Positive Parenting Practices, Health Disparities, and Developmental Progress.
To describe interactive activities between parents and young children in a nationally representative sample. We hypothesized that the frequency of participation in interactive activities would be different across economic strata and would be associated with developmental delay. Children 4 to 36 months of age were identified by using The National Survey of Children's Health 2011-2012. Interactive caregiving practices were reported by poverty status. Developmental concerns were derived from caregiver responses and scoring of the Parents Evaluation of Developmental Status. Multivariable logistic regressions with weighting were used to explore the effect of interactive practices on risk for developmental delay across poverty levels. Covariates including age, gender, insurance type, maternal education, parenting stress, and ethnicity were adjusted in the models. In our sample (n = 12,642), caregivers with the lowest income versus highest income reported lower participation in reading (33% vs 64%; P < .0001), singing or telling stories (52% vs 77%, P < .0001), and taking their child on an outing (13% vs 22%, P < .0001). Less frequent participation in interactive activities during the week were associated with increased risk of developmental delay among low-income families (Reading odds ratio [OR] 1.57, 95% confidence interval [CI] 1.15-2.13; Singing songs/Telling Stories OR 1.66, 95% CI 1.15-2.40; Outings OR 1.48, 95% CI 1.11-1.97). Despite evidence emphasizing the protective effects of supportive parenting practices on early child development, our work demonstrates significant disparities in parenting practices that promote early child development between economically advantaged and disadvantaged parents. Innovative population-level strategies that enrich parenting practices for vulnerable children in early childhood are needed.


Conditional ablation of NKp46+ cells using a novel Ncr1(greenCre) mouse strain: NK cells are essential for protection against pulmonary B16 metastases.
To study gene functions specifically in NKp46+ cells we developed novel Cre mice allowing for conditional gene targeting in cells expressing Ncr1 (encoding NKp46). We generated transgenic Ncr1(greenCre) mice carrying an EGFPcre fusion under the control of a proximal Ncr1 promoter that faithfully directed EGFPcre expression to NKp46+ cells from lymphoid and nonlymphoid tissues. This approach allowed for direct detection of Cre-expressing NKp46+ cells via their GFP signature by flow cytometry and histology. Cre was functional as evidenced by the NKp46+ cell-specific expression of RFP in Ncr1(greenCre) Rosa-dtRFP reporter mice. We generated Ncr1(greenCre) Il2rg(fl/fl) mice that lack NKp46+ cells in an otherwise intact hematopoietic environment. Il2rg encodes the common gamma chain (γc ), which is an essential receptor subunit for cytokines (IL-2, -4, -7, -9, -15, and -21) that stimulate lymphocyte development and function. In Ncr1(greenCre) Il2rg(fl/fl) mice, NK cells are severely reduced and the few remaining NKp46+ cells escaping γc deletion failed to express GFP. Using this new NK-cell-deficient model, we demonstrate that the homeostasis of NKp46+ cells from all tissues (including the recently described intraepithelial ILC1 subset) requires Il2rg. Finally, Ncr1(greenCre) Il2rg(fl/fl) mice are unable to reject B16 lung metastases demonstrating the essential role of NKp46+ cells in antimelanoma immune responses.


The CYP1A2 genotype modifies the association between coffee consumption and breast cancer risk among BRCA1 mutation carriers.
We have recently reported that, among BRCA1 mutation carriers, the consumption of caffeinated coffee was associated with a significant reduction in breast cancer risk. Because the metabolism of caffeine is primarily by CYP1A2, we examined whether or not the CYP1A2 genotype modifies the association between a history of coffee consumption and the risk of breast cancer. A common A to C polymorphism in the CYP1A2 gene is associated with decreased enzyme inducibility and impaired caffeine metabolism. Information regarding coffee consumption habits and the CYP1A2 genotype was available for 411 BRCA1 mutation carriers (170 cases and 241 controls). We estimated the odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer associated with the CYP1A2 genotype and a history of coffee consumption before age 35, adjusting for potential confounders. The CYP1A2 genotype did not affect breast cancer risk. Among women with at least one variant C allele (AC or CC), those who consumed coffee had a 64% reduction in breast cancer risk, compared with women who never consumed coffee (OR, 0.36; 95% CI, 0.18-0.73). A significant protective effect of coffee consumption was not observed among women with the CYP1A2 AA genotype (OR, 0.93; 95% CI, 0.49-1.77). Similar results were obtained when the analysis was restricted to caffeinated coffee. This study suggests that caffeine protects against breast cancer in women with a BRCA1 mutation and illustrates the importance of integrating individual genetic variability when assessing diet-disease associations.


Cell-mediated and humoral immune responses to bovine herpesvirus type 1 and bovine viral diarrhea virus in calves following administration of a killed-virus vaccine and bovine herpesvirus type 1 challenge.
OBJECTIVE To evaluate cell-mediated and humoral immune responses of calves receiving 2 doses of a dual-adjuvanted vaccine containing inactivated bovine herpesvirus type 1 (BHV1) and bovine viral diarrhea virus types 1 (BVDV1) and 2 (BVDV2) before and after exposure to BHV1. ANIMALS 24 Holstein steers negative for anti-BHV1 antibodies and proliferative cell-mediated immune responses against BHV1 and BVDV. PROCEDURES Calves were randomly assigned to 3 groups. The vaccinated group (n = 10) received 2 doses of vaccine on days 0 and 21. Control (n = 10) and seeder (4) groups remained unvaccinated. Calves were commingled during the study except for the 3-day period (days 53 to 55) when seeders were inoculated with BHV1 (1.04 × 107 TCID50, IV) to serve as a source of virus for challenge (days 56 through 84). Rectal temperature and clinical illness scores were monitored, and blood and nasal specimens were obtained for determination of clinicopathologic and immunologic variables. RESULTS After BHV1 challenge, mean rectal temperature and clinical illness scores were lower for vaccinates than controls. In vaccinates, antibody titers against BHV1 and BVDV2, but not BVDV1, increased after challenge as did extracellular and intracellular interferon-γ expression, indicating a T helper 1 memory response. Additional results of cell marker expression were variable, with no significant increase or decrease associated with treatment. CONCLUSIONS AND CLINICAL RELEVANCE Calves administered 2 doses of a killed-virus vaccine developed cell-mediated and humoral immune responses to BHV1 and BVDV, which were protective against disease when those calves were subsequently exposed to BHV1.


Does MR perfusion imaging impact management decisions for patients with brain tumors? A prospective study.
MR perfusion imaging can be used to help predict glial tumor grade and disease progression. Our purpose was to evaluate whether perfusion imaging has a diagnostic or therapeutic impact on clinical management planning in patients with glioma. Standard MR imaging protocols were interpreted by a group of 3 NRs in consensus, with each case being interpreted twice: first, including routine sequences; and second, with the addition of perfusion imaging. A multidisciplinary team of treating physicians assessed tumor status and created hypothetical management plans, on the basis of clinical presentation and routine MR imaging and then routine MR imaging plus perfusion MR imaging. Physicians' confidence in the tumor status assessment and management plan was measured by using Likert-type items. Fifty-nine consecutive subjects with glial tumors were evaluated; 50 had known pathologic diagnoses. NRs and the treatment team agreed on tumor status in 45/50 cases (κ = 0.81). With the addition of perfusion, confidence in status assessment increased in 20 (40%) for NRs and in 28 (56%) for the treatment team. Of the 59 patient-care episodes, the addition of perfusion was associated with a change in management plan in 5 (8.5%) and an increase in the treatment team's confidence in their management plan in 34 (57.6%). NRs and the treatment team found perfusion useful in most episodes of care and wanted perfusion included in future MR images for >80% of these subjects. Perfusion imaging appears to have a significant impact on clinical decision-making and subspecialist physicians' confidence in management plans for patients with brain tumor.


Glycoprotein D of herpes simplex virus (HSV) binds directly to HVEM, a member of the tumor necrosis factor receptor superfamily and a mediator of HSV entry.
Glycoprotein D (gD) is a structural component of the herpes simplex virus (HSV) envelope which is essential for virus entry into host cells. Chinese hamster ovary (CHO-K1) cells are one of the few cell types which are nonpermissive for the entry of many HSV strains. However, when these cells are transformed with the gene for the herpesvirus entry mediator (HVEM), the resulting cells, CHO-HVEM12, are permissive for many HSV strains, such as HSV-1(KOS). By virtue of its four cysteine-rich pseudorepeats, HVEM is a member of the tumor necrosis factor receptor superfamily of proteins. Recombinant forms of gD and HVEM, gD-1(306t) and HVEM(200t), respectively, were used to demonstrate a specific physical interaction between these two proteins. This interaction was dependent on native gD conformation but independent of its N-linked oligosaccharides, as expected from previous structure-function studies. Recombinant forms of gD derived from HSV-1(KOS)rid1 and HSV-1(ANG) did not bind to HVEM(200t), explaining the inability of these viruses to infect CHO-HVEM12 cells. A variant gD protein, gD-1(delta290-299t), showed enhanced binding to HVEM(200t) relative to the binding of gD-1(306t). Competition studies showed that gD-1(delta290-299t) and gD-1(306t) bound to the same region of HVEM(200t), suggesting that the differences in binding to HVEM are due to differences in affinity. These differences were also reflected in the ability of gD-1(delta290-299t) but not gD-1(306t) to block HSV type 1 infection of CHO-HVEM12 cells. By gel filtration chromatography, the complex between gD-1(delta290-299t) and HVEM(200t) had a molecular mass of 113 kDa and a molar ratio of 1:2. We conclude that HVEM interacts directly with gD, suggesting that HVEM is a receptor for virion gD and that the interaction between these proteins is a step in HSV entry into HVEM-expressing cells.


