Environmental influences predominate in remission from alcohol use disorder in young adult twins.
Familial influences on remission from alcohol use disorder (AUD) have been studied using family history of AUD rather than family history of remission. The current study used a remission phenotype in a twin sample to examine the relative contributions of genetic and environmental influences to remission. The sample comprised 6183 twins with an average age of 30 years from the Australian Twin Registry. Lifetime history of alcohol abuse and dependence symptoms and symptom recency were assessed with a structured telephone interview. AUD was defined broadly and narrowly as history of two or more or three or more abuse or dependence symptoms. Remission was defined as absence of symptoms at time of interview among individuals with lifetime AUD. Standard bivariate genetic analyses were conducted to derive estimates of genetic and environmental influences on AUD and remission. Environmental influences alone accounted for remission in males and for 89% of influences on remission in females, with 11% due to genetic influences shared with AUD, which decreased the likelihood of remission. For women, more than 80% of influences on remission were distinct from influences on AUD, and environmental influences were from individual experiences only. For men, just over 50% of influences on remission were distinct from those on AUD, and the influence of environments shared with the co-twin were substantial. The results for the broad and narrow phenotypes were similar. The current study establishes young adult remission as a phenotype distinct from AUD and highlights the importance of environmental influences on remission.


A novel method for detecting association between DNA methylation and diseases using spatial information.
DNA methylation may represent an important contributor to the missing heritability described in complex trait genetics. However, technology to measure DNA methylation has outpaced statistical methods for analysis. Taking advantage of the recent finding that methylated sites cluster together, we propose a Spatial Clustering Method (SCM) to detect differentially methylated regions (DMRs) in the genome in case and control studies using spatial location information. This new method compares the distribution of distances in cases and controls between DNA methylation marks in the genomic region of interest. A statistic is computed based on these distances. Proper type I error rate is maintained and statistical significance is evaluated using permutation test. The effectiveness of the SCM we propose is evaluated by a simulation study. By simulating a simple disease model, we demonstrate that SCM has good power to detect DMRs associated with the disease. Finally, we applied the SCM to an exploratory analysis of chromosome 14 from a colorectal cancer data set and identified statistically significant genomic regions. Identification of these regions should lead to a better understanding of methylated sites and their contribution to disease. The SCM can be used as a reliable statistical method for the identification of DMRs associated with disease states in exploratory epigenetic analyses.


Long-term correction of murine phenylketonuria by viral gene transfer: liver versus muscle.
Current therapy for phenylketonuria (PKU) consists of life-long dietary restriction of phenylalanine (Phe), which presents problems of adherence for patients. Alternative therapies under investigation include, among others, the use of gene therapy to provide copies of wild-type, non-mutant, phenylalanine hydroxylase (PAH) enzyme. Expression of PAH in both liver (the usual metabolic source of this enzyme) and skeletal muscle is under investigation. Liver gene therapy, using a viral vector based on the adeno-associated viruses (AAVs), provided effective clearance of serum Phe that was sustained for 1 year in some mice. In order for PAH expression to be effective in skeletal muscle, the essential metabolic cofactor, tetrahydrobiopterin (BH(4)), must also be provided, either by supplementation or gene therapy. Both these approaches were effective. When transgenic PKU mice that constitutively expressed PAH in muscle were given intraperitoneal supplementation with BH(4), this produced (transient) effective clearance of Phe to normal levels. In addition, use of an AAV vector containing the genes for PAH, and for two key synthetic enzymes for BH(4), provided substantial and long-lasting correction (more than 1 year) of blood Phe levels when injected into skeletal muscle of PKU mice. These two strategies provide promising treatment alternatives for the management of PKU in patients.


High mobility in a van der Waals layered antiferromagnetic metal.
Van der Waals (vdW) materials with magnetic order have been heavily pursued for fundamental physics as well as for device design. Despite the rapid advances, so far, they are mainly insulating or semiconducting, and none of them has a high electronic mobility-a property that is rare in layered vdW materials in general. The realization of a high-mobility vdW material that also exhibits magnetic order would open the possibility for novel magnetic twistronic or spintronic devices. Here, we report very high carrier mobility in the layered vdW antiferromagnet GdTe3. The electron mobility is beyond 60,000 cm2 V-1 s-1, which is the highest among all known layered magnetic materials, to the best of our knowledge. Among all known vdW materials, the mobility of bulk GdTe3 is comparable to that of black phosphorus. By mechanical exfoliation, we further demonstrate that GdTe3 can be exfoliated to ultrathin flakes of three monolayers.


ESCMID* guideline for the diagnosis and management of Candida diseases 2012: patients with HIV infection or AIDS.
Mucosal candidiasis is frequent in immunocompromised HIV-infected highly active antiretroviral (HAART) naive patients or those who have failed therapy. Mucosal candidiasis is a marker of progressive immune deficiency. Because of the frequently marked and prompt immune reconstitution induced by HAART, there is no recommendation for primary antifungal prophylaxis of mucosal candidiasis in the HIV setting in Europe, although it has been evidenced as effective in the pre-HAART era. Fluconazole remains the first line of therapy for both oropharyngeal candidiasis and oesophageal candidiasis and should be preferred to itraconazole oral solution (or capsules when not available) due to fewer side effects. For patients who still present with fluconazole-refractory mucosal candidiasis, oral treatment with any other azole should be preferred based on precise Candida species identification and susceptibility testing results in addition to the optimization of HAART when feasible. For vaginal candidiasis, topical therapy is preferred.


Human body odour, symmetry and attractiveness.
Several studies have found body and facial symmetry as well as attractiveness to be human mate choice criteria. These characteristics are presumed to signal developmental stability. Human body odour has been shown to influence female mate choice depending on the immune system, but the question of whether smell could signal general mate quality, as do other cues, was not addressed in previous studies. We compared ratings of body odour, attractiveness, and measurements of facial and body asymmetry of 16 male and 19 female subjects. Subjects wore a T-shirt for three consecutive nights under controlled conditions. Opposite-sex raters judged the odour of the T-shirts and another group evaluated portraits of the subjects for attractiveness. We measured seven bilateral traits of the subject's body to assess body asymmetry. Facial asymmetry was examined by distance measurements of portrait photographs. The results showed a significant positive correlation between facial attractiveness and sexiness of body odour for female subjects. We found positive relationships between body odour and attractiveness and negative ones between smell and body asymmetry for males only if female odour raters were in the most fertile phase of their menstrual cycle. The outcomes are discussed in the light of different male and female reproductive strategies.


Ground water contamination in the United States.
Ground water contamination is of increasing concern in the United States because about 50 percent of our drinking water comes from well water. The causes of contamination stem from both point sources and nonpoint sources. Since ground water moves slowly, the contaminant may affect only a small portion of an aquifer for a considerable period of time. Deleterious effects on human health have resulted from pathogenic organisms in ground water and from its toxic chemical composition. It is difficult to estimate the extent of contamination on a national basis as the frequency of instances of contamination is very variable. Remedial actions to clean up aquifers are difficult, expensive, and sometimes not feasible. Many of the laws and regulations that control ground water contamination are designed with other main objectives.


Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer.
Genome-wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study-identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior. Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single-variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls. We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38-3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01-16.56), prolyl 3-hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75-15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10-0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility. Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.


LSD1-ERRα complex requires NRF1 to positively regulate transcription and cell invasion.
Lysine-specific demethylase 1 (LSD1) exerts dual effects on histone H3, promoting transcriptional repression via Lys4 (H3K4) demethylation or transcriptional activation through Lys9 (H3K9) demethylation. These activities are often exerted at transcriptional start sites (TSSs) and depend on the type of enhancer-bound transcription factor (TFs) with which LSD1 interacts. In particular, the Estrogen-Receptor Related α (ERRα) TF interacts with LSD1 and switches its activities toward H3K9 demethylation, resulting in transcriptional activation of a set of common target genes. However, how are the LSD1-TF and, in particular LSD1-ERRα, complexes determined to act at TSSs is not understood. Here we show that promoter-bound nuclear respiratory factor 1 (NRF1), but not ERRα, is essential to LSD1 recruitment at the TSSs of positive LSD1-ERRα targets. In contrast to ERRα, NRF1 does not impact on the nature of LSD1 enzymatic activity. We propose a three factor model, in which the LSD1 histone modifier requires a TSS tethering factor (NRF1) as well as an activity inducer (ERRα) to transcriptionally activate common targets. The relevance of this common network is illustrated by functional data, showing that all three factors are required for cell invasion in an MMP1 (Matrix MetalloProtease 1)-dependent manner, the expression of which is regulated by NRF1/LSD1/ERRα-mediated H3K9me2 demethylation.


The Stigma of Exclusive Breastfeeding Among Both HIV-Positive and HIV-Negative Women in Nairobi, Kenya.
Exclusive breastfeeding (EBF) means giving only breast milk to an infant. Although it is the optimal mode of feeding for infants younger than 6 months, its prevalence is low in HIV-endemic regions. Extensive promotion of EBF for 6 months in prevention of mother-to-child HIV transmission (PMTCT) programs could inadvertently result in stigma due to women's perceived association of EBF with HIV infection. In this qualitative study, we describe how stigma impacts the uptake of EBF among HIV-positive and -negative women. Pregnant and postpartum women and their male partners were recruited to participate in a total of 22 focus group discussions (FGDs). Transcripts were analyzed using ATLAS.ti. Codes were identified both a priori and inductively using the open coding approach. Major themes and subthemes were identified. There was a broad and strong consensus among some FGD participants that HIV-related stigma was a barrier to EBF. EBF was perceived as a practice for HIV-positive women. Thus, fear of discrimination deterred both HIV-positive and -negative women from EBF. However, with health education, peer counselor, and male partner support, some women were able to breastfeed exclusively regardless of opposing social norms. Stigma related to HIV poses a formidable barrier to EBF in HIV-endemic regions. There is an urgent need to widely target all women with EBF information and support EBF practices regardless of maternal HIV infection status. The lessons learned from this study indicate that vertical programs can hinder promotion of infant health interventions and therefore negatively affect child survival.


