advantage for left- over right-key responses to small numbers and right- over left-key responses to large numbers) and in overall performance efficiency. We found that, during magnitude judgment with unimanual key-press responses, TMS reduced the SNARC effect in the earlier period of the fitted functions (∼25-60 msec) when delivered over rFEF (small and large numbers) and rIFG (small numbers); TMS further reduced the SNARC effect for small numbers in a later period when delivered to rFEF (∼200 msec). In contrast, TMS of rPPC did not interfere with the SNARC effect but generally reduced performance for small numbers and enhanced it for large numbers, thus producing a pattern reminiscent of "neglect" in mental number space. Our results confirm the causal role of an intact right frontoparietal network in the processing of mental number space. They also indicate that rPPC is specifically tied to explicit number magnitude processing and that rFEF and rIFG contribute to interfacing mental visuospatial codes with lateralized response codes. Overall, our findings suggest that both ventral and dorsal frontoparietal circuits are causally involved and functionally connected in the mapping of numbers to space.


Predictors of smoking among Swedish adolescents.
Smoking most often starts in adolescence, implying that understanding of predicting factors for smoking initiation during this time period is essential for successful smoking prevention. The aim of this study was to examine predicting factors in early adolescence for smoking in late adolescence. Longitudinal cohort study, involving 649 Swedish adolescents from lower secondary school (12-13 years old) to upper secondary school (17-18 years old). Tobacco habits, behavioural, intra- and interpersonal factors and socio-demographic variables were assessed through questionnaires. Descriptive statistics, univariable and multivariable logistic regression were used to identify predicting factors. Smoking prevalence increased from 3.3% among 12-13 year olds to 25.1% among 17-18 year olds. Possible predictors of smoking were: female sex, lower parental education, poorer family mood, poorer self-rated health, poorer self-esteem, less negative attitude towards smoking, binge drinking, snus use and smoking. In a multivariable logistic regression analysis, female sex (OR 1.64, CI 1.08-2.49), medium and low self-esteem (medium: OR 1.57, CI 1.03-2.38, low: 2.79, CI 1.46-5.33), less negative attitude towards smoking (OR 2.81, CI 1.70-4.66) and ever using snus (OR 3.43, CI 1.78-6.62) remained significant independent predicting factors. The study stresses the importance of strengthening adolescents' self-esteem, promoting anti-smoking attitudes in early adolescence, as well as avoidance of early initiation of snus. Such measures should be joint efforts involving parents, schools, youth associations, and legislating authorities.


Left ventricular hypertrophy and diastolic dysfunction in children with sickle cell disease are related to asleep and waking oxygen desaturation.
Premature death and cardiac abnormalities are described in individuals with sickle cell disease (SCD), but the mechanisms are not well characterized. We tested the hypothesis that cardiac abnormalities in children with SCD are related to sleep-disordered breathing. We enrolled 44 children with SCD (mean age, 10.1 years; range, 4-18 years) in an observational study. Standard and tissue Doppler echocardiography, waking oxygen saturation averaged over 5 minutes, and overnight polysomnography were obtained in participants, each within 7 days. Eccentric left ventricular (LV) hypertrophy was present in 46% of our cohort. After multivariable adjustment, LV mass index was inversely related to average asleep and waking oxygen saturation. For every 1% drop in the average asleep oxygen saturation, there was a 2.1 g/m(2.7) increase in LV mass index. LV diastolic dysfunction, as measured by the E/E' ratio, was present in our subjects and was also associated with low oxygen saturation (sleep or waking). Elevated tricuspid regurgitant velocity (> or = 2.5 m/sec), a measure of pulmonary hypertension, was not predicted by either oxygen saturation or sleep variables with multivariable logistic regression analysis. These data provide evidence that low asleep and waking oxygen saturations are associated with LV abnormalities in children with SCD.


Health and fertility in World Health Organization group 2 anovulatory women.
Disruption of ovulation occurs in different types of clinical infertility. The World Health Organization (WHO) has provided a classification of ovulation disorders. This review focuses on WHO group 2 anovulation. Searches were performed in Medline/PubMed and EMBASE. Each subject summary was presented to the European Society of Human Reproduction and Embryology (ESHRE) Workshop Group, where omissions or disagreements were resolved by discussion. Disorders resulting in ovulatory disturbances are a relatively common cause of infertility. They occur most frequently in the context of WHO group 2 anovulation as reflected, for example, in the polycystic ovary syndrome (PCOS). The aetiology of PCOS remains unclear but evidence exists for a multifactorial origin with a genetic predisposition. Women with PCOS show an increased time to pregnancy but their eventual family size is not necessarily reduced. Also their frequency of miscarriage does not appear increased. Clomiphene citrate is still the first-line treatment in subfertile anovulatory patients with PCOS, with gonadotrophins and laparoscopic ovarian surgery as second-line options. Aromatase inhibitors show promising results. Long-term health risks in patients with WHO group 2 anovulation demand their general health be monitored, even after their reproductive needs have been fulfilled. Metabolic and cardiovascular risk prevention in women with PCOS should start as early as possible. It is not easy to analyse the possible role of PCOS, independent of obesity, metabolic syndrome, insulin resistance and diabetes, on long-term health.


