Characterization of human uroguanylin: a member of the guanylin peptide family.
Guanylin, a peptide homologue of the bacterial heat-stable enterotoxins (ST), is an endogenous activator of guanylate cyclase C (GC-C). We have initiated a search for other members of the guanylin peptide family and in the current study describe a "guanylin-like peptide" from human urine. Bioactivity was monitored by determining the effect of urine extracts on T84 cell guanosine 3',5'-cyclic monophosphate (cGMP) levels. Purification yielded two bioactive peaks of peptides that, when sequenced by NH2-terminal analysis, possessed 15 and 16 amino acids. The sequence of the smaller peptide represented an NH2-terminal truncation of the larger peptide. We have termed the larger peptide human uroguanylin; it has the following amino acid sequence: NDDCELCVNVACTGCL. Human uroguanylin shares amino acid sequence homology with guanylin and ST. Synthetic uroguanylin increased cGMP levels in T84 cells, competed with 125I-labeled ST for receptors, and stimulated Cl- secretion as reflected by an increased short-circuit current. Thus we report the isolation from human urine of a unique peptide, uroguanylin, that behaves in a manner similar to guanylin and appears to be a new member of this peptide family.


Cardiac angiotensin II receptors are upregulated by long-term inhibition of nitric oxide synthesis in rats.
It has been shown that nitric oxide (NO) may regulate angiotensin II (Ang II) receptors in vitro. To determine whether the chronic inhibition of NO synthesis upregulates cardiac Ang II receptors in a rat model, we evaluated the in vivo effect of Nomega-nitro-L-arginine methyl ester (L-NAME) on several Ang II receptors and on the expression of AT1 receptor mRNA in heart tissue. The chronic administration of L-NAME to normal rats increased the arterial blood pressure. The number of AT1 and AT2 receptors was increased, with no change in affinity, during the first week of L-NAME administration but returned to control levels after 4 weeks of treatment. The AT1 receptor mRNA was changed parallel to AT1 receptor number. Inflammatory changes (monocyte infiltration and myofibroblast formation) in perivascular areas surrounding coronary vessels and myocardial interstitial spaces were observed during the first week. The immunohistochemistry revealed that myofibroblasts expressed AT1 receptor. AT1 receptor blockade or cotreatment with L-arginine, but not cotreatment with hydralazine, prevented the L-NAME-induced increase in Ang II receptors and inflammatory changes. In conclusion, rat cardiac Ang II receptors are upregulated at an early phase of chronic inhibition of NO synthesis. This may contribute to cardiovascular inflammatory changes in an early phase and to remodeling at the later phase, which occurs after inhibition of NO synthesis.


Integrating lay knowledge and practice into snakebite prevention and care in central Africa, a hotspot for envenomation.
The WHO has identified the goal of halving deaths and disability from snakebite envenomation (SBE) by 2030 through a four-pillar program that promotes accessible and affordable treatments, strengthens health systems, promotes community and multi-level engagement, and mobilizes partnerships, coordination and resources to advocate for global action. This initiative could accelerate multi-disciplinary research and action in central Africa, a "hotspot" for SBE, but it offers little specific guidance about anthropological research to be conducted. This commentary develops that research agenda. It surveys anthropological, ethnohistorical investigations in the central African forest to elaborate the socio-cultural and historical significance and practices around snakes and snakebites. It draws from south and southeast Asian and Latin American literatures to illustrate anthropological contributions to SBE research. It then outlines a Central African research agenda employing ethnobiological investigation of snake ecologies, participatory evaluations of humans-snake contacts, and interviews and participant-observation of local prevention and treatment practices and knowledge. This research will co-develop policies and practices with forest communities and leaders and regional and national authorities to reduce the burden of SBE.


Crowdsourcing neuroscience: Inter-brain coupling during face-to-face interactions outside the laboratory.
When we feel connected or engaged during social behavior, are our brains in fact "in sync" in a formal, quantifiable sense? Most studies addressing this question use highly controlled tasks with homogenous subject pools. In an effort to take a more naturalistic approach, we collaborated with art institutions to crowdsource neuroscience data: Over the course of 5 years, we collected electroencephalogram (EEG) data from thousands of museum and festival visitors who volunteered to engage in a 10-min face-to-face interaction. Pairs of participants with various levels of familiarity sat inside the Mutual Wave Machine-an artistic neurofeedback installation that translates real-time correlations of each pair's EEG activity into light patterns. Because such inter-participant EEG correlations are prone to noise contamination, in subsequent offline analyses we computed inter-brain coupling using Imaginary Coherence and Projected Power Correlations, two synchrony metrics that are largely immune to instantaneous, noise-driven correlations. When applying these methods to two subsets of recorded data with the most consistent protocols, we found that pairs' trait empathy, social closeness, engagement, and social behavior (joint action and eye contact) consistently predicted the extent to which their brain activity became synchronized, most prominently in low alpha (~7-10 Hz) and beta (~20-22 Hz) oscillations. These findings support an account where shared engagement and joint action drive coupled neural activity and behavior during dynamic, naturalistic social interactions. To our knowledge, this work constitutes a first demonstration that an interdisciplinary, real-world, crowdsourcing neuroscience approach may provide a promising method to collect large, rich datasets pertaining to real-life face-to-face interactions. Additionally, it is a demonstration of how the general public can participate and engage in the scientific process outside of the laboratory. Institutions such as museums, galleries, or any other organization where the public actively engages out of self-motivation, can help facilitate this type of citizen science research, and support the collection of large datasets under scientifically controlled experimental conditions. To further enhance the public interest for the out-of-the-lab experimental approach, the data and results of this study are disseminated through a website tailored to the general public (wp.nyu.edu/mutualwavemachine).