"Race salience" in juror decision-making: misconceptions, clarifications, and unanswered questions.
In two frequently cited articles, Sommers and Ellsworth (2000, 2001) concluded that the influence of a defendant's race on White mock jurors is more pronounced in interracial trials in which race remains a silent background issue than in trials involving racially charged incidents. Referring to this variable more generally as "race salience," we predicted that any aspect of a trial that leads White mock jurors to be concerned about racial bias should render the race of a defendant less influential. Though subsequent researchers have further explored this idea of "race salience," they have manipulated it in the same way as in these original studies. As such, the scope of the extant literature on "race salience" and juror bias is narrower than many realize. The present article seeks to clarify this and other misconceptions regarding "race salience" and jury decision-making, identifying in the process avenues for future research on the biasing influence of defendant race.


A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain.
Microvascular sequestration was assessed in the brains of 50 Thai and Vietnamese patients who died from severe malaria (Plasmodium falciparum, 49; P. vivax, 1). Malaria parasites were sequestered in 46 cases; in 3 intravascular malaria pigment but no parasites were evident; and in the P. vivax case there was no sequestration. Cerebrovascular endothelial expression of the putative cytoadherence receptors ICAM-1, VCAM-1, E-selectin, and chondroitin sulfate and also HLA class II was increased. The median (range) ratio of cerebral to peripheral blood parasitemia was 40 (1.8 to 1500). Within the same brain different vessels had discrete but different populations of parasites, indicating that the adhesion characteristics of cerebrovascular endothelium change asynchronously during malaria and also that significant recirculation of parasitized erythrocytes following sequestration is unlikely. The median (range) ratio of schizonts to trophozoites (0.15:1; 0.0 to 11.7) was significantly lower than predicted from the parasite life cycle (P < 0.001). Antimalarial treatment arrests development at the trophozoite stages which remain sequestered in the brain. There were significantly more ring form parasites (age < 26 hours) in the cerebral microvasculature (median range: 19%; 0-90%) than expected from free mixing of these cells in the systemic circulation (median range ring parasitemia: 1.8%; 0-36.2%). All developmental stages of P. falciparum are sequestered in the brain in severe malaria.


Combining bioaccumulation and coping mechanism to enhance long-term site-specific risk assessment for zinc susceptibility of bivalves.
The purpose of this study is to conduct a long-term site-specific risk assessment for zinc (Zn) susceptibility of bivalves, green mussel Perna viridis and hard clam Ruditapes philippinarum, based on published experimental data by linking the biologically-based damage assessment model with the subcellular partitioning concept. A comprehensive risk modeling framework was developed to predict susceptibility probability of two bivalve species exposed to waterborne Zn. The results indicated that P. viridis accumulates more Zn toxicity, whereas both toxic potency and the recovery rate of Zn are higher for R. philippinarum. We found that negative linear correlations exist in elimination-recovery and elimination-detoxification relationships, whereas a positive linear correlation was observed in recovery-detoxification relationships for bivalves exposed to waterborne Zn. Simulation results showed that the spatial differences of susceptibility primarily resulted from the variation of waterborne Zn concentration under field conditions. We found that R. philippinarum is more susceptible of Zn than P. viridis under the same exposure condition. Results also suggested that Zn posed no significant susceptibility risk to two bivalve species in Taiwan. We suggested that these two species can be used to biomonitor the water quality on Taiwan coastal areas.


Identification of Potential Gene Interactions in Heart Failure Caused by Idiopathic Dilated Cardiomyopathy.
BACKGROUND Many heart failure (HF) cases are caused by idiopathic dilated cardiomyopathy (iDCM). This study explored the mechanisms of the development and progression of HF caused by iDCM. MATERIAL AND METHODS The gene expression profiles of 102 samples were downloaded from the GEO database (GSE5406). Differentially expressed genes (DEGs) were identified through GO analysis and a KEGG pathway analysis, respectively. A protein-protein interaction (PPI) network was constructed and analyzed to screen potential regulatory proteins. In addition, MCODE and a cytoHubba plugin were used to identify the module and hub genes of DEGs. Finally, transcription factors (TFs) were predicted using PASTAA. We did not perform whole-exome sequencing (WES) for detecting mitochondrial DNA (mtDNA). RESULTS A total of 197 DEGs were screened, and 3 modules, and 4 upregulated and 11 downregulated hub genes were screened. The GO analysis focused on the terms and 12 KEGG pathways were enriched. The FOS, TIMP1, and SERPINE1 hub genes, as well as some key TFs, demonstrated important roles in the progression of HF caused by iDCM. CEBPD, CEBOB, CDC37L1, and SRGN may be new targets for HF in iDCM patients. CONCLUSIONS The identified DEGs and their enriched pathways provide references for exploring the mechanisms of the development and progression of HF patients with iDCM. Moreover, modules, hub genes, and TFs may be useful in the treatment and diagnosis of HF patients with iDCM. However, mtDNA was not investigated.


Y chromosome STR allelic and haplotype diversity in five ethnic Tamil populations from Tamil Nadu, India.
We have analyzed 17 Y chromosomal STR loci in a population sample of 154 unrelated male individuals of the Tamil ethnic group residing in the state of Tamil Nadu, Southern India using AmpFlSTR(R) Yfiler PCR amplification kit. The population samples consist of the following castes: Kongu Gounder (KOG), Nadar Hindu (NAH), Agamudayar (AGA), Parayar (PAR) and other Tamil individuals (MCT) of mixed castes. A total of 152 unique haplotypes were identified among the 154 individuals studied. The haplotype diversity was found to be 0.9935 or higher for all the five groups. The results of population pairwise Fst p values indicate no statistically significant differentiation between the five populations in this study, but the results were highly significant when compared with 12 other global populations (p<0.05). Comparison of populations in this study with other national and global populations using Principal co-ordinate analysis (PCA) using Rst distance matrix indicates a delineation of all the Indian populations from other unrelated populations.


Strategies to improve global influenza surveillance: a decision tool for policymakers.
Global pandemic influenza preparedness relies heavily on public health surveillance, but it is unclear that current surveillance fully meets pandemic preparedness needs. We first developed a conceptual framework to help systematically identify strategies to improve the detection of an early case or cluster of novel human influenza disease during the pre-pandemic period. We then developed a process model (flow diagram) depicting nine major pathways through which a case in the community could be detected and confirmed, and mapped the improvement strategies onto this model. Finally, we developed an interactive decision tool by building quantitative measures of probability and time into each step of the process model and programming it to calculate the net probability and time required for case detection through each detection pathway. Input values for each step can be varied by users to assess the effects of different improvement strategies, alone or in combination. We illustrate application of the tool using hypothetical input data reflecting baseline and 12-month follow-up scenarios, following concurrent implementation of multiple improvement strategies. We compared outputs from the tool across detection pathways and across time, at baseline and 12-month follow up. The process model and outputs from the tool suggest that traditional efforts to build epidemiology and laboratory capacity are efficient strategies, as are more focused strategies within these, such as targeted laboratory testing; expedited specimen transport; use of technologies to streamline data flow; and improved reporting compliance. Other promising strategies stem from community detection - better harnessing of electronic data mining and establishment of community-based monitoring. Our practical tool allows policymakers to use their own realistic baseline values and program projections to assess the relative impact of different interventions to improve the probability and timeliness of detecting early human cases or clusters caused by a novel influenza virus, a possible harbinger of a new pandemic. Policymakers can use results to target investments to improve their surveillance infrastructure. Multi-national planners can also use the tool to help guide directions in surveillance system improvements more globally. Finally, our systematic approach can also be tailored to help improve surveillance for other diseases.


The Association between Treatment Components and Mental Health Outcomes Among Young Children Exposed to Violence.
When treating violence-exposed children, clinicians often modify psychotherapy protocols or use only a subset of treatment components (e.g., a clinical technique, strategy). However, there is little evidence of the effectiveness of individual treatment components. Our study aimed to determine: i) the best fitting factor structure of individual treatment components; ii) the association of child characteristics (i.e., demographics, treatment dosage, environmental risk factors) with mental health outcomes (i.e., post-treatment internalizing and externalizing symptoms); and iii) the association of individual treatment factors (i.e., sets of treatment components) with mental health outcomes. A sample of 459 violence-exposed children aged 1.5-5 years was examined. Principal component analyses were conducted to factor-analyze 22 child treatment components and 18 caregiver treatment components, respectively. Multiple linear regression analyses were conducted to determine the relationship between child and caregiver treatment factors and outcomes. Children who received grief work showed significant improvement in externalizing symptoms. Children of caregivers who received parent training, attachment skills building, psychoeducation about domestic violence, safety planning, and anger management training showed significantly less externalizing symptom improvement. Gender, race/ethnicity, and treatment dosage were also associated with outcomes. This is the first study to examine treatment components in a sample of young children exposed to violence with a standardized quantitative measure. Our findings suggest that acknowledging children's loss and sorrow expressed through externalizing behavior and helping them process bereavement may help alleviate their symptoms. Clinical recommendations are discussed.


Ring-in-Ring(s) Complexes Exhibiting Tunable Multicolor Photoluminescence.
One ring threaded by two other rings to form a non-intertwined ternary ring-in-rings motif is a challenging task in noncovalent synthesis. Constructing multicolor photoluminescence systems with tunable properties is also a fundamental research goal, which can lead to applications in multidimensional biological imaging, visual displays, and encryption materials. Herein, we describe the design and synthesis of binary and ternary ring-in-ring(s) complexes, based on an extended tetracationic cyclophane and cucurbit[8]uril. The formation of these complexes is accompanied by tunable multicolor fluorescence outputs. On mixing equimolar amounts of the cyclophane and cucurbit[8]uril, a 1:1 ring-in-ring complex is formed as a result of hydrophobic interactions associated with a favorable change in entropy. With the addition of another equivalent of cucurbit[8]uril, a 1:2 ring-in-rings complex is formed, facilitated by additional ion-dipole interactions involving the pyridinium units in the cyclophane and the carbonyl groups in cucurbit[8]uril. Because of the narrowing in the energy gaps of the cyclophane within the rigid hydrophobic cavities of cucurbit[8]urils, the binary and ternary ring-in-ring(s) complexes emit green and bright yellow fluorescence, respectively. A series of color-tunable emissions, such as sky blue, cyan, green, and yellow with increased fluorescence lifetimes, can be achieved by simply adding cucurbit[8]uril to an aqueous solution of the cyclophane. Notably, the smaller cyclobis(paraquat-p-phenylene), which contains the same p-xylylene linkers as the extended tetracationic cyclophane, does not form ring-in-ring(s) complexes with cucurbit[8]uril. The encapsulation of this extended tetracationic cyclophane by both one and two cucurbit[8]urils provides an incentive to design and synthesize more advanced supramolecular systems, as well as opening up a feasible approach toward achieving tunable multicolor photoluminescence with single chromophores.