Treatments of Sexual Dysfunction in Opioid Substitution Therapy Patients: A Systematic Review and Meta-Analysis.
Sexual dysfunction is a common condition in the opioid substitution therapy (OST) population. We aimed to determine the efficacy and safety of treatment for sexual dysfunction in the OST population. We searched for interventional studies from Medline, PubMed, and Scopus. Three independent authors conducted a risk-of-bias assessment (RoB 2). A total of seven studies (five randomized-controlled trials, two quasi-experimental), including 473 patients with sexual dysfunction, were identified. Among these, three bupropion (n=207), one trazodone (n=75), two rosa Damascena (n=100), and one ginseng (n=91) studies had reported significantly improve various sexual functioning domains in both genders. In a meta-analysis, bupropion significantly increased male sexual function with standardized mean difference of 0.53; 95% confidence interval of 0.19-0.88; P < 0.01; I2=0. The adverse effects were minor for all agents, and no significant difference between treatment and placebo groups in randomized-controlled trials. These agents have a promising future as therapy for sexual dysfunction in the OST population. However, given the limited sample size and number of studies, further studies should be conducted to confirm the use of these agents.


Xanthine oxidoreductase inhibition causes reverse remodeling in rats with dilated cardiomyopathy.
Increased reactive oxygen species (ROS) generation is implicated in cardiac remodeling in heart failure (HF). As xanthine oxidoreductase (XOR) is 1 of the major sources of ROS, we tested whether XOR inhibition could improve cardiac performance and induce reverse remodeling in a model of established HF, the spontaneously hypertensive/HF (SHHF) rat. We randomized Wistar Kyoto (WKY, controls, 18 to 21 months) and SHHF (19 to 21 months) rats to oxypurinol (1 mmol/L; n=4 and n=15, respectively) or placebo (n=3 and n=10, respectively) orally for 4 weeks. At baseline, SHHF rats had decreased fractional shortening (FS) (31+/-3% versus 67+/-3% in WKY, P<0.0001) and increased left-ventricular (LV) end-diastolic dimension (9.7+/-0.2 mm versus 7.0+/-0.4 mm in WKY, P<0.0001). Whereas placebo and oxypurinol did not change cardiac architecture in WKY, oxypurinol attenuated decreased FS and elevated LV end-diastolic dimension, LV end-systolic dimension, and LV mass in SHHF. Increased myocyte width in SHHF was reduced by oxypurinol. Additionally, fetal gene activation, altered calcium cycling proteins, and upregulated phospho-extracellular signal-regulated kinase were restored toward normal by oxypurinol (P<0.05 versus placebo-SHHF). Importantly, SHHF rats exhibited increased XOR mRNA expression and activity, and oxypurinol treatment reduced XOR activity and superoxide production toward normal, but not expression. On the other hand, NADPH oxidase activity remained unchanged, despite elevated subunit protein abundance in treated and untreated SHHF rats. Together these data demonstrate that chronic XOR inhibition restores cardiac structure and function and offsets alterations in fetal gene expression/Ca2+ handling pathways, supporting the idea that inhibiting XOR-derived oxidative stress substantially improves the HF phenotype.


Fluctuating asymmetry and environmental stress: understanding the role of trait history.
While fluctuating asymmetry (FA; small, random deviations from perfect symmetry in bilaterally symmetrical traits) is widely regarded as a proxy for environmental and genetic stress effects, empirical associations between FA and stress are often weak or heterogeneous among traits. A conceptually important source of heterogeneity in relationships with FA is variation in the selection history of the trait(s) under study, i.e. traits that experienced a (recent) history of directional change are predicted to be developmentally less stable, potentially through the loss of canalizing modifiers. Here we applied X-ray photography on museum specimens and live captures to test to what extent the magnitude of FA and FA-stress relationships covary with directional shifts in traits related to the flight apparatus of four East-African rainforest birds that underwent recent shifts in habitat quality and landscape connectivity. Both the magnitude and direction of phenotypic change varied among species, with some traits increasing in size while others decreased or maintained their original size. In three of the four species, traits that underwent larger directional changes were less strongly buffered against random perturbations during their development, and traits that increased in size over time developed more asymmetrically than those that decreased. As we believe that spurious relationships due to biased comparisons of historic (museum specimens) and current (field captures) samples can be ruled out, these results support the largely untested hypothesis that directional shifts may increase the sensitivity of developing traits to random perturbations of environmental or genetic origin.


Alcohol and the risk for latent autoimmune diabetes in adults: results based on Swedish ESTRID study.
Moderate alcohol consumption is associated with a reduced risk of type 2 diabetes. Our aim was to investigate whether alcohol consumption is associated with the risk of latent autoimmune diabetes in adults (LADA), an autoimmune form of diabetes with features of type 2 diabetes. A population-based case-control study was carried out to investigate the association of alcohol consumption and the risk of LADA. We used data from the ESTRID case-control study carried out between 2010 and 2013, including 250 incident cases of LADA (glutamic acid decarboxylase antibodies (GADAs) positive) and 764 cases of type 2 diabetes (GADA negative), and 1012 randomly selected controls aged ≥35. Logistic regression was used to estimate the odds ratios (ORs) of diabetes in relation to alcohol intake, adjusted for age, sex, BMI, family history of diabetes, smoking, and education. Alcohol consumption was inversely associated with the risk of type 2 diabetes (OR 0.95, 95% CI 0.92-0.99 for every 5-g increment in daily intake). Similar results were observed for LADA, but stratification by median GADA levels revealed that the results only pertained to LADA with low GADA levels (OR 0.85, 95% CI 0.76-0.94/5 g alcohol per day), whereas no association was observed with LADA having high GADA levels (OR 1.00, 95% CI 0.94-1.06/5 g per day). Every 5-g increment of daily alcohol intake was associated with a 10% increase in GADA levels (P=0.0312), and a 10% reduction in homeostasis model assessment of insulin resistance (P=0.0418). Our findings indicate that alcohol intake may reduce the risk of type 2 diabetes and type 2-like LADA, but has no beneficial effects on diabetes-related autoimmunity.


No magic targets! Changing clinical practice to become more evidence based.
This article focuses on the diffusion and adoption of innovations in clinical practice. The authors are specifically interested in underresearched questions concerning the latter stages of the creation, diffusion, and adoption of new knowledge, namely: What makes this information credible and therefore utilized? Why do actors decide to use new knowledge? And what is the significance of the social context of which actors are a part? This article first appeared in Health Care Management Review, 27(3), 35-47.


The influence of patients' and primary care practitioners' beliefs and expectations about chronic musculoskeletal pain on the process of care: a systematic review of qualitative studies.
To review qualitative, empirical studies exploring the influence of patients' and primary care practitioners' beliefs and expectations on the process of care for chronic musculoskeletal pain. A multidisciplinary review group searched 9 bibliographic databases. The group worked in pairs to screen titles and abstracts for relevance, to quality appraise relevant studies, to extract data from high-quality studies and to undertake a thematic analysis of this data. We identified 12,994 abstracts from our searches, of which we obtained 113 full-text articles as their abstracts contained insufficient information for us to decide on their eligibility. We appraised 22 qualitative studies, 15 of which were included in the analysis. Themes identified included; (1) beliefs about pain, (2) expectations of treatment, (3) trust, and (4) patient education. Both patients and practitioners wanted clear communication within the consultation and to be respected, but conflicts existed on nearly all other aspects of the consultation, some of which at present may seem insurmountable and may lead to difficulties in achieving positive outcomes. To tackle the challenges and conflicts identified within the review, change may have to occur, not just in individual patient and practitioner beliefs and behavior, but also at an organizational and system level, for example, changes in undergraduate and postgraduate education and changes in the organization and availability of health services.


Arsenic induces DNA damage in environmentally exposed Mexican children and adults. Influence of GSTO1 and AS3MT polymorphisms.
Inorganic arsenic (i-As) is an environmental carcinogen to which millions of people are chronically exposed mainly via drinking water. In this study, we used the comet assay to evaluate DNA damage in i-As-exposed inhabitants of the north of Mexico. The environmental monitoring and the exposure assessment were done by measuring both drinking water arsenic (As) content and total urinary As. In addition, the studied population was genetically characterized for four different glutathione S-transferase omega1 (GSTO1) polymorphisms (Ala140Asp, Glu155del, Glu208Lys, and Ala236Val) and the As (+3 oxidation state) methyltransferase (AS3MT) Met287Thr polymorphism to determine whether such variants influence As-related genotoxicity. As content in the drinking water of the population was found to range between 1 and 187 microg/l, with a mean concentration value of 16 microg/l. The total urinary As content of the exposed individuals was found to be correlated with the As content in drinking water, and subjects were classified as low (< 30 microg As/g creatinine), medium (31-60 microg As/g creatinine), and highly exposed (> 61 microg As/g creatinine). A positive association was found between the level of exposure and the genetic damage measured as percentage of DNA in tail (p < 0.001), and AS3MT Met287Thr was found to significantly influence the effect (p < 0.034) among children carrying the 287Thr variant allele. Altogether, our results evidenced that people living in As-contaminated areas are at risk and that AS3MT genetic variation may play an important role modulating such risk in northern Mexico, especially among children.