First Record of Steinernema kraussei (Rhabditida: Steinernematidae) from Turkey and Its Virulence against Agrotis segetum (Lepidoptera: Noctuidae).
During a survey of entomopathogenic nematodes (EPNs) in the eastern Black Sea region of Turkey in 2009-2012, a steinernematid species was recorded and isolated using the Galleria-baiting method. The isolate was identified as Steinernema kraussei based on its morphological and molecular properties. The analysis of the ITS rDNA sequence placed the Turkish population of S. kraussei in the "feltiae-kraussei" group in the clade that contains different isolates of the species. This is the first record of S. kraussei from Turkey. The efficacy of S. kraussei was tested on Agrotis segetum (Lepidoptera: Noctuidea) larvae at different densities (100, 300, and 500 infective juveniles (IJs) g(-1) dry sand ) in laboratory conditions at 25 °C. The highest mortality (98%) was obtained with 500 IJs g(-1) dry sand within 7 d after inoculation. Our results indicate that the new isolate is a highly promising biological control agent against A. segetum, one of the most serious soil pests of agricultural area and fruits worldwide.


Automated J wave detection from digital 12-lead electrocardiogram.
In this report we provide a method for automated detection of J wave, defined as a notch or slur in the descending slope of the terminal positive wave of the QRS complex, using signal processing and functional data analysis techniques. Two different sets of ECG tracings were selected from the EPICARE ECG core laboratory, Wake Forest School of Medicine, Winston Salem, NC. The first set was a training set comprised of 100 ECGs of which 50 ECGs had J-wave and the other 50 did not. The second set was a test set (n=116 ECGs) in which the J-wave status (present/absent) was only known by the ECG Center staff. All ECGs were recorded using GE MAC 1200 (GE Marquette, Milwaukee, Wisconsin) at 10mm/mV calibration, speed of 25mm/s and 500HZ sampling rate. All ECGs were initially inspected visually for technical errors and inadequate quality, and then automatically processed with the GE Marquette 12-SL program 2001 version (GE Marquette, Milwaukee, WI). We excluded ECG tracings with major abnormalities or rhythm disorder. Confirmation of the presence or absence of a J wave was done visually by the ECG Center staff and verified once again by three of the coauthors. There was no disagreement in the identification of the J wave state. The signal processing and functional data analysis techniques applied to the ECGs were conducted at Duke University and the University of Toronto. In the training set, the automated detection had sensitivity of 100% and specificity of 94%. For the test set, sensitivity was 89% and specificity was 86%. In conclusion, test results of the automated method we developed show a good J wave detection accuracy, suggesting possible utility of this approach for defining and detection of other complex ECG waveforms.


Cytochrome P4501A1 expression in blubber biopsies of endangered false killer whales (Pseudorca crassidens) and nine other odontocete species from Hawai'i.
Odontocetes (toothed whales) are considered sentinel species in the marine environment because of their high trophic position, long life spans, and blubber that accumulates lipophilic contaminants. Cytochrome P4501A1 (CYP1A1) is a biomarker of exposure and molecular effects of certain persistent organic pollutants. Immunohistochemistry was used to visualize CYP1A1 expression in blubber biopsies collected by non-lethal sampling methods from 10 species of free-ranging Hawaiian odontocetes: short-finned pilot whale, melon-headed whale, pygmy killer whale, common bottlenose dolphin, rough-toothed dolphin, pantropical spotted dolphin, Blainville's beaked whale, Cuvier's beaked whale, sperm whale, and endangered main Hawaiian Islands insular false killer whale. Significantly higher levels of CYP1A1 were observed in false killer whales and rough-toothed dolphins compared to melon-headed whales, and in general, trophic position appears to influence CYP1A1 expression patterns in particular species groups. No significant differences in CYP1A1 were found based on age class or sex across all samples. However, within male false killer whales, juveniles expressed significantly higher levels of CYP1A1 when compared to adults. Total polychlorinated biphenyl (∑PCBs) concentrations in 84% of false killer whales exceeded proposed threshold levels for health effects, and ∑PCBs correlated with CYP1A1 expression. There was no significant relationship between PCB toxic equivalent quotient and CYP1A1 expression, suggesting that this response may be influenced by agonists other than the dioxin-like PCBs measured in this study. No significant differences were found for CYP1A1 expression among social clusters of false killer whales. This work provides a foundation for future health monitoring of the endangered stock of false killer whales and other Hawaiian odontocetes.


