Reading the signs: impact of signed versus written questionnaires on the prevalence of psychopathology among deaf adolescents.
There are no empirically validated measures of psychopathology that can be easily understood by signing deaf children and little reliable data on the prevalence of psychiatric disturbance in this population. The aim was to meet this need by developing an Australian Sign Language (Auslan) version of a widely used measure (the Youth Self-Report; YSR) which could be administered in an interactive CD-ROM format, to assess its reliability, and to compare the prevalence of clinically significant psychopathology in deaf adolescents when using the Auslan questionnaire versus the standard written version. This would also allow examining the validity of written questionnaires in this population. Twenty-nine male and 25 female adolescents with severe or profound hearing loss from public and private schools in the Australian States of Tasmania (n = 11) and New South Wales (n = 43) agreed to participate and completed the written and the interactive Auslan versions of the YSR. Parallel forms were completed by parents (Child Behaviour Checklist) and teachers (Teacher's Report Form). The Auslan version showed comparable reliability to that reported for the standard YSR: internal consistency (alpha) ranging from 0.77 to 0.97 and test-retest agreement (r) from 0.49 to 0.78. The interactive Auslan version yielded a prevalence of clinically significant emotional and behavioural problems in deaf adolescents of 42.6% compared with 21.4% when using the standard English version. Prevalence for the wider Australian adolescent population (18.9%) was similar to that obtained among deaf adolescents when using the standard YSR (21.4%). However, it was higher among deaf adolescents (42.6%) when using the Auslan version (OR = 3.2, 95% CI = 1.83-5.58). According to the Auslan version, the syndromes Withdrawn/Depressed (OR = 6.5, 95% CI = 2.96-14.25), Somatic Complaints (OR = 4.8, 95% CI = 2.53-9.22), Social Problems (OR = 8.3, 95% CI = 4.16-16.47) and Thought Problems (OR = 5.7, 95% CI = 2.50-12.80) were much more prevalent among deaf adolescents than in the wider adolescent population, while Attention Problems (OR = 1.1, 95% CI = 0.39-3.17) and Rule-Breaking Behaviour (OR = 1.5, 95% CI = 0.73-3.17) were not. An interactive Auslan version of the YSR is reliable, better accepted and yields higher rates of disturbance than the standard written questionnaire. Clinicians should be aware that using written instruments to assess psychopathology in deaf adolescents may produce invalid results or may underestimate the level of disturbance, particularly emotional problems.


An Overview of Open-Ended Evolution: Editorial Introduction to the Open-Ended Evolution II Special Issue.
Nature's spectacular inventiveness, reflected in the enormous diversity of form and function displayed by the biosphere, is a feature of life that distinguishes living most strongly from nonliving. It is, therefore, not surprising that this aspect of life should become a central focus of artificial life. We have known since Darwin that the diversity is produced dynamically, through the process of evolution; this has led life's creative productivity to be called Open-Ended Evolution (OEE) in the field. This article introduces the second of two special issues on current research in OEE and provides an overview of the contents of both special issues. Most of the work was presented at a workshop on open-ended evolution that was held as a part of the 2018 Conference on Artificial Life in Tokyo, and much of it had antecedents in two previous workshops on open-ended evolution at artificial life conferences in Cancun and York. We present a simplified categorization of OEE and summarize progress in the field as represented by the articles in this special issue.


Single-Cell Transcriptomics of the Human Endocrine Pancreas.
Human pancreatic islets consist of multiple endocrine cell types. To facilitate the detection of rare cellular states and uncover population heterogeneity, we performed single-cell RNA sequencing (RNA-seq) on islets from multiple deceased organ donors, including children, healthy adults, and individuals with type 1 or type 2 diabetes. We developed a robust computational biology framework for cell type annotation. Using this framework, we show that α- and β-cells from children exhibit less well-defined gene signatures than those in adults. Remarkably, α- and β-cells from donors with type 2 diabetes have expression profiles with features seen in children, indicating a partial dedifferentiation process. We also examined a naturally proliferating α-cell from a healthy adult, for which pathway analysis indicated activation of the cell cycle and repression of checkpoint control pathways. Importantly, this replicating α-cell exhibited activated Sonic hedgehog signaling, a pathway not previously known to contribute to human α-cell proliferation. Our study highlights the power of single-cell RNA-seq and provides a stepping stone for future explorations of cellular heterogeneity in pancreatic endocrine cells.


Microdeletion of the Down syndrome critical region at 21q22.
The concept of the Down syndrome critical region implies the existence of several dosage-sensitive genes that result in an abnormal phenotype when duplicated. Among the genes in the presumed Down syndrome critical region, DYRK1A and SIM2 are thought to be particularly important because of their critical roles in the development of the central nervous system in model organisms. Considering that regulatory imbalances resulting in an altered amount of expression from crucial target genes tend to produce phenotypic effects in both monosomics and trisomics, haploinsufficiency for the Down syndrome critical region is expected to be associated with an abnormal phenotype. We report on a patient with severe microcephaly, a developmental delay, hypospadias, and corneal opacity who had a microdeletion spanning the Down syndrome critical region, including DYRK1A and SIM2. He presented with intrauterine growth retardation, hypospadias, corneal clouding, arched eyebrows, upslanting and narrow palpebral fissures, bifid uvula, prominent nasal root, short columella, prominent central incisors, pegged shaped teeth, retrognathia, hypoplastic nipples, and severe developmental delay. His G-banded karyotype was normal, but array comparative genomic hybridization showed a de novo deletion of 3.97 Mb at chromosome 21q22. The extreme degree of microcephaly in this patient may be ascribed to the haploinsufficiency of DYRK1A, since brain size is severely reduced in heterozygotes for the Dyrk1a null mutation in mice.


Effect of subinhibitory concentrations of antibiotics on mutation frequency in Streptococcus pneumoniae.
To investigate the effect of subinhibitory concentrations of ciprofloxacin, streptomycin, trimethoprim, ampicillin and erythromycin on mutation frequency in Streptococcus pneumoniae. Frequency of mutation to rifampicin resistance was determined in three clinical isolates grown with or without antibiotic treatment. dinB was analysed using PCR and DNA sequence determination. Subinhibitory levels of ciprofloxacin and streptomycin increased the frequency of mutation to rifampicin resistance between 2- and 5-fold for all three isolates, which is comparable to the increase seen in mismatch repair mutants of this species. These increases appeared not to be dependent on the function of the error-prone DNA polymerase encoded by dinB, since one of the isolates was a naturally occurring deletion mutant for this gene. Trimethoprim increased the mutation frequency for two isolates, but not the dinB mutant; ampicillin and erythromycin had no significant effect on mutation frequencies for any isolate. Exposure to quinolones and aminoglycosides at subinhibitory concentrations may result in increased mutability in pneumococci, as well as selecting for resistance per se.


Potential future impact of a partially effective HIV vaccine in a southern African setting.
It is important for public health and within the HIV vaccine development field to understand the potential population level impact of an HIV vaccine of partial efficacy--both in preventing infection and in reducing viral load in vaccinated individuals who become infected--in the context of a realistic future implementation scenario in resource limited settings. An individual level model of HIV transmission, progression and the effect of antiretroviral therapy was used to predict the outcome to 2060 of introduction in 2025 of a partially effective vaccine with various combinations of efficacy characteristics, in the context of continued ART roll-out in southern Africa. In the context of our base case epidemic (in 2015 HIV prevalence 28% and incidence 1.7 per 100 person years), a vaccine with only 30% preventative efficacy could make a substantial difference in the rate with which HIV incidence declines; the impact on incidence in relative terms is projected to increase over time, with a projected 67% lower HIV incidence in 2060 compared with no vaccine introduction. The projected mean decline in the general adult population death rate 2040-2060 is 11%. A vaccine with no prevention efficacy but which reduces viral load by 1 log is predicted to result in a modest (14%) reduction in HIV incidence and an 8% reduction in death rate in the general adult population (mean 2040-2060). These effects were broadly similar in multivariable uncertainty analysis. Introduction of a partially effective preventive HIV vaccine would make a substantial long-term impact on HIV epidemics in southern Africa, in addition to the effects of ART. Development of an HIV vaccine, even of relatively low apparent efficacy at the individual level, remains a critical global public health goal.


Compliance study of contact lens wearers in Japan--part 2: evaluation of a subscribed membership system.
To examine the hypothesis that membership in a contact lens (CL) supply system is associated with better compliance for regular wearers (members) who belong to the subscription membership system. Subjects were 104 members and 100 nonmember wearers of 2-week frequent replacement silicone hydrogel CLs whose clinical information was retrospectively available for 1.5 to 2 years in the interval between September 2010 and August 2012. The average duration of use of a single lens was calculated from the number of lenses supplied during the observation period and surveyed using questionnaires. Subjective symptoms and eye complications were also documented and compared. The average duration of use of a lens was significantly longer in nonmembers (17.8±5.6 days/lens; n=91) than in members (14.2±3.5 days/lens; n=98) (P<0.001, Mann-Whitney U test). The number of wearers who replaced their lenses within 15.4 days per lens wear was significantly higher in members (74.5%) as compared with nonmembers (45.1%) (P<0.001, Fisher exact test). Levels of compliance reported by wearers did not match with those indicated in clinical records. In recorded eye complications, the rate of incidence of allergic and giant papillary conjunctivitis tended to be higher in nonmembers as compared with members. The hypothesis that a membership system could be associated with better compliance was found to be supported by clinical records. It is suggested that a membership system is useful for identifying wearers who want to be more compliant and that better compliance may reduce long-term complications of lens wear.