Effects of perinatal mental disorders on the fetus and child.
Perinatal mental disorders are associated with increased risk of psychological and developmental disturbances in children. However, these disturbances are not inevitable. In this Series paper, we summarise evidence for associations between parental disorders and offspring outcomes from fetal development to adolescence in high-income, middle-income, and low-income countries. We assess evidence for mechanisms underlying transmission of disturbance, the role of mediating variables (underlying links between parent psychopathology and offspring outcomes) and possible moderators (which change the strength of any association), and focus on factors that are potentially modifiable, including parenting quality, social (including partner) and material support, and duration of the parental disorder. We review research of interventions, which are mostly about maternal depression, and emphasise the need to both treat the parent's disorder and help with associated caregiving difficulties. We conclude with policy implications and underline the need for early identification of those parents at high risk and for more early interventions and prevention research, especially in socioeconomically disadvantaged populations and low-income countries.


Peer and self-reported victimization: Do non-victimized students give victimization nominations to classmates who are self-reported victims?
Using data from 2413 Dutch first-year secondary school students (M age=13.27, SD age=0.51, 49.0% boys), this study investigated as to what extent students who according to their self-reports had not been victimized (referred to as reporters) gave victimization nominations to classmates who according to their self-reports had been victimized (referred to as receivers). Using a dyadic approach, characteristics of the reporter-receiver dyad (i.e., gender similarity) and of the reporter (i.e., reporters' behavior during bullying episodes) that were possibly associated with reporter-receiver agreement were investigated. Descriptive analyses suggested that numerous students who were self-reported victims were not perceived as victimized by their non-victimized classmates. Three-level logistic regression models (reporter-receiver dyads nested in reporters within classrooms) demonstrated greater reporter-receiver agreement in same-gender dyads, especially when the reporter and the receiver were boys. Furthermore, reporters who behaved as outsiders during bullying episodes (i.e., reporters who actively shied away from the bullying) were less likely to agree on the receiver's self-reported victimization, and in contrast, reporters who behaved as defenders (i.e., reporters who helped and supported victims) were more likely to agree on the victimization. Moreover, the results demonstrated that reporters gave fewer victimization nominations to receivers who reported they had been victimized sometimes than to receivers who reported they had been victimized often/very often. Finally, this study suggested that reporter-receiver agreement may not only depend on characteristics of the reporter-receiver dyad and of the reporter, but on classroom characteristics as well (e.g., the number of students in the classroom).


SARS-CoV-2 Variant Delta Potently Suppresses Innate Immune Response and Evades Interferon-Activated Antiviral Responses in Human Colon Epithelial Cells.
The Delta variant of SARS-CoV-2 has caused more severe infections than its previous variants. We studied the host innate immune response to Delta, Alpha, and two earlier variants to map the evolution of the recent ones. Our biochemical and transcriptomic studies in human colon epithelial cell line Caco2 reveal that Alpha and Delta have progressively evolved over the ancestral variants by silencing the innate immune response, thereby limiting cytokine and chemokine production. Though Alpha silenced the retinoic acid-inducible gene (RIG)-I-like receptor (RLR) pathway just like Delta did, it failed to persistently silence the innate immune response, unlike Delta. Both Alpha and Delta have evolved to resist interferon (IFN) treatment, while they are still susceptible to RLR activation, further highlighting the importance of RLR-mediated, IFN-independent mechanisms in restricting SARS-CoV-2. Our studies reveal that SARS-CoV-2 Delta has integrated multiple mechanisms to silence the host innate immune response and evade the IFN response. We speculate that Delta's silent replication and sustained suppression of the host innate immune response, thereby resulting in delayed or reduced intervention by the adaptive immune response, could have potentially contributed to the severe symptoms and poor recovery index associated with it. It is likely that this altered association with the host would play an important role in the coevolution of SARS-CoV-2 with humans. IMPORTANCE Viruses generally learn to coexist with the host during the process of evolution. It is expected that SARS-CoV-2 would also evolve to coexist in humans by trading off its virulence for longer persistence, causing milder disease. Clinically, the fatality associated with COVID-19 has been declining due to vaccination and preinfections, but the Delta variant caused the most severe disease and fatality across several parts of the world. Our study identified an evolving trend of SARS-CoV-2 variants where the variants that emerged during early parts of the pandemic caused a more robust innate immune response, while the later emerging variant Delta showed features of suppression of the response. The features that Delta has acquired could have strongly influenced the distinct pathophysiology associated with its infection. How these changed associations with the host influence the long-term evolution of the virus and the disease outcome should be closely studied to understand the process of viral evolution.


An atlas of active enhancers across human cell types and tissues.
Enhancers control the correct temporal and cell-type-specific activation of gene expression in multicellular eukaryotes. Knowing their properties, regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis. Here we use the FANTOM5 panel of samples, covering the majority of human tissues and cell types, to produce an atlas of active, in vivo-transcribed enhancers. We show that enhancers share properties with CpG-poor messenger RNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used to compare regulatory programs between different cells at unprecedented depth, to identify disease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific and ubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents a unique resource for studies on cell-type-specific enhancers and gene regulation.


Effect of mold treatment by solvent on PDMS molding into nanoholes.
Polydimethylsiloxane (PDMS) is the most popular and versatile material for soft lithography due to its flexibility and easy fabrication by molding process. However, for nanoscale patterns, it is challenging to fill uncured PDMS into the holes or trenches on the master mold that is coated with a silane anti-adhesion layer needed for clean demolding. PDMS filling was previously found to be facilitated by diluting it with toluene or hexane, which was attributed to the great reduction of viscosity for diluted PDMS. Here, we suggest that the reason behind the improved filling for diluted PDMS is that the diluent solvent increases in situ the surface energy of the silane-treated mold and thus the wetting of PDMS to the mold surface. We treated the master mold surface (that was already coated with a silane anti-adhesion monolayer) with toluene or hexane, and found that the filling by undiluted PMDS into the nanoscale holes on the master mold was improved despite the high viscosity of the undiluted PDMS. A simple estimation based on capillary filing into a channel also gives a filling time on the millisecond scale, which implies that the viscosity of PMDS should not be the limiting factor. We achieved a hole filling down to sub-200-nm diameter that is smaller than those of the previous studies using regular Sylgard PDMS (not hard PDMS, Dow Corning Corporation, Midland, MI, USA). However, we are not able to explain using a simple argument based on wetting property why smaller, e.g., sub-100-nm holes, cannot be filled, for which we suggested a few possible factors for its explanation.


Principal components analysis of the hypomanic attitudes and positive predictions inventory and associations with measures of personality, cognitive style and analogue symptoms in a student sample.
An integrative cognitive model proposed that ascribing extreme personal appraisals to changes in internal state is key to the development of the symptoms of bipolar disorder. The Hypomanic Attitudes and Positive Predictions Inventory (HAPPI) was developed to measure these appraisals. The aim of the current study was to validate an expanded 61-item version of the HAPPI. In a largely female student sample (N = 134), principal components analysis (PCA) was performed on the HAPPI. Associations between the HAPPI and analogue bipolar symptoms after 3 months were examined. PCA of the HAPPI revealed six categories of belief: Self Activation, Self-and-Other Critical, Catastrophic, Extreme Appraisals of Social Approval, Appraisals of Extreme Agitation, and Loss of Control. The HAPPI predicted all analogue measures of hypomanic symptoms after 3 months when controlling for baseline symptoms. In a more stringent test incorporating other psychological measures, the HAPPI was independently associated only with activation (e.g. thoughts racing) at 3 months. Dependent dysfunctional attitudes predicted greater conflict (e.g. irritability), depression and reduced well-being, hypomanic personality predicted self-reported diagnostic bipolar symptoms, and behavioural dysregulation predicted depression. Extreme beliefs about internal states show a modest independent association with prospective analogue bipolar symptoms, alongside other psychological factors. Further work will be required to improve the factor structure of the HAPPI and study its validity in clinical samples.


Discrete cilia modelling with singularity distributions: application to the embryonic node and the airway surface liquid.
We discuss in detail techniques for modelling flows due to finite and infinite arrays of beating cilia. An efficient technique, based on concepts from previous 'singularity models' is described, that is accurate in both near and far-fields. Cilia are modelled as curved slender ellipsoidal bodies by distributing Stokeslet and potential source dipole singularities along their centrelines, leading to an integral equation that can be solved using a simple and efficient discretisation. The computed velocity on the cilium surface is found to compare favourably with the boundary condition. We then present results for two topics of current interest in biology. 1) We present the first theoretical results showing the mechanism by which rotating embryonic nodal cilia produce a leftward flow by a 'posterior tilt,' and track particle motion in an array of three simulated nodal cilia. We find that, contrary to recent suggestions, there is no continuous layer of negative fluid transport close to the ciliated boundary. The mean leftward particle transport is found to be just over 1 mum/s, within experimentally measured ranges. We also discuss the accuracy of models that represent the action of cilia by steady rotlet arrays, in particular, confirming the importance of image systems in the boundary in establishing the far-field fluid transport. Future modelling may lead to understanding of the mechanisms by which morphogen gradients or mechanosensing cilia convert a directional flow to asymmetric gene expression. 2) We develop a more complex and detailed model of flow patterns in the periciliary layer of the airway surface liquid. Our results confirm that shear flow of the mucous layer drives a significant volume of periciliary liquid in the direction of mucus transport even during the recovery stroke of the cilia. Finally, we discuss the advantages and disadvantages of the singularity technique and outline future theoretical and experimental developments required to apply this technique to various other biological problems, particularly in the reproductive system.