Interpretable multimodal deep learning for real-time pan-tissue pan-disease pathology search on social media.
Pathologists are responsible for rapidly providing a diagnosis on critical health issues. Challenging cases benefit from additional opinions of pathologist colleagues. In addition to on-site colleagues, there is an active worldwide community of pathologists on social media for complementary opinions. Such access to pathologists worldwide has the capacity to improve diagnostic accuracy and generate broader consensus on next steps in patient care. From Twitter we curate 13,626 images from 6,351 tweets from 25 pathologists from 13 countries. We supplement the Twitter data with 113,161 images from 1,074,484 PubMed articles. We develop machine learning and deep learning models to (i) accurately identify histopathology stains, (ii) discriminate between tissues, and (iii) differentiate disease states. Area Under Receiver Operating Characteristic (AUROC) is 0.805-0.996 for these tasks. We repurpose the disease classifier to search for similar disease states given an image and clinical covariates. We report precision@k = 1 = 0.7618 ± 0.0018 (chance 0.397 ± 0.004, mean ±stdev ). The classifiers find that texture and tissue are important clinico-visual features of disease. Deep features trained only on natural images (e.g., cats and dogs) substantially improved search performance, while pathology-specific deep features and cell nuclei features further improved search to a lesser extent. We implement a social media bot (@pathobot on Twitter) to use the trained classifiers to aid pathologists in obtaining real-time feedback on challenging cases. If a social media post containing pathology text and images mentions the bot, the bot generates quantitative predictions of disease state (normal/artifact/infection/injury/nontumor, preneoplastic/benign/low-grade-malignant-potential, or malignant) and lists similar cases across social media and PubMed. Our project has become a globally distributed expert system that facilitates pathological diagnosis and brings expertise to underserved regions or hospitals with less expertise in a particular disease. This is the first pan-tissue pan-disease (i.e., from infection to malignancy) method for prediction and search on social media, and the first pathology study prospectively tested in public on social media. We will share data through http://pathobotology.org . We expect our project to cultivate a more connected world of physicians and improve patient care worldwide.


Exploring Attitudes and Beliefs towards Implementing Cattle Disease Prevention and Control Measures: A Qualitative Study with Dairy Farmers in Great Britain.
Disease prevention and control practices are frequently highlighted as important to ensure the health and welfare of farmed animals, although little is known as to why not many practices are carried out. The aim of this study was to identify the motivators and barriers of dairy cattle farmers towards the use of biosecurity measures on dairy farms using a health psychology approach. Twenty-five farmers on 24 farms in Great Britain (GB) were interviewed using the Theory of Planned Behaviour framework. Results indicated that farmers perceived they had the ability to control what happened on their farms in terms of preventing and controlling disease, and described benefits from being proactive and vigilant. However, barriers were cited in relation to testing inaccuracies, effectiveness and time-efficiency of practices, and disease transmission route (e.g., airborne transmission). Farmers reported they were positively influenced by veterinarians and negatively influenced by the government (Department for Environment Food & Rural Affairs (DEFRA)) and the general public. Decisions to implement practices were influenced by the perceived severity of the disease in question, if disease was diagnosed on the farm already, or was occurring on other farms. Farmers described undertaking a form of personal risk assessment when deciding if practices were worth doing, which did not always involve building in disease specific factors or opinions from veterinarians or other advisors. These results indicate that further guidance about the intricacies of control and prevention principles in relation to specific animal diseases may be required, with an obvious role for veterinarians. There appears to be an opportunity for farm advisors and herd health professionals to further understand farmer beliefs behind certain attitudes and target communication and advice accordingly to further enhance dairy cattle health and welfare.


Evaluating the Training Effects of Two Swallowing Rehabilitation Therapies Using Surface Electromyography--Chin Tuck Against Resistance (CTAR) Exercise and the Shaker Exercise.
In this study, the efficacy of two dysphagia interventions, the Chin Tuck against Resistance (CTAR) and Shaker exercises, were evaluated based on two principles in exercise science-muscle-specificity and training intensity. Both exercises were developed to strengthen the suprahyoid muscles, whose contractions facilitate the opening of the upper esophageal sphincter, thereby improving bolus transfer. Thirty-nine healthy adults performed two trials of both exercises in counter-balanced order. Surface electromyography (sEMG) recordings were simultaneously collected from suprahyoid muscle group and sternocleidomastoid muscle during the exercises. Converging results using sEMG amplitude analyses suggested that the CTAR was more specific in targeting the suprahyoid muscles than the Shaker exercise. Fatigue analyses on sEMG signals further indicated that the suprahyoid muscle group were equally or significantly fatigued (depending on metric), when participants carried out CTAR compared to the Shaker exercise. Importantly, unlike during Shaker exercise, the sternocleidomastoid muscles were significantly less activated and fatigued during CTAR. Lowering the chin against resistance is therefore sufficiently specific and intense to fatigue the suprahyoid muscles.


Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice.
The premature fusion of the paired frontal bones results in metopic craniosynostosis (MC) and gives rise to the clinical phenotype of trigonocephaly. Deletions of chromosome 9p22.3 are well described as a cause of MC with variably penetrant midface hypoplasia. In order to identify the gene responsible for the trigonocephaly component of the 9p22.3 syndrome, a cohort of 109 patients were assessed by high-resolution arrays and MLPA for copy number variations (CNVs) involving 9p22. Five CNVs involving FREM1, all of which were de novo variants, were identified by array-based analyses. The remaining 104 patients with MC were then subjected to targeted FREM1 gene re-sequencing, which identified 3 further mutant alleles, one of which was de novo. Consistent with a pathogenic role, mouse Frem1 mRNA and protein expression was demonstrated in the metopic suture as well as in the pericranium and dura mater. Micro-computed tomography based analyses of the mouse posterior frontal (PF) suture, the human metopic suture equivalent, revealed advanced fusion in all mice homozygous for either of two different Frem1 mutant alleles, while heterozygotes exhibited variably penetrant PF suture anomalies. Gene dosage-related penetrance of midfacial hypoplasia was also evident in the Frem1 mutants. These data suggest that CNVs and mutations involving FREM1 can be identified in a significant percentage of people with MC with or without midface hypoplasia. Furthermore, we present Frem1 mutant mice as the first bona fide mouse model of human metopic craniosynostosis and a new model for midfacial hypoplasia.