Physiotherapy versus placebo or no intervention in Parkinson's disease.
Despite medical therapies and surgical interventions for Parkinson's disease (PD), patients develop progressive disability. The role of physiotherapy aims to maximise functional ability and minimise secondary complications through movement rehabilitation within a context of education and support for the whole person. The overall aim is to optimise independence, safety and well-being, thereby enhancing quality of life. To assess the effectiveness of physiotherapy intervention compared with no intervention in patients with PD. We identified relevant trials by electronic searches of numerous literature databases (e.g. MEDLINE, EMBASE) and trial registers, plus handsearching of major journals, abstract books, conference proceedings and reference lists of retrieved publications. The literature search included trials published up to end of December 2010. Randomised controlled trials of physiotherapy intervention versus no physiotherapy intervention in patients with PD. Two review authors independently extracted data from each article. We used standard meta-analysis methods to assess the effectiveness of physiotherapy intervention compared with no physiotherapy intervention. Trials were classified into the following intervention comparisons: general physiotherapy, exercise, treadmill training, cueing, dance and martial arts. We used tests for heterogeneity to assess for differences in treatment effect across these different physiotherapy interventions. We identified 33 trials with 1518 participants. Compared with no-intervention, physiotherapy significantly improved the gait outcomes of velocity (mean difference 0.05 m/s, 95% confidence interval (CI): 0.02 to 0.07, P = 0.0002), two- or six-minute walk test (16.40 m, CI: 1.90 to 30.90, P = 0.03) and step length (0.03 m, CI: 0 to 0.06, P = 0.04); functional mobility and balance outcomes of Timed Up & Go test (-0.61 s, CI: -1.06 to -0.17, P = 0.006), Functional Reach Test (2.16 cm, CI: 0.89 to 3.43, P = 0.0008) and Berg Balance Scale (3.36 points, CI: 1.91 to 4.81, P < 0.00001); and clinician-rated disability using the Unified Parkinson's Disease Rating Scale (UPDRS) (total: -4.46 points, CI -7.16 to -1.75, P = 0.001; activities of daily living: -1.36, CI -2.41 to -0.30, P = 0.01; and motor: -4.09, CI: -5.59 to -2.59, P < 0.00001). There was no difference between arms in falls or patient-rated quality of life. Indirect comparisons of the different physiotherapy interventions found no evidence that the treatment effect differed across the physiotherapy interventions for any of the outcomes assessed. Benefit for physiotherapy was found in most outcomes over the short-term (i.e. < three months), but was only significant for velocity, two- or six-minute walk test, step length, Timed Up & Go, Functional Reach Test, Berg Balance Scale and clinician-rated UPDRS. Most of the observed differences between the treatments were small. However, for some outcomes (e.g. velocity, Berg Balance Scale and UPDRS), the differences observed were at, or approaching, what are considered minimally clinical important changes.The review illustrates that a wide range of approaches are employed by physiotherapists to treat PD. However, there was no evidence of differences in treatment effect between the different types of physiotherapy interventions being used, though this was based on indirect comparisons. There is a need to develop a consensus menu of 'best-practice' physiotherapy, and to perform large well-designed randomised controlled trials to demonstrate the longer-term efficacy and cost-effectiveness of 'best practice' physiotherapy in PD.


Generic Repeat Finder: A High-Sensitivity Tool for Genome-Wide De Novo Repeat Detection.
Comprehensive and accurate annotation of the repeatome, including transposons, is critical for deepening our understanding of repeat origins, biogenesis, regulatory mechanisms, and roles. Here, we developed Generic Repeat Finder (GRF), a tool for genome-wide repeat detection based on fast, exhaustive numerical calculation algorithms integrated with optimized dynamic programming strategies. GRF sensitively identifies terminal inverted repeats (TIRs), terminal direct repeats (TDRs), and interspersed repeats that bear both inverted and direct repeats. GRF also detects DNA or RNA transposable elements characterized by these repeats in plant and animal genomes. For TIRs and TDRs, GRF identifies spacers in the middle and mismatches/insertions or deletions in terminal repeats, showing their alignment or base-pairing information. GRF helps improve the annotation for various DNA transposons and retrotransposons, such as miniature inverted-repeat transposable elements (MITEs), long terminal repeat (LTR) retrotransposons, and non-LTR retrotransposons, including long interspersed nuclear elements and short interspersed nuclear elements in plants. We used GRF to perform TIR/TDR, interspersed-repeat, and MITE detection in several species, including Arabidopsis (Arabidopsis thaliana), rice (Oryza sativa), and mouse (Mus musculus). As a generic bioinformatics tool in repeat finding implemented as a parallelized C++ program, GRF was faster and more sensitive than the existing inverted repeat/MITE detection tools based on numerical approaches (i.e. detectIR and detectMITE) in Arabidopsis and mouse. GRF is more sensitive than Inverted Repeat Finder in TIR detection, LTR_FINDER in short TDR detection (≤1,000 nt), and phRAIDER in interspersed repeat detection in Arabidopsis and rice. GRF is an open source available from Github.