The second European interdisciplinary Ewing sarcoma research summit--A joint effort to deconstructing the multiple layers of a complex disease.
Despite multimodal treatment, long term outcome for patients with Ewing sarcoma is still poor. The second "European interdisciplinary Ewing sarcoma research summit" assembled a large group of scientific experts in the field to discuss their latest unpublished findings on the way to the identification of novel therapeutic targets and strategies. Ewing sarcoma is characterized by a quiet genome with presence of an EWSR1-ETS gene rearrangement as the only and defining genetic aberration. RNA-sequencing of recently described Ewing-like sarcomas with variant translocations identified them as biologically distinct diseases. Various presentations adressed mechanisms of EWS-ETS fusion protein activities with a focus on EWS-FLI1. Data were presented shedding light on the molecular underpinnings of genetic permissiveness to this disease uncovering interaction of EWS-FLI1 with recently discovered susceptibility loci. Epigenetic context as a consequence of the interaction between the oncoprotein, cell type, developmental stage, and tissue microenvironment emerged as dominant theme in the discussion of the molecular pathogenesis and inter- and intra-tumor heterogeneity of Ewing sarcoma, and the difficulty to generate animal models faithfully recapitulating the human disease. The problem of preclinical development of biologically targeted therapeutics was discussed and promising perspectives were offered from the study of novel in vitro models. Finally, it was concluded that in order to facilitate rapid pre-clinical and clinical development of novel therapies in Ewing sarcoma, the community needs a platform to maintain knowledge of unpublished results, systems and models used in drug testing and to continue the open dialogue initiated at the first two Ewing sarcoma summits.


COVID-19 Place Confinement, Pro-Social, Pro-environmental Behaviors, and Residents' Wellbeing: A New Conceptual Framework.
Residents' wellbeing in the present COVID-19 global health crisis requires a deeper understanding to determine appropriate management strategies to promote sustainable behaviors and contribute to human and planetary health. Residents' behavior can have a profound influence in contributing to personal and global community's health by responding effectively to emergency strategies in disease outbreaks such as the Coronavirus. It is evident that an understanding of residents' behavior(s) pre COVID-19 across fields have relied on over-simplistic models, many of which will need to be revisited. Our interaction with people and nature while respecting social distancing has profound positive impacts on our physical, mental, emotional, and spiritual wellbeing. The current health pandemic has called that people be confined in their homes across many nations as a means to control the spread of the virus and save lives. This calls for research exploring the mechanisms; this paper develops and proposes a conceptual framework suggesting that place confinement promotes pro-social and household pro-environmental behaviors which could become habitual and contribute further to our people's and our planet's health. The proposed model concerns socio-economically favored social sectors whose survival is not as threatened by the pandemic as the poor sectors where wellbeing (and mental health) are at high risk. Some evidence shows that human connectedness to place may contribute to engagement in desirable behaviors. Interaction with other members of the household can help create meanings leading to collective actions promoting psychological wellbeing. Promoting hygienic behaviors in the household (frequent hand washing) while at the same time being conscious not to keep the water flowing when not required would contribute to a range of benefits (health, financial, biospheric, altruistic) and promote wellbeing. Engaging in pro-social behaviors may result in positive effects on psychological wellbeing, reducing mental distress giving rise to a sense of attachment and belongingness, trust and overall life satisfaction. Engaging people in low-effort pro-environmental behavior to maintain some levels of physical activity and biological harmony with natural environmental settings (e.g., gardening) may help reduce anxiety and distress. This is the first study exploring the interplay of relationships between place confinement, pro-social behavior, household pro-environmental behaviors, place attachment as a multi-dimensional construct and presenting their relationships to residents' wellbeing. Behavioral change interventions are proposed to promote lifestyle change for people's wellbeing and broader societal benefits.


A collaborative study on a Nordic standard protocol for detection and enumeration of thermotolerant Campylobacter in food (NMKL 119, 3. Ed., 2007).
A Nordic standard protocol for detection and enumeration of thermotolerant Campylobacter in food has been elaborated (NMKL 119, 3. Ed., 2007). Performance and precision characteristics of this protocol were evaluated in a collaborative study with participation of 14 laboratories from seven European countries. The laboratories performed qualitative, semi-quantitative and quantitative analyses on samples of chicken meat, cut lettuce, and milk artificially inoculated with different concentrations including blank duplicates of one strain of Campylobacter coli (SLV-271) and one strain of Campylobacter jejuni (SLV-542). Expected concentrations (95% C.I.) (cfu g(-1) or ml(-1)) of both strains in matrices were 0.6-1.4 and 23-60 for qualitative detection, and 0.6-1.4; 23-60; and 420-1200 for semi-quantitative detection. For quantitative determination, the expected concentrations of C. jejuni/C. coli were 420-1200/580-1100; 2100-6000/6300-11,000; and 4100-11,000/53,000-97,000 cfu g(-1) or ml(-1). The qualitative and semi-quantitative techniques resulted in comparable detection. The overall specificity and sensitivity of the detection techniques was 98.6% (95% C.I.: 95.1-99.8%) and 82.8% (C.I.: 78.4-86.6%), respectively. The sensitivity was not influenced by food matrix (P=0.359), but was significantly lower for C. coli compared to C. jejuni (P=0.007) and for concentrations below 1.4 cfu g(-1) (P<0.001). The detection techniques were therefore only considered satisfactory for detection of Campylobacter concentrations above approximately 25 cfu g(-1) for all matrices tested, which was supported by calculation of values for accordance, concordance, and concordance odds ratio. No statistical difference was found between enumerations obtained by the semi-quantitative and quantitative techniques for comparable concentrations of Campylobacter (420-1200 cfu g(-1) or cfu ml(-1)) (P=0.104). Both techniques underestimated concentrations of thermotolerant Campylobacter in milk. The semi-quantitative technique estimated low inoculation levels of Campylobacter more correctly than the high inoculation levels. Counts obtained on the two selective plating media, Abeyta-Hunt-Bark agar added to it 0.1% triphenyl tetrazolium chloride and modified charcoal cephoperazone desoxycholate agar were not significantly different (P=0.143). Expressed as an absolute difference between log(10)-transformed results, the overall values for repeatability (r) and reproducibility (R) were r=log(10) 0.43 and R=log(10) 1.99, respectively. By omitting results from laboratories with high level of variability in results, R was reduced to log(10) 1.88. We suggest that the poor detection of low numbers, the underestimation in milk samples, and the large variation between laboratories can be explained by the general difficulties in handling Campylobacter. In conclusion, NMKL 119, 3. Ed., 2007, is regarded as an acceptable protocol for detection of thermotolerant Campylobacter at concentrations above 25 cfu g(-1) and also for enumeration of thermotolerant Campylobacter in chicken meat.


A flatbed scanner for large-area thickness determination of ultra-thin layers in printed electronics.
Enabling solution-based printing techniques for sub-100 nm thin semiconductors for the application in large-area organic electronics is a challenging task. In order to optimize the process parameters, the layers have to be characterized on a large lateral scale while determining the nanometer thickness at the same time. We present a lateral and vertical resolving measurement method for large-area, semi-transparent thin films based on optical interference effects. We analyzed the RGB color images of up to 150 mm square-sized thin film samples obtained by a modified commercial flatbed scanner. Utilizing and comparing theoretical and measured color contrast values, we determined most probable thickness values of the imaged sample area pixel by pixel. Within specific boundary conditions, we found very good agreement between the presented imaging color reflectometry and reference methods. Due to its simple setup, our method is suitable to be implemented as part of a color vision inspection system in in-line printing and coating processes.


Milk protein and the restoration of fluid balance after exercise.
Sweat is produced during exercise to help dissipate some of the extra heat produced due to an increase in metabolic rate. Inadequate drink ingestion during exercise means athletes finish exercise hypohydrated and when the time between exercise bouts is short, effective rehydration strategies will be necessary to prevent subsequent performance impairment. For complete rehydration, drink volume must be sufficient to replace sweat losses as well as the additional water losses during recovery. Once a sufficient volume of drink is ingested it is the drink composition that dictates the rehydration success of the drink. It is well known that addition of sodium and some other nutrients to rehydration drinks enhances fluid balance restoration after exercise, but the effects of milk proteins have been less well documented. Skimmed milk is an effective post-exercise rehydration solution and enhances the restoration of fluid balance after exercise-induced dehydration to a greater extent than a carbohydrate-electrolyte sports drink. Whilst there are a number of factors in skimmed milk that might be responsible for this enhancement of rehydration, it appears that some of the effect is due to the milk protein, as milk protein has been shown to be more effective for post-exercise rehydration than an isoenergetic amount of carbohydrate. Whilst the effects of whey protein on post-exercise rehydration are equivocal, whey protein addition to a carbohydrate-electrolyte rehydration solution certainly does not impair rehydration. Therefore, in situations where protein ingestion after exercise might be advantageous for the athlete, this protein might also enhance restoration of fluid balance.


A pH-sensitive peptide-containing lasso molecular switch.
The synthesis of a peptide-containing lasso molecular switch by a self-entanglement strategy is described. The interlocked rotaxane molecular machine consists of a benzometaphenylene[25]crown-8 (BMP25C8) macrocycle surrounding a molecular axle. This molecular axle contains a tripeptidic sequence and two molecular stations: a N-benzyltriazolium and a pH-sensitive anilinium station. The tripeptide is located between the macrocycle and the triazolium station, so that its conformation can be tailored depending on the shuttling of the macrocycle from one station to the other. At acidic pH, the macrocycle resides around the anilinium moiety, whereas it shuttles around the triazolium station after deprotonation. This molecular machinery thus forces the lasso to adopt a tightened or a loosened conformation.