Evaluation of lipid oxidative stress status in Sjögren syndrome patients.
We evaluated the levels of lipid oxidative stress markers and inflammatory cells from tears and conjunctiva of patients with Sjögren syndrome (SS) and normal subjects. We examined 31 eyes of 16 patients (16 females) with SS and 15 eyes of 10 healthy controls (2 males and 8 females) in this prospective study. All subjects underwent a Schirmer test, measurement of tear film break-up time, vital stainings, confocal microscopy of the conjunctiva, tear collection for hexanoyl-lysine (HEL), ELISA, and conjunctival brush cytology. Brush cytology samples underwent immunohistochemistry (IHC) staining with HEL and 4-hydroxy-2-nonenal (4HNE). Hematoxylin-eosin and IHC staining with HEL and 4HNE also were performed on conjunctival samples of SS patients and controls. The tear stability and vital staining scores were significantly worse in eyes of SS patients compared to the controls. Conjunctival inflammatory cell density was significantly higher in SS subjects compared to controls. The numbers of conjunctival cells stained positively for HEL and 4HNE were significantly higher in SS patients compared to controls. Tear HEL concentrations correlated significantly with staining scores and inflammatory cell density in confocal microscopy. Conjunctival specimens also revealed higher numbers of cells stained positively for inflammatory markers, as well as HEL and 4HNE in the IHC stainings. Increase of the oxidative stress status in the conjunctiva of SS patients appears to have a role in the pathogenesis of dry eye disease. A close relationship may exist between reactive oxygen species (ROS) production, lipid peroxidation related membrane damage, and inflammatory processes in dry eye.


Wide-angle beam splitting by use of positive-negative refraction in photonic crystals.
We present a positive-negative refraction effect in which, under certain conditions, an incident plane wave launched into a photonic crystal excites a positive-refracted Bloch wave and a negative-refracted Bloch wave simultaneously, both of which maintain the polarization. By utilizing this phenomenon, wide-angle beam splitting can be realized at the microscale level. Numerical simulations are employed to demonstrate this anomalous refraction behavior.


Weight loss via diet and exercise improves exercise breathing mechanics in obese men.
Obesity alters breathing mechanics during exercise. Weight loss improves lung function at rest, but the effect of weight loss, especially regional fat loss, on exercise breathing mechanics is unclear. We hypothesized that weight loss, especially a decrease in abdominal fat, would improve breathing mechanics during exercise because of an increase in end-expiratory lung volume (EELV). Nine obese men were studied before and after weight loss (13% ± 8% of total fat weight, mean ± SD). Subjects underwent pulmonary function testing, underwater weighing, fat distribution estimates (MRI), and graded cycle ergometry before and after a 12-week diet and exercise program. In seven men, esophageal and gastric pressures were measured. The effects of weight loss were analyzed at rest, at ventilatory threshold (VTh), and during peak exercise by dependent Student t test, and the relationship among variables was determined by correlation analysis. Subjects lost 7.4 ± 4.2 kg of body weight (P < .001), but the distribution of fat remained unchanged. After weight loss, lung volume subdivisions at rest were increased (P < .05) and were moderately associated (P < .05) with changes in chest, waist, and hip circumferences. At VTh, EELV increased, and gastric pressure decreased significantly (P < .05). The changes in waist circumference, hip circumference, BMI, and sum of chest, waist, and hip circumferences were also consistently and significantly correlated (P < .05) with changes in gastric pressure during exercise at VTh. Modest weight loss improves breathing mechanics during submaximal exercise in otherwise healthy obese men, which is clinically encouraging. Improvement appears to be related to the cumulative loss of chest wall fat.


Ultrasequencing of the meiofaunal biosphere: practice, pitfalls and promises.
Biodiversity assessment is the key to understanding the relationship between biodiversity and ecosystem functioning, but there is a well-acknowledged biodiversity identification gap related to eukaryotic meiofaunal organisms. Meiofaunal identification is confounded by the small size of taxa, morphological convergence and intraspecific variation. However, the most important restricting factor in meiofaunal ecological research is the mismatch between diversity and the number of taxonomists that are able to simultaneously identify and catalogue meiofaunal diversity. Accordingly, a molecular operational taxonomic unit (MOTU)-based approach has been advocated for en mass meiofaunal biodiversity assessment, but it has been restricted by the lack of throughput afforded by chain termination sequencing. Contemporary pyrosequencing offers a solution to this problem in the form of environmental metagenetic analyses, but this represents a novel field of biodiversity assessment. Here, we provide an overview of meiofaunal metagenetic analyses, ranging from sample preservation and DNA extraction to PCR, sequencing and the bioinformatic interrogation of multiple, independent samples using 454 Roche sequencing platforms. We report two examples of environmental metagenetic nuclear small subunit 18S (nSSU) analyses of marine and tropical rainforest habitats and provide critical appraisals of the level of putative recombinant DNA molecules (chimeras) in metagenetic data sets. Following stringent quality control measures, environmental metagenetic analyses achieve MOTU formation across the eukaryote domain of life at a fraction of the time and cost of traditional approaches. The effectiveness of Roche 454 sequencing brings substantial advantages to studies aiming to elucidate the molecular genetic richness of not only meiofaunal, but also all complex eukaryotic communities.


Inhibition by Dications of in vitro growth of Leishmania major and Leishmania tropica: causative agents of old world cutaneous leishmaniasis.
Old World cutaneous leishmaniasis is caused by infection with Leishmania major and Leishmania tropica. Pentamidine and related dications exhibit broad spectrum antiprotozoal activity. Based on the previously reported efficacy of these compounds against related organisms, 18 structural analogs of pentamidine were evaluated for in vitro antileishmanial activity, using pentamidine as the standard reference drug for comparison. Furan analogs and reversed amidine compounds were examined for activity against L. major and L. tropica promastigotes. The most active compounds against both Leishmania species were in the reversed amidine series. DB745 and DB746 exhibited the highest activity against L. major and DB745 was the most active compound against L. tropica. Both of these compounds exhibited 50% inhibitory concentrations (IC50) below 1 nM for L. major. Ten reversed amidines were also tested for their ability to inhibit growth in an axenic amastigote model. Nine of 10 reversed amidine analogs were active at concentrations below 1 nM. These results justify further study of dicationic compounds as potential new agents for treating cutaneous leishmaniasis.


Affective instability prior to and after thoughts about self-injury in individuals with and at-risk of psychosis: a mobile phone based study.
It has been proposed that affective instability may be associated with thoughts about self-injury. The aim of this study was to test the hypotheses that instability in feelings of depression, but not anxiety, guilt, or hostility, would predict greater concurrent and subsequent thoughts about self-injury. Thirty-six individuals with psychosis completed questions on touch-screen mobile phones at semi-random times each day for one week. The instability of depression predicted greater concurrent and subsequent levels of thoughts about self-injury, even when controlling for depression level. Conversely, self-injurious thoughts predicted more stable depression. The instability of guilt, anxiety, and hostility did not significantly predict levels of thoughts about self-injury. Results indicate that a variable depressive state may trigger the onset of thoughts about self-injury, which increases the risk of its subsequent recurrence. The onset of self-injurious thoughts may, however, have a stabilizing effect on subsequent depression.


Evolution of the pygmy phenotype: evidence of positive selection fro genome-wide scans in African, Asian, and Melanesian pygmies.
Human pygmy populations inhabit different regions of the world, from Africa to Melanesia. In Asia, short-statured populations are often referred to as "negritos." Their short stature has been interpreted as a consequence of thermoregulatory, nutritional, and/or locomotory adaptations to life in tropical forests. A more recent hypothesis proposes that their stature is the outcome of a life history trade-off in high-mortality environments, where early reproduction is favored and, consequently, early sexual maturation and early growth cessation have coevolved. Some serological evidence of deficiencies in the growth hormone/insulin-like growth factor axis have been previously associated with pygmies' short stature. Using genome-wide single-nucleotide polymorphism genotype data, we first tested whether different negrito groups living in the Philippines and Papua New Guinea are closely related and then investigated genomic signals of recent positive selection in African, Asian, and Papuan pygmy populations. We found that negritos in the Philippines and Papua New Guinea are genetically more similar to their nonpygmy neighbors than to one another and have experienced positive selection at different genes. These results indicate that geographically distant pygmy groups are likely to have evolved their short stature independently. We also found that selection on common height variants is unlikely to explain their short stature and that different genes associated with growth, thyroid function, and sexual development are under selection in different pygmy groups.


Computer Vision Applied to Detect Lethargy through Animal Motion Monitoring: A Trial on African Swine Fever in Wild Boar.
Early detection of infectious diseases is the most cost-effective strategy in disease surveillance for reducing the risk of outbreaks. Latest deep learning and computer vision improvements are powerful tools that potentially open up a new field of research in epidemiology and disease control. These techniques were used here to develop an algorithm aimed to track and compute animal motion in real time. This algorithm was used in experimental trials in order to assess African swine fever (ASF) infection course in Eurasian wild boar. Overall, the outcomes showed negative correlation between motion reduction and fever caused by ASF infection. In addition, infected animals computed significant lower movements compared to uninfected animals. The obtained results suggest that a motion monitoring system based on artificial vision may be used in indoors to trigger suspicions of fever. It would help farmers and animal health services to detect early clinical signs compatible with infectious diseases. This technology shows a promising non-intrusive, economic and real time solution in the livestock industry with especial interest in ASF, considering the current concern in the world pig industry.


Prospective External Validation of Three Preoperative Risk Scores for Prediction of New Onset Atrial Fibrillation After Cardiac Surgery.
Postoperative atrial fibrillation (POAF) is associated with early and late morbidity and mortality of cardiac surgical patients. Prophylactic treatment of atrial fibrillation (AF) has been recommended to improve outcome in cardiac surgical patients at high risk of developing POAF. Reliable models for prediction of POAF are needed to achieve that goal. This study attempted to externally validate 3 risk models proposed for preoperative prediction of POAF in cardiac surgical patients: the POAF score, the CHA2DS2-VASc score, and the Atrial Fibrillation Risk Index. This was a prospective cohort study of 1416 adult patients who underwent nonemergent coronary artery bypass graft and/or valve surgery in a single cardiac surgical center between February 2014 and September 2015. A risk score for each of the 3 prediction models was calculated in each patient. All patients were followed for up to 2 weeks, or until hospital discharge, to observe the primary outcome of new onset AF requiring treatment. Discrimination was assessed using receiver operating characteristic curves. Calibration was assessed using the Pearson χ goodness-of-fit test and calibration plots. Utility of the score to implement AF prophylaxis based on the risk of POAF, in comparison to strategies of treating all patients, or not treating any patients, was assessed via a net benefit analysis. Of the 1416 patients included in this study, 478 had the primary outcome (33.8%). The areas under the receiver operating characteristic curve for prediction of POAF in the population subsets for which the scores were validated were as follows: 0.651 (95% confidence interval [CI], 0.621-0.681) for the POAF score, 0.593 (95% CI, 0.557-0.629) for the CHA2DS2-VASc score (P < .001 versus POAF score, P < .222 versus Atrial Fibrillation Risk Index), and 0.563 (95% CI, 0.522-0.604) for the Atrial Fibrillation Risk Index (P < .001 versus POAF score). The calibration analysis showed that the predictive models had a poor fit between the observed and expected rates of POAF. Net benefit analysis showed that AF preventive strategies based on these scores, and targeting patients with moderate or high risk of POAF, improve decision-making in comparison to preventive strategies of treating all patients. The 3 prediction scores evaluated in this study have limited ability to predict POAF in cardiac surgical patients. Despite this, they may be useful in preventive strategies targeting patients with moderate or high risk of PAOF in comparison with preventive strategies applied to all patients.