Genes differentially expressed in conidia and hyphae of Aspergillus fumigatus upon exposure to human neutrophils.
Aspergillus fumigatus is the most common etiologic agent of invasive aspergillosis in immunocompromised patients. Several studies have addressed the mechanism involved in host defense but only few have investigated the pathogen's response to attack by the host cells. To our knowledge, this is the first study that investigates the genes differentially expressed in conidia vs hyphae of A. fumigatus in response to neutrophils from healthy donors as well as from those with chronic granulomatous disease (CGD) which are defective in the production of reactive oxygen species. Transcriptional profiles of conidia and hyphae exposed to neutrophils, either from normal donors or from CGD patients, were obtained by using the genome-wide microarray. Upon exposure to either normal or CGD neutrophils, 244 genes were up-regulated in conidia but not in hyphae. Several of these genes are involved in the degradation of fatty acids, peroxisome function and the glyoxylate cycle which suggests that conidia exposed to neutrophils reprogram their metabolism to adjust to the host environment. In addition, the mRNA levels of four genes encoding proteins putatively involved in iron/copper assimilation were found to be higher in conidia and hyphae exposed to normal neutrophils compared to those exposed to CGD neutrophils. Deletants in several of the differentially expressed genes showed phenotypes related to the proposed functions, i.e. deletants of genes involved in fatty acid catabolism showed defective growth on fatty acids and the deletants of iron/copper assimilation showed higher sensitivity to the oxidative agent menadione. None of these deletants, however, showed reduced resistance to neutrophil attack. This work reveals the complex response of the fungus to leukocytes, one of the major host factors involved in antifungal defense, and identifies fungal genes that may be involved in establishing or prolonging infections in humans.


Methyl and t-butyl group rotation in a molecular solid: (1)H NMR spin-lattice relaxation and X-ray diffraction.
We report solid state (1)H nuclear magnetic resonance spin-lattice relaxation experiments and X-ray diffractometry in 2-t-butyldimethylsilyloxy-6-bromonaphthalene. This compound offers an opportunity to simultaneously investigate, and differentiate between, the rotations of a t-butyl group [C(CH3)3] and its three constituent methyl groups (CH3) and, simultaneously, a pair of 'lone' methyl groups (attached to the Si atom). The solid state (1)H relaxation experiments determine activation energies for these rotations. We review the models for the dynamics of both 'lone' methyl groups (ones whose rotation axes do not move on the NMR time scale) and models for the dynamics of the t-butyl group and its constituent methyl groups (whose rotation axes reorient on the NMR time scale as the t-butyl group rotates).


Association of HSD17B13 rs72613567:TA with non-alcoholic fatty liver disease in Hispanics/Latinos.
Non-alcoholic fatty liver disease (NAFLD) disproportionately affects Hispanic/Latinos and rates of NAFLD vary among Hispanics from different background groups. Genetic variants and continental ancestry contribute to NAFLD disparities among Hispanics. We evaluated two newly identified NAFLD-associated single nucleotide polymorphisms of HSD17B13, rs72613567:TA and rs62305723:A in Hispanics/Latinos. Clinical data, genotypes of variants of interest and estimates of continental ancestry were extracted from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) database, which includes a cohort of 16 415 US Hispanic/Latinos. Surrogate endpoints for NAFLD were suspected NAFLD based on unexplained aminotransferase elevation, continuous ALT levels and FIB-4 scores to estimate hepatic fibrosis. In all, 9342 participants were included for analysis. The rs72613567:TA allele was found in 15.3% and the rs62305723:A allele was identified in 4.5% of HCHS/SOL participants. rs72613567:TA was less frequent in persons with vs without suspected NAFLD (12.4% vs 15.7%, P < .001) and rs72613567:TA was associated with lower FIB-4 scores (P = .01). For persons with the NAFLD-associated PNPLA3 rs738409:G allele, the presence of rs72613567:TA was associated with a lower rate of suspected NAFD (odds ratio = 0.76, P < .001). rs72613567:TA was less frequent in Hispanic/Latino background groups with higher rates of suspected NAFLD. The rs62305723:A allele was not associated with suspected NAFLD or FIB-4 score. The rs72613567:TA allele is associated with lower rates of suspected NAFLD and lower FIB-4 scores among Hispanic/Latinos and with lower rates of suspected NAFLD in persons with the PNPLA3 rs738409:G allele. The rs72613567:TA allele contributes to NAFLD disparities among Hispanic/Latino background groups.


Synthesis of diffractive optical bar codes.
A new type of diffractive optical bar code (DOBC) is proposed. Rather than scanning directly, the DOBC is coherently illuminated, and the first diffraction order is sensed. The spacing between the bars is chosen so that the thresholded diffraction pattern yields a specified binary code. Two approaches are investigated for synthesis of the DOBC: phase shaping and a gradient-based, nonlinear, constrained optimization technique. The two design methods are compared based on numerical results, and the validity of the overall design approach is verified by optically sensing the diffraction patterns for a number of fabricated DOBC's.


ETS and plastid sequence data indicate a spontaneous origin of Scandinavian betony, Betonica officinalis L.
Betony (Betonica officinalis L.) is one of the rarest and most spectacular plants in the Scandinavian flora. A long-term question has been whether it is spontaneous or introduced, or whether it comprises both spontaneous and introduced populations. This study aimed to answer this question by analyzing sequence data from the nuclear external transcribed spacer (ETS) region and three regions of the plastid genome, the trnT-trnL intergenic spacer (IGS) region, tRNA-Leu (trnL) intron, and the trnS-trnG IGS. Altogether 41 samples from 11 European countries were analyzed. A unique duplication in the trnT-trnL IGS was detected in material from Skåne (southern Sweden), the "Skåne-duplication." Populations with this duplication are united on a moderately supported branch in the phylogeny based on plastid sequences. A distinct heath genotype from Yorkshire was discovered in the phylogeny based on plastid sequences and in a comparative cultivation. Phylogeny based on ETS sequences does not support any Scandinavian group, whereas a principal coordinates analysis ordination based on variable ETS positions indicated a spontaneous origin for all Scandinavian populations, which comprise a genetically well-defined subgroup of the species, most closely related to other spontaneous populations from adjacent parts of continental parts of northern Europe. Seven possible naturally occurring localities remain in Scandinavia, five in central Skåne, southernmost Sweden, and two on the southwestern part of the Danish island of Lolland.


A stereological study of glomerular number and volume: preliminary findings in a multiracial study of kidneys at autopsy.
This report describes preliminary results of a study of glomerular number and volume and their associations, in kidneys of people coming to autopsy. Both kidneys were weighed at autopsy and the right kidney was perfusion-fixed and sub-sampled for stereological estimation of total glomerular number, and of mean renal corpuscle volume, using the physical disector/fractionator combination. The 78 kidneys studied so far were from Australian Aborigines, Australian non-Aborigines, US blacks and US whites, ages newborn to 84 years. Glomerular number ranged almost ninefold (from 210,332 to 1,825,380), with mean (SD) of 784,909 (314,686); it decreased throughout adult life (r=-0.32, P=0.009). Mean renal corpuscle volume varied 5.6-fold in adults and was inversely correlated with glomerular number (r=-0.38, P=0.001). Total renal corpuscle volume varied in adults by a factor of 15.8. Kidney weight correlated with body surface area (BSA) at all ages (r=0.76, P < 0.001); it varied 3.4-fold among adults, while kidney weight/m2 varied 3.7-fold. The percentage of sclerosed glomeruli varied from 0 to 23%, and it correlated strongly with age (r=0.58, P < 0.001). Females had smaller kidneys than males, and, marginally, fewer glomeruli. There were no significant variations by ethnic group. These extraordinary ranges of glomerular number and size among ostensibly "normal" people, and their inverse relationship, probably have important implications for susceptibility to renal insufficiency. People with low glomerular (nephron) numbers are likely to be particularly predisposed, with the process marked by compensatory hypertrophy of residual nephrons, which, in turn, accelerates their obsolescence. Much, however, remains to be done, including evaluation of history, clinical features, accompanying pathology, detailed renal morphology, and further pursuit of potentially defining characteristics in high risk groups.


Interferon-associated therapies toward HIV control: The back and forth.
Human immunodeficiency virus (HIV) induces a persistent and incurable infection. However, the combined antiretroviral treatment (cART) has markedly changed the evolution of the infection and transformed a deadly disease into a manageable chronic infection. Withdrawal of cART generally leads though to resumption of the viral replication. The eradication of the virus from its cellular and anatomical reservoirs remains a goal-to-achieve for a cure. In this context, developing novel therapies contributing to this aim are an important field of research. Type I IFN has antiviral activity, which, before the presence of efficient anti-HIV drugs, has led to the testing of IFN-based therapeutic strategies during the early years of the pandemic. A historical overview of the results and its limitations that were put into light are reviewed here. In addition, several lessons could be drawn. For instance, the efficacy of the IFN-I depends on the timing of its administration and the context. Thus, the persistence of an endogenous IFN-signature, such as that generally observed in viremic patients, seems to be associated with a lower efficacy of IFN. Based on the lessons from previous trials, and in the context of cART and research for a cure, type I Interferon has regained interest and novel therapeutic approaches are currently tested in combination with cART, some with disappointing, other with encouraging results with regard to a reduction in the size of the HIV reservoir and/or delays in viral rebound after cessation of cART. Additional strategies are currently developed in addition to improve the antiviral function of the IFN-I, by using for instance other IFN subtypes than IFN-Iα2. In parallel, the development of innovative strategies aimed at counteracting the excessive activation of the IFN-pathways have been continued and their results are reviewed here as well. Altogether, the use of IFN-I in anti-HIV therapies has gone through distinct phases and many lessons could be drawn. Novel combinations are currently be tested that might provide interesting results.


Long non-coding RNA Linc00312 modulates the sensitivity of ovarian cancer to cisplatin via the Bcl-2/Caspase-3 signaling pathway.
Chemotherapy is one of the main treatments for ovarian cancer (OC). Cisplatin combined with paclitaxel is a commonly used chemotherapy regimen. However, effective cancer therapy is hindered by a patient's resistance to cisplatin. The mechanism that potentially leads to that resistance is unclear. The current study examined the mechanism by which Linc00312 is involved in resistance to cisplatin in OC. Quantitative real-time PCR (RT-qPCR) was used to test for expression of Linc00312 in freshly frozen tissue samples of OC and in SKOV3 and SKOV3/DDP cells. In situ hybridization was performed to examine the distribution of Linc00312 expression in paraffin-embedded histological sections that were sensitive or resistant to cisplatin. The cell counting kit-8 assay was used to detect cell viability. Flow cytometry was used to measure cell apoptosis. RT-qPCR was performed to confirm changes in expression of MDR1, MRP1, Bcl-2, Bax, Caspase-3, and Caspase-9 mRNA. Levels of MDR1, Bcl-2, Bax, Caspase-3, and Caspase-9 protein were detected with Western blotting. Experiments indicated that the expression of Linc00312 decreased significantly in SKOV3/DDP cells compared to that in SKOV3 cells. Upregulation of Linc00312 can considerably increase the sensitivity of SKOV3/DDP cells to cisplatin, while down-regulation of Linc00312 has the exact opposite effect in SKOV3 cells. Linc00312 enhanced the sensitivity of SKOV3/DDP cells to cisplatin by promoting cell apoptosis via the Bcl-2/Caspase-3 signaling pathway. These findings suggest that Linc00312 may be a promising clinical strategy for the treatment of drug-resistant OC.