Catalytic addition of C-H bonds across C-C unsaturated systems promoted by iridium(i) and its group IX congeners.
Transition metal-catalyzed hydrocarbonations of unsaturated substrates have emerged as powerful synthetic tools for increasing molecular complexity in an atom-economical manner. Although this field was traditionally dominated by low valent rhodium and ruthenium catalysts, in recent years, there have been many reports based on the use of iridium complexes. In many cases, these reactions have a different course from those of their rhodium homologs, and even allow performing otherwise inviable transformations. In this review we aim to provide an informative journey, from the early pioneering examples in the field, most of them based on other metals than iridium, to the most recent transformations catalyzed by designed Ir(i) complexes. The review is organized by the type of C-H bond that is activated (with C sp2, sp or sp3), as well as by the C-C unsaturated partner that is used as a hydrocarbonation partner (alkyne, allene or alkene). Importantly, we discuss the mechanistic foundations of the methods highlighting the differences from those previously proposed for processes catalyzed by related metals, particularly those of the same group (Co and Rh).


Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews.
For adults with asthma that is poorly controlled on inhaled corticosteroids (ICS), guidelines suggest adding a long-acting beta2-agonist (LABA). The LABA can be taken together with ICS in a single (combination) inhaler. Improved symptom control can be assessed in the individual; however, the long-term risk of hospital admission or death requires evidence from randomised controlled trials. Clinical trials record these safety outcomes as non-fatal and fatal serious adverse events (SAEs), respectively. To assess the risk of serious adverse events in adults with asthma treated with regular maintenance formoterol or salmeterol compared with placebo, or when randomly assigned in combination with regular ICS, compared with the same dose of ICS. We included Cochrane reviews on the safety of regular formoterol and salmeterol from a June 2013 search of the Cochrane Database of Systematic Reviews. We carried out a search for additional trials in September 2013 and incorporated the new data. All reviews were independently assessed for inclusion and for quality (using the AMSTAR tool). We extracted from each review data from trials recruiting adults (participants older than 12 or 18 years of age).We combined the results from reviews on formoterol and salmeterol to assess the safety of twice-daily regular LABA as a class effect, both as monotherapy versus placebo and as combination therapy versus the same dose of ICS.We did not combine the results of direct and indirect comparisons of formoterol and salmeterol, or carry out a network meta-analysis, because of concerns over transitivity assumptions that posed a threat to the validity of indirect comparisons. We identified six high-quality, up-to-date Cochrane reviews. Of these, four reviews (89 trials with 61,366 adults) related to the safety of regular formoterol or salmeterol as monotherapy or combination therapy. Two reviews assessed safety from trials in which adults were randomly assigned to formoterol versus salmeterol. These included three trials with 1116 participants given monotherapy (all prescribed background ICS) and 10 trials with 8498 adults receiving combination therapy. An additional search for trials in September 2013 identified five new included studies contributing data from 693 adults with asthma treated with combination formoterol/fluticasone in comparison with the same dose of inhaled fluticasone, as well as from 447 adults for whom formoterol monotherapy was compared with placebo.No trials reported separate results in adolescents. Overall, risks of bias for the primary outcomes were assessed as low. Death of any causeNone of the reviews found a significant increase in death of any cause from direct comparisons; however, none of the reviews could exclude the possibility of a two-fold increase in mortality on regular formoterol or salmeterol (as monotherapy vs placebo or as combination therapy versus ICS) in adults with asthma. Pooled mortality results from direct comparisons were as follows: formoterol monotherapy (odds ratio (OR) 4.49, 95% confidence interval (CI) 0.24 to 84.80, 13 trials, N = 4824), salmeterol monotherapy (OR 1.33, 95% CI 0.85 to 2.08, 10 trials, N = 29,128), formoterol combination (OR 3.56, 95% CI 0.79 to 16.03, 25 trials, N = 11,271) and salmeterol combination (OR 0.90, 95% CI 0.31 to 2.6, 35 trials, N = 13,447). In each case, we did not detect heterogeneity, and the quality of evidence was rated as moderate. Absolute differences in mortality were very small, translating into an increase of 7 per 10,000 over 26 weeks on any monotherapy (95% CI 2 less to 23 more) and 3 per 10,000 over 32 weeks on any combination therapy (95% CI 3 less to 17 more).Very few deaths were reported in the combination therapy trials, and combination therapy trial designs were different from those of monotherapy trials. Therefore we could not use indirect evidence to assess whether regular combination therapy was safer than regular monotherapy.Only one death occurred in the monotherapy trials comparing formoterol versus salmeterol, so evidence was insufficient to compare mortality. Non-fatal serious adverse events of any causeDirect evidence showed that non-fatal serious adverse events were increased in adults receiving salmeterol monotherapy (OR 1.14, 95% 1.01 to 1.28, I(2) = 0%,13 trials, N = 30,196) but were not significantly increased in any of the other reviews: formoterol monotherapy (OR 1.26, 95% CI 0.78 to 2.04, I(2) = 15%, 17 trials, N = 5758), formoterol combination (OR 0.99, 95% CI 0.77 to 1.27, I(2) = 0%, 25 trials, N = 11,271) and salmeterol combination (OR 1.15, 95% CI 0.91 to 1.44, I(2) = 0%, 35 trials, N = 13,447). This represents an absolute increase on any monotherapy of 43 per 10,000 over 26 weeks (95% CI 6 more to 85 more) and 16 per 10,000 over 32 weeks (95% CI 22 less to 60 more) on any combination therapy.Direct comparisons of formoterol and salmeterol detected no significant differences between risks of all non-fatal events in adults (as monotherapy or as combination therapy). Available evidence from the reviews of randomised trials cannot definitively rule out an increased risk of fatal serious adverse events when regular formoterol or salmeterol was added to an inhaled corticosteroid (as background or as randomly assigned treatment) in adults or adolescents with asthma.An increase in non-fatal serious adverse events of any cause was found with salmeterol monotherapy, and the same increase cannot be ruled out when formoterol or salmeterol was used in combination with an inhaled corticosteroid, although possible increases are small in absolute terms.However, if the addition of formoterol or salmeterol to an inhaled corticosteroid is found to improve symptomatic control, it is safer to give formoterol or salmeterol in the form of a combination inhaler (as recommended by the US Food and Drug Administration (FDA)). This prevents the substitution of LABA for an inhaled corticosteroid if symptom control is improved on LABA.The results of three large ongoing trials in adults and adolescents are awaited; these will provide more information on the safety of combination therapy under less supervised conditions and will report separate results for the adolescents included.


PhyloMap: an algorithm for visualizing relationships of large sequence data sets and its application to the influenza A virus genome.
Results of phylogenetic analysis are often visualized as phylogenetic trees. Such a tree can typically only include up to a few hundred sequences. When more than a few thousand sequences are to be included, analyzing the phylogenetic relationships among them becomes a challenging task. The recent frequent outbreaks of influenza A viruses have resulted in the rapid accumulation of corresponding genome sequences. Currently, there are more than 7500 influenza A virus genomes in the database. There are no efficient ways of representing this huge data set as a whole, thus preventing a further understanding of the diversity of the influenza A virus genome. Here we present a new algorithm, "PhyloMap", which combines ordination, vector quantization, and phylogenetic tree construction to give an elegant representation of a large sequence data set. The use of PhyloMap on influenza A virus genome sequences reveals the phylogenetic relationships of the internal genes that cannot be seen when only a subset of sequences are analyzed. The application of PhyloMap to influenza A virus genome data shows that it is a robust algorithm for analyzing large sequence data sets. It utilizes the entire data set, minimizes bias, and provides intuitive visualization. PhyloMap is implemented in JAVA, and the source code is freely available at http://www.biochem.uni-luebeck.de/public/software/phylomap.html.


Interim 2018/19 influenza vaccine effectiveness: six European studies, October 2018 to January 2019.
Influenza A(H1N1)pdm09 and A(H3N2) viruses both circulated in Europe in October 2018-January 2019. Interim results from six studies indicate that 2018/19 influenza vaccine effectiveness (VE) estimates among all ages in primary care was 32-43% against influenza A; higher against A(H1N1)pdm09 and lower against A(H3N2). Among hospitalised older adults, VE estimates were 34-38% against influenza A and slightly lower against A(H1N1)pdm09. Influenza vaccination is of continued benefit during the ongoing 2018/19 influenza season.


Luminal influences on potassium secretion: sodium concentration and fluid flow rate.
Two methods of in vivo continuous microperfusion were used to evaluate separately luminal sodium concentration and fluid flow rate as factors regulating potassium secretion by the renal distal tubule of the rat. Emphasis was placed on evaluating changes in sodium concentration (43-97 mM) and flow rate (4-27 nl/min) within the physiological range. Absolute rates of Na, K, Cl, and H2O transport were measured. Results showed that increasing early distal flow rate without increasing early distal Na concentration significantly increased the absolute rate of potassium secretion by the distal tubule. In contrast, increasing early distal Na concentration, distal Na delivery, and distal Na absorption did not affect potassium secretion if flow rate was not changed. Further studies showed that reducing early distal Na concentration below the physiological range (to 15 mM) caused the direction of net sodium transport to be reversed but did not significantly reduce potassium secretion. Increasing early distal K concentration (to 34 mM) caused the direction of net potassium transport to be reversed. The rate of potassium secretion appears to depend in part on the luminal potassium concentration. Increases in luminal flow rate may increase the rate of potassium secretion by lowering the luminal K concentration.


Healthcare utilization and costs among relapsed or refractory multiple myeloma patients on carfilzomib or pomalidomide as monotherapy or in combination with dexamethasone.
Aim: To compare monthly healthcare resource utilization (HRU) and costs among adult patients with multiple myeloma (MM) receiving second or subsequent line of treatment (LOT) with carfilzomib or pomalidomide as monotherapy or in combination with dexamethasone. Methods and materials: Adult MM patients who received carfilzomib or pomalidomide as second/subsequent LOT between 2006 and 2014 were selected from the MarketScan databases. LOT was determined using Medical/pharmacy claims using a published algorithm. For each patient, first LOT with carfilzomib or pomalidomide was defined as index LOT. Patients with first LOT as index LOT, who received other chemotherapy in combination with carfilzomib or pomalidomide, or who underwent stem cell transplant (STC) during index LOT were excluded. Monthly HRU and costs during index LOT were compared using inverse probability of treatment weights (IPTW) based on propensity scores for receipt of carfilzomib estimated by logistic regression with LOT, patient demographics, Charlson index, comorbidities, pre-index healthcare cost, and receipt of prior SCT as covariates. Results: After weighting, baseline characteristics were well balanced among 114 carfilzomib and 144 pomalidomide patients. Mean (95% CI) numbers of outpatient visits per month were 7.1 (5.2-8.0) with carfilzomib and 4.7 (3.9-6.1) with pomalidomide (p = 0.006). Otherwise, there were no statistically significant differences between the groups in mean monthly HRU and costs or median time to therapy discontinuation. Mean (95% CI) monthly total healthcare costs were $19,776 (15,322-27,748) with pomalidomide and $17,321 (12,412-21,874) with carfilzomib (p = 0.522). Limitations: Comparison of carfilzomib vs pomalidomide may be biased if there are unobserved factors not balanced by IPTW. The relatively small sample size limits the power of analyses to detect potential differences between treatment groups. Conclusions: Monthly HRU and costs are similar among patients with relapse or refractory MM patients receiving carfilzomib or pomalidomide as monotherapy or in combination with dexamethasone.