The replication, partition and yop regulation of the pYV plasmids are highly conserved in Yersinia enterocolitica and Y. pseudotuberculosis.
The replication genes (rep) of the virulence plasmid pYVe439-80 of Yersinia enterocolitica were localized and characterized by restriction endonuclease analysis. Comparison with pIB1, a virulence plasmid of Y. pseudotuberculosis, indicates that while the plasmids carry homologous rep genes their location with respect to the highly conserved 'calcium region' is different. This replication function is thermosensitive. Mini-derivatives of pYVe439-80 appear to be rather unstable. The region of pYVe439-80 containing homology to the incD determinant of F was shown to contain a plasmid-stabilization system (par). The region encoding par was characterized by restriction endonuclease analysis. pIB1 contained an homologous par region but located differently. The pYV plasmids thus underwent rearrangements during their divergent evolution. While the positions of rep and par in the two plasmids are inverted with respect to the surrounding loci, our determination of the orientation of each locus rules out the hypothesis of a simple inversion of a quadrant of pYV. The gene encoding YOP5, a 26 kDa protein encoded by pIB1, was cloned on a mobilizable vector and introduced in Y. enterocolitica W22708 containing pYVe227 (indistinguishable from pYVe439-80), mutated in the homologous gene. The recombinant Y. enterocolitica secreted YOP5. Hence, the transcriptional activation and secretion systems of pYVe227 act on a yop gene from pIB1 and on its product, indicating that these systems are interchangeable.


Timing of malaria in pregnancy and impact on infant growth and morbidity: a cohort study in Uganda.
Malaria in pregnancy (MiP) is a major cause of fetal growth restriction and low birth weight in endemic areas of sub-Saharan Africa. Understanding of the impact of MiP on infant growth and infant risk of malaria or morbidity is poorly characterized. The objective of this study was to describe the impact of MIP on subsequent infant growth, malaria and morbidity. Between 2006 and 2009, 82 % (832/1018) of pregnant women with live-born singletons and ultrasound determined gestational age were enrolled in a prospective cohort with active weekly screening and treatment for malaria. Infants were followed monthly for growth and morbidity and received active monthly screening and treatment for malaria during their first year of life. Multivariate analyses were performed to analyse the association between malaria exposure during pregnancy and infants' growth, malaria infections, diarrhoea episodes and acute respiratory infections. Median time of infant follow-up was 12 months and infants born to a mother who had MiP were at increased risk of impaired height and weight gain (-2.71 cm, 95 % CI -4.17 to -1.25 and -0.42 kg, 95 % CI -0.76 to -0.08 at 12 months for >1 MiP compared to no MiP) and of malaria infection (relative risk 10.42, 95 % CI 2.64-41.10 for infants born to mothers with placental malaria). The risks of infant growth restriction and infant malaria infection were maximal when maternal malaria occurred in the 12 weeks prior to delivery. Recurrent MiP was also associated with acute respiratory infection (RR 1.96, 95 % CI 1.25-3.06) and diarrhoea during infancy (RR 1.93, 95 % CI 1.02-3.66). This study shows that despite frequent active screening and prompt treatment of MiP, impaired growth and an increased risk of malaria and non-malaria infections can be observed in the infants. Effective preventive measures in pregnancy remain a research priority. This study was registered with ClinicalTrials.gov, number NCT00495508.


Genomic analysis of immunity in a Urochordate and the emergence of the vertebrate immune system: "waiting for Godot".
Genome-wide sequence analysis in the invertebrate chordate, Ciona intestinalis, has provided a comprehensive picture of immune-related genes in an organism that occupies a key phylogenetic position in vertebrate evolution. The pivotal genes for adaptive immunity, such as the major histocompatibility complex (MHC) class I and II genes, T-cell receptors, or dimeric immunoglobulin molecules, have not been identified in the Ciona genome. Many genes involved in innate immunity have been identified, including complement components, Toll-like receptors, and the genes involved in intracellular signal transduction of immune responses, and show both expansion and unexpected diversity in comparison with the vertebrates. In addition, a number of genes were identified which predicted integral membrane proteins with extracellular C-type lectin or immunoglobulin domains and intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based activation motifs (ITAMs) (plus their associated signal transduction molecules), suggesting that activating and inhibitory receptors have an MHC-independent function and an early evolutionary origin. A crucial component of vertebrate adaptive immunity is somatic diversification, and the recombination activating genes (RAG) and activation-induced cytidine deaminase (AID) genes responsible for the Generation of diversity are not present in Ciona. However, there are key V regions, the essential feature of an immunoglobulin superfamily VC1-like core, and possible proto-MHC regions scattered throughout the genome waiting for Godot.


Hologram formation in hardened dichromated gelatin films.
Hardened gelatin films sensitized with ammonium dichromate can be utilized to record high quality holograms. The maximum diffraction efficiency of the hologram approaches 90%. The light scattering from the hologram is so low that under ordinary light the hologram plate appears almost indistinguishable from a clear glass plate. Either a transmission or a reflection hologram can be recorded. Linear recording range of light amplitude is large. A practical method of preparing and processing the film is described, and the exposure characteristics are presented.