Interfacial electrochemical electron transfer processes in bacterial biofilm environments on Au(111).
We have studied Streptococcus mutans (S. mutans) biofilm growth and growth inhibition on Au(111)-surfaces using atomic force microscopy (AFM) and interfacial electrochemistry of a number of redox probe molecules. AFM of the biofilm growth and growth inhibition on both mica and Au(111)-surfaces was followed by sampling at given times, drying the samples naturally, and imaging. The electrochemical investigations were based on single-crystal Au(111)-electrode surfaces to exclude polycrystallinity as a cause of inhomogeneous voltammetric broadening on the biofilm covered electrode surfaces. The redox couples were chosen for their positive ([Ru(NH(3))(6)](3+/2+), [Co(terpy)(2)](3+/2+), terpy = 2,2',2''-terpyridine) or negative ([Fe(CN)(6)](3-/4-), [IrCl(6)](3-/4-)) electrostatic charge. [Co(NH(3))(6)](3+/2+) and [Co(phen)(3)](3+/2+) (phen = 1,10-phenanthroline) were other inhibition factors investigated. The positively and negatively charged redox probe couples displayed antagonistic inhibition and voltammetric patterns. [Ru(NH(3))(6)](3+/2+) and the homologous compound [Co(NH(3))(6)](3+/2+) were the only probe compounds to effect growth inhibition. On the other hand, cyclic voltammetry (CV) of both [Ru(NH(3))(6)](3+/2+) (positively charged, biofilm growth inhibitor) and [Co(terpy)(2)](3+/2+) (positively charged, no biofilm growth inhibition) displayed fully reversible CV on biofilm covered electrodes, almost indistinguishable from CV at bare Au(111)-electrode surfaces. In comparison, CVs of [Fe(CN)(6)](3-/4-) and [IrCl(6)](3-/4-) (both negatively charged and no growth inhibition) were distorted from planar diffusion behavior on bare Au(111)-electrode surfaces toward spherical diffusion behavior on S. mutans biofilm covered Au(111)-electrode surfaces. DNAase treatment of the biofilm covered Au(111)-electrode surface partly restores planar diffusion CV of [Fe(CN)(6)](3-/4-) and [IrCl(6)](3-/4-). This is reflected in a decrease of the growth rate and the appearance of molecular-scale structures near the bacterial edges as imaged by AFM after DNAase treatment. A rationale for the different voltammetric behavior of positively and negatively charged redox probe molecules based on electrostatic properties of the local surface environment is offered.


Hippocampal acetylcholine depletion has no effect on anxiety, spatial novelty preference, or differential reward for low rates of responding (DRL) performance in rats.
We investigated the role of the septo-hippocampal cholinergic projection in anxiety, spatial novelty preference, and differential reward for low rates of responding (DRL) performance. Cholinergic neurons of the rat medial septum (MS) and the vertical limb of the diagonal band of Broca (VDB) were lesioned using the selective immunotoxin, 192 IgG-saporin. Rats were then tested on several behavioral tests previously shown to be sensitive to either (a) hippocampal lesions or (b) nonselective MS/VDB lesions which target both cholinergic and γ-aminobutyric acid (GABA)-ergic projections, or both. Saporin lesions substantially reduced hippocampal cholinergic innervation, resulting in an absence of acetyl cholinesterase staining and markedly reduced choline acetyltransferase activity (mean reduction: 80 ± 5%; range: 50-97%). However, the saporin-lesioned rats did not differ from control rats in any of the behavioral tests. Thus we found no evidence from these lesion studies that the septo-hippocampal cholinergic projection plays an essential role in anxiety, spatial novelty preference, or DRL.


Low risk patients with acute atrial fibrillation and elevated high-sensitivity troponin do not have increased incidence of pathological stress tests.
Many patients with atrial fibrillation (AF) or atrial flutter (AFL) and rapid ventricular response (RVR) have elevated high-sensitivity troponin T (hsTnT) values. Elevated hsTnT is an independent risk marker for cardiovascular events and mortality. The aim was to examine if AF/AFL patients with RVR and elevated hsTnT have an increased incidence of pathological cardiac stress tests, indicating need of further evaluation for coronary artery disease (CAD). Design: We prospectively included 90 AF/AFL patients without known heart failure and CAD presenting with AF/AFL and RVR. Half of the patients had elevated hsTnT (cases) and half had levels below the 99th percentile (controls). All patients were discharged in sinus rhythm. After approximately one week in sinus rhythm a new hsTnT was analysed and the patients performed a bicycle exercise stress test within the 30 day follow-up. The primary endpoint was a pathological stress test confirmed by a pathological SPECT myocardial perfusion imaging or a coronary angiography. Results: None of the controls reached the primary endpoint. Two patients (4%) out of the 45 cases reached the primary endpoint (p = .49 vs controls), but only one was found to have significant CAD at subsequent coronary angiography. Conclusion: Patients with paroxysmal AF/AFL, without a history of CAD and heart failure, who present with a RVR and minor hsTnT elevations were not found to have an increased incidence of pathological stress tests compared to patients with hsTnT values below the 99th percentile.


Determinants of health status in fibromyalgia: a comparative study with systemic lupus erythematosus.
To compare perceived health status in women with fibromyalgia (FM) and systemic lupus erythematosus (SLE) using the Medical Outcomes Study (MOS) Short Form Health Survey (SF-36); and to identify determinants of physical and mental health in each patient group. A cross sectional study of 46 women with FM (mean age 48.13 yrs, SD 9.40) and 59 women with SLE (mean age 42.36 yrs, SD 11.31). Patients with FM were recruited from a rheumatology clinic and a rheumatology practice, while patients with SLE were recruited from 4 rheumatology clinics. Clinical examination determined disease activity (by Systemic Lupus Activity Measure) in SLE and a tender point count was used for FM. Patients completed questionnaires assessing health status (SF-36), stress (Hassles), social support (Social Support Questionnaire 6), and coping (Coping Inventory for Stressful Situations). Patients with FM reported more impairment on the following SF-36 subscales: physical function (p < 0.001), role physical (p < 0.001), bodily pain (p < 0.001), and vitality (p < 0.001). Physical component summary scores were also significantly lower (p < 0.001) for the FM group. Four hierarchical regression analyses were computed to determine factors related to physical and mental health in each patient group, with the following variables in the equation: age, income, disease activity (Step 1), hassles (Step 2), emotional and task coping, and social support (Step 3). Better physical health in FM was related to higher income (R2 = 0.17, p < 0.05). In the SLE group, better physical health was associated with younger age, less disease activity, and lower hassles (R2 = 0.37, p < 0.0001). Worse mental health among women with FM was associated with more hassles, more emotional coping, and less satisfaction with social support (R2 = 0.64, p < 0.0001), while lower income, higher hassles, and more emotional coping were linked to worse mental health in SLE (R2 = 0.46, p < 0.0001). Health related quality of life (HRQL) is impaired among women with FM and SLE, with FM patients reporting greater impairment along several dimensions. Enhancing the HRQL of patients with FM and SLE requires targeting specific modifiable psychosocial factors.


Gadolinium-Based Contrast Agents in Kidney Disease: Comprehensive Review and Clinical Practice Guideline Issued by the Canadian Association of Radiologists.
Use of gadolinium-based contrast agents (GBCAs) in renal impairment is controversial, with physician and patient apprehension in acute kidney injury (AKI), chronic kidney disease (CKD), and dialysis because of concerns regarding nephrogenic systemic fibrosis (NSF). The position that GBCAs are absolutely contraindicated in AKI, CKD stage 4 or 5 (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) and dialysis-dependent patients is outdated, and may limit access to clinically necessary contrast-enhanced MRI examinations. Following a comprehensive review of the literature and reported NSF cases to date, a committee of radiologists and nephrologists developed clinical practice guidelines to assist physicians in making decisions regarding GBCA administrations. In patients with mild-to-moderate CKD (eGFR ≥30 and <60 mL/min/1.73 m2), administration of standard doses of GBCA is safe and no additional precautions are necessary. In patients with AKI, with severe CKD (eGFR <30 mL/min/1.73 m2), or on dialysis, administration of GBCAs should be considered individually and alternative imaging modalities utilized whenever possible. If GBCAs are necessary, newer GBCAs may be administered with patient consent obtained by a physician (or their delegate), citing an exceedingly low risk (much less than 1%) of developing NSF. Standard GBCA dosing should be used; half or quarter dosing is not recommended and repeat injections should be avoided. Dialysis-dependent patients should receive dialysis; however, initiating dialysis or switching from peritoneal to hemodialysis to reduce the risk of NSF is unproven. Use of a macrocyclic ionic instead of macrocyclic nonionic GBCA or macrocyclic instead of newer linear GBCA to further prevent NSF is unproven. Gadopentetate dimeglumine, gadodiamide, and gadoversetamide remain absolutely contraindicated in patients with AKI, with stage 4 or 5 CKD, or on dialysis. The panel agreed that screening for renal disease is important but less critical when using macrocyclic and newer linear GBCAs. Monitoring for and reporting of potential cases of NSF in patients with AKI or CKD who have received GBCAs is recommended.