Decoding stimulus duration from neural responses in the auditory midbrain.
Neurons with responses selective for the duration of an auditory stimulus are called duration-tuned neurons (DTNs). Temporal specificity in their spiking suggests that one function of DTNs is to encode stimulus duration; however, the efficacy of duration encoding by DTNs has yet to be investigated. Herein, we characterize the information content of individual cells and a population of DTNs from the mammalian inferior colliculus (IC) by measuring the stimulus-specific information (SSI) and estimated Fisher information (FI) of spike count responses. We found that SSI was typically greatest for those stimulus durations that evoked maximum spike counts, defined as best duration (BD) stimuli, and that FI was maximal for stimulus durations off BD where sensitivity to a change in duration was greatest. Using population data, we demonstrate that a maximum likelihood estimator (MLE) can accurately decode stimulus duration from evoked spike counts. We also simulated a two-alternative forced choice task by having MLE models decide whether two durations were the same or different. With this task we measured the just-noticeable difference threshold for stimulus duration and calculated the corresponding Weber fractions across the stimulus domain. Altogether, these results demonstrate that the spiking responses of DTNs from the mammalian IC contain sufficient information for the CNS to encode, decode, and discriminate behaviorally relevant auditory signal durations.


Functional characterization of cotton genes responsive to Verticillium dahliae through bioinformatics and reverse genetics strategies.
Verticillium wilt causes dramatic cotton yield loss in China. Although some genes or biological processes involved in the interaction between cotton and Verticillium dahliae have been identified, the molecular mechanism of cotton resistance to this disease is still poorly understood. The basic innate immune response for defence is somewhat conserved among plant species to defend themselves in complex environments, which makes it possible to characterize genes involved in cotton immunity based on information from model plants. With the availability of Arabidopsis databases, a data-mining strategy accompanied by virus-induced gene silencing (VIGS) and heterologous expression were adopted in cotton and tobacco, respectively, for global screening and gene function characterization. A total of 232 Arabidopsis genes putatively involved in basic innate immunity were screened as candidate genes, and bioinformatic analysis suggested a role of these genes in the immune response. In total, 38 homologous genes from cotton were singled out to characterize their response to V. dahliae and methyl jasmonate treatment through quantitative real-time PCR. The results revealed that 24 genes were differentially regulated by pathogen inoculation, and most of these genes responded to both Verticillium infection and jasmonic acid stimuli. Furthermore, the efficiency of the strategy was illustrated by the functional identification of six candidate genes via heterologous expression in tobacco or a knock-down approach using VIGS in cotton. Functional categorization of these 24 differentially expressed genes as well as functional analysis suggest that reactive oxygen species, salicylic acid- and jasmonic acid-signalling pathways are involved in the cotton disease resistance response to V. dahliae. Our data demonstrate how information from model plants can allow the rapid translation of information into non-model species without complete genome sequencing, via high-throughput screening and functional identification of target genes based on data-mining and VIGS.


Fast single-photon avalanche diode arrays for laser Raman spectroscopy.
We incorporate newly developed solid-state detector technology into time-resolved laser Raman spectroscopy, demonstrating the ability to distinguish spectra from Raman and fluorescence processes. As a proof of concept, we show fluorescence rejection on highly fluorescent mineral samples willemite and spodumene using a 128×128 single-photon avalanche diode (SPAD) array with a measured photon detection efficiency of 5%. The sensitivity achieved in this new instrument architecture is comparable to the sensitivity of a technically more complicated system using a traditional photocathode-based imager. By increasing the SPAD active area and improving coupling efficiency, we expect further improvements in sensitivity by over an order of magnitude. We discuss the relevance of these results to in situ planetary instruments, where size, weight, power, and radiation hardness are of prime concern. The potential large-scale manufacturability of silicon SPAD arrays makes them prime candidates for future portable and in situ Raman instruments spanning numerous applications where fluorescence interference is problematic.


The Influence of Clinical Decision Support on Diagnostic Accuracy in Nurse Practitioners.
Clinical decision support systems (CDSSs) at the point of care are evidence-based interventions that have demonstrated incremental positive impact on quality of healthcare delivery over the past two decades. Existing best practices inform strategies to promote adoption and achievement of targeted outcomes. The purpose of this improvement project was to conduct a pilot implementation to understand the contextual factors and readiness for dissemination of a newly acquired electronic CDSS by evaluating its influence on diagnostic accuracy in nurse practitioners (NPs) functioning in a community health setting. The specific aims of this project were to measure and compare diagnostic accuracy in a pilot group before and after CDSS use, educate clinicians about the system and pilot its use, and then leverage the experience to design the practice-wide CDSS dissemination strategy. The project engaged a subset of NPs from a home-based primary care practice and other organizational stakeholders who provided tangible support and necessary resources for successful adoption of this innovation in practice. A structured conceptual model of Evidence-Based Practice Improvement enhanced with elements of the Promoting Action on Research Implementation in Health Sciences framework was used to guide the development, implementation and evaluation of this practice improvement initiative. A group of seven NP representatives of the practice participated in the project. Data collection was composed of small tests of change (plan-do-study-act) cycles at the local practice level, measuring achievement of improvement of the chosen outcome of correctness of medical diagnosis evidenced by appropriate substantiating clinical documentation. In this home visiting primary care practice setting, use of a CDSS by NPs achieved eventual improvement in diagnostic accuracy and clinical documentation, as demonstrated on chart audit, though the improvement was not sustained over time. The pilot findings ultimately informed decision making about CDSS dissemination strategies and future uses of the system. When appropriately deployed, a CDSS offers the potential to improve professional practice, support differential diagnosis and evidence-based treatment, and provide detailed information about the disease state to facilitate robust clinical documentation.


A Candida auris Outbreak and Its Control in an Intensive Care Setting.
Candida auris is an emerging and multidrug-resistant pathogen. Here we report the epidemiology of a hospital outbreak of C. auris colonization and infection. After identification of a cluster of C. auris infections in the neurosciences intensive care unit (ICU) of the Oxford University Hospitals, United Kingdom, we instituted an intensive patient and environmental screening program and package of interventions. Multivariable logistic regression was used to identify predictors of C. auris colonization and infection. Isolates from patients and from the environment were analyzed by whole-genome sequencing. A total of 70 patients were identified as being colonized or infected with C. auris between February 2, 2015, and August 31, 2017; of these patients, 66 (94%) had been admitted to the neurosciences ICU before diagnosis. Invasive C. auris infections developed in 7 patients. When length of stay in the neurosciences ICU and patient vital signs and laboratory results were controlled for, the predictors of C. auris colonization or infection included the use of reusable skin-surface axillary temperature probes (multivariable odds ratio, 6.80; 95% confidence interval [CI], 2.96 to 15.63; P<0.001) and systemic fluconazole exposure (multivariable odds ratio, 10.34; 95% CI, 1.64 to 65.18; P=0.01). C. auris was rarely detected in the general environment. However, it was detected in isolates from reusable equipment, including multiple axillary skin-surface temperature probes. Despite a bundle of infection-control interventions, the incidence of new cases was reduced only after removal of the temperature probes. All outbreak sequences formed a single genetic cluster within the C. auris South African clade. The sequenced isolates from reusable equipment were genetically related to isolates from the patients. The transmission of C. auris in this hospital outbreak was found to be linked to reusable axillary temperature probes, indicating that this emerging pathogen can persist in the environment and be transmitted in health care settings. (Funded by the National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at Oxford University and others.).


How animals move: comparative lessons on animal locomotion.
Comparative physiology often provides unique insights in animal structure and function. It is specifically through this lens that we discuss the fundamental properties of skeletal muscle and animal locomotion, incorporating variation in body size and evolved difference among species. For example, muscle frequencies in vivo are highly constrained by body size, which apparently tunes muscle use to maximize recovery of elastic recoil potential energy. Secondary to this constraint, there is an expected linking of skeletal muscle structural and functional properties. Muscle is relatively simple structurally, but by changing proportions of the few muscle components, a diverse range of functional outputs is possible. Thus, there is a consistent and predictable relation between muscle function and myocyte composition that illuminates animal locomotion. When animals move, the mechanical properties of muscle diverge from the static textbook force-velocity relations described by A. V. Hill, as recovery of elastic potential energy together with force and power enhancement with activation during stretch combine to modulate performance. These relations are best understood through the tool of work loops. Also, when animals move, locomotion is often conveniently categorized energetically. Burst locomotion is typified by high-power outputs and short durations while sustained, cyclic, locomotion engages a smaller fraction of the muscle tissue, yielding lower force and power. However, closer examination reveals that rather than a dichotomy, energetics of locomotion is a continuum. There is a remarkably predictable relationship between duration of activity and peak sustainable performance.