The electroretinogram components in Abyssinian cats with hereditary retinal degeneration.
To examine phototransduction using the a-wave and other aspects of retinal function with the intraretinal b- and c-waves at different stages of an inherited photoreceptor degeneration in Abyssinian cats. Vitreal and intraretinal ERGs were recorded from eight dark-adapted, anesthetized Abyssinian cats. Brief bright flashes were used to elicit vitreal a- and b-waves. Longer, weaker flashes were used to elicit intraretinal b- and c-waves. Stages 1 through 4 of the disease were characterized ophthalmoscopically. Parameters of the Lamb and Pugh a-wave model (a(max), A, and t(eff)) for the Abyssinian cats were compared with those for normal cats. Light microscopy was used to count photoreceptor nuclei. The maximum a-wave amplitude, a(max), was significantly smaller in stage 1, and continued to decrease (stage 1: 50% of normal, stage 2: 28%, stage 3: 27%; and stage 4: unrecordable). There was a small, but not significant, decrease in the amplification constant A from 0.24 +/- 0.11 s(-2) in normal cats to 0.16 +/- 0.08 s(-2) in Abyssinian cats. The intraretinal b- and c-wave amplitudes decreased most dramatically during the early stage of the disease. Affected animals had fewer photoreceptors than unaffected Abyssinians or control animals. The number of photoreceptors declined most rapidly in the inferior periphery. The amplitudes of all ERG components were already reduced significantly by stage 1 and progressively declined. The lack of major changes in a-wave model parameters indicates that the degeneration is probably not due to a mutation in transduction proteins. Losses of photoreceptor function were larger than losses of photoreceptor nuclei.


Population Knowledge, Attitude, and Practice Regarding Helicobacter pylori Transmission and Outcomes: A Literature Review.
Helicobacter pylori infection is associated with the development of chronic gastritis, peptic ulcer disease, and gastric cancer. Current clinical recommendations are that H. pylori test-and-treat should be individualized based on comorbidities and patient preferences among populations at increased risk for certain morbidities. However, knowledge, attitudes and practices regarding H. pylori among potential patient populations are largely unknown. We conducted a literature review to assess knowledge, attitudes, and practices of patients or community populations around H. pylori transmission, prevention, and associated morbidity. Nine studies met the inclusion criteria, all published between 1997 and 2014. Eight studies evaluated perception of H. pylori among at-risk populations, while one study evaluated perception among a general population. The studies suggest inconsistencies between the perceptions of these populations and the established understanding of knowledge, attitude, and preventive practices for H. pylori among even at-risk populations. To adequately respond to current test-and-treat recommendations for treatment of H. pylori, general population education must be implemented, especially among at-risk populations. Further work is needed within at-risk populations in the United States to determine prevalence of H. pylori and their current knowledge if adequate prevention strategies are to be designed.


Progression of familial and non-familial dilated cardiomyopathy: long term follow up.
It is unknown whether progression of familial idiopathic dilated cardiomyopathy differs from progression in the non-familial form. It has been suggested that familial disease indicates a worse prognosis, and that this should be considered when planning the timing of heart transplantation. To compare five year survival or time to heart transplantation in an unselected series of patients with dilated cardiomyopathy who had been evaluated for familial v non-familial disease through the echocardiographic investigation of first degree relatives. Medical records were reviewed and questionnaires were mailed to all patients who had previously participated in a family based study of dilated cardiomyopathy. Information was gathered about survival, heart transplantation, and left ventricular ejection fraction (LVEF) measurements. Survival data were censored at the time of cardiac transplantation. Follow up data were obtained for 99 of 101 patients (69 with non-familial and 30 with familial disease). Five year survival was 55% for non-familial and 51% for familial patients (NS). The main predictor of mortality was an LVEF of < 30%. Familial status did not predict mortality. There was no significant difference in follow up LVEF values between the groups. Five year survival is not significantly different in the familial and non-familial forms of dilated cardiomyopathy.


Auditing concept categorizations in the UMLS.
The Unified Medical Language System (UMLS) integrates about 880,000 concepts from 100 biomedical terminologies. Each concept is categorized to at least one semantic type of the Semantic Network. During the integration, it is unavoidable that some categorization errors and inconsistencies will be introduced. In this paper, we present an auditing technique to find such errors and inconsistencies. Our technique is based on an expert reviewing the pure intersections of meta-semantic types of a metaschema, a compact abstract view of the UMLS Semantic Network. We use a divide and conquer approach, handling differently small pure intersections and medium to large pure intersections. By using this approach, we limit the number of concepts reviewed, for which we expect a high percentage of errors. We reviewed all concepts in 657 pure intersections containing one to 10 concepts. Various kinds of errors are identified and the analysis of the results are presented in the paper. Also, we checked the pure intersections containing more than 10 concepts for their semantic soundness, where the semantically suspicious pure intersections are presented in the paper and their concepts are reviewed.