[Validity of a standard questionnaire to assess physical activity for specific medical checkups and health guidance].
This study aimed to determine the validity of a standard questionnaire to assess amount of physical activity (PA) and cardiorespiratory fitness (VO2peak). A total of 483 men and women, aged 20 to 69 years, participated. The standard questionnaire included 3 items about exercise, PA, and walking speed. All questions were designed to require an answer of Yes or No. Subjects were classified into one of four groups regarding the number of Yes answers to the three questions, giving activity levels of 0 to 3. The amount of PA was measured objectively with a tn-axial accelerometer which could also calculate daily step counts, and the amounts of PA under 3 metabolic equivalents (METs) and at 3 METs or more. VO2peak. was measured by incremental cycle exercise tests with indirect calorimetry. The daily step counts, the amount of PA at 3 METs or more, and the VO2peak. were significantly higher in subjects who answered Yes to each question than in those who answered No. Sensitivity and specificity of each question were 62-73% and 45-71% for the amount of PA established with the "Exercise and Physical Activity Reference for Health Promotion 2006 (EPAR2006)". The sum of sensitivity and specificity was the highest when the cutoff value was activity level 2 (sensitivity 73%, specificity 68%). Sensitivity and specificity for VO2max established by EPAR2006 were lower than those for the amount of PA. These results suggest that only answering simple questions with a standard questionnaire is sufficient for estimation of PA levels for specific medical checkups and health guidance, even though the accuracy is somewhat limited.


Emergent neutrality in adaptive asexual evolution.
In nonrecombining genomes, genetic linkage can be an important evolutionary force. Linkage generates interference interactions, by which simultaneously occurring mutations affect each other's chance of fixation. Here, we develop a comprehensive model of adaptive evolution in linked genomes, which integrates interference interactions between multiple beneficial and deleterious mutations into a unified framework. By an approximate analytical solution, we predict the fixation rates of these mutations, as well as the probabilities of beneficial and deleterious alleles at fixed genomic sites. We find that interference interactions generate a regime of emergent neutrality: all genomic sites with selection coefficients smaller in magnitude than a characteristic threshold have nearly random fixed alleles, and both beneficial and deleterious mutations at these sites have nearly neutral fixation rates. We show that this dynamic limits not only the speed of adaptation, but also a population's degree of adaptation in its current environment. We apply the model to different scenarios: stationary adaptation in a time-dependent environment and approach to equilibrium in a fixed environment. In both cases, the analytical predictions are in good agreement with numerical simulations. Our results suggest that interference can severely compromise biological functions in an adapting population, which sets viability limits on adaptive evolution under linkage.


Kinetic analysis of IgG antibodies to beta-amyloid oligomers with surface plasmon resonance.
Surface plasmon resonance was used to investigate the kinetics, affinity, and specificity of binding between anti-Aβ (beta-amyloid) IgG antibodies and oligomeric Aβ. Two factors were needed to accurately characterize the IgG binding kinetics. First, a bivalent model was necessary to properly fit the kinetic association and dissociation sensograms. Second, a high concentration of IgG was necessary to overcome a significant mass transport limitation that existed regardless of oligomer density on the sensor surface. Using high IgG concentrations and bivalent fits, consistent kinetic parameters were found at varying sensor surface ligand densities. A comparison of binding specificity, affinity, and kinetic flux between monoclonal and natural human anti-Aβ IgG antibodies revealed the following findings. First, monoclonal antibodies 6E10 and 4G8 single-site binding affinity is similar between Aβ oligomers and monomers. Second, natural human anti-Aβ IgG binding readily binds Aβ oligomers but does not bind monomers. Third, natural human anti-Aβ IgG binds Aβ oligomers with a higher affinity and kinetic flux than 6E10 and 4G8. Both the current analytical methodology and antibody binding profiles are important for advances in antibody drug development and kinetic biomarker applications for Alzheimer's disease.


Alberta Provincial Pediatric EnTeric Infection TEam (APPETITE): epidemiology, emerging organisms, and economics.
Each year in Canada there are 5 million episodes of acute gastroenteritis (AGE) with up to 70% attributed to an unidentified pathogen. Moreover, 90% of individuals with AGE do not seek care when ill, thus, burden of disease estimates are limited by under-diagnosing and under-reporting. Further, little is known about the pathogens causing AGE as the majority of episodes are attributed to an "unidentified" etiology. Our team has two main objectives: 1) to improve health through enhanced enteric pathogen identification; 2) to develop economic models incorporating pathogen burden and societal preferences to inform enteric vaccine decision making. This project involves multiple stages: 1) Molecular microbiology experts will participate in a modified Delphi process designed to define criteria to aid in interpreting positive molecular enteric pathogen test results. 2) Clinical data and specimens will be collected from children aged 0-18 years, with vomiting and/or diarrhea who seek medical care in emergency departments, primary care clinics and from those who contact a provincial medical advice line but who do not seek care. Samples to be collected will include stool, rectal swabs (N = 2), and an oral swab. Specimens will be tested employing 1) stool culture; 2) in-house multiplex (N = 5) viral polymerase chain reaction (PCR) panel; and 3) multi-target (N = 15) PCR commercially available array. All participants will have follow-up data collected 14 days later to enable calculation of a Modified Vesikari Scale score and a Burden of Disease Index. Specimens will also be collected from asymptomatic children during their well child vaccination visits to a provincial public health clinic. Following the completion of the initial phases, discrete choice experiments will be conducted to enable a better understanding of societal preferences for diagnostic testing and vaccine policy. All of the results obtained will be integrated into economic models. This study is collecting novel samples (e.g., oral swabs) from previously untested groups of children (e.g., those not seeking medical care) which are then undergoing extensive molecular testing to shed a new perspective on the epidemiology of AGE. The knowledge gained will provide the broadest understanding of the epidemiology of vomiting and diarrhea of children to date.


Leader protein of foot-and-mouth disease virus is required for cleavage of the p220 component of the cap-binding protein complex.
Suppression of host protein synthesis in cells infected by poliovirus and certain other picornaviruses involves inactivation of the cap-binding protein complex. Inactivation of this complex has been correlated with the proteolytic cleavage of p220, a component of the cap-binding protein complex. Since picornaviral RNA is not capped, it continues to be translated as the cap-binding protein complex is inactivated. The cleavage of p220 can be induced to occur in vitro, catalyzed by extracts from infected cells or by reticulocyte lysates translating viral RNA. Expression of polioviral protease 2A is sufficient to induce p220 cleavage, and the presence in 2A of an 18-amino-acid sequence representing a putative cysteine protease active site correlates with the ability of different picornaviruses to induce p220 cleavage. Foot-and-mouth disease virus (FMDV) infection induces complete cleavage of p220, yet the FMDV genome codes for a 2A protein of only 16 amino acids, which does not include the putative cysteine protease active site. Using cDNA plasmids encoding various regions of the FMDV genome, we have determined that the leader protein is required to initiate p220 cleavage. This is the first report of a function for the leader protein, other than that of autocatalytic cleavage from the FMDV polyprotein.


Efficacy and Safety of a Novel Blunt Cannula Trans-Sub-Tenon's Retrobulbar Block for Vitreoretinal Surgery.
To evaluate a novel trans-sub-Tenon's retrobulbar block (TSTRB) compared to sub-Tenon's block (STB) and peribulbar block (PBB) anesthesia for vitreoretinal surgery. This study was a prospective evaluation of cases undergoing TSTRB, STB, or PBB. The Kallio scale and Brahma scales were used to score hemorrhage and extraocular motility, respectively. Pain was documented on a visual analog score graded (1-10) at induction, intraoperatively, and postoperatively, any confounding variables were noted. Seventy eyes have been used in this analysis, of which TSTRB was used in 37% (n = 26), PBB in 34% (n = 24), and STB in 29% (n = 20). Postoperative analgesia was required by 10% (n = 2) of STB and 8% (n = 2) of PBB; none of the TSTRB cases required analgesia (P = 0.003). The mean volume required with each technique was as follows: TSTRB, 4.8 ml; STB, 5.3 ml; and PBB, 10.4 ml (P = 0.030). The volume of anesthesia was correlated with the level of proptosis and even more important affected the ease of surgery most (P = 0.005). Akinesia was greatest with TSTRB > PBB > STB (P = 0.040). There were no complications such as brainstem anesthesia, globe perforation, or retrobulbar hemorrhage. Intentionally extending a STB into the retrobulbar space, via a TSTRB fenestration utilizes a familiar skill set. TSTRB produced the best levels of reduced kinesia during surgery and increased duration of postoperative analgesia. The technique uses a small-volume anesthesia.


On the Characteristics of the Autoassociative Memory with Nonzero-Diagonal Terms in the Memory Matrix.
A statistical method is applied to explore the unique characteristics of a certain class of neural network autoassociative memory with N neurons and first-order synaptic interconnections. The memory matrix is constructed to store M = αN vectors based on the outer-product learning algorithm. We theoretically prove that, by setting all the diagonal terms of the memory matrix to be M and letting the input error ratio ρ = 0, the probability of successful recall Pr steadily decreases as α increases, but as α increases past 1.0, Pr begins to increase slowly. When 0 < ρ ≤ 0.5, the network exhibits strong error-correction capability if α ≤ 0.15 and this capability is shown to rapidly decrease as α increases. The network essentially loses all its error-correction capability at α = 2, regardless of the value of ρ. When 0 < ρ ≤ 0.5, and under the constraint of Pr > 0.99, the tradeoff between the number of stable states and their attraction force is analyzed and the memory capacity is shown to be 0.15N at best.


Two-photon absorption cross sections within equation-of-motion coupled-cluster formalism using resolution-of-the-identity and Cholesky decomposition representations: Theory, implementation, and benchmarks.
The equation-of-motion coupled-cluster (EOM-CC) methods provide a robust description of electronically excited states and their properties. Here, we present a formalism for two-photon absorption (2PA) cross sections for the equation-of-motion for excitation energies CC with single and double substitutions (EOM-CC for electronically excited states with single and double substitutions) wave functions. Rather than the response theory formulation, we employ the expectation-value approach which is commonly used within EOM-CC, configuration interaction, and algebraic diagrammatic construction frameworks. In addition to canonical implementation, we also exploit resolution-of-the-identity (RI) and Cholesky decomposition (CD) for the electron-repulsion integrals to reduce memory requirements and to increase parallel efficiency. The new methods are benchmarked against the CCSD and CC3 response theories for several small molecules. We found that the expectation-value 2PA cross sections are within 5% from the quadratic response CCSD values. The RI and CD approximations lead to small errors relative to the canonical implementation (less than 4%) while affording computational savings. RI/CD successfully address the well-known issue of large basis set requirements for 2PA cross sections calculations. The capabilities of the new code are illustrated by calculations of the 2PA cross sections for model chromophores of the photoactive yellow and green fluorescent proteins.