HPV vaccination coverage and course completion rates for Indigenous Australian adolescents, 2015.
To estimate human papillomavirus (HPV) vaccination coverage and course completion rates for Indigenous adolescents in four Australian states and territories. Adolescents who were 12 years old in 2015 and received the quadrivalent HPV vaccine (three doses: 0, 2, 6 months) as part of the National HPV Vaccination Program in 2015 or 2016 in New South Wales, Queensland, the Northern Territory, or the Australian Capital Territory. Estimated HPV vaccination coverage by dose and by Indigenous status and sex, based on National HPV Vaccination Program Register data; vaccination course completion rates (proportion of dose 1 recipients who received dose 3) for 12-year-olds vaccinated during 2013-2016, by sex, jurisdiction, and Indigenous status. Dose 1 coverage exceeded 80% for all Indigenous status/jurisdiction/sex groups (range, 83.3-97.7%). Coverage was similar for Indigenous and non-Indigenous girls in Queensland (87.3% v 87.0%), lower for Indigenous girls in the ACT (88.7% v 97.7%) and the NT (91.1% v 97.0%), and higher in NSW (95.9% v 89.9%); it was similar for Indigenous and non-Indigenous boys in all jurisdictions except the NT (88.6% v 96.3%). Dose 3 coverage (range, 61.2-87.7%) was markedly lower for Indigenous than non-Indigenous 12-year-olds in all jurisdictions, except for girls in NSW (82.6% v 83.6%). HPV vaccine coverage is high, but course completion is generally lower for Indigenous adolescents. Strategies for improving completion rates for Indigenous Australians are needed to end the higher burden of cervical cancer among Indigenous than non-Indigenous women.


The Hantavirus Surface Glycoprotein Lattice and Its Fusion Control Mechanism.
Hantaviruses are rodent-borne viruses causing serious zoonotic outbreaks worldwide for which no treatment is available. Hantavirus particles are pleomorphic and display a characteristic square surface lattice. The envelope glycoproteins Gn and Gc form heterodimers that further assemble into tetrameric spikes, the lattice building blocks. The glycoproteins, which are the sole targets of neutralizing antibodies, drive virus entry via receptor-mediated endocytosis and endosomal membrane fusion. Here we describe the high-resolution X-ray structures of the heterodimer of Gc and the Gn head and of the homotetrameric Gn base. Docking them into an 11.4-Å-resolution cryoelectron tomography map of the hantavirus surface accounted for the complete extramembrane portion of the viral glycoprotein shell and allowed a detailed description of the surface organization of these pleomorphic virions. Our results, which further revealed a built-in mechanism controlling Gc membrane insertion for fusion, pave the way for immunogen design to protect against pathogenic hantaviruses.


Clean image synthesis and target numerical marching for optical imaging with backscattering light.
Scanning backscattering imaging and independent component analysis (ICA) are used to probe targets hidden in the subsurface of a turbid medium. A new correction procedure is proposed and used to synthesize a "clean" image of a homogeneous host medium numerically from a set of raster-scanned "dirty" backscattering images of the medium with embedded targets. The independent intensity distributions on the surface of the medium corresponding to individual targets are then unmixed using ICA of the difference between the set of dirty images and the clean image. The target positions are localized by a novel analytical method, which marches the target to the surface of the turbid medium until a match with the retrieved independent component is accomplished. The unknown surface property of the turbid medium is automatically accounted for by this method. Employing clean image synthesis and target numerical marching, three-dimensional (3D) localization of objects embedded inside a turbid medium using independent component analysis in a backscattering geometry is demonstrated for the first time, using as an example, imaging a small piece of cancerous prostate tissue embedded in a host consisting of normal prostate tissue.


Field analysis of electro-optic probes for minimally invasive microwave sampling.
We numerically and experimentally investigate the field invasiveness of microwave signals using an electro-optic technique. The distortion of the standing wave voltage and pulse waveform probed by the electro-optic technique is explored through both minimally invasive external and non-invasive internal sensing configurations. First, we analyzed the continuous wave microwave field imaging on a millimeter- scale coaxial transmission line using a highly accurate and stable electro- optic scanning system. The electric field images from the microwave device are attained virtually non-invasively using a miniaturized fiber-coupled electro-optic probe. The accuracy of the field imaging associated with various probe styles is investigated by numerical analysis and experiment. Then, we analyzed the waveform of the coaxial transmission line up to 50 GHz using a pulsed electro-optic system with an external probe set. Finally, the invasive analysis was extended to the sub-millimeter-scale on-wafer coplanar waveguides, where the voltage waveforms are measured using a minimally invasive external probe as well as an internal wafer probe for non-invasive sampling.