Formulation, long-term physicochemical and microbiological stability of 15% topical resorcinol for hidradenitis suppurativa.
Topical resorcinol 15% is a self-treatment for painful hidradenitis suppurativa nodules and abscesses with good results in reducing pain and lesion duration. The aim of this study is to establish a 15% topical resorcinol formula, to develop a physicochemical and microbiological stability study and to further determine the compounding shelf-life in different package conditions following the European Pharmacopoeia (Ph. Eur.) specifications. Physicochemical and microbiological stability studies of the formulation were conducted for 12 months at room temperature (25°C±2°C) in different package conditions: aluminium tubes (aluminium A7-99.7% varnish DF-6172), plastic tubes (low density polyethylene) and amber plastic containers (polyethylene terephthalate). High performance liquid chromatography (HPLC) was developed as a method of indicating the stability of the resorcinol formulation. A microbiological growth assay was also validated according to the Ph. Eur. Physical properties were inspected to determine parameters such as odour, colour, pH, emulsion phase and extensibility index and its evolution. The HPLC method was validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. At day 365, visual inspection remained unchanged only for preparations packaged in aluminium tubes. The pH did not vary by more than 0.3 units in all conditions. The extensibility index decreased in the preparations packaged in plastic and amber plastic containers. HPLC analysis conducted over 1 year did not show a degradation greater than 7% of resorcinol in the preparation in plastic and aluminium packages. The ability of ATCC strains to grow in resorcinol formulation was confirmed under the suitability test. Resorcinol packed in aluminium tubes achieved microbiological stability at day 365. Only the formulation package in aluminium tubes showed physicochemical and microbiological stability of resorcinol for 12 months at room temperature (25°C±2°C).


Head-to-head comparison of first-pass MR perfusion imaging during adenosine and high-dose dobutamine/atropine stress.
To directly compare the stressor capabilities of adenosine and high-dose dobutamine/atropine using first pass myocardial perfusion magnetic resonance imaging. Fourty-one patients with suspected or known coronary artery disease underwent cardiac magnetic resonance (CMR) perfusion imaging at 1.5 Tesla on two consecutive days prior to invasive coronary angiography. On day 1 a standard CMR perfusion protocol during adenosine stress was carried out (adenosine infusion with 140 μg/kg/min, 0.1 mmol/kg Gd-DTPA). On day 2, the identical CMR perfusion sequence was repeated during a standard high-dose dobutamine/atropine stress protocol at rest and during target heart rate (85% of maximum age-predicted heart rate). Stress-inducible perfusion deficits were evaluated visually regarding presence and transmural extent. Quantitative coronary angiography served as the reference standard with significant stenosis defined as ≥50% luminal diameter reduction. Twenty-five patients (61%) had significant coronary stenoses. Adenosine and dobutamine stress CMR perfusion imaging resulted in an equally high sensitivity and specificity for the stenosis detection on a per patient basis (92 and 75% for both stressors, respectively). Agreement of both stressors with regard to the presence or absence of stress-inducible perfusion deficits was nearly perfect using patient- and segment based analysis (kappa 1.0 and 0.92, respectively). Adenosine and dobutamine/atropine stress CMR perfusion imaging are equally capable to identify stress inducible deficits and resulted in an almost identical extent of ischemic reactions. Though adenosine stress CMR perfusion imaging is widely employed, dobutamine stress CMR perfusion represents a valid alternative and may be particularly useful in patients with contraindications to vasodilator testing.


Lymphocyte Galactocerebrosidase Activity by LC-MS/MS for Post-Newborn Screening Evaluation of Krabbe Disease.
Deficiency of the lysosomal enzyme galactosylcerebrosidase (GALC) causes Krabbe disease. Newborn screening for Krabbe disease is ongoing, but improved methods for follow-up analysis of screen-positive babies are needed to better advise families and to optimize treatment. We report a new assay for the enzymatic activity of GALC in lymphocytes. T lymphocytes were isolated from venous blood by magnetic bead technology. The assay used a close structural analog of the natural substrate and LC-MS/MS to quantify the amount of product with the aid of a chemically identical internal standard. The analytical range of the assay (ratio of assay response for the QC high standard to that from all non-enzymatic-dependent processes) was 20-fold greater than that for the conventional radiometric GALC assay. The LC-MS/MS could distinguish cells that were null in GALC from those that contained traces of active enzyme (down to 0.3% of normal). There was a good correlation between the level of residual GALC activity in lymphocytes and the severity of Krabbe disease. The new assay can measure small amounts of residual GALC activity in leukocytes with high accuracy compared to previous assays and can contribute, along with genotyping, biomarker analysis, and neurological imaging, a better plan for post-newborn screening follow-up for Krabbe disease.


Age and gender differences in substance screening may underestimate injury severity: a study of 9793 patients at level 1 trauma center from 2006 to 2010.
Although the relationship between psychoactive substance use and injury is known, evidence remains conflicting on the impact of substance use on clinical outcomes after injury. We hypothesized that preinjury substance use would negatively impact clinical outcomes. National Trauma Registry American College of Surgeons identified patients (n = 9793) presenting to Duke Hospital from 2006 to 2010. Logistic regression models assessed potential predictors of receiving substance screening, mortality, length of stay, ventilator requirement, intensive care admission, or emergency department disposition. Forty-seven percent (4607/9793) of patients received blood alcohol screen (BAS) and 31% (3017/9793) received urine drug screen (UDS). Men were more likely to receive both BASs (P < 0.001) and UDSs (P = 0.001) than women after controlling for potential confounders. There was no significant difference between men and women over the legal limit for alcohol (OLLA; 27.2%, 95% confidence interval [CI]: 25.7%-28.8% versus 24.8%, 95% CI: 22.3%-27.5%). Similarly, younger patients more likely received both BASs (P < 0.001) and UDSs (P < 0.001) compared with older patients. The proportion of patients aged ≤45 y OLLA (26.5 %, 95% CI: 24.9%-28.2%) was similar to those aged >45 y OLLA (26.8%, 95% CI: 24.5%-29.3%). After controlling for potential confounders neither alcohol, nor tetrahydrocannabinol, nor cocaine was predictive of mortality, ventilator requirement, length of stay, or emergency department disposition, but a higher alcohol level (P = 0.0174) predicted intensive care admission. Females and those aged >45 y are less likely to receive BASs and UDSs. Differential screening that is biased may place patients at risk for receiving inadequate care.


Bayesian integration in force estimation.
When we interact with objects in the world, the forces we exert are finely tuned to the dynamics of the situation. As our sensors do not provide perfect knowledge about the environment, a key problem is how to estimate the appropriate forces. Two sources of information can be used to generate such an estimate: sensory inputs about the object and knowledge about previously experienced objects, termed prior information. Bayesian integration defines the way in which these two sources of information should be combined to produce an optimal estimate. To investigate whether subjects use such a strategy in force estimation, we designed a novel sensorimotor estimation task. We controlled the distribution of forces experienced over the course of an experiment thereby defining the prior. We show that subjects integrate sensory information with their prior experience to generate an estimate. Moreover, subjects could learn different prior distributions. These results suggest that the CNS uses Bayesian models when estimating force requirements.


Increased prevalence of risk factors for morbidity and mortality in the US Hispanic CF population.
Hispanic ethnicity is an independent risk factor for increased morbidity and mortality in cystic fibrosis (CF) patients. In order to compare the prevalence of risk factors for morbidity and mortality between the Hispanic CF population and the non-Hispanic CF population, we performed a cross-sectional study of patients in the 2004 Cystic Fibrosis Foundation Patient Registry. Among 22,714 CF patients, 1,511 were identified as ethnic Hispanic. Hispanic patients were diagnosed earlier (2.8 vs. 3.3 years, P = 0.005) and acquired Pseudomonas aeruginosa at a younger age (6.6 years vs. 10 years, P < 0.001). FEV(1) was lower for Hispanic patients (81.5% vs. 87% predicted for those under 18 years old [P < 0.001] and 2.1 L vs. 2.3 L for those 18 years and older [P = 0.01]). Hispanic patients had similar or better nutritional status. Hispanic patients were more likely to be diagnosed with liver disease (OR 1.31 [1.1, 1.56]) but less likely to be diagnosed with depression (OR 0.53 [0.39, 0.68]), bone and joint disease (OR 0.55 [0.41, 0.71]), or CF-related diabetes (OR 0.53 [0.43, 0.62]). Hispanic patients had lower median income by zip code ($41,930 vs. $47,341; P < 0.001), a higher rate of government insurance (55.2% vs. 32.0%; P < 0.001), and greater percentage of mothers with less than a high school education (26.7% vs. 6.5%; P < 0.001). We conclude that there is an increased prevalence of important risk factors for morbidity and mortality in the Hispanic CF population.