Maximizing the Potential of Longitudinal Cohorts for Research in Neurodegenerative Diseases: A Community Perspective.
Despite a wealth of activity across the globe in the area of longitudinal population cohorts, surprisingly little information is available on the natural biomedical history of a number of age-related neurodegenerative diseases (ND), and the scope for intervention studies based on these cohorts is only just beginning to be explored. The Joint Programming Initiative on Neurodegenerative Disease Research (JPND) recently developed a novel funding mechanism to rapidly mobilize scientists to address these issues from a broad, international community perspective. Ten expert Working Groups, bringing together a diverse range of community members and covering a wide ND landscape [Alzheimer's, Parkinson's, frontotemporal degeneration, amyotrophic lateral sclerosis (ALS), Lewy-body and vascular dementia] were formed to discuss and propose potential approaches to better exploiting and coordinating cohort studies. The purpose of this work is to highlight the novel funding process along with a broad overview of the guidelines and recommendations generated by the ten groups, which include investigations into multiple methodologies such as cognition/functional assessment, biomarkers and biobanking, imaging, health and social outcomes, and pre-symptomatic ND. All of these were published in reports that are now publicly available online.


Lung cancer in asbestos cement workers in Denmark.
To study the relative and absolute risks of main types of lung cancer in a cohort of asbestos cement workers from Denmark. A cohort of 7887 men and 576 women employed between 1928 and 1984 was compiled from the personnel files of Danish Eternit Production. The cohort was followed up for deaths, emigrations, and incident cancer cases during the period 1943-90. The observed number of lung cancer cases in the cohort was compared with the expected number based on incidences for the Danish population. Internal comparison was made with Poisson modelling. A total of 226 lung cancer cases were observed (223 men and three women). The standardised incidence ratio (SIR) for all lung cancer among men was 1.7 (observed number 223, expected number 129.7, 95% confidence interval (95% CI) 1.5-2.0). The SIRs were raised for all main types of lung cancer; adenocarcinoma 2.6, squamous cell carcinoma 1.7, and anaplastic carcinoma 1.5. The higher SIR for adenocarcinomas was found particularly with a latency period of 25 years or more. Among the 93 excess lung cancer cases, 36 were squamous cell carcinomas and 32 were adenocarcinomas. Asbestos cement work is associated with an increased risk of lung cancer of all main types. During the first 25 years after the start of employment this excess risk is shared almost equally between the different histological types of lung cancer, but the risk of adenocarcinomas is clearly higher after this point.


Technology spillovers and sustainable environment: Evidence from time-series analyses with Fourier extension.
Globalization and human capital accumulation are the main drivers of technology spillovers and essential for economic growth. At the same time, globalization and human capital are drivers to construct a green growth path that prevents pollution and the overuse of resources, and thus mitigates environmental degradation and achieves sustainable development. This mechanism, known as the 'technique/technology effect', may occur by stimulating technological development and creating environmental awareness and is of utmost importance in developed and developing countries to protect the environment. The aim of this study is to evaluate these outcomes, investigating how the environment reacts to developments in globalization and human capital accumulation by performing time-series analyses augmented with Fourier extensions, for countries in the BRICS group (Brazil, Russia, India, China and South Africa). The study first checks unit root and cointegration relationship by using Fourier unit root and Fourier cointegration approaches. Having confirmed a cointegration relationship, the FMOLS estimator extended with Fourier terms is applied to estimate cointegration parameters. Empirical results show that globalization and human capital are beneficial to protect the environment and to build a sustainable blueprint for the future, which specifically refer to more investment in the educational system and more efforts promoting social and cultural interaction across the globe.


Dinosaur evolution. A Jurassic ornithischian dinosaur from Siberia with both feathers and scales.
Middle Jurassic to Early Cretaceous deposits from northeastern China have yielded varied theropod dinosaurs bearing feathers. Filamentous integumentary structures have also been described in ornithischian dinosaurs, but whether these filaments can be regarded as part of the evolutionary lineage toward feathers remains controversial. Here we describe a new basal neornithischian dinosaur from the Jurassic of Siberia with small scales around the distal hindlimb, larger imbricated scales around the tail, monofilaments around the head and the thorax, and more complex featherlike structures around the humerus, the femur, and the tibia. The discovery of these branched integumentary structures outside theropods suggests that featherlike structures coexisted with scales and were potentially widespread among the entire dinosaur clade; feathers may thus have been present in the earliest dinosaurs.


Quercetin abrogates chemoresistance in melanoma cells by modulating deltaNp73.
The alkylating agent dacarbazine (DTIC) has been used in the treatment of melanoma for decades, but when used as a monotherapy for cancer only moderate response rates are achieved. Recently, the clinical use of temozolomide (TMZ) has become the more commonly used analog of DTIC-related oral agents because of its greater bioavailability and ability to cross the blood brain barrier. The response rates achieved by TMZ are also unsatisfactory, so there is great interest in identifying compounds that could be used in combination therapy. We have previously demonstrated that the bioflavonoid quercetin (Qct) promoted a p53-mediated response and sensitized melanoma to DTIC. Here we demonstrate that Qct also sensitizes cells to TMZ and propose a mechanism that involves the modulation of a truncated p53 family member, deltaNp73. DB-1 melanoma (p53 wildtype), and SK Mel 28 (p53 mutant) cell lines were treated with TMZ (400 microM) for 48 hrs followed by Qct (75 microM) for 24 hrs. Cell death was determined by Annexin V-FITC staining and immunocytochemical analysis was carried out to determine protein translocation. After treatment with TMZ, DB-1 cells demonstrated increased phosphorylation of ataxia telangiectasia mutated (ATM) and p53. However, the cells were resistant to TMZ-induced apoptosis and the resistance was associated with an increase in nuclear localization of deltaNp73. Qct treatment in combination with TMZ abolished drug insensitivity and caused a more than additive induction of apoptosis compared to either treatment alone. Treatment with Qct, caused redistribution of deltaNp73 into the cytoplasm and nucleus, which has been associated with increased p53 transcriptional activity. Knockdown of deltaNp73 restored PARP cleavage in the TMZ treated cells, confirming its anti-apoptotic role. The response to treatment was predominantly p53 mediated as the p53 mutant SK Mel 28 cells showed no significant enhancement of apoptosis. This study demonstrates that Qct can sensitize cells to TMZ and that the mechanisms of sensitization involve modulation of p53 family members.


Sequence polymorphisms of MC1R gene and their association with depression and antidepressant response.
Melanocortin 1 receptor (MC1R) is involved in various functions, such as pigmentation, antipyretic and anti-inflammatory actions, development of melanoma, susceptibility to ultraviolet-induced sun damage, modification of oculocutaneous albinism, development of freckles, and mediation of female-specific mechanisms of analgesia. MC1R's natural agonists include α-melanocyte-stimulating hormone and corticotrophin (ACTH1-39), which are important components of hypothalamic pituitary adrenal axis and increase in response to stress. Given the multiple relevant roles of MC1R, we studied whether the MC1R gene would be associated with susceptibility to major depressive disorder or with response to antidepressant treatment. The human MC1R gene is highly polymorphic; therefore, we sequenced the entire MC1R coding region of 1122 bp in 181 depressed Mexican-American patients and 185 Mexican-American controls. A total of 23 single nucleotide polymorphisms (SNPs, 15 known and eight new) were found within the sequenced region. Among the common SNPs, the nonsynonymous SNP, rs885479 (R163Q) was associated with the diagnosis of depression (P=0.04). The nonsynonymous SNP, rs2228479 (V92M) and the synonymous SNP, rs2228478 were found to be associated with the remission with desipramine treatment. No associations were found for remission with fluoxetine treatment or for the combined sample treated with fluoxetine or desipramine. The frequency of one (H2) of the five haplotypes identified was higher in depressed patients when compared with controls (P=0.05). In-silico functional analysis indicates that SNPs rs885479 and rs2228479 have significant impact on the protein function. The MC1R gene might be associated with major depressive disorder and with treatment response to desipramine.


Hummingbird hovering energetics during moult of primary flight feathers.
How does a hovering hummingbird compensate for the loss of flight feathers during moult when the mechanism of lift force generation by flapping wings is impaired? The flight performance of five individual ruby-throated hummingbirds with moulting primary flight feathers and reduced wing area was compared with that before their moult. Hummingbirds were flown in reduced air densities using normoxic heliox so that a range of flight energetics was displayed. The rate of moulting and the extent of wing area loss varied among individuals. One female could tolerate a 30% loss of wing area in moulting and flew with only three outer primaries per wing. Further exploratory study using the artificial reduction of wing area, either by cutting the tips of the outer primaries of a male or by plucking the secondaries of two females, suggested that secondaries play a minor role in lift force generation during hovering whereas the tip area of primaries is crucial. For the five birds, ranges of whole-bird oxygen consumption rates, wingbeat kinematics (stroke amplitude) and lift coefficients did not vary during the moult. This constancy was mainly achieved through weight loss that alleviated aerodynamic force requirements for weight support during hovering. Since the metabolic power expenditure during moult was similar to that of normal birds but the mechanical power requirement was reduced, the flight efficiency also showed a sharp reduction during moult. This increased cost of flight may result from disruption of the integrity of the flight machinery. Overall, the control of body mass in hummingbirds can provide similar aerodynamic, muscle mechanical and physiological capacities under conditions of variable flight demand.