cDNA cloning, expression and chromosomal localization of the human sarco/endoplasmic reticulum Ca(2+)-ATPase 3 gene.
cDNA and genomic clones encoding human sarco/endoplasmic reticulum Ca(2+)-ATPase 3 (SERCA3) were isolated. The composite nucleotide sequence of the 4.6 kb cDNA, as well as the partial structure of 25 kb of genomic DNA encoding all but the 5' region of the gene, was determined. The nucleotide sequence coding for the last six amino acids of the pump and the 3'-untranslated region were identified within the sequence of the last exon. Northern blot hybridization analysis using cDNA probes derived from this exon detected a 4.8 kb transcript in several human tissues. Using a cDNA probe derived from the 5'-coding region an unexpected mRNA distribution pattern, consisting of two mRNA species of 4.8 and 4.0 kb, was detected in thyroid gland and bone marrow only. This is the first indication of an alternative splicing mechanism operating on the SERCA3 gene transcript, which most likely generates SERCA3 isoforms with altered C-termini. Human SERCA3 expressed in platelets and in COS cells transfected with the corresponding cDNA was detected with the previously described antibody N89 (directed against the N-terminal region of rat SERCA3) and with a new SERCA3-specific antiserum C91, directed against the extreme C-terminus of the human isoform. A monoclonal antibody PL/IM430, previously assumed to recognize SERCA3 in human platelets, does not react with the 97 kDa human SERCA3 transiently expressed in COS cells. Therefore the 97 kDa isoform detected by PL/IM430 more likely represents a novel SERCA pump, as recently suggested [Kovács, Corvazier, Papp, Magnier, Bredoux, Enyedi, Sarkadi and Enouf (1994) J. Biol. Chem. 269, 6177-6184]. Finally, by fluorescence in situ hybridization and chromosome G-banding analyses, the SERCA3 gene was assigned to human chromosome 17p13.3.


Computational Analysis of the Interplay between Deep Level Traps and Perovskite Solar Cell Efficiency.
New deposition methods of halide perovskites are being developed with the aim of improving solar cell power conversion efficiency by controlling the physiochemical properties of the perovskite film. In the case of methylammonium lead iodide (MAPbI3), deep level traps limit efficiency by participating in charge carrier recombination. Prior work has shown that the solar cell efficiency of MAPbI3 solar cells varied significantly with deposition method; specifically, efficiencies of 13.5 and 17.7% were observed for MAPbI3 processed with a one- and two-step method, respectively. However, the origin of the difference in efficiency remains unclear. In this study, we analyze the interplay between deep level traps and efficiency by simulating the photoexcited charge carrier pathway across solar cells processed via the one- and two-step method using finite-element drift-diffusion modeling. We determined that in the case of one-step processing, the traps propagate throughout the bulk, while for two-step, the traps congregate at the interface where the MAPbI3 was grown (mesoporous TiO2). Composition and structural analysis are used to propose a plausible explanation as to why the difference in processing changes the spatial distribution of the traps.


Drivers of wetland conversion: a global meta-analysis.
Meta-analysis of case studies has become an important tool for synthesizing case study findings in land change. Meta-analyses of deforestation, urbanization, desertification and change in shifting cultivation systems have been published. This present study adds to this literature, with an analysis of the proximate causes and underlying forces of wetland conversion at a global scale using two complementary approaches of systematic review. Firstly, a meta-analysis of 105 case-study papers describing wetland conversion was performed, showing that different combinations of multiple-factor proximate causes, and underlying forces, drive wetland conversion. Agricultural development has been the main proximate cause of wetland conversion, and economic growth and population density are the most frequently identified underlying forces. Secondly, to add a more quantitative component to the study, a logistic meta-regression analysis was performed to estimate the likelihood of wetland conversion worldwide, using globally-consistent biophysical and socioeconomic location factor maps. Significant factors explaining wetland conversion, in order of importance, are market influence, total wetland area (lower conversion probability), mean annual temperature and cropland or built-up area. The regression analyses results support the outcomes of the meta-analysis of the processes of conversion mentioned in the individual case studies. In other meta-analyses of land change, similar factors (e.g., agricultural development, population growth, market/economic factors) are also identified as important causes of various types of land change (e.g., deforestation, desertification). Meta-analysis helps to identify commonalities across the various local case studies and identify which variables may lead to individual cases to behave differently. The meta-regression provides maps indicating the likelihood of wetland conversion worldwide based on the location factors that have determined historic conversions.