Pediatric Nonalcoholic Fatty Liver Disease in New York City: An Autopsy Study.
To assess the prevalence and severity of nonalcoholic liver disease (NAFLD) in children in a diverse population sample in New York City. Liver specimens were examined from children 2-19 years old who died of unexpected causes within 48 hours of medical presentation and underwent autopsy in New York City from 2005 to 2010. Records were reviewed for age, sex, weight, height, and race. Two hepatopathologists evaluated each liver specimen to determine pathologic diagnosis. The final study cohort (n = 582) was 50% black, 33% Hispanic, 12% white, 3% Asian, and 2% other; 36% had a body mass index >85%. There were 26 cases of NAFLD (4.5%) of which 10 had nonalcoholic steatohepatitis (1.7%). There were no cases with severe fibrosis or cirrhosis. One percent (3/290) of black children had NAFLD and none had nonalcoholic steatohepatitis. White and Hispanic children had the highest percentages of NAFLD at 8.3% and 7.9%, respectively. In multiple logistic regression models, we observed that body mass index z-score (P < .001) was associated with NAFLD, and that white (P = .003) and Hispanic (P = .005) children had higher odds of having NAFLD compared with black children. This review of liver tissue demonstrates a lower prevalence and severity of NAFLD in black children compared with the general obese pediatric population. Hispanic children did not have a significantly increased rate of NAFLD compared with white children, most likely related to the large proportion of Caribbean Hispanic children in New York City.


Hepatitis C virus envelope proteins bind lactoferrin.
Hepatitis C virus (HCV) has two envelope proteins, E1 and E2, which form a heterooligomer. During dissection of interacting regions of HCV E1 and E2, we found the presence of an interfering compound or compounds in skim milk. Here we report that human as well as bovine lactoferrin, a multifunctional immunomodulator, binds two HCV envelope proteins. As determined by far-Western blotting, the bacterially expressed E1 and E2 could bind lactoferrin in human milk directly separated or immunopurified and separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The bindings of lactoferrin and HCV envelope proteins in vitro were confirmed by another method, the pull-down assay, with immunoprecipitated lactoferrin-bound protein A resin. By the same assay, mammal-expressed recombinant E1 and E2 were also demonstrated to bind human lactoferrin efficiently in vitro. Direct interaction between E2 and lactoferrin was proved in vivo, since anti-human lactoferrin antibody efficiently coimmunoprecipitated with secreted and intracellular forms of the E2 protein, but not glutathione S-transferase (GST), from lysates of HepG2 cells transiently cotransfected with the expression plasmids of human lactoferrin and gE2t-GST (the N-terminal two-thirds of E2 fused to GST) or GST. The N-terminal loop of lactoferrin, the region important for the antibacterial activity, has only a little role in the binding ability to HCV E2 but affected the secretion or stability of lactoferrin. Taken together, these results indicate the specific interaction between lactoferrin and HCV envelope proteins in vivo and in vitro.


The serine/threonine kinase MINK1 directly regulates the function of promigratory proteins.
Upregulation of the developmental Wnt planar cell polarity (Wnt/PCP) pathway is observed in many cancers and is associated with cancer development. We have recently shown that PRICKLE1, a core Wnt/PCP pathway component, is a marker of poor prognosis in triple-negative breast cancer (TNBC). PRICKLE1 is phosphorylated by the serine/threonine kinase MINK1 and contributes to TNBC cell motility and invasiveness. However, the identity of the substrates of MINK1 and the role of MINK1 enzymatic activity in this process remain to be addressed. We used a phosphoproteomic strategy to identify MINK1 substrates, including LL5β (also known as PHLDB2). LL5β anchors microtubules at the cell cortex through its association with CLASP proteins to trigger focal adhesion disassembly. LL5β is phosphorylated by MINK1, promoting its interaction with CLASP proteins. Using a kinase inhibitor, we demonstrate that the enzymatic activity of MINK1 is involved in PRICKLE1-LL5β complex assembly and localization, as well as in cell migration. Analysis of gene expression data reveals that the concomitant upregulation of levels of mRNA encoding PRICKLE1 and LL5β, which are MINK1 substrates, is associated with poor metastasis-free survival in TNBC patients. Taken together, our results suggest that MINK1 may represent a potential target for treatment of TNBC.


Perspective: Lessons from COVID-19 of countries in the European region in light of findings from the health system response monitor.
Decision-makers initially had limited data to inform their policy responses to the COVID-19 pandemic. The research community developed several online databases to track cases, deaths, and hospitalizations; however, a major deficiency was the lack of detailed information on how health systems were responding to the pandemic and how they would need to be transformed going forward. In an effort to fill this information gap, in March 2020, the European Observatory on Health Systems and Policies, the WHO European Regional Office and the European Commission created the COVID-19 Health System Response Monitor (HSRM) to collect and organise up-to-date information on how health systems, mainly in the WHO European Region, were responding to the COVID-19 pandemic. The HSRM analysis and broader Observatory work on COVID-19 shone light on a range of health system challenges and weaknesses and catalogued policy options countries put in place during the pandemic to address these. Countries prioritised policies on investing in public health, supporting the workforce, maintaining financial stability, and strengthening governance in their response to COVID-19. COVID-19 is likely to continue to impact health systems for the foreseeable future; the ability to cope with this pressure, and other shocks, depends on having good information on what other countries have done so that health systems develop adequate policy options. In support of this, the country information on the COVID-19 HSRM will remain available as a repository to inform decision makers on options for actions and possible measures against COVID-19 and other public health emergencies. Building on its previous work on health systems resilience, the European Observatory on Health Systems and Policies will sustain its focus on analysing key issues related to the recovery from the pandemic and making health systems more resilient. This includes policy knowledge transfer between countries and systematic resilience testing, aiming at contributing to an improved understanding of health system response, recovery, and preparedness. The COVID-19 Health System Response Monitor (HSRM) was the first database in the WHO European Region to collect and organise up-to-date information on how health systems were responding to the COVID-19 pandemic. The HSRM provides a repository of policies which can be used to inform decision makers in health and other policy domains on options for action and possible measures against COVID-19 and other public health emergencies. This initiative proved particularly valuable, especially during the early phases of the pandemic, when there was limited information for countries to draw on as they formulated their own policy response to the pandemic. Our perspectives paper highlights some key challenges within health systems that the HSRM was able to identify during the pandemic and considers policy options countries put in place in response. Our research contributes to literature on emergency responses and recovery, health systems performance assessment, particularly health system resilience, and showcases the Observatory experience on how to design such a data collection tool, as well as how to leverage its findings to support cross-country learning.


Adaptive multi/demultiplexers for optical signals with arbitrary wavelength spacing.
We propose and demonstrate the principle of a novel adaptive wavelength division multiplexer/demultiplexer structure based on Opto-VLSI processing. By driving an Opto-VLSI processor with an appropriate phase hologram, optical signals of arbitrary wavelengths from different input fiber ports can be multiplexed into a common output fiber port. In addition, wavelength division multiplexed channels of arbitrary wavelength spacings can also be demultiplexed and dynamically routed into arbitrary output fiber ports. A proof-of-principle 1x3 adaptive multiplexer/demultiplexers is experimentally demonstrated.


Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension.
Pulmonary arterial hypertension (PAH) is a rare progressive disease of the pulmonary vasculature that is characterized by endothelial dysfunction, inflammation, and right ventricular dysfunction. The main objective was to determine whether endothelial, inflammatory, and cardiac biomarkers would be associated with the World Health Organization functional assessment and survival in patients with PAH. We performed a retrospective cohort study of patients with PAH enrolled in the Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension (ASA-STAT). Biomarkers (N-terminal fragment of pro-BNP [NT-pro-BNP], von Willebrand factor [vWF], soluble P selectin, C-reactive protein, total and high-density lipoprotein cholesterol, triglycerides, tumor necrosis factor, IL-6, β-thromboglobulin, and thromboxane B2) were measured at baseline. Patients from the study were followed until lung transplantation, death, or August 1, 2013. Ordinal logistic regression and Cox regression analyses were performed. Sixty-five patients with PAH were enrolled. The mean age was 51 years, and 86% were women. Higher vWF activity, lower high-density lipoprotein cholesterol, and higher thromboxane B2 levels were associated with worse World Health Organization functional class after adjustment for age, sex, and etiology of PAH. Higher NT-pro-BNP levels, lower vWF activity, and lower total cholesterol were associated with an increased risk of death or lung transplant after adjustment for age, sex, etiology of PAH, and 6-minute-walk distance. In patients with PAH, lower vWF activity and cholesterol levels and higher NT-pro-BNP levels at baseline were associated with an increased risk of death or transplantation. Clinical trial registered with www.clinicaltrials.gov (NCT00384865).


Development and implementation of eco-genomic tools for aquatic ecosystem biomonitoring: the SYNAQUA French-Swiss program.
The effectiveness of environmental protection measures is based on the early identification and diagnosis of anthropogenic pressures. Similarly, restoration actions require precise monitoring of changes in the ecological quality of ecosystems, in order to highlight their effectiveness. Monitoring the ecological quality relies on bioindicators, which are organisms revealing the pressures exerted on the environment through the composition of their communities. Their implementation, based on the morphological identification of species, is expensive because it requires time and experts in taxonomy. Recent genomic tools should provide access to reliable and high-throughput environmental monitoring by directly inferring the composition of bioindicators' communities from their DNA (metabarcoding). The French-Swiss program SYNAQUA (INTERREG France-Switzerland 2017-2019) proposes to use and validate the tools of environmental genomic for biomonitoring and aims ultimately at their implementation in the regulatory bio-surveillance. SYNAQUA will test the metabarcoding approach focusing on two bioindicators, diatoms, and aquatic oligochaetes, which are used in freshwater biomonitoring in France and Switzerland. To go towards the renewal of current biomonitoring practices, SYNAQUA will (1) bring together different actors: scientists, environmental managers, consulting firms, and biotechnological companies, (2) apply this approach on a large scale to demonstrate its relevance, (3) propose robust and reliable tools, and (4) raise public awareness and train the various actors likely to use these new tools. Biomonitoring approaches based on such environmental genomic tools should address the European need for reliable, higher-throughput monitoring to improve the protection of aquatic environments under multiple pressures, guide their restoration, and follow their evolution.