Effects of digital filtering on peak acceleration and force measurements for artistic gymnastics skills.
Low-pass filters are ideal when filtering human movements, however the effectiveness of such filters relies on the correct selection of the cut-off frequency. The aim of this study was to determine the most appropriate filter cut-off for acceleration- and force-time data when measuring peak resultant acceleration (PRA) and ground reaction force (PRGRF) during gymnastics landings. Sixteen gymnasts executed backward handsprings and backward somersault landings onto a matted force plate while wearing four inertial measurement units (IMUs). Acceleration- and force-time data were filtered using a fourth-order Butterworth filter at different cut-off frequencies ranging from raw through to 250 Hz. Residual analysis plots were produced, and the PRGRF and PRA for all IMUs were calculated for each participant and skill at all cut-off frequencies. Descriptive statistics, model II linear regressions and Bland-Altman plots were conducted. Results indicated that a minimum 85 Hz cut-off is optimal. High cut-off frequencies (>80 Hz) showed good linear relationships and had minimal mean bias compared with raw values, indicating that either filtered (above ~85 Hz) or raw signals can be used. It is suggested that for applied sports settings no filtering is needed, however a minimum cut-off of 85 Hz should be implemented for research purposes.


Choosing experiments to accelerate collective discovery.
A scientist's choice of research problem affects his or her personal career trajectory. Scientists' combined choices affect the direction and efficiency of scientific discovery as a whole. In this paper, we infer preferences that shape problem selection from patterns of published findings and then quantify their efficiency. We represent research problems as links between scientific entities in a knowledge network. We then build a generative model of discovery informed by qualitative research on scientific problem selection. We map salient features from this literature to key network properties: an entity's importance corresponds to its degree centrality, and a problem's difficulty corresponds to the network distance it spans. Drawing on millions of papers and patents published over 30 years, we use this model to infer the typical research strategy used to explore chemical relationships in biomedicine. This strategy generates conservative research choices focused on building up knowledge around important molecules. These choices become more conservative over time. The observed strategy is efficient for initial exploration of the network and supports scientific careers that require steady output, but is inefficient for science as a whole. Through supercomputer experiments on a sample of the network, we study thousands of alternatives and identify strategies much more efficient at exploring mature knowledge networks. We find that increased risk-taking and the publication of experimental failures would substantially improve the speed of discovery. We consider institutional shifts in grant making, evaluation, and publication that would help realize these efficiencies.


Stress and cognitive biases in schizotypy: A two-site study of bias against disconfirmatory evidence and jumping to conclusions.
The dysfunctional cognitive and reasoning biases which underpin psychotic symptoms are likely to present prior to the onset of a diagnosable disorder and should therefore be detectable along the psychosis continuum in individuals with schizotypal traits. Two reasoning biases, Bias Against Disconfirmatory Evidence (BADE) and Jumping to Conclusions (JTC), describe how information is selected and weighed under conditions of uncertainty during decision making. It is likely that states such as elevated stress exacerbates JTC and BADE in individuals with high schizotypal traits vulnerable to displaying these information gathering styles. Therefore, we evaluated whether stress and schizotypy interacted to predict these reasoning biases using separate samples from the US (JTC) and England (BADE). Generally speaking, schizotypal traits and stress were not independently associated with dysfunctional reasoning biases. However, across both studies, the interaction between schizotypy traits and stress significantly predicted reasoning biases such that increased stress was associated with increased reasoning biases, but only for individuals low in schizotypal traits. These patterns were observed for positive schizotypal traits (in both samples), for negative traits (in the England sample only), but not for disorganization traits. For both samples, our findings suggest that the presence of states such as stress is associated with, though not necessarily dysfunctional, reasoning biases in individuals with low schizotypy. These reasoning biases seemed, in some ways, relatively immutable to stress in individuals endorsing high levels of positive schizotypal traits.


Internal and external validity in two studies that compared treatment methods.
Research comparing the effectiveness of two treatments offers both strengths and weaknesses for occupational therapy. Although it is worthwhile to determine which of two treatments works best for a particular problem, methodological problems may arise that preclude a valid conclusion. To draw valid conclusions from research, criteria for internal validity and external validity must be satisfied. The two preceding articles in this issue are examples of studies that used between-groups experimental methodology to compare the effectiveness of two different treatments. This paper evaluates the above-mentioned studies on the basis of principles of internal and external validity. One of these studies (Jongbloed, Stacey, & Brighton, 1989) was truly experimental, whereas the other study (Groves & Rider, 1989) was quasi-experimental. Results from both studies were similar because, in each study, both of the treatment groups improved, but there were no significant differences between treatments. Absence of a true control group in both studies presented limitations on the conclusion that both treatments worked equally well.


Cognitive Evaluation of Self-Report Questions for Surveillance of Periodontitis.
This paper describes the cognitive testing of eight self-report questions as part of a broader effort to evaluate and validate the use of these questions in estimating the prevalence of periodontitis in the United States population. This study examined how United States respondents understood and processed the proposed questions in English and Spanish, as well as identifying and correcting for possible response errors. The set of eight questions was selected by the Centers for Disease Control and Prevention Periodontal Disease Surveillance Workgroup for further testing after analytical assessments and field testing of an array of potential questions. Evaluation of these eight oral health questions was based on 40 in-depth, semi-structured cognitive interviews in English and Spanish. Results of this cognitive test study are presented. The recommendations from this cognitive testing evaluation served as the basis to improve the original questions in English and Spanish to be more inclusive and consistent and improve the estimation of periodontal disease in the United States population.


Involvement of epithelial-mesenchymal transition in methotrexate-induced pulmonary fibrosis.
Epithelial-mesenchymal transition (EMT) plays a pivotal event in the development of pulmonary fibrosis. We have previously reported that methotrexate (MTX)-induced alveolar epithelial cell injury followed by pulmonary fibrosis as a result of the recruitment and proliferation of myofibroblasts. However, there is no data concerning whether EMT occurs in MTX-induced pulmonary fibrosis. In the present study, therefore, we investigated the expression of EMT markers such as E-cadherin, α-SMA, and vimentin by immunofluorescence analysis in mouse lung tissues after administration of MTX. We found that vimentin and α-SMA-positive cells of the MTX-induced pulmonary fibrosis were increased; on the other hand, E-cadherin was decreased, indicating that epithelial cells act as the main source of mesenchymal expansion. These results exhibited the down-regulation of E-cadherin expression and the up-regulation of α-smooth muscle actin (α-SMA) in primary mouse alveolar epithelial cells (MAECs) and A549 cell lines. Additionally, MTX-induced A549 cells exhibited an EMT-like phenotype accompanied by the elevation of the expression of interleukin-6 (IL-6) and transforming growth factor (TGF)-β1, as well as an enhancement of migration. All of these findings suggest that MTX-induced pulmonary fibrosis occurs via EMT.


Insights into chromatographic separation using core-shell metal-organic frameworks: Size exclusion and polarity effects.
Porous metal-organic frameworks (MOFs) [Cu3(BTC)2(H2O)3]n (also known as HKUST-1; BTC, benzene-1,3,5-tricarboxylic acid) were synthesized as homogeneous shell onto carboxyl functionalized magnetic microparticles through a liquid phase epitaxy (LPE) process. The as-synthesized core-shell HKUST-1 magnetic microparticles composites were characterized by XRD and SEM, and used as stationary phase in high performance liquid chromatography (HPLC). The effects of the unique properties of MOFs onto the chromatographic performance are demonstrated by the experiments. First, remarkable separation of pyridine and bipyridine is achieved, although both molecules show a strong interaction between the Cu-ions in HKUST-1 and the nitrogen atoms in their heterocyles. The difference can be explained due to size exclusion of bipyridine from the well defined pore structure of crystalline HKUST-1. Second, the enormous variety of possible interactions of sample molecules with the metal ions and linkers within MOFs allows for specifically tailored solid phases for challenging separation tasks. For example, baseline separation of three chloroaniline (CLA) isomers tested can be achieved without the need for gradient elution modes. Along with the experimental HPLC runs, in-depth modelling with a recently developed chromatography modelling software (ChromX) was applied and proofs the software to be a powerful tool for exploring the separation potential of thin MOF films. The pore diffusivity of pyridine and CLA isomers within HKUST-1 are found to be around 2.3×10(-15)m(2)s(-1). While the affinity of HKUST-1 to the tested molecules strongly differs, the maximum capacities are in the same range, with 0.37molL(-1) for pyridine and 0.23molL(-1) for CLA isomers, corresponding to 4.0 and 2.5 molecules per MOF unit cell, respectively.


Printed Organic Transistor-based Biosensors for Non-invasive Sweat Analysis.
This review describes recent advances in biosensors for non-invasive human healthcare applications, especially focusing on sweat analysis, along with approaches for fabricating these biosensors based on printed electronics technology. Human sweat contains various kinds of biomarkers. The relationship between a trace amount of sweat biomarkers partially partitioned from blood and diseases has been investigated by omic analysis. Recent progress in wearable or portable biosensors has enabled periodic or continuous monitoring of some sweat biomarkers while supporting the results of the omic analysis. In this review, we particularly focused on a transistor-based biosensor that is highly sensitive in quantitatively detecting the low level of sweat biomarkers. Furthermore, we showed a new approach of flexible hybrid electronics that has been applied to advanced sweat biosensors to realize fully integrated biosensing systems wirelessly connected to a networked IoT system. These technologies are based on uniquely advanced printing techniques that will facilitate mass fabrication of high-performance biosensors at low cost for future smart healthcare.


An hypothesis on the early evolution of the development of the isocortex.
We propose an hypothesis on the evolutionary origin of the unique inside-out developmental gradient of the isocortex, in which deep layers originate before superficial layers. This contrasts with the development of the reptilian cortex, which originates in an outside-in gradient. In mice, a mutated protein, reelin, produces the reeler phenotype, whose cortex has an outside-in neurogenetic gradient like in reptiles. Reelin is normally located in the marginal layer of the developing cerebral cortex, and its normal function has been proposed to be a stop signal that prevents radially migrating cells from moving into the marginal zone. Additionally, mutations on the kinase Cdk5, or in its neuronal-specific activator p35, produce a deficit similar to reeler in that the neurogenetic gradient is outside-in. However, contrary to reeler, in which no cell-sparse layer I is observed, in these mice, a well-defined layer I exists, which suggests that migrating cells respond normally to reelin. Apparently, Cdk5/p35 participate in permitting cortical cells to move across pre-existing (earlier produced) cortical layers, in order to be able to contact reelin once they reach the marginal zone. We suggest that the evolutionary advent of the mammalian cortical inside-out gradient became partly possible through the activation of the Cdk5/p35 pathway, which permitted migrating cells to move across layers of older cells. At about the same time, reelin became an important element in cortical development as it prevented neuronal migration into the marginal zone (cortical layer I) and facilitated the migration of neurons past postmigratory elements.