Novel insights into P450 BM3 interactions with FDA-approved antifungal azole drugs.
Flavocytochrome P450 BM3 is a natural fusion protein constructed of cytochrome P450 and NADPH-cytochrome P450 reductase domains. P450 BM3 binds and oxidizes several mid- to long-chain fatty acids, typically hydroxylating these lipids at the ω-1, ω-2 and ω-3 positions. However, protein engineering has led to variants of this enzyme that are able to bind and oxidize diverse compounds, including steroids, terpenes and various human drugs. The wild-type P450 BM3 enzyme binds inefficiently to many azole antifungal drugs. However, we show that the BM3 A82F/F87V double mutant (DM) variant binds substantially tighter to numerous azole drugs than does the wild-type BM3, and that their binding occurs with more extensive heme spectral shifts indicative of complete binding of several azoles to the BM3 DM heme iron. We report here the first crystal structures of P450 BM3 bound to azole antifungal drugs - with the BM3 DM heme domain bound to the imidazole drugs clotrimazole and tioconazole, and to the triazole drugs fluconazole and voriconazole. This is the first report of any protein structure bound to the azole drug tioconazole, as well as the first example of voriconazole heme iron ligation through a pyrimidine nitrogen from its 5-fluoropyrimidine ring.


Breakdown of the Stokes-Einstein water transport through narrow hydrophobic nanotubes.
In this paper the transport properties of water confined inside hydrophobic and hydrophilic nanotubes are compared for different nanotube radii and densities. While for wider nanotubes the nature of the wall plays no relevant role in the water mobility, for small nanotubes the hydrophobic confinement presents a peculiar behavior. As the density is increased the viscosity shows a huge increase associated with a small increase in the diffusion coefficient. This breakdown in the Stokes-Einstein relation for diffusion and viscosity was observed in the hydrophobic, but not in the hydrophilic nanotubes. The mechanism underlying this behavior is explained in terms of the structure of water under confinement. This result indicates that some of the features observed for water inside hydrophobic carbon nanotubes cannot be observed in other nanopores.


Melatonin for non-respiratory sleep disorders in visually impaired children.
Exogenous melatonin helps in regulating the circadian rhythm and is widely used for the management of sleep disorders in visually impaired children. The aim of the review was to assess melatonin therapy for treatment of non-respiratory sleep disorders in visually impaired children, with regard to improvement in sleep habit, sleep scheduling and sleep maintenance, when compared with placebo or no treatment. We searched the following databases between February 2011 and July 2011: the Cochrane Central Register of Controlled Trials (CENTRAL) 2011(1) searched on 4th February 2011; MEDLINE (1950 to June Week 3, 2011) searched on 20th June 2011; EMBASE (1980 to June Week 4, 2011) searched on 7th July 2011; CINAHL (1937 to 21 September 2011); the metaRegister of Controlled Trials (this includes ClinicalTrial.gov) searched 20 July 2011, and reference lists of papers identified after initial screening. We planned to include randomized controlled trials (RCTs) and quasi-RCTs, including cross-over studies. Treatment would be exogenous melatonin. Control groups could be placebo, other medication for sleep disorders or no treatment. Outcomes sought were improved sleep with regard to timing and duration, quality of life and adverse events. Three review authors independently assessed trials for inclusion in the review. We did not find any studies fulfilling the inclusion criteria, therefore no outcome data are reported.We identified nine studies after initial screening and, after further evaluation, we excluded these. The excluded studies involved a total of 163 individuals aged two years to 18 years. We excluded studies for three main reasons: they were non-randomized or case series studies, they were studies of people over 18 years of age or even where the study was randomised, the study population was mixed and results pertaining to the visually impaired cohort could not be independently evaluated. No significant adverse effects of melatonin were reported in these excluded studies. There is currently no high quality data to support or refute the use of melatonin for sleep disorders in visually impaired children. Placebo-controlled trials examining important clinical outcomes such as sleep quality, sleep latency, duration of sleep and night-time awakenings are needed. As the numbers of children meeting study inclusion criteria are likely to be low at individual sites, multicentre collaboration between developmental paediatricians, sleep physicians and other health care professionals is essential to achieve sufficient sample size for controlled studies. Such collaboration would help facilitate local recruitment at multiple sites, with study oversight being provided by paediatricians with expertise in sleep disorders. Participation of collaborators with experience in evidence-based practice research is also desirable due to the lack of protocols on melatonin therapy in the target population.


Periconceptional intake of vitamins and fetal death: a cohort study on multivitamins and folate.
Women planning to conceive are often advised to take multivitamins. Whether this affects the survival of the fetus is not known. We used data from 35 914 women in the Danish National Birth Cohort who at recruitment had reported the number of weeks of supplement use during a 12-week periconceptional period. A telephone interview provided information about maternal characteristics and data on fetal death came from registers. The associations between periconceptional multivitamin or folate-only use and early (<20 weeks) and late (≥20 weeks) fetal death were estimated by hazard ratios (HR) with 95% confidence intervals (CI). Follow-up started at 8 completed weeks of gestation, and comparisons were made with no supplement use at any time during the periconceptional period. Any multivitamin use was associated with a small increased crude risk of fetal death [HR 1.12 (1.01-1.25)], which was restricted to early losses [HR 1.18 (1.05-1.33)] compared with late losses [HR 0.82 (0.62-1.10)]. Adjustment for maternal factors increased this excess risk further. Whereas regular users of multivitamins (4-6 weeks of 6) before conception had more early losses [HR 1.29 (1.12-1.48)], a decreased risk of late losses was indicated when use started after conception [HR 0.65 (0.39-1.09)]. Folate-only use was not associated with fetal death. Multivitamin use was associated with a modest increased risk of early fetal death. For late fetal death, regular supplement use after conception may decrease risk, but numbers were small. Further studies on preconceptional multivitamin use are needed to guide public health recommendations.