Genome-wide analysis of dietary eicosapentaenoic acid- and oleic acid-induced modulation of colon inflammation in interleukin-10 gene-deficient mice.
Dietary n-3 polyunsaturated fatty acids can reduce inflammation via a range of mechanisms. This study tested the effect of dietary eicosapentaenoic acid (EPA) on intestinal inflammation using interleukin-10 gene-deficient (Il10(-/-)) mice. At 35 days of age, 12 weaned Il10(-/-) and 12 C57 mice were randomly assigned to one of two modified AIN-76A diets, supplemented with 3.7% purified ethyl esters of either EPA (n-3) or oleic acid (OA, control). To identify genes relevant to colon inflammation, transcription profiling (microarrays and qRT-PCR) and bioinformatic analyses were used. In this study, dietary EPA reversed the decrease in colon fatty acid beta-oxidation gene expression observed in OA-fed Il10(-/-) compared to C57 mice. Il10(-/-) mice fed the OA diet showed decreased expression of antioxidant enzyme genes, as well as those involved in detoxification of xenobiotics, compared to C57 mice on the same diet. In contrast, dietary EPA increased the expression of these genes in Il10(-/-) mice. These data indicate that dietary EPA-induced endogenous lipid oxidation which might have a potential anti-inflammatory effect on colon tissue. This is supported by the activation of the Ppara gene that regulates the expression of pro-inflammatory and immunomodulatory genes and proteins.


Increased IL-6-production by cells isolated from the fibrous bone dysplasia tissues in patients with McCune-Albright syndrome.
McCune-Albright syndrome (MAS) is characterized by café-au-lait spot, multiple endocrine hyperfunction, and polyostotic fibrous dysplasia. A somatic point mutation of Gsalpha protein was reported to decrease GTPase activity, leading to increase in the GSalpha-associated hormone actions via cAMP. IL-6 is known to stimulate osteoclast formation and in the IL-6 promoter, a cAMP responsive element has been identified. In this paper, we investigated the role of IL-6 in the bone lesions of MAS, using the isolated fibrous cells from the polyostotic fibrous dysplasia tissues in bones of the two patients with MAS. Bone biopsy specimen revealed the increased osteoclast in number. In both patients, a GSalpha mutation (Arg201 -> His) was identified in the cultured fibrous cells. Intracellular cAMP content and IL-6 secretion by the patient cells were increased. Rp-8Br-cAMP significantly inhibited IL-6 production in the patient cells, while it had no effect on normal control. The addition of dibutyryl cAMP significantly increased the synthesis of IL-6 in normal control cells. In contrast, no effect of dibutyryl cAMP on IL-6 synthesis was observed in the cells from one of the MAS patients. These data suggest that IL-6 is, at least, one of the downstream effectors of cAMP and that the increased IL-6 synthesis has a pathogenic role in the bone lesions of MAS patients via increasing the number of osteoclasts. These results may provide a new strategy for the therapy of MAS patients.


History of depressive and anxiety disorders and paroxetine response in patients with irritable bowel syndrome: post hoc analysis from a placebo-controlled study.
Although irritable bowel syndrome (IBS) is highly comorbid with depressive and anxiety disorders, information on the clinical implications of this comorbidity is limited. We investigated whether a history of depressive and/or anxiety disorders was associated with response to treatment in a double-blind, randomized, placebo-controlled trial of paroxetine controlled release (CR) in IBS. Seventy-two IBS subjects (diagnosed using Rome II criteria) were recruited from August 2003 to November 2005 and randomly assigned to receive flexibly dosed paroxetine CR (dose, 12.5-50 mg/day) or placebo for 12 weeks. The Mini-International Neuropsychiatric Interview (MINI-Plus version) was used to ascertain current (exclusionary) or past diagnoses of depressive and anxiety disorders. Subjective depression, anxiety, and stress were assessed at entry and throughout the trial using the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Perceived Stress Scale (PSS). Severity of IBS symptoms was determined by the Composite Pain Score (CPS), administered via Interactive Voice Response System, and the Clinical Global Impressions scale (CGI). The primary outcome was treatment response defined as ≥ 25% reduction in CPS from randomization to end of treatment. A post hoc analysis (multivariate logistic regression) was done to evaluate whether a history of depressive and/or anxiety disorder was associated with response to medication. Baseline demographic and clinical characteristics (CPS, BDI, BAI, PSS, CGI scores) were similar between groups (history of depressive/anxiety disorder vs. no history). In multivariate logistic regression analysis, treatment response was not predicted by history of depressive and/or anxiety disorder (OR = 0.58, CI = 0.29 to 1.68, p = .32) or drug status (paroxetine CR vs. placebo) (OR = 1.26, CI = 0.68 to 3.21, p = .19). Drug status was significantly associated with the secondary outcome variable of treatment response as defined by a CGI improvement score of 1 to 2 (OR = 12.14, CI = 2.9 to 48.4, p < .001). Paroxetine CR was safe and well tolerated during the study. History of depressive and/or anxiety disorder was not associated with response of IBS symptoms to paroxetine CR. Conclusions are limited due to insufficient statistical power. Further research is needed to clarify the role of selective serotonin reuptake inhibitors in the treatment of IBS and to elucidate the treatment ramifications of comorbid psychiatric disorders. clinicaltrials.gov Identifier: NCT00610909.


Comparative effects of optical-correlator signal-dependent and signal-independent noise on pattern-recognition performance with the phase-only filter.
The comparative effects of optical-correlator signal-dependent and additive signal-independent noise on correlation-filter performance are analyzed by three different performance measures. For an identical value of the signal-to-noise ratio imposed on each type of noise in a binary input image, computer simulations performed with the phase-only filter show (i) that additive Gaussian signal-independent noise yields a much larger correlation-performance degradation than signal-dependent noise and (ii) that the different types of signal-dependent noise lead to similar correlation results because of similar effects on the input image that are inherent to the nature of the noise.