Variation in resource allocation in urgent and emergency Care Systems in Ireland.
A key challenge for most systems is how to provide effective access to urgent and emergency care across rural and urban populations. Tensions about the placement and scope of hospital emergency services are longstanding in Irish political life and there has been recent reform to centralise hospital services in some regions. The focus of this paper is a system approach to examine the geographic variation in resourcing and utilisation of such care across GP practices, out-of-hours care, ambulance services, Emergency Departments and Local Injury Units in Ireland. We used a cross-sectional study design to evaluate variation in resource allocation by aggregating geographic funding to various elements of the urgent and emergency care system and assessing patterns in hospital resource utilisation across the population. Expenditure, staffing, access and activity data were gathered from government sources, individual facilities and service providers, health professional bodies, private firms and central statistics. Data on costs and activity in 2014 are collated and presented at both county and regional levels. Analyses focus on resources spent on urgent and emergency care across geographic areas, the role of population concentration in allocation, the relationship between pre-hospital spending and in-hospital spending, and the utilisation of hospital-based emergency care resources by residents of each county. An array of funding mechanisms exists, resulting in a fragmented approach to the resourcing of urgent and emergency care. There are large differences in spending per capita at the county-level, ranging from between €50 and €200 per capita; however, these are less pronounced regionally. Distribution of hospital emergency care resources is highly skewed to the North East of the country, and away from the recently reconfigured South and Mid-West regions. This analysis advances the traditional approach of evaluating individual services or hospital resourcing. There are notable differences in utilisation of hospital-based emergency care resources at the regional level, indicating that populations within those regions which have been reconfigured have lower utilisation of hospital resources. There is a clear case for more integration in decision-making around funding and consideration of key principles, such as equity, to guide that process.


Cervical lymph node metastasis in oral cancer: the importance of even microscopic extracapsular spread.
The prognostic significance of extracapsular spread of cervical metastases in oral cancer is still controversial. To investigate the importance of extent of extracapsular spread; the relationship between extracapsular spread and both traditional measures of metastatic disease and clinical/histological features of the primary tumour, and to determine their relative prognostic significance. The survival of 173 patients undergoing radical surgery and simultaneous neck dissection for oral/oropharyngeal squamous cell carcinoma with histologically confirmed nodal metastasis and followed for 2.2-12.3 years is reported and related to pathological features. The most predictive clinical/histopathological features were determined by Cox regression modelling. The 3-year survival probability was similar for patients with macroscopic and only microscopic extracapsular spread (33 and 36%, respectively, compared with 72% for patients with intranodal metastasis). The Cox model showed the most predictive factor was extracapsular spread followed by status of resection margins. Extracapsular spread should be incorporated into pathological staging systems. Even microscopic extracapsular spread is of critical importance and must be sought especially in small-volume metastatic disease.


Critical anomalies in thermal diffusivity of liquid-crystalline terephthal-bis-(4-n-butylaniline).
A temperature wave method has been applied to observe the thermal diffusivity through the isotropic (Iso)-nematic (N)-smectic Sm-A-Sm-C-Sm-B-crystals VI-VII-VIII phase transitions of terephthal-bis-(4-n-butylaniline) (TBBA). Critical anomalies have been found in the N-Sm-A and Sm-C-Sm-B phase transitions as diplike shaped, consistent with the predictions based on the dissipative couplings between the order parameter and the conserved free-energy density. Singular points with a gap have been observed at the Sm-B-crystal VI, crystals VI-VII, and crystals VII-VIII phase transitions, which show polymorphic behaviors on heating and cooling. The second-order Sm-A-Sm-C phase transition emerged as a singular temperature dependence. In all the phases thermal diffusivity decreases with increasing temperature except for Sm-C, where thermal diffusivity increases with increasing temperature. The origin of the anomaly in the thermal diffusivity in Sm-C is discussed based on the parametric analysis of dynamic critical behavior in the Sm-A-Sm-C phase transitions together with the tilt angle change obtained by use of simultaneous measurements of x-ray diffraction and differential scanning calorimetry.


Differences of migratory behavior between direct progeny of apical progenitors and basal progenitors in the developing cerebral cortex.
Cerebral cortical neurons are known to be produced from both apical progenitors in the ventricular zone (VZ) and basal (intermediate) progenitors in the subventricular zone (SVZ). On the other hand, we have shown that many SVZ cells assume multipolar morphology and show a characteristic movement termed "multipolar migration." The relationship between multipolar cells and basal progenitors in the SVZ has yet to be investigated. Herein, we followed postmitotic cells generated in the VZ and found that they stayed for more than 10 h in the VZ after becoming postmitotic and then accumulated in the lower part of the SVZ (multipolar cell accumulation zone: MAZ) as multipolar cells (slowly exiting population: SEP), whereas basal progenitors rapidly migrated into the SVZ or intermediate zone (IZ) (rapidly exiting population: REP) with somal translocation morphology. Although REP reached the SVZ/IZ earlier than the SEP, REP stayed within in the SVZ/IZ, whereas SEP moved steadily and entered the CP prior to the REP. We also observed SEP to eventually differentiate into pyramidal neurons in layers II/III. This study provides in vivo evidence of differences in migration modes between postmitotic cells generated from apical progenitors and basal progenitors.


Classifying Drivers' Cognitive Load Using EEG Signals.
A growing traffic safety issue is the effect of cognitive loading activities on traffic safety and driving performance. To monitor drivers' mental state, understanding cognitive load is important since while driving, performing cognitively loading secondary tasks, for example talking on the phone, can affect the performance in the primary task, i.e. driving. Electroencephalography (EEG) is one of the reliable measures of cognitive load that can detect the changes in instantaneous load and effect of cognitively loading secondary task. In this driving simulator study, 1-back task is carried out while the driver performs three different simulated driving scenarios. This paper presents an EEG based approach to classify a drivers' level of cognitive load using Case-Based Reasoning (CBR). The results show that for each individual scenario as well as using data combined from the different scenarios, CBR based system achieved approximately over 70% of classification accuracy.


Intrarenal oxygenation: unique challenges and the biophysical basis of homeostasis.
The kidney is faced with unique challenges for oxygen regulation, both because its function requires that perfusion greatly exceeds that required to meet metabolic demand and because vascular control in the kidney is dominated by mechanisms that regulate glomerular filtration and tubular reabsorption. Because tubular sodium reabsorption accounts for most oxygen consumption (Vo2) in the kidney, renal Vo2 varies with glomerular filtration rate. This provides an intrinsic mechanism to match changes in oxygen delivery due to changes in renal blood flow (RBF) with changes in oxygen demand. Renal Vo2 is low relative to supply of oxygen, but diffusional arterial-to-venous (AV) oxygen shunting provides a mechanism by which oxygen superfluous to metabolic demand can bypass the renal microcirculation. This mechanism prevents development of tissue hyperoxia and subsequent tissue oxidation that would otherwise result from the mismatch between renal Vo2 and RBF. Recent evidence suggests that RBF-dependent changes in AV oxygen shunting may also help maintain stable tissue oxygen tension when RBF changes within the physiological range. However, AV oxygen shunting also renders the kidney susceptible to hypoxia. Given that tissue hypoxia is a hallmark of both acute renal injury and chronic renal disease, understanding the causes of tissue hypoxia is of great clinical importance. The simplistic paradigm of oxygenation depending only on the balance between local perfusion and Vo2 is inadequate to achieve this goal. To fully understand the control of renal oxygenation, we must consider a triad of factors that regulate intrarenal oxygenation: local perfusion, local Vo2, and AV oxygen shunting.


Attitudes Toward Violence Against Women and the Factors That Affect Them in Kutahya, Turkey.
This cross-sectional descriptive study was conducted to determine the attitudes of women and men living in Kutahya, Turkey towards violence against women, and the factors that affect them. The data were collected using an Information Form for Women, an Information Form for Men, and the Attitude towards Violence Scale. The study was completed with 2959 participants; 1481 women and 1478 men. In the study, 41.3% of the women and 22.6% of the men reported being subject to violence. The mean score of the attitude towards violence scale was 41.57±11.83 for women and 49.38±11.52 for men (p <0.001). The mean scores on the attitude towards violence scale were found to be statistically significantly related to gender, education status, occupation, income status, co-educational status, co-occupation, marital age, family type, and subjection to violence (p <0.05). Socio-demographic and socio-cultural factors were found to influence the attitudes of women and men towards violence against women. The attitudes towards violence against women were found to be more positive in women. The rate of accepting violence as natural (acceptable) phenomena was found to be higher among men. That is, the attitudes of men towards violence against women are closer to the traditional approach, away from the modern approach.


Biomarkers and Surrogate Endpoints: Lessons Learned From Glaucoma.
With the recent progress in imaging technologies for assessment of structural damage in glaucoma, a debate has emerged on whether these measurements can be used as valid surrogate endpoints in clinical trials evaluating new therapies for the disease. A discussion of surrogates should be grounded on knowledge acquired from their use in other areas of medicine as well as regulatory requirements. This article reviews the conditions for valid surrogacy in the context of glaucoma clinical trials and critically evaluates the role of biomarkers such as IOP and imaging measurements as potential surrogates for clinically relevant outcomes. Valid surrogate endpoints must be able to predict a clinically relevant endpoint, such as loss of vision or decrease in quality of life. In addition, the effect of a proposed treatment on the surrogate must capture the effect of the treatment on the clinically relevant endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has yet been conducted for any class of IOP-lowering treatments. Although strong evidence has accumulated about imaging measurements as predictors of relevant functional outcomes in glaucoma, there is still insufficient evidence to support their use as valid surrogate endpoints. However, imaging biomarkers could potentially be used as part of composite endpoints in glaucoma trials, overcoming weaknesses of the use of structural or functional endpoints in isolation. Efforts should be taken to properly design and conduct studies that can provide proper validation of potential biomarkers in glaucoma clinical trials.