Effectiveness of a long-term use of a minimalist footwear versus habitual shoe on pain, function and mechanical loads in knee osteoarthritis: a randomized controlled trial.
Recent studies have shown an important reduction of joint overload during locomotion in elderly women with knee osteoarthritis (OA) after short-term use of minimalist shoes. Our aim is to investigate the chronic effect of inexpensive and minimalist footwear on the clinical and functional aspects of OA and gait biomechanics of elderly women with knee OA. Fifty-six elderly women with knee OA grade 2 or 3 (Kellgren and Lawrence) are randomized into blocks and allocated to either the intervention group, which will use flexible, non-heeled shoes- Moleca®-for six months for at least six hours daily, or the control group, which could not use these shoes. Neither group is undergoing physical therapy treatment throughout the intervention period. Moleca® is a women's double canvas, flexible, flat walking shoe without heels, with a 5-mm anti-slip rubber sole and a 3-mm internal wedge of ethylene vinyl acetate. Both groups will be followed for six months and will be assessed at baseline condition, after three months, and after six months (end of intervention). All the assessments will be performed by a physiotherapist that is blind to the group allocation. The primary outcome is the pain Western Ontario and McMaster Universities Osteoarthritis (WOMAC) score. The secondary outcomes are global WOMAC score; joint stiffness and disability WOMAC scores; knee pain with a visual analogue scale; walking distance in the six-minute walk test; Lequesne score; amount and frequency (number of days) of paracetamol (500 mg) intake over six months; knee adduction moment during gait; global medical assessment score; and global patient auto-assessment score. At baseline, all patients receive a diary to record the hours of daily use of the footwear intervention; every two weeks, the same physiotherapist makes phone calls to all patients in order to verify adherence to treatment. The statistical analysis will be based on intention-to-treat analysis, as well as general linear models of analysis of variance for repeated measure to detect treatment-time interactions (α = 5%). This is the first randomized, clinical trial protocol to assess the chronic effect of minimalist footwear on the clinical and functional aspects and gait biomechanics of elderly women with knee osteoarthritis. We expect that the use of Moleca® shoes for six months will provide pain relief, reduction of the knee adduction moment when walking, and improve joint function in elderly women with knee OA, and that the treatment, thus, can be considered another inexpensive and easy-to-use option for conservative OA treatment. NCT01342458.


A framework for computational fluid dynamic analyses of patient-specific stented coronary arteries from optical coherence tomography images.
The clinical challenge of percutaneous coronary interventions (PCI) is highly dependent on the recognition of the coronary anatomy of each individual. The classic imaging modality used for PCI is angiography, but advanced imaging techniques that are routinely performed during PCI, like optical coherence tomography (OCT), may provide detailed knowledge of the pre-intervention vessel anatomy as well as the post-procedural assessment of the specific stent-to-vessel interactions. Computational fluid dynamics (CFD) is an emerging investigational tool in the setting of optimization of PCI results. In this study, an OCT-based reconstruction method was developed for the execution of CFD simulations of patient-specific coronary artery models which include the actual geometry of the implanted stent. The method was applied to a rigid phantom resembling a stented segment of the left anterior descending coronary artery. The segmentation algorithm was validated against manual segmentation. A strong correlation was found between automatic and manual segmentation of lumen in terms of area values. Similarity indices resulted >96% for the lumen segmentation and >77% for the stent strut segmentation. The 3D reconstruction achieved for the stented phantom was also assessed with the geometry provided by X-ray computed micro tomography scan, used as ground truth, and showed the incidence of distortion from catheter-based imaging techniques. The 3D reconstruction was successfully used to perform CFD analyses, demonstrating a great potential for patient-specific investigations. In conclusion, OCT may represent a reliable source for patient-specific CFD analyses which may be optimized using dedicated automatic segmentation algorithms.


Objective Assessment of the Quality and Accuracy of Deformable Image Registration.
The increased use of deformable registration algorithms in clinical practice has also increased the need for their validation. The purpose of the study was to investigate the quality, accuracy, and plausibility of three commercial image registration algorithms for 4-dimensional computed tomography (4DCT) datasets using various similarity measures. 4DCT datasets were acquired for 10 lung cancer patients. 23 similarity measures were used to evaluate image registration quality. To ensure selected method's invertibility and assess resultant mechanical stress, the determinant of the Jacobian for the displacement field and 3-D Eulerian strain tensor were calculated. All the measures and calculations were applied on to extended deformable multi pass (EXDMP) and deformable multi pass (DMP) methods. The results indicate the same trend for several of the studied measures. The Jacobian determinant values were always positive for the DMP method. The Eulerian strain tensor had smaller values for the DMP method than EXDMP in all of the studied cases. The negative values of the Jacobian determinant point to non-physical behavior of the EXDMP method. The Eulerian strain tensor values indicate less tissue strain for the DMP method. Large differences were also observed in the results between complete and cropped datasets (coefficient of determination: 0.55 vs. 0.93). A number of error and distance measures showed the best performance among the tested measures. The evaluated measures might detect CT dataset differences with higher precision if the analysis is restricted to a smaller volume.