Small molecule enhancers of rapamycin-induced TOR inhibition promote autophagy, reduce toxicity in Huntington's disease models and enhance killing of mycobacteria by macrophages.
Upregulation of autophagy may have therapeutic benefit in a range of diseases that includes neurodegenerative conditions caused by intracytosolic aggregate-prone proteins, such as Huntington's disease, and certain infectious diseases, such as tuberculosis. The best-characterized drug that enhances autophagy is rapamycin, an inhibitor of the TOR (target of rapamycin) proteins, which are widely conserved from yeast to man. Unfortunately, the side effects of rapamycin, especially immunosuppression, preclude its use in treating certain diseases including tuberculosis, which accounts for approximately 2 million deaths worldwide each year, spurring interest in finding novel drugs that selectively enhance autophagy. We have recently reported a novel two-step screening process for the discovery of such compounds. We first identified compounds that enhance the growth-inhibitory effects of rapamycin in the budding yeast Saccharomyces cerevisiae, which we termed small molecule enhancers of rapamycin (SMERs). Next we showed that three SMERs induced autophagy independently, or downstream of mTOR, in mammalian cells, and furthermore enhanced the clearance of a mutant huntingtin fragment in Huntington's disease cell models. These SMERs also protected against mutant huntingtin fragment toxicity in Drosophila. We have subsequently tested two of the SMERs in models of tuberculosis and both enhance the killing of mycobacteria by primary human macrophages.


High prevalence of celiac disease in Mexican Mestizo adults with type 1 diabetes mellitus.
Recent studies have shown that celiac disease (CD) could affect 0.5% to 3% of the general population, including Mexican Mestizos, which represents a complex mixture of genetics, and constitutes the core of Mexican and Latin American populations. However, the association between CD and other conditions, specifically type-1 diabetes mellitus, in this population remains unknown. Thus, our aim was to determine the prevalence of both serologic and biopsy proven CD in Mexican Mestizo adults with type-1 diabetes. Over a 6-month period, serum samples obtained from consecutive Mexican Mestizo adult patients (age >or=18 y) with type-1 diabetes were tested with a new generation human recombinant protein based IgA tissue transglutaminase enzyme-linked immunosorbent assay commercial kit. All patients with positive serologic test results underwent upper gastrointestinal endoscopy and small intestinal biopsies to confirm CD. Eighty-four type-1 diabetic patients were included (62 women, mean age 28.9+/-9 y). Overall, 9 patients (9/84) were positive for IgA tissue transglutaminase with a point prevalence of 10.7% (95% CI, 4%-17%). Seven patients agreed to undergo endoscopy. Five subjects had biopsy-proven CD (5.9%, 95% CI, 1.9%-13.3%). One patient had chronic diarrhea and other abdominal bloating; whereas the remaining 3 were asymptomatic. CD associated type-1 diabetic patients tended to have higher hemoglobin A1c levels (P=0.07), reflecting poor glycemic control. As in other populations, we demonstrated a high prevalence of biopsy-proven CD (5.9%) among Mexican Mestizo patients with type-1 diabetes. Clinicians should be aware of this common association in this ethnic group.


Filthy lucre: A metagenomic pilot study of microbes found on circulating currency in New York City.
Paper currency by its very nature is frequently transferred from one person to another and represents an important medium for human contact with-and potential exchange of-microbes. In this pilot study, we swabbed circulating $1 bills obtained from a New York City bank in February (Winter) and June (Summer) 2013 and used shotgun metagenomic sequencing to profile the communities found on their surface. Using basic culture conditions, we also tested whether viable microbes could be recovered from bills. Shotgun metagenomics identified eukaryotes as the most abundant sequences on money, followed by bacteria, viruses and archaea. Eukaryotic assemblages were dominated by human, other metazoan and fungal taxa. The currency investigated harbored a diverse microbial population that was dominated by human skin and oral commensals, including Propionibacterium acnes, Staphylococcus epidermidis and Micrococcus luteus. Other taxa detected not associated with humans included Lactococcus lactis and Streptococcus thermophilus, microbes typically associated with dairy production and fermentation. Culturing results indicated that viable microbes can be isolated from paper currency. We conducted the first metagenomic characterization of the surface of paper money in the United States, establishing a baseline for microbes found on $1 bills circulating in New York City. Our results suggest that money amalgamates DNA from sources inhabiting the human microbiome, food, and other environmental inputs, some of which can be recovered as viable organisms. These monetary communities may be maintained through contact with human skin, and DNA obtained from money may provide a record of human behavior and health. Understanding these microbial profiles is especially relevant to public health as money could potentially mediate interpersonal transfer of microbes.


SU-F-BRCD-08: Uncertainty Quantification by Generalized Polynomial Chaos for MR-Guided Laser Induced Thermal Therapy.
Magnetic resonance-guided laser induced thermal therapy (MRgLITT) is a minimally invasive thermal treatment for metastatic brain lesions, offering an alternative to conventional surgery. The purpose of this investigation is to incorporate uncertainty quantification (UQ) into the biothermal parameters used in the Pennes bioheat transfer equation (BHT), in order to account for imprecise values available in the literature. The BHT is a partial differential equation commonly used in thermal therapy models. MRgLITT was performed on an in vivo canine brain in a previous investigation. The canine MRgLITT was modeled using the BHT. The BHT has four parameters'" microperfusion, conductivity, optical absorption, and optical scattering'"which lack precise measurements in living brain and tumor. The uncertainties in the parameters were expressed as probability distribution functions derived from literature values. A univariate generalized polynomial chaos (gPC) expansion was applied to the stochastic BHT. The gPC approach to UQ provides a novel methodology to calculate spatio-temporal voxel-wise means and variances of the predicted temperature distributions. The performance of the gPC predictions were evaluated retrospectively by comparison with MR thermal imaging (MRTI) acquired during the MRgLITT procedure in the canine model. The comparison was evaluated with root mean square difference (RMSD), isotherm contours, spatial profiles, and z-tests. The peak RMSD was ∼1.5 standard deviations for microperfusion, conductivity, and optical absorption, while optical scattering was ∼2.2 standard deviations. Isotherm contours and spatial profiles of the simulation's predicted mean plus or minus two standard deviations demonstrate the MRTI temperature was enclosed by the model's isotherm confidence interval predictions. An a = 0.01 z-test demonstrates agreement. The application of gPC for UQ is a potentially powerful means for providing predictive simulations despite poorly known input parameters. gPC provides an output that represents the probable distribution of outcomes for MRgLITT.


Heat-modified citrus pectin induces apoptosis-like cell death and autophagy in HepG2 and A549 cancer cells.
Cancer is still one of the leading causes of death worldwide, and finding new treatments remains a major challenge. Previous studies showed that modified forms of pectin, a complex polysaccharide present in the primary plant cell wall, possess anticancer properties. Nevertheless, the mechanism of action of modified pectin and the pathways involved are unclear. Here, we show that citrus pectin modified by heat treatment induced cell death in HepG2 and A549 cells. The induced cell death differs from classical apoptosis because no DNA cleavage was observed. In addition, Z-VAD-fmk, a pan-caspase inhibitor, did not influence the observed cell death in HepG2 cells but appeared to be partly protective in A549 cells, indicating that heat-modified citrus pectin might induce caspase-independent cell death. An increase in the abundance of the phosphatidylethanolamine-conjugated Light Chain 3 (LC3) protein and a decrease in p62 protein abundance were observed in both cell types when incubated in the presence of heat-modified citrus pectin. These results indicate the activation of autophagy. To our knowledge, this is the first time that autophagy has been revealed in cells incubated in the presence of a modified form of pectin. This autophagy activation appears to be protective, at least for A549 cells, because its inhibition with 3-methyladenine increased the observed modified pectin-induced cytotoxicity. This study confirms the potential of modified pectin to improve chemotherapeutic cancer treatments.


Elastin content of the renal pelvis and ureter determines post-pyeloplasty recovery.
We evaluated the collagen-to-smooth muscle tissue matrix ratio and percentage of elastin in the renal pelvis, ureteropelvic junction (UPJ) and ureter, and compared these findings with the degree of obstruction, patient age and post-pyeloplasty renal recovery. We analyzed histological sections from 75 patients with UPJ obstruction. Nine patients were excluded owing to bilateral UPJ obstruction and an improper specimen. We divided the specimen obtained from pyeloplasty into 3 parts, namely the renal pelvis above the obstruction, the obstructed UPJ portion and the ureter below the obstruction. To examine the collagen and smooth muscle, sections were stained using Masson's trichrome, and elastic van Giesson stain was used for elastin, smooth muscle and collagen. Collagen, smooth muscle and elastin populations were identified, and the tissue matrix ratio and percentage of elastin were calculated by color image analysis. In patients with lower ratios of collagen-to-smooth muscle in the UPJ proper hydronephrosis was more improved postoperatively (p = 0.049). In patients with a lower percentage of elastin in the renal pelvis, UPJ and ureter hydronephrosis was more improved postoperatively (p <0.0001). Because the UPJ portion was resected during pyeloplasty, the renal pelvis and the ureter remaining after pyeloplasty are likely to be related to improved hydronephrosis. A higher percentage of elastin in the renal pelvis and ureter contributes to inelasticity and low compliance, and results in a slower recovery from hydronephrosis after pyeloplasty.


Replacing dairy fat with rapeseed oil causes rapid improvement of hyperlipidaemia: a randomized controlled study.
Rapeseed oil (RO), also known as canola oil, principally contains the unsaturated fatty acids 18:1n-9, 18:2n-6 and 18:3n-3 and may promote cardiometabolic health. To investigate the effects on lipoprotein profile, factors of coagulation and insulin sensitivity of replacing a diet rich in saturated fat from dairy foods (DF diet) with a diet including RO-based fat (RO diet). During a 2×3-week randomized, controlled, cross-over trial, 20 free-living hyperlipidaemic subjects were provided with isocaloric test diets that differed in fat composition alone. Blood lipoprotein profile, coagulation and fibrinolytic factors and insulin sensitivity (euglycaemic clamp) were determined before and after the dietary intervention. All subjects completed the study, and compliance was high according to changes in serum fatty acids. The RO diet, but not the DF diet, reduced the levels of serum cholesterol (-17%), triglycerides (-20%) and low-density lipoprotein cholesterol (-17%), cholesterol/high-density lipoprotein (HDL) cholesterol ratio (-21%), apolipoprotein (apo) B/apo A-I ratio (-4%) and factor VII coagulant activity (FVIIc) (-5%) from baseline. These changes were significantly different between the diets (P=0.05 to P<0.0001), except for FVIIc (P=0.1). The RO diet, but not the DF diet, modestly increased serum lipoprotein(a) (+6%) and tended to increase the glucose disappearance rate (K-value, +33%). HDL cholesterol, insulin sensitivity, fibrinogen and tissue plasminogen activator inhibitor-1 levels did not change from baseline or differ between the two diets. In a diet moderately high in total fat, replacing dairy fat with RO causes a rapid and clinically relevant improvement in serum lipoprotein profile including lowering of triglycerides in hyperlipidaemic individuals.