Copper, iron, zinc and tannin concentrations throughout the digestive tract of tropical goats and sheep fed a high-fibre tannin-rich diet.
The dry season in tropical regions urges livestock to feed on nutritionally very poor diets. It has not been explored how tropical sheep-assumed grazers-and tropical goats-intermediate browsers-cope with a high-fibre tannin-rich diet. This study was designed to determine the effects of a high-fibre and tannin-rich diet on the flow of important microminerals iron (Fe), zinc (Zn) and copper (Cu) throughout the digestive tract of tropical sheep and goats. The feeding trial was set up with twelve adult male animals, six sheep with mean body weight (BW) of 30.3 ± 1.6 kg and six goats with mean BW of 26.4 ± 2.2 kg. The feed consisted of 36% leaves of Millettia ferruginea, 61% hay and 3% concentrate and was offered at 3% of BW (all on dry matter (DM) basis). The total faecal collection was carried out for 7 consecutive days. At the end of the experimental period, the animals were slaughtered to collect liver and digesta samples from the gastrointestinal tract. Feed, digesta and faecal samples underwent analysis of Fe, Zn, and Cu and total tannins (TT). Goats had significantly higher reticulum Cu concentrations expressed on DM as compared to sheep. Faecal Cu concentrations were higher for goats compared to sheep. Reticulum and colon digesta Zn levels were higher in goats than sheep. Abomasum and colon Fe levels were higher in sheep than goats when expressed on DM. These results suggest differences in feed intake, micromineral absorption, secretion and excretion between sheep and goats, pointing to a divergent mineral metabolism as an adaptation to the challenge of a dry season diet having very low nutritive value.


Discovery of a Cynomolgus Monkey Family With Retinitis Pigmentosa.
To accelerate the development of new therapies, an inherited retinal degeneration model in a nonhuman primate would be useful to confirm the efficacy in preclinical studies. In this study, we describe the discovery of retinitis pigmentosa in a cynomolgus monkey (Macaca fascicularis) pedigree. First, screening with fundus photography was performed on 1443 monkeys at the Tsukuba Primate Research Center. Ophthalmic examinations, such as indirect ophthalmoscopy, ERGs using RETeval, and optic coherent tomography (OCT) measurement, were then performed to confirm diagnosis. Retinal degeneration with cystoid macular edema was observed in both eyes of one 14-year-old female monkey. In her examinations, the full-field ERGs were nonrecordable and the outer layer of the retina in the parafoveal area was not visible on OCT imaging. Moreover, less frequent pigmentary retinal anomalies also were observed in her 3-year-old nephew. His full-field ERGs were almost nonrecordable and the outer layer was not visible in the peripheral retina. His father was her cousin (the son of her mother's older brother) and his mother was her younger half-sibling sister with a different father. The hereditary nature is highly probable (autosomal recessive inheritance suspected). However, whole-exome analysis performed identified no pathogenic mutations in these monkeys.


Comparison Between the Internal and External Pressure Filtration Method of Cell-Free and Concentrated Ascites Reinfusion Therapy Using the Same Cancerous Ascites.
Cell-free and concentrated ascites reinfusion therapy (CART) by internal filtration pressure method (internal method) and external filtration pressure method (external method) using the same cancerous ascites was performed. The rate of rise in circuit pressure and recovered components were compared between the two methods. The factors related to circuit pressure rise were also researched. In both methods, circuit pressure rose in 50% of cases. The recovery rates of IgG, IgA, IgM, and haptoglobin were significantly higher for the internal method than for the external method, whereas the recovery rate of α1 -antitrypsin was significantly lower in the internal method than in the external method. The levels of IL-6, haptoglobin, α1 -antitrypsin, and fibrinogen/fibrindegradation products (FDP) in the original ascites were significantly higher in the group wherein circuit pressure rose than in that without circuit pressure rise. These proteins might be related to the rise in circuit pressure.


Quantitative assessments of water-use efficiency in Temperate Eurasian Steppe along an aridity gradient.
Water-use efficiency (WUE), defined as the ratio of net primary productivity (NPP) to evapotranspiration (ET), is an important indicator to represent the trade-off pattern between vegetation productivity and water consumption. Its dynamics under climate change are important to ecohydrology and ecosystem management, especially in the drylands. In this study, we modified and used a late version of Boreal Ecosystem Productivity Simulator (BEPS), to quantify the WUE in the typical dryland ecosystems, Temperate Eurasian Steppe (TES). The Aridity Index (AI) was used to specify the terrestrial water availability condition. The regional results showed that during the period of 1999-2008, the WUE has a clear decreasing trend in the spatial distribution from arid to humid areas. The highest annual average WUE was in dry and semi-humid sub-region (DSH) with 0.88 gC mm-1 and the lowest was in arid sub-region (AR) with 0.22 gC mm-1. A two-stage pattern of WUE was found in TES. That is, WUE would enhance with lower aridity stress, but decline under the humid environment. Over 65% of the region exhibited increasing WUE. This enhancement, however, could not indicate that the grasslands were getting better because the NPP even slightly decreased. It was mainly attributed to the reduction of ET over 70% of the region, which is closely related to the rainfall decrease. The results also suggested a similar negative spatial correlation between the WUE and the mean annual precipitation (MAP) at the driest and the most humid ends. This regional pattern reflected the different roles of water in regulating the terrestrial ecosystems under different aridity levels. This study could facilitate the understanding of the interactions between terrestrial carbon and water cycles, and thus contribute to a sustainable management of nature resources in the dryland ecosystems.