Hippocampal dysfunction in Gulf War veterans: investigation with ASL perfusion MR imaging and physostigmine challenge.
To determine, with arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging and physostigmine challenge, if abnormal hippocampal blood flow in ill Gulf War veterans persists 11 years after initial testing with single photon emission computed tomography and nearly 20 years after the 1991 Gulf War. The local institutional review board approved this HIPAA-compliant study. Veterans were screened for contraindications and gave written informed consent before the study. In a semiblinded retrospective protocol, veterans in three Gulf War illness groups-syndrome 1 (impaired cognition), syndrome 2 (confusion-ataxia), and syndrome 3 (central neuropathic pain)-and a control group received intravenous infusions of saline in an initial session and physostigmine in a second session, 48 hours later. Each infusion was followed by measurement of hippocampal regional cerebral blood flow (rCBF) with pulsed ASL. A mixed-effects linear model adjusted for age was used to test for differences in rCBF after the cholinergic challenge across the four groups. Physostigmine significantly decreased hippocampal rCBF in control subjects (P < .0005) and veterans with syndrome 1 (P < .05) but significantly increased hippocampal rCBF in veterans with syndrome 2 (P < .005) and veterans with syndrome 3 (P < .002). The abnormal increase in rCBF was found to have progressed to the left hippocampus of the veterans with syndrome 2 and to both hippocampi of the veterans with syndrome 3. Chronic hippocampal perfusion dysfunction persists or worsens in veterans with certain Gulf War syndromes. ASL MR imaging examination of hippocampal rCBF in a cholinergic challenge experiment may be useful as a diagnostic test for this condition.


Reconsidering the age thresholds for type II diabetes screening in the U.S.
Type II diabetes and its complications can sometimes be prevented, if identified and treated early. One fifth of diabetics in the U.S. remain undiagnosed. Commonly used screening guidelines are inconsistent. To examine the optimal age cut-point for opportunistic universal screening, compared to targeted screening, which is recommended by U.S. Preventive Services Task Force (USPSTF) and American Diabetes Association (ADA) guidelines. Cross-sectional analysis of a nationally representative sample from the National Health and Nutrition Examination Survey, 2007-2010. Number of people needed to screen (NNS) to obtain one positive test result was calculated for different guidelines. Sampling weights were applied to construct national estimates. The 2010 Medicare fee schedule was used for cost estimation. Analysis was conducted in January 2014. NNS, under universal screening, drops sharply at age 35 years, from 80 (30-34-year-olds) to 31 (35-39-year-olds). Opportunistic universal screening of eligible people aged ≥35 years would yield an NNS of 15, translating to $66 per positive test. Among people aged 35-44 years (who are not recommended for universal screening by ADA), most (71%) were overweight or obese and all had at least one other ADA risk factor. Only 34% of individuals aged ≥35 years met USPSTF criteria. Strictly enforcing USPSTF guidelines would have resulted in a majority (61%) of potential positive test cases being missed (5,508,164 cases nationwide). Opportunistic universal screening among individuals aged ≥35 years could greatly reduce the national prevalence of undiagnosed pre-diabetes or diabetes at relatively low cost.


Structural characterization of the fibrillar form of the yeast Saccharomyces cerevisiae prion Ure2p.
The protein Ure2 from the yeast Saccharomyces cerevisiae has prion properties. It assembles in vitro into long, straight, insoluble fibrils that are similar to amyloids in that they bind Congo Red and show green-yellow birefringence and have an increased resistance to proteolysis. We recently showed that Ure2p fibrils assembled under physiologically relevant conditions are devoid of a cross-beta-core. A model for fibril formation, where assembly is driven by non-native inter- and/or intramolecular interaction between Ure2p monomers following subtle conformational changes was proposed [Bousset et al. (2002) EMBO J. 21, 2903-2911]. An alternative model for the assembly of Ure2p into fibrils where assembly is driven by the stacking of 40-70 N-terminal amino acid residues of Ure2p into a central beta-core running along the fibrils from which the C-terminal domains protrude was proposed [Baxa et al. (2003) J. Biol. Chem. 278, 43717-43727]. We show here that Ure2p fibril congophilia and the associated yellow-green birefringence in polarized light are not indicative that the fibrils are of amyloid nature. We map the structures of the fibrillar and soluble forms of Ure2p using limited proteolysis and identify the reaction products by microsequencing and mass spectrometry. Finally, we demonstrate that the C-terminal domain of Ure2p is tightly involved in the fibrillar scaffold using a sedimentation assay and a variant Ure2p where a highly specific cleavage site between the N- and C-terminal domains of the protein was engineered. Our results are inconsistent with the cross-beta-core model and support the model for Ure2p assembly driven by subtle conformational changes and underline the influence of the natural context of the N-terminal domain on the assembly of Ure2p.


Relationship of stress-induced histidine decarboxylase to circulatory homeostasis and shock.
Histidine decarboxylase activity of mouse tissues is increased by stress and by injection of epinephrine and norepinephrine, suggesting a balance between histamine and catechol amines producing a component of circulatory homeostasis. Imbalance during intense stress might lead to failure of circulatory homeostasis and to shock. Reasons for discounting histamine as "shock toxin" may be invalid.


Ready for Transfer to Adult Care? A Triadic Evaluation of Transition Readiness in Adolescents With Congenital Heart Disease and Their Parents.
Transfer to adult care for adolescents with chronic conditions ought to be determined by transition readiness. The aims of this study were (a) to describe the level of readiness for transition in adolescents with congenital heart disease, (b) to compare adolescents' assessment of transition readiness with their parents' assessments, and (c) to study potential correlates of transition readiness. A total of 157 triads of adolescents aged 14 to 18 years and their parents completed the Readiness for Transition Questionnaire. Adolescents scored higher on overall readiness than their parents. Multivariable analyses revealed that higher levels of adolescents' overall readiness were associated with a less threatening view of the illness, a higher level of empowerment, and with higher mothers' and fathers' overall readiness scores. Adolescents' responsibility scores were positively associated with age and parental adolescent responsibility scores. Parental involvement scores were negatively associated with adolescents' age and positively with the mothers' parental involvement scores. By using a triadic evaluation, the results of the present study significantly extend what is currently known about this population.


Modulation of the dimer interface at ionotropic glutamate-like receptor delta2 by D-serine and extracellular calcium.
GluRdelta2 is a member of the iGluR family, but despite a prominent role in cerebellar synaptic plasticity, this receptor does not appear to function as an ion channel. Endogenous ligands that modulate the activity of native GluRdelta2 in the cerebellum have not been identified, but two candidate modulators are d-serine and extracellular calcium. Taking advantage of known crystal structures and spontaneously active GluRdelta2 receptors containing the lurcher mutation (GluRdelta2(Lc)), we investigated the mechanism by which calcium and d-serine regulate the activity of GluRdelta2(Lc). Our data suggest that calcium binding stabilizes the dimer interface formed between two agonist-binding domains and increases GluRdelta2(Lc) currents. The data further suggest that d-serine binding induces rearrangements at the dimer interface to diminish GluRdelta2(Lc) currents by a mechanism that resembles desensitization at AMPA and kainate receptors. Thus, we propose that calcium and d-serine binding have opposing effects on the stability of the dimer interface. Furthermore, the effects of calcium are observed at concentrations that are within the physiological range, suggesting that the ability of native GluRdelta2 to respond to ligand binding may be modulated by extracellular calcium. These findings place GluRdelta2 among AMPA and kainate receptors, where the dimer interface is not only a biologically important site for functional regulation, but also an important target for exogenous and endogenous ligands that modulate receptor function.


Long-Term Follow-up of Complex Calcaneal Osteomyelitis Treated With Modified Gaenslen Approach.
The treatment of chronic calcaneal osteomyelitis is a challenging and increasing problem because of the high prevalence of diabetes mellitus and operative fixation of heel fractures. In 1931, Gaenslen reported treatment of hematogenous calcaneal osteomyelitis by surgical excision through a midline, sagittal plantar incision. We have refined this approach to allow successful healing and early mobilization in a modern series of complex patients with hematogenous, diabetic, and postsurgical osteomyelitis. Twenty-eight patients (mean age 54.6 years, range 20-94) with Cierny-Mader stage IIIB chronic calcaneal osteomyelitis were treated with sagittal incision and calcaneal osteotomy, excision of infected bone, and wound closure. All patients received antibiotics for at least 6 weeks, and bone defects were filled with an antibiotic carrier in 20 patients. Patients were followed for a mean of 31 months (SD 25.4). Primary outcome measures were recurrence of calcaneal osteomyelitis and below-knee amputation. Secondary outcome measures included 30-day postoperative mortality and complications, duration of postoperative inpatient stay, footwear adaptions, mobility, and use of walking aids. All 28 patients had failed previous medical and surgical treatment. Eighteen patients (64%) had significant comorbidities. The commonest causes of infection were diabetes ± ulceration (11 patients), fracture-related infection (4 patients), pressure ulceration, hematogenous spread, and penetrating soft tissue trauma. The overall recurrence rate of calcaneal osteomyelitis was 18% (5 patients) over the follow-up period, of which 2 patients (7%) required a below-knee amputation. Eighteen patients (64%) had a foot that comfortably fitted into a normal shoe with a custom insole. A further 6 patients (21%) required a custom-made shoe, and only 3 patients required a custom-made boot. Our results show that a repurposed Gaenslen calcanectomy is simple, safe, and effective in treating this difficult condition in a patient group with significant local and systemic comorbidities. Level III, case series.