Male participation in prevention programmes of mother to child transmission of HIV: a protocol for a systematic review to identify barriers, facilitators and reported interventions.
Infection with the HIV and AIDS are leading causes of morbidity and mortality among women and children worldwide. Prevention of mother-to-child transmission of HIV (PMTCT) programs were developed to protect women and their babies from having HIV infection. However, knowledge on how male participation has been applied to these programs is limited. We present a research protocol for a review which seeks to determine the effects of male participation on female uptake of PMTCT programs, and assess how this male participation has been investigated and documented worldwide. This is a systematic review of published literature. We will attempt to identify all studies relevant to the subject written in the English language from January 1998 to June 2011. Electronic searches of the PubMED, EMBASE, CINAHL, and LILACS databases will be conducted using the relevant medical subject headings. Reference lists of identified studies and previous reviews will be manually checked for articles of interest. We shall also contact authors on the field for any relevant material. Two authors (FM and LM) will independently screen potential articles for eligibility using well-defined inclusion and exclusion criteria. They will independently assess the methodological quality of each included paper using the Jadad scale for randomized controlled trials, and the Newcastle-Ottawa scale for observational studies. Then they will independently extract data from the studies using a pre-established data extraction form. The primary outcome data will be female uptake of PMTCT services following a male/couple intervention, while secondary outcome measures will include indicators and barriers of male participation in PMTCT activities among others. During the data extraction process, discrepancies between the two authors will be sorted out by discussion or consultation with a third party (LT). The analysis and reporting of the review will be according to the PRISMA and MOOSE guidelines. Any identified clinical or statistical heterogeneity will be explored. Where possible, a random-effects meta-analysis will be performed to obtain aggregate estimates. We will also assess publication bias using funnel plots. Analysis of other outcomes will be descriptive.


Effect of inspiratory training on mitochondrial DNA and cytochrome-c oxidase expression in the diaphragm.
We have previously shown that respiratory training with inspiratory flow-resistive (IFR) loads improves diaphragm performance and is associated with an increase in cytochrome-c oxidase (COX) activity (1). The present study was conducted to define the level at which the increase in COX activity is controlled. Six sheep were trained with IFR loads for 3 h/day for 3 wk. The diaphragm was sampled from the six trained sheep and from six control sheep. Quantitative DNA and RNA slot-blot analyses with mitochondrially coded COX subunit III and nuclearly coded subunit IV probes and immunoblotting with anti-COX holoenzyme antibodies were performed. We found that in the diaphragm the amount of COX subunit proteins coded in either genetic system was greater in the trained than in the control sheep. Neither the amount of mitochondrial DNA nor mRNA for COX subunits was different between the two groups. We conclude that the increase in COX activity in the diaphragm after chronic respiratory training is determined by the amount of subunit proteins, possibly involving translation/degradation of these proteins.


GOES-R Advanced Baseline Imager: spectral response functions and radiometric biases with the NPP Visible Infrared Imaging Radiometer Suite evaluated for desert calibration sites.
The Advanced Baseline Imager (ABI), which will be launched in late 2015 on the National Oceanic and Atmospheric Administration's Geostationary Operational Environmental Satellite R-series satellite, will be evaluated in terms of its data quality postlaunch through comparisons with other satellite sensors such as the recently launched Visible Infrared Imaging Radiometer Suite (VIIRS) aboard the Suomi National Polar-orbiting Partnership satellite. The ABI has completed much of its prelaunch characterization and its developers have generated and released its channel spectral response functions (response versus wavelength). Using these responses and constraining a radiative transfer model with ground reflectance, aerosol, and water vapor measurements, we simulate observed top of atmosphere (TOA) reflectances for analogous visible and near infrared channels of the VIIRS and ABI sensors at the Sonoran Desert and White Sands National Monument sites and calculate the radiometric biases and their uncertainties. We also calculate sensor TOA reflectances using aircraft hyperspectral data from the Airborne Visible/Infrared Imaging Spectrometer to validate the uncertainties in several of the ABI and VIIRS channels and discuss the potential for validating the others. Once on-orbit, calibration scientists can use these biases to ensure ABI data quality and consistency to support the numerical weather prediction community and other data users. They can also use the results for ABI or VIIRS anomaly detection and resolution.


The validity of intraoperative angiography for the treatment of spinal arteriovenous fistula.
Retrospective study of patients with spinal arteriovenous fistula (AVF) who underwent surgical treatment. To evaluate the validity of the intraoperative angiography (IA) for the surgical treatment of spinal AVF. Owing to the development of interventional techniques, endovascular embolization has become the treatment of choice for AVF, but it is not applicable for every spinal AVF owing to anatomic complexity of the spinal cord vessels. To get effective occlusion of the AVF, IA has been routinely used in the management of cerebral vascular diseases, but report of its use for spinal AVF is rare. Since 2004, 4 consecutive cases of spinal AVF (3 males and 1 female, 3 thoracic, and 1 thoracolumbar) were involved in this study. The mean age at the time of operation was 62.3 years (range from 48 to 76 y). Types of AVFs and surgical techniques were reviewed retrospectively and the outcomes were assessed using the Japanese Orthopedic Association scoring system. AVFs in 3 patients were diagnosed as the dural type and that in the remaining patient as the perimedullary type; all feeding arteries were derived from the ninth to 10th intercostal arteries. Preoperative angiography demonstrated that the feeding arteries in 2 patients with a dural AVF were the branches of Adamkiewicz artery and in another dural AVF case, the Adamkiewicz artery could not be determined, therefore, endovascular embolization was not feasible. Including a patient with perimedullary AVF, a microsurgical clipping combined with IA was selected as the treatment. Complete occlusion of the fistula was achieved in all cases, the mean preoperative Japanese Orthopedic Association score of 4.5 improved to 6 at the final follow-up, and no perioperative complications were observed during the follow-up period. The favorable clinical results in our spinal AVF cases confirmed that IA ensures safe and accurate occlusion of the fistula. This technique provides satisfactory surgical results for spinal AVFs.


Quantitative trait loci for floral morphology in Arabidopsis thaliana.
A central question in biology is how genes control the expression of quantitative variation. We used statistical methods to estimate genetic variation in eight Arabidopsis thaliana floral characters (fresh flower mass, petal length, petal width, sepal length, sepal width, long stamen length, short stamen length, and pistil length) in a cosmopolitan sample of 15 ecotypes. In addition, we used genome-wide quantitative trait locus (QTL) mapping to evaluate the genetic basis of variation in these same traits in the Landsberg erecta x Columbia recombinant inbred line population. There was significant genetic variation for all traits in both the sample of naturally occurring ecotypes and in the Ler x Col recombinant inbred line population. In addition, broad-sense genetic correlations among the traits were positive and high. A composite interval mapping (CIM) analysis detected 18 significant QTL affecting at least one floral character. Eleven QTL were associated with several floral traits, supporting either pleiotropy or tight linkage as major determinants of flower morphological integration. We propose several candidate genes that may underlie these QTL on the basis of positional information and functional arguments. Genome-wide QTL mapping is a promising tool for the discovery of candidate genes controlling morphological development, the detection of novel phenotypic effects for known genes, and in generating a more complete understanding of the genetic basis of floral development.


Chemical conversion of human fibroblasts into functional Schwann cells.
Direct transdifferentiation of somatic cells is a promising approach to obtain patient-specific cells for numerous applications. However, conversion across germ-layer borders often requires ectopic gene expression with unpredictable side effects. Here, we present a gene-free approach that allows efficient conversion of human fibroblasts via a transient progenitor stage into Schwann cells, the major glial cell type of peripheral nerves. Using a multikinase inhibitor, we transdifferentiated fibroblasts into transient neural precursors that were subsequently further differentiated into Schwann cells. The resulting induced Schwann cells (iSCs) expressed numerous Schwann cell-specific proteins and displayed neurosupportive and myelination capacity in vitro. Thus, we established a strategy to obtain mature Schwann cells from human postnatal fibroblasts under chemically defined conditions without the introduction of ectopic genes.


[Pre-pregnancy nutritional status, maternal weight gain, prenatal care, and adverse perinatal outcomes among adolescent mothers].
To identify the association between pre-gestational nutritional status, maternal weight gain, and prenatal care with low birth weight (LBW) and prematurity outcomes in infants of adolescent mothers. Cross-sectional study with 542 pairs of adolescent mothers and their children attending a public maternity hospital in Rio de Janeiro. Data were collected from medical records. To determine the association between independent variables and the outcomes studied, odds ratio (OR) and a 95% confidence interval (CI) were estimated With respect to pre-pregnancy nutritional status of adolescents, 87% had normal weight, 1% were underweight, 10% were overweight, and 2% obese. Inadequate total gestational weight gain (72%) exceeded adequacy (28%). Birth weight was favored with greater gestational weight gain, and reduced with late onset of prenatal care. The comparison between the low birth weight and normal birth weight groups revealed significant differences between variable means: interval between the past pregnancy and current pregnancy (p = 0.022), pre-gestational weight (p = 0.018); pre-gestational body mass index (p < 0.001), and total gestational weight gain (p = 0.047). The odds of LBW (OR 2.70, 95% CI 1.45 to 5.06) and prematurity (OR 5.82, 95% CI 3.10 to 10.92) fell when the adolescent received six or more prenatal visits. Birth weight was associated with inter-gestational interval, pre-pregnancy weight and body mass index before pregnancy. The minimum frequency of six prenatal care visits was a protective factor against LBW and prematurity.