Influence of green solvent on levulinic acid production from lignocellulosic paper waste.
Lignocellulosic wastes constitute a significant portion of the municipal solid waste, which should be valorised for the synthesis of value-added chemicals to achieve circular bioeconomy. This study evaluates the use of γ-valerolactone (GVL) and acetone as green co-solvents to produce levulinic acid (LA) from lignocellulosic paper towel waste at different temperatures using dilute H2SO4. At the highest reaction temperature (200 °C), H2O-only system achieved ~15 Cmol% of LA at maximum. while GVL/H2O and acetone/H2O co-solvent systems enhanced the depolymerisation of paper towel waste and the subsequent conversion to LA, with the highest yield amounted to ~32 Cmol%. Acetone/H2O solvent system generated ~17 Cmol% LA at a lower temperature (180 °C), while higher temperature induced polymerisation of soluble sugars and intermediates, hindering further conversion to LA. In contrast, the availability of soluble sugars was higher in the GVL/H2O system, which favoured the production of LA at higher temperatures.


Adalimumab for the treatment of Japanese patients with intestinal Behçet's disease.
Behçet's disease is a chronic, relapsing inflammatory disease that can involve the mouth, skin, eyes, genitals, and intestines. Active intestinal Behçet's disease can be complicated by gastrointestinal (GI) bleeding and perforation. We performed a multicenter, open-label, uncontrolled study to evaluate the efficacy and safety of adalimumab, a fully human monoclonal antibody against tumor necrosis factor α, in patients with intestinal Behçet's disease who were refractory to corticosteroid and/or immunomodulator therapies. The study was conducted at 12 sites in Japan, from November 2010 through October 2012. Twenty patients were given 160 mg adalimumab at the start of the study and 80 mg 2 weeks later, followed by 40 mg every other week for 52 weeks; for some patients, the dose was increased to 80 mg every other week. A composite efficacy index, combining GI symptom and endoscopic assessments, was used to evaluate efficacy. The primary efficacy end point was the percentage of patients with scores of 1 or lower for GI symptom and endoscopic assessments at week 24. Secondary end points included complete remission and resolution of non-GI Behçet's-related symptoms. Nine patients (45%) had GI symptom and endoscopic assessment scores of 1 or lower at week 24 of treatment, and 12 patients (60%) had these scores by week 52. Four patients (20%) achieved complete remission at weeks 24 and 52. Individual global GI symptom and endoscopic scores improved for most patients at weeks 24 and 52. Two thirds of patients with oral aphthous ulcers, skin symptoms, and genital ulcers, and 88% of patients with erythema nodosum had complete resolution of these conditions at week 52. A total of 9 of 13 patients (69%) taking steroids at baseline were able to taper (n = 1) or completely discontinue steroids (n = 8) during the study. No new safety signals were observed. Adalimumab is a potentially effective treatment for intestinal Behçet's disease in Japanese patients who are refractory to conventional treatments. ClinicalTrials.gov number: NCT01243671.


Light absorption and emission in nanowire array solar cells.
Inorganic nanowires are under intense research for large scale solar power generation intended to ultimately contribute a substantial fraction to the overall power mix. Their unique feature is to allow different pathways for the light absorption and carrier transport. In this publication we investigate the properties of a nanowire array acting as a photonic device governed by wave-optical phenomena. We solve the Maxwell equations and calculate the light absorption efficiency for the AM1.5d spectrum and give recommendations on the design. Due to concentration of the incident sunlight at a microscopic level the absorptivity of nanowire solar cells can exceed the absorptivity of an equal amount of material used in thin-film devices. We compute the local density of photon states to assess the effect of emission enhancement, which influences the radiative lifetime of excess carriers. This allows us to compute the efficiency limit within the framework of detailed balance. The efficiency is highly sensitive with respect to the diameter and distance of the nanowires. Designs featuring nanowires below a certain diameter will intrinsically feature low short-circuit current that cannot be compensated even by increasing the nanowire density. Optimum efficiency is not achieved in densely packed arrays, in fact spacing the nanowires further apart (simultaneously decreasing the material use) can even improve efficiency in certain scenarios. We observe absorption enhancement reducing the material use. In terms of carrier generation per material use, nanowire devices can outperform thin-film devices by far.