Health Literacy Status and Understanding of the Prescription Instructions in Diabetic Patients.
This study aimed to assess the health literacy (HL) of patients having diabetes mellitus, their understanding of prescription instructions (PI), and the correlation between HL and understanding of PI. A cross-sectional survey was conducted in 263 adult diabetic patients who were assessed for their understanding of route of intake of the prescribed medication(s), frequency of intake, number of medication(s) to be consumed each time, indication for the medication(s), and the relation of drug intake with food. The HL of the patients was assessed by using Rapid Estimate of Adult Literacy in Medicine, a screening test comprising of 66 health-related words. The number of correctly pronounced words was used to assign a grade-equivalent reading level. There was a significant difference in the understanding of PI in patients with low and high HL levels. A significant difference was observed between the mean total score for interpreting PI in patients with 7 or fewer years of education compared with the other groups with a higher educational status (P < 0.001). To conclude, diabetic patients with low HL level will have difficulty in understanding PI. Hence, an alternative comprehensive strategy needs to be adopted in clinical practice in these patients to provide them the instructions to take medications properly.


Wild emmer genome architecture and diversity elucidate wheat evolution and domestication.
Wheat (Triticum spp.) is one of the founder crops that likely drove the Neolithic transition to sedentary agrarian societies in the Fertile Crescent more than 10,000 years ago. Identifying genetic modifications underlying wheat's domestication requires knowledge about the genome of its allo-tetraploid progenitor, wild emmer (T. turgidum ssp. dicoccoides). We report a 10.1-gigabase assembly of the 14 chromosomes of wild tetraploid wheat, as well as analyses of gene content, genome architecture, and genetic diversity. With this fully assembled polyploid wheat genome, we identified the causal mutations in Brittle Rachis 1 (TtBtr1) genes controlling shattering, a key domestication trait. A study of genomic diversity among wild and domesticated accessions revealed genomic regions bearing the signature of selection under domestication. This reference assembly will serve as a resource for accelerating the genome-assisted improvement of modern wheat varieties.


Biogenetic mechanisms predisposing to complex phenotypes in parents may function differently in their children.
This study focuses on the participants of the Long Life Family Study to elucidate whether biogenetic mechanisms underlying relationships among heritable complex phenotypes in parents function in the same way for the same phenotypes in their children. Our results reveal 3 characteristic groups of relationships among phenotypes in parents and children. One group composed of 3 pairs of phenotypes confirms that associations among some phenotypes can be explained by the same biogenetic mechanisms working in parents and children. Two other groups including 9 phenotype pairs show that this is not a common rule. Our findings suggest that biogenetic mechanisms underlying relationships among different phenotypes, even if they are causally related, can function differently in successive generations or in different age groups of biologically related individuals. The results suggest that the role of aging-related processes in changing environment may be conceptually underestimated in current genetic association studies using genome wide resources.


A Systematic Review of International Clinical Guidelines for Rehabilitation of People With Neurological Conditions: What Recommendations Are Made for Upper Limb Assessment?
Background: Upper limb impairment is a common problem for people with neurological disabilities, affecting activity, performance, quality of life, and independence. Accurate, timely assessments are required for effective rehabilitation, and development of novel interventions. International consensus on upper limb assessment is needed to make research findings more meaningful, provide a benchmark for quality in clinical practice, more cost-effective neurorehabilitation and improved outcomes for neurological patients undergoing rehabilitation. Aim: To conduct a systematic review, as part of the output of a European COST Action, to identify what recommendations are made for upper limb assessment. Methods: We systematically reviewed published guidance on measures and protocols for assessment of upper limb function in neurological rehabilitation via electronic databases from January 2007-December 2017. Additional records were then identified through other sources. Records were selected for inclusion based on scanning of titles, abstracts and full text by two authors working independently, and a third author if there was disagreement. Records were included if they referred to "rehabilitation" and "assessment" or "measurement". Reasons for exclusion were documented. Results: From the initial 552 records identified (after duplicates were removed), 34 satisfied our criteria for inclusion, and only six recommended specific outcome measures and /or protocols. Records were divided into National Guidelines and other practice guidelines published in peer reviewed Journals. There was agreement that assessment is critical, should be conducted early and at regular intervals and that there is a need for standardized measures. Assessments should be conducted by a healthcare professional trained in using the measure and should encompass body function and structure, activity and participation. Conclusions: We present a comprehensive, critical, and original summary of current recommendations. Defining a core set of measures and agreed protocols requires international consensus between experts representing the diverse and multi-disciplinary field of neurorehabilitation including clinical researchers and practitioners, rehabilitation technology researchers, and commercial developers. Current lack of guidance may hold-back progress in understanding function and recovery. Together with a Delphi consensus study and an overview of systematic reviews of outcome measures it will contribute to the development of international guidelines for upper limb assessment in neurological conditions.


Characterising and communicating the potential hazard posed by potentially toxic elements in indoor dusts from schools across Lagos, Nigeria.
Ambient and indoor air pollution results in an estimated 7 million premature deaths globally each year, representing a major contemporary public health challenge, but one poorly quantified from a toxicological and source perspective. Indoor exposure represents possibly the greatest potential overall exposure, yet our indoor environments are still poorly understood, modelled and characterized. In rapidly growing cities, such as Lagos, Nigeria, environmental monitoring can play an important role in establishing baseline data, monitoring urban pollution trends and in environmental education. Classroom dust samples were collected from 40 locations from across the twenty local government areas (LGAs) of Lagos, in June 2019. The aim of the study was to assess the potential hazard posed by PTE in indoor dusts and to develop a suitable risk communication strategy to inform and educate the public, promoting environmental health literacy. Concentrations of total PTE in indoor dusts were assessed using Energy Dispersive X-Ray Fluorescence (ED-XRF) spectrometry. Oral bioaccessibility determinations using the unified BARGE method, and analysis by Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES) were also performed on the dust samples to determine the fraction available for absorption in the gastrointestinal tract. Results showed that the indoor dust samples were largely uncontaminated, with only few exceptions (2 samples). Enrichment factor pollution trend for the total PTE concentrations was in the order of Pb > Zn > U > Cr > Cu > Ba > Mn > V > As > Cd > Ni > Al. Source apportionment studies using factor analysis suggests concentrations of Al, As, Fe, Mn, Ni, and U may be influenced largely by lithogenic factors, while Cd, Cu and Pb originated principally from anthropogenic sources. Chromium, V and Zn appear to originate from mixed sources of both lithogenic and anthropogenic origin. Our oral bioaccessibility determinations indicate that the assumption of 100% bioavailability based on pseudototal or total concentrations would overestimate the hazard potential of PTE in these indoor dusts. Zinc was the most bioaccessible PTE (mean of 88%), with Mn (57%), Pb (48%), Ba (48%), Al (41%), As (37%), Cu (36%), Ni (28%), Cr (10%) and Fe (7%) the least bioaccessible. Human health risk assessment, for both children and adults using the bioaccessible fraction, showed values to be within acceptable risk levels.


A multidisciplinary approach to clitoral reconstruction after female genital mutilation: the crucial role of counselling.
Female genital mutilation (FGM) is becoming more widely seen in the West, due to immigration and population movement. Health services are being confronted with the need to provide care for women with FGM. One of the more recent trends is the provision of clitoral reconstruction. It remains unclear, however, what constitutes good practice with regard to this type of surgery. Based on a keynote presentation about reconstructive clitoral surgery, we briefly discuss the possible consequences of FGM and the findings from recent publications on clitoral reconstruction. Recognising individual differences in women, we suggest a multidisciplinary counselling model to provide appropriate care for women requesting clitoral reconstruction. The literature shows that FGM influences physical, mental and sexual health. Clitoral reconstructive surgery can lead to an increase in sexual satisfaction and orgasm in some, but not all, women. A multidisciplinary approach would enable a more satisfactory and individually tailored approach to care. The multidisciplinary team should consist of a midwife, a gynaecological surgeon, a psychologist-psychotherapist, a sexologist and a social worker. Comprehensive health counselling should be the common thread in this model of care. Our proposed care pathway starts with taking a thorough history, followed by medical, psychological and sexological consultations. Women with FGM requesting clitoral reconstruction might primarily be looking to improve their sexual life, to recover their identity and to reduce pain. Surgery may not always be the right answer. Thorough counselling that includes medical, psychological and sexual advice is therefore necessary as part of a multidisciplinary approach.


Maternal nonstandard work schedules and adolescent overweight.
We investigated whether nonstandard work schedules by mothers were associated with adolescent overweight. We conducted multiple regression analyses using a sample of mother-child pairs (n=2353) from the National Longitudinal Survey of Youth to examine the association between the number of years mothers worked at nonstandard schedules and adolescent overweight at age 13 or 14 years. Separate analyses were also conducted by family income and family type. Child's body mass index increased significantly if mothers worked either a few years or many years at nonstandard schedules. Risk of overweight was also significantly associated with 1 to 4 and 10 or more years of maternal nonstandard work schedules. In both cases, results were driven by those families with predicted incomes in the 2nd quartile ("near-poor"), with a few or many years of nonstandard work schedules also associated with increased risk of adolescent overweight in 2-parent families. Results indicate the importance of the overlooked association between maternal nonstandard work schedules and adolescent overweight at age 13 or 14 years. Nonstandard work schedules among near-poor families and in 2-parent families may disrupt the work-family balance, affecting adolescent overweight.


Selected reaction monitoring mass spectrometry reveals the dynamics of signaling through the GRB2 adaptor.
Signaling pathways are commonly organized through inducible protein-protein interactions, mediated by adaptor proteins that link activated receptors to cytoplasmic effectors. However, we have little quantitative data regarding the kinetics with which such networks assemble and dissolve to generate specific cellular responses. To address this deficiency, we designed a mass spectrometry method, affinity purification-selected reaction monitoring (AP-SRM), which we used to comprehensively and quantitatively investigate changes in protein interactions with GRB2, an adaptor protein that participates in a remarkably diverse set of protein complexes involved in multiple aspects of cellular function. Our data reliably define context-specific and time-dependent networks that form around GRB2 after stimulation, and reveal core and growth factor-selective complexes comprising 90 proteins identified as interacting with GRB2 in HEK293T cells. Capturing a key hub protein and dissecting its interactions by SRM should be equally applicable to quantifying signaling dynamics for a range of hubs in protein interaction networks.