EuroPineDB: a high-coverage web database for maritime pine transcriptome.
Pinus pinaster is an economically and ecologically important species that is becoming a woody gymnosperm model. Its enormous genome size makes whole-genome sequencing approaches are hard to apply. Therefore, the expressed portion of the genome has to be characterised and the results and annotations have to be stored in dedicated databases. EuroPineDB is the largest sequence collection available for a single pine species, Pinus pinaster (maritime pine), since it comprises 951 641 raw sequence reads obtained from non-normalised cDNA libraries and high-throughput sequencing from adult (xylem, phloem, roots, stem, needles, cones, strobili) and embryonic (germinated embryos, buds, callus) maritime pine tissues. Using open-source tools, sequences were optimally pre-processed, assembled, and extensively annotated (GO, EC and KEGG terms, descriptions, SNPs, SSRs, ORFs and InterPro codes). As a result, a 10.5× P. pinaster genome was covered and assembled in 55 322 UniGenes. A total of 32 919 (59.5%) of P. pinaster UniGenes were annotated with at least one description, revealing at least 18 466 different genes. The complete database, which is designed to be scalable, maintainable, and expandable, is freely available at: http://www.scbi.uma.es/pindb/. It can be retrieved by gene libraries, pine species, annotations, UniGenes and microarrays (i.e., the sequences are distributed in two-colour microarrays; this is the only conifer database that provides this information) and will be periodically updated. Small assemblies can be viewed using a dedicated visualisation tool that connects them with SNPs. Any sequence or annotation set shown on-screen can be downloaded. Retrieval mechanisms for sequences and gene annotations are provided. The EuroPineDB with its integrated information can be used to reveal new knowledge, offers an easy-to-use collection of information to directly support experimental work (including microarray hybridisation), and provides deeper knowledge on the maritime pine transcriptome.


Racial/Ethnic Disparities in Genomic Sequencing.
Although poorly understood, there is heterogeneity in the molecular biology of cancer across race and ethnicities. The representation of racial minorities in large genomic sequencing efforts is unclear, and could have an impact on health care disparities. To determine the racial distribution among samples sequenced within The Cancer Genome Atlas (TCGA) and the deficit of samples needed to detect moderately common mutational frequencies in racial minorities. This was a retrospective review of individual patient data from TCGA data portal accessed in July 2015. TCGA comprises samples from a wide array of institutions primarily across the United States. Samples from 10 of the 31 currently available tumor types were analyzed, comprising 5729 samples from the approximately 11 000 available. Using the estimated median somatic mutational frequency, the samples needed beyond TCGA to detect a 10% and 5% mutational frequency over the background somatic mutation frequency were calculated for each tumor type by racial ethnicity. Of the 5729 samples, 77% (n = 4389) were white, 12% (n = 660) were black, 3% (n = 173) were Asian, 3% (n = 149) were Hispanic, and less than 0.5% combined were from patients of Native Hawaiian, Pacific Islander, Alaskan Native, or American Indian decent. This overrepresents white patients compared with the US population and underrepresents primarily Asian and Hispanic patients. With a somatic mutational frequency of 0.7 (prostate cancer) to 9.9 (lung squamous cell cancer), all tumor types from white patients contained enough samples to detect a 10% mutational frequency. This is in contrast to all other racial ethnicities, for which group-specific mutations with 10% frequency would be detectable only for black patients with breast cancer. Group-specific mutations with 5% frequency would be undetectable in any racial minority, but detectable in white patients for all cancer types except lung (adenocarcinoma and squamous cell carcinoma) and colon cancer. It is probable, but poorly understood, that ethnic diversity is related to the pathogenesis of cancer, and may have an impact on the generalizability of findings from TCGA to racial minorities. Despite the important benefits that continue to be gained from genomic sequencing, dedicated efforts are needed to avoid widening the already pervasive gap in health care disparities.


Observation of Single Top Quark Production in Association with a Z Boson in Proton-Proton Collisions at sqrt[s]=13 TeV.
The observation of single top quark production in association with a Z boson and a quark (tZq) is reported. Events from proton-proton collisions at a center-of-mass energy of 13 TeV containing three charged leptons (either electrons or muons) and at least two jets are analyzed. The data were collected with the CMS detector in 2016 and 2017 and correspond to an integrated luminosity of 77.4fb^{-1}. The increased integrated luminosity, a multivariate lepton identification, and a redesigned analysis strategy improve significantly the sensitivity of the analysis compared to previous searches for tZq production. The tZq signal is observed with a significance well over 5 standard deviations. The measured tZq production cross section is σ(pp→tZq→tℓ^{+}ℓ^{-}q)=111±13(stat)_{-9}^{+11}(syst) fb, for dilepton invariant masses above 30 GeV, in agreement with the standard model expectation.


Radiation exposure of German aircraft crews under the impact of solar cycle 23 and airline business factors.
The exposure of German aircraft crews to cosmic radiation varies both with solar activity and operational factors of airline business. Data come from the German central dose registry and cover monthly exposures of up to 37,000 German aircraft crewmembers that were under official monitoring. During the years 2004 to 2009 of solar cycle 23 (i.e., in the decreasing phase of solar activity), the annual doses of German aircraft crews increased by an average of 20%. Decreasing solar activity allows more galactic radiation to reach the atmosphere, increasing high-altitude doses. The rise results mainly from the less effective protection from the solar wind but also from airline business factors. Both cockpit and cabin personnel differ in age-dependent professional and social status. This status determines substantially the annual effective dose: younger cabin personnel and the elder pilots generally receive higher annual doses than their counterparts. They also receive larger increases in their annual dose when the solar activity decreases. The doses under this combined influence of solar activity and airline business factors result in a maximum of exposure for German aircrews for this solar cycle. With the increasing solar activity of the current solar cycle 24, the doses are expected to decrease again.


The serotonin transporter gene alters sensitivity to attention bias modification: evidence for a plasticity gene.
Attention bias modification (ABM) procedures have been shown to modify biased attention with important implications for emotional vulnerability and resilience. The use of ABM to reduce potentially toxic biases, for instance, is a newly emerging therapy for anxiety disorders. A separate line of gene-by-environment interaction research proposes that many so-called vulnerability genes or risk alleles are better seen as plasticity genes, as they seem to make individuals more susceptible to environmental influences for better and for worse. A standard ABM procedure was used with a sample of 116 healthy adults. Participants were randomly assigned to one of two training groups. One received an ABM procedure designed to induce a bias in attention toward negative material, while the other was trained toward positive pictures. Individuals with low- and high-expressing forms of the serotonin transporter gene (5-HTTLPR) were compared. Those with a low-expression form (S/S, S/Lg, or Lg/Lg) of the 5-HTTLPR gene developed stronger biases for both negative and positive affective pictures relative to those with the high-expression (La/La) form of the gene. Here, we report the first evidence that allelic variation in the promotor region of the 5-HTTLPR gene predicts different degrees of sensitivity to ABM. These results suggest a potential cognitive mechanism for the gene-by-environment interactions that have been found in relation to the serotonin transporter gene. Variation on this genotype may therefore determine who will benefit most (and least) from therapeutic interventions, adversity, and supportive environments.


Immune Responses in Acute and Convalescent Patients with Mild, Moderate and Severe Disease during the 2009 Influenza Pandemic in Norway.
Increased understanding of immune responses influencing clinical severity during pandemic influenza infection is important for improved treatment and vaccine development. In this study we recruited 46 adult patients during the 2009 influenza pandemic and characterized humoral and cellular immune responses. Those included were either acute hospitalized or convalescent patients with different disease severities (mild, moderate or severe). In general, protective antibody responses increased with enhanced disease severity. In the acute patients, we found higher levels of TNF-α single-producing CD4+T-cells in the severely ill as compared to patients with moderate disease. Stimulation of peripheral blood mononuclear cells (PBMC) from a subset of acute patients with peptide T-cell epitopes showed significantly lower frequencies of influenza specific CD8+ compared with CD4+ IFN-γ T-cells in acute patients. Both T-cell subsets were predominantly directed against the envelope antigens (HA and NA). However, in the convalescent patients we found high levels of both CD4+ and CD8+ T-cells directed against conserved core antigens (NP, PA, PB, and M). The results indicate that the antigen targets recognized by the T-cell subsets may vary according to the phase of infection. The apparent low levels of cross-reactive CD8+ T-cells recognizing internal antigens in acute hospitalized patients suggest an important role for this T-cell subset in protective immunity against influenza.


Time- and Oil-Dependent Transcriptomic and Physiological Responses to Deepwater Horizon Oil in Mahi-Mahi (Coryphaena hippurus) Embryos and Larvae.
The Deepwater Horizon (DWH) oil spill contaminated the spawning habitats for numerous commercially and ecologically important fishes. Exposure to the water accommodated fraction (WAF) of oil from the spill has been shown to cause cardiac toxicity during early developmental stages across fishes. To better understand the molecular events and explore new pathways responsible for toxicity, RNA sequencing was performed in conjunction with physiological and morphological assessments to analyze the time-course (24, 48, and 96 h post fertilization (hpf)) of transcriptional and developmental responses in embryos/larvae of mahi-mahi exposed to WAF of weathered (slick) and source DWH oils. Slick oil exposure induced more pronounced changes in gene expression over time than source oil exposure. Predominant transcriptomic responses included alteration of EIF2 signaling, steroid biosynthesis, ribosome biogenesis and activation of the cytochrome P450 pathway. At 96 hpf, slick oil exposure resulted in significant perturbations in eye development and peripheral nervous system, suggesting novel targets in addition to the heart may be involved in the developmental toxicity of DHW oil. Comparisons of changes of cardiac genes with phenotypic responses were consistent with reduced heart rate and increased pericardial edema in larvae exposed to slick oil but not source oil.


Comparison of Scapular Manipulation With External Rotation Method of Reduction of Acute Anterior Shoulder Dislocation for Sedation Requirements and Success Rates.
Anterior shoulder dislocation is a common sports-related musculoskeletal injury. Various methods have been described for reduction of the dislocation. A method that requires less sedation without compromising the success rate is likely to be highly useful in austere and prehospital settings. This study compares scapular manipulation with external rotation method for requirement of sedation and success rates. Forty-six patients with anterior shoulder dislocation were allocated alternatively to reduction using either scapular manipulation (SMM) or external rotation (ERM) techniques. The groups were compared for sedation requirements, pain scores, and success rates. Reductions using SMM had fewer requirements for sedation (13% versus 39%; p < .05) and higher first-pass success rates (87% versus 61%; p < .05) as compared with ERM for anterior shoulder dislocation reduction. The numeric rating score of pain during reduction procedures was less in SMM (mean, 1.65 [standard deviation, 1.6]) than in ERM group (mean, 4.30 [standard deviation, 1.8]; p < .01). The SMM required less sedation and had higher first-pass success rates than ERM for reduction of anterior shoulder dislocation. The SMM is thus likely to be of advantage in resource-limited austere settings.