Testosterone and gonadotropin levels in men with dementia.
Sex steroids such as testosterone and estradiol might protect the brain against Alzheimer's disease (AD). We previously found lower levels of testosterone in men with AD compared with controls. We wanted to assess levels of pituitary gonadotropins that regulate sex steroid levels, to determine whether primary or secondary hypogonadism was responsible for low levels of testosterone in cases. We included 45 men with AD (McKhann, 1987), 15 men with other types of dementia and 133 elderly controls from the Oxford Project to Investigate Memory and Ageing. Gonadotropins (follicle stimulating hormone or FSH and luteinizing hormone or LH), sex hormone binding globulin (SHBG, which determines the amount of free testosterone) and testosterone were measured using enzyme immunoassays. We found no difference in average LH (8.7 +/- 9 UI/L), FSH (13 +/- 17 UI/L) or SHBG (44 +/- 18 nmol/L) levels between AD cases and controls. Similar to our earlier findings, testosterone levels were significantly lower in men with AD (13 +/- 6 nmol/L) compared with controls (17 +/- 8, O.R. = 0.92, 95% C.I. = 0.87 to 0.97, p<0.005). Results were unchanged when controlled for age, SHBG and gonadotropin levels. Although normal, the levels of gonadotropins were inappropriately low for the levels of testosterone. Our results support a preliminary conclusion that secondary hypogonadism occurs in men with AD. This could be a consequence of brain degeneration. This is contrary to an earlier study (Bowen, 1999) that found raised levels of gonadotropins in cases with AD, suggesting primary hypogonadism. Our cohort was younger than theirs and gonadotropin levels increase with age. We are enlarging our data set to investigate whether primary hypogonadism occurs in older cases with AD or whether secondary hypogonadism precedes cognitive dysfunction in men at risk for AD. If this is true, testosterone replacement therapy for hypogonadal men at risk for dementia may be indicated.


The role of older women in contesting norms associated with female genital mutilation/cutting in Senegambia: A factorial focus group analysis.
Social norms theory has become prominent framework for understanding the perpetuation of female genital mutilation/cutting (FGM/C), and has influenced the design of interventions aimed at stopping the practice. Theoretical advances draw attention to the fact that FGM/C is often upheld by multiple interconnected norms that may vary and shift over time, offering a potential resource for social transformation. Analyzing focus group data from Senegambian women, the questions we explore are: What are the constellation of norms associated with FGM/C? When are existing practices and norms being contested, and how does this reflect prevailing structures of power and authority? Our research identifies four overarching themes: 1) pressure to conform with FGM/C arising from sanctions such as ostracization, and moral norms linked to the embodiment of virtue; 2) upholding tradition as a means of venerating ancestors; 3) upholding social hierarchy by displaying respect for elders; and 4) shifting beliefs about the healthful vs. harmful nature of FGM/C. While strong value is placed on upholding tradition, there is also an appreciation that elements of tradition must be revised to meet fluctuating realities, including the novel threat of HIV infection. Moreover, older women are uniquely positioned to realize the dual goal of honoring tradition while negotiating change. Rather than resisting change, we find that some older women express an openness to reassessing norms and practices as they seek solutions to maintaining the physical well-being, moral integrity and cultural identity of girls in their families. Moreover, given the authority of older women over younger women, they also have power to negotiate change. By recognizing older women as potential change leaders, and drawing on variability and fluidity in social norms, it may be increasingly possible to design interventions that will shape possibilities for action and accelerate abandonment of FGM/C without undermining the cultural value of tradition.


Genome-wide and gene-based association studies of anxiety disorders in European and African American samples.
Anxiety disorders (ADs) are common mental disorders caused by a combination of genetic and environmental factors. Since ADs are highly comorbid with each other, partially due to shared genetic basis, studying AD phenotypes in a coordinated manner may be a powerful strategy for identifying potential genetic loci for ADs. To detect these loci, we performed genome-wide association studies (GWAS) of ADs. In addition, as a complementary approach to single-locus analysis, we also conducted gene- and pathway-based analyses. GWAS data were derived from the control sample of the Molecular Genetics of Schizophrenia (MGS) project (2,540 European American and 849 African American subjects) genotyped on the Affymetrix GeneChip 6.0 array. We applied two phenotypic approaches: (1) categorical case-control comparisons (CC) based upon psychiatric diagnoses, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. Linear and logistic models were used to analyse the association with ADs using FS and CC traits, respectively. At the single locus level, no genome-wide significant association was found. A trans-population gene-based meta-analysis across both ethnic subsamples using FS identified three genes (MFAP3L on 4q32.3, NDUFAB1 and PALB2 on 16p12) with genome-wide significance (false discovery rate (FDR] <5%). At the pathway level, several terms such as transcription regulation, cytokine binding, and developmental process were significantly enriched in ADs (FDR <5%). Our approaches studying ADs as quantitative traits and utilizing the full GWAS data may be useful in identifying susceptibility genes and pathways for ADs.