Self-optimized superconductivity attainable by interlayer phase separation at cuprate interfaces.
Stabilizing superconductivity at high temperatures and elucidating its mechanism have long been major challenges of materials research in condensed matter physics. Meanwhile, recent progress in nanostructuring offers unprecedented possibilities for designing novel functionalities. Above all, thin films of cuprate and iron-based high-temperature superconductors exhibit remarkably better superconducting characteristics (for example, higher critical temperatures) than in the bulk, but the underlying mechanism is still not understood. Solving microscopic models suitable for cuprates, we demonstrate that, at an interface between a Mott insulator and an overdoped nonsuperconducting metal, the superconducting amplitude is always pinned at the optimum achieved in the bulk, independently of the carrier concentration in the metal. This is in contrast to the dome-like dependence in bulk superconductors but consistent with the astonishing independence of the critical temperature from the carrier density x observed at the interfaces of La2CuO4 and La2-x Sr x CuO4. Furthermore, we identify a self-organization mechanism as responsible for the pinning at the optimum amplitude: An emergent electronic structure induced by interlayer phase separation eludes bulk phase separation and inhomogeneities that would kill superconductivity in the bulk. Thus, interfaces provide an ideal tool to enhance and stabilize superconductivity. This interfacial example opens up further ways of shaping superconductivity by suppressing competing instabilities, with direct perspectives for designing devices.


First fossil lamprey: a record from the Pennsylvanian of Illinois.
A fossil record of lampreys has previously been unknown. A new genus demonstrates the presence of this group in the Pennsylvanian. The body outline, parts of the head skeleton, rasping tongue mechanism, gill basket, and other internal organs are preserved. The fossils are very similar in structure to modern forms. The absence of hagfish characters in the fossil supports the view that the common ancestor of lampreys and hagfishes lived prior to the Pennsylvanian.


Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial.
SENECA (StEm cell iNjECtion in cAncer survivors) is a phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and feasibility of delivering allogeneic mesenchymal stromal cells (allo-MSCs) transendocardially in subjects with anthracycline-induced cardiomyopathy (AIC). AIC is an incurable and often fatal syndrome, with a prognosis worse than that of ischemic or nonischemic cardiomyopathy. Recently, cell therapy with MSCs has emerged as a promising new approach to repair damaged myocardium. The study population is 36 cancer survivors with a diagnosis of AIC, left ventricular (LV) ejection fraction ≤40%, and symptoms of heart failure (NYHA class II-III) on optimally-tolerated medical therapy. Subjects must be clinically free of cancer for at least two years with a ≤ 30% estimated five-year risk of recurrence. The first six subjects participated in an open-label, lead-in phase and received 100 million allo-MSCs; the remaining 30 will be randomized 1:1 to receive allo-MSCs or vehicle via 20 transendocardial injections. Efficacy measures (obtained at baseline, 6 months, and 12 months) include MRI evaluation of LV function, LV volumes, fibrosis, and scar burden; assessment of exercise tolerance (six-minute walk test) and quality of life (Minnesota Living with Heart Failure Questionnaire); clinical outcomes (MACE and cumulative days alive and out of hospital); and biomarkers of heart failure (NT-proBNP). This is the first clinical trial using direct cardiac injection of cells for the treatment of AIC. If administration of allo-MSCs is found feasible and safe, SENECA will pave the way for larger phase II/III studies with therapeutic efficacy as the primary outcome.


Measuring nursing unit environments with four composite measure.
Understanding the context in which nurses work is an important step to designing work environments in which nurses can achieve targeted quality. Developing a usable instrument for describing the work environment and the relationship to staffing is essential for the development of evidence-based staffing decisions. The major implications of the research reported here are that the work environment of nurses, while complex, can be modeled with composite variables that reflect various dimensions of that environment. This ability to model the environment with fewer variables enhances the interpretation of environmental factors that have the greatest impact on patient outcomes. This reduction is valuable to the clinician, manager, and administrator in determining the key factors that need to be altered in the work environment to improve the quality of the patient experience.


Biodegradation of 17beta-estradiol, estrone and testosterone in stream sediments.
Biodegradation of 17beta-estradiol (E2), estrone (E1), and testosterone (T) was investigated in three wastewater treatment plant (WWTP) affected streams in the United States. Relative differences in the mineralization of [4-(14)C] substrates were assessed in oxic microcosms containing saturated sediment or water-only from locations upstream and downstream of the WWTP outfall in each system. Upstream sediment demonstrated significant mineralization of the "A" ring of E2, E1, and T, with biodegradation of T consistently greater than that of E2 and no systematic difference in E2 and E1 biodegradation. "A" ring mineralization also was observed in downstream sediment, with E1 and T mineralization being substantially depressed relative to upstream samples. In marked contrast, E2 mineralization in sediment immediately downstream from the WWTP outfalls was more than double that in upstream sediment. E2 mineralization was observed in water, albeit at insufficient rate to prevent substantial downstream transport. The results indicate that, in combination with sediment sorption processes which effectively scavenge hydrophobic contaminants from the water column and immobilize them in the vicinity of the WWTP outfall, aerobic biodegradation of reproductive hormones can be an environmentally important mechanism for noncon-servative (destructive) attenuation of hormonal endocrine disruptors in effluent-affected streams.


Lesser in vitro anaerobic cecal isoflavone disappearance was associated with greater apparent absorption of daidzein and genistein in Golden Syrian hamsters.
Our hypothesis in this study was that in vitro disappearance of isoflavones from fecal or cecal contents of Golden Syrian hamsters paralleled the apparent absorption of these compounds, comparable with previous findings from in vitro human fecal incubations. Two studies were conducted to test this idea: one on in vitro fecal (study 1, n = 20/sex) and the other on in vitro cecal contents (study 2, n = 10/sex) ability to degrade isoflavones. According to HPLC analysis, urinary isoflavone excretion was significantly less by 2-4 fold in males compared with females in both studies. Fecal isoflavone excretion was not significantly different between sexes or isoflavones (study 1) and was <0.5% of ingested dose. In vitro anaerobic fecal isoflavone degradation rate constants from study 1 were minimal with no significant correlation between urinary and fecal isoflavone excretion. However, in vitro anaerobic cecal isoflavone degradation rate constants (study 2) were greater and significantly correlated with urinary excretion of daidzein (R = 0.90; p = 0.01) and genistein (R = 0.93; p = 0.004), but not glycitein (R = 0.50; p = 0.3). Both male and female hamsters showed a pattern of urinary isoflavone excretion similar to that found in humans (daidzein > genistein). Hamster in vitro cecal isoflavone degradation rate constants seemed to be analogous to human in vitro fecal isoflavone degradation rate constants for genistein and daidzein. The sex difference in isoflavone excretion in hamsters and the instability in glycitein excretion across studies coupled with the paucity of human data on this isoflavone deserve further investigation.


Dental caries from a molecular microbiological perspective.
Dental caries results from an imbalance of the metabolic activity in the dental biofilm. The microbial communities of teeth have traditionally been studied by standard cultural approaches. More recently, cloning and sequencing of the 16S rRNA gene have been used to characterize the microbial composition of the oral biofilm, but the methodological limitations of this approach have now been recognized. Next-generation high-throughput sequencing methods have the potential to reveal the composition and functioning of the biofilm by means of metagenomic and metatranscriptomic analyses. Currently available high-throughput sequencing approaches are reviewed and discussed in relation to studying the biofilm associated with dental caries. Important in understanding the dynamic processes in caries is the metabolic activity of the biofilm; metabolome analysis is a new tool that might enable us to assess such activity. As caries is a localized disease, it is essential that biofilm samples are taken from precisely determined tooth sites; pooling samples is not appropriate. This paper presents the case that culture-based studies are important, but that the fullest understanding of the role of the biofilm in the caries process will only come from an integrated approach determining biological function and metabolic output.


An Integrated, Multifactorial Approach to Periodization for Optimal Performance in Individual and Team Sports.
Sports periodization has traditionally focused on the exercise aspect of athletic preparation, while neglecting the integration of other elements that can impact an athlete's readiness for peak competition performances. Integrated periodization allows the coordinated inclusion of multiple training components best suited for a given training phase into an athlete's program. The aim of this article is to review the available evidence underpinning integrated periodization, focusing on exercise training, recovery, nutrition, psychological skills, and skill acquisition as key factors by which athletic preparation can be periodized. The periodization of heat and altitude adaptation, body composition, and physical therapy is also considered. Despite recent criticism, various methods of exercise training periodization can contribute to performance enhancement in a variety of elite individual and team sports, such as soccer. In the latter, both physical and strategic periodization are useful tools for managing the heavy travel schedule, fatigue, and injuries that occur throughout a competitive season. Recovery interventions should be periodized (ie, withheld or emphasized) to influence acute and chronic training adaptation and performance. Nutrient intake and timing in relation to exercise and as part of the periodization of an athlete's training and competition calendar can also promote physiological adaptations and performance capacity. Psychological skills are a central component of athletic performance, and their periodization should cater to each athlete's individual needs and the needs of the team. Skill acquisition can also be integrated into an athlete's periodized training program to make a significant contribution to competition performance.


Suppression of stimulated Brillouin scattering in high-power single-frequency fiber amplifiers.
The effect of temperature variation along a high-power fiber amplifier on the stimulated Brillouin scattering (SBS) threshold is considered theoretically. We show that for an end-pumped rare-earth-doped double-clad fiber the inhomogeneous distribution of temperature, which is caused by the absorption of pump radiation, may result in total suppression of SBS even for output powers well above 200 W.