The validity of the Menopause-specific Quality of Life questionnaire in women with type 2 diabetes.
To examine the validity and reliability of the Menopause-specific Quality of Life (MENQOL) questionnaire in a sample of women with diabetes in Malaysia, with the secondary aim of determining whether MENQOL domain scores were associated with depression and diabetes. A total of 337 postmenopausal women (241 with diabetes, 96 controls) were evaluated. Construct validity was evaluated using principal components analysis (PCA) and comparing scale items against the mental component score of the Short Form-12 (SF-12 MCS), and against the Center for Epidemiologic Studies Depression Scale 10 (CES-D 10). Consistency assessment was conducted using Cronbach's α. The internal consistencies for the physical (PHS), psychosocial (PS), sexual (VSS) and vasomotor domains were 0.86, 0.79, 0.79 and 0.70, and 0.90 for the full scale of MENQOL. PCA revealed a four-factorial model. Diabetes and non-diabetes subjects experienced their first period (13.25 vs. 13.10 years, p = 0.680) and achieved menopause around the same age (49.35 vs. 48.87 years, p = 0.426). We found significant variations in the MENQOL's PHS and PS domain scores that could be explained by SF-12 PCS (25%) and SF-12 MCS (20%) sub-scales. The validity of the MENQOL domains was demonstrated through significant associations with the equivalent SF-12 MCS and PCS subscales. The PS domain of the MENQOL also predicted the likelihood of symptoms of depression (1.42, 95% confidence interval 1.01-2.02). This study confirms the validity and internal consistency of the MENQOL questionnaire for measuring quality of life in postmenopausal women with diabetes, suggesting that the instrument can be used to screen people for menopausal symptoms.


Protein kinase C and an endogenous substrate associated with adenohypophyseal secretory granules.
Secretory granules isolated from anterior pituitary glands were examined for Ca2+/phospholipid-dependent protein kinase (protein kinase C) activity as well as the occurrence of granule-associated substrate proteins. Sheep adenohypophyses were fractionated by differential and sucrose-density-gradient centrifugation to yield a granule fraction enriched for luteinizing-hormone (lutropin)-containing secretory granules. Marker-enzyme analysis showed no detectable cytosolic contamination, although there were small amounts of plasma membranes (2-4%) and lysosomes (4-6%) associated with the preparation. As determined by histone-H1 phosphorylation after DEAE-cellulose DE-52 chromatography, protein kinase C activity with a marked dependence on Ca2+ and lipid (4-fold increase in their presence) was evident in the secretory-granule fraction. Phosphorylation in vitro of the secretory-granule fraction by endogenous and exogenous protein kinase C revealed a protein of Mr 36,000, which by two-dimensional SDS/polyacrylamide-gel electrophoresis showed multiple sites of phosphorylation. The Mr-36,000 protein was not found in cytosolic or plasma-membrane fractions and was not phosphorylated by the catalytic subunit of cyclic AMP-dependent protein kinase. Several secretory-granule proteins served as substrates for the catalytic subunit, the most prominent of which were of Mr 63,000, 23,000 and 21,000. From these data, we suggest that phosphorylation of secretory-granule-associated proteins by protein kinase C and by cyclic AMP-dependent protein kinase may be important in secretion regulation in the anterior pituitary gland.


Epidemiology and possible causes of autism.
To review the recent literature on possible causes of the increase in frequency of diagnosed autism reported from three countries, and to compare the medical diagnoses and drug therapy from a new series of autistic boys and their mothers with that of comparable nonautistic boys and their mothers. Case-control evaluation. Members of over 250 general practices in the United Kingdom. Frequency of exposure to drugs and presence of preexisting clinical illnesses in autistic children and their mothers were compared with nonautistic children and their mothers over time. According to published studies, the incidence of boys diagnosed with autism rose dramatically in the 1990s. Numerous published studies have concluded that the measles-mumps-rubella vaccine is not responsible for the large rise in diagnosed autism. In our study, boys diagnosed with autism had medical and drug histories, such as vaccines, before diagnosis, that were closely similar to those of nonautistic boys, except that developmental and sensory disorders were far more common in autistic boys. No material differences during pregnancy were found between the mothers of autistic boys and those of nonautistic boys in relation to illness or drug therapy. In the early 1990s, boys with diagnosed developmental disorders were infrequently diagnosed with autism. In the later 1990s, such boys more often were diagnosed with autism. A major cause of the recent large increase in the number of boys diagnosed with autism probably is due to changing diagnostic practices.


Fugu (Takifugu rubripes) sexual differentiation: CYP19 regulation and aromatase inhibitor induced testicular development.
In order to assess the involvement of aromatase CYP19 isoforms and endogenous sex steroids in gonadal sex differentiation and development of the Japanese fugu (Takifugu rubripes), an aromatase inhibitor (AI, fadrozole) was administered to developing fishes from the 'first feeding' till the 100th day after hatching. It was observed that ovarian cavity formation was inhibited by fadrozole at doses of 500 and 1000 microg/g diet, which was followed by testicular differentiation in all treated fugu. In the non-treated fugu, CYP19A was predominantly expressed in the ovary and CYP19B in the brain (in both sexes), although both were expressed interchangeably at low levels. An exceptionally high expression of CYP19B was also evident in testis throughout the study period. Both forms of CYP19 mRNA showed low levels of expression in brain and gonad with no significant differences between the two AI treatments. AI treatment inhibited CYP19A mRNA in trunk during the crucial period of ovarian cavity formation and CYP19B in gonad and brain by the end of gonadal sex differentiation. An elevation of testosterone and 11-ketotestosterone was observed which can be associated with the down-regulation of the circulating 17beta-estradiol production during the AI treatment period. After stopping AI treatment, both circulating estrogen and androgen were normalized. The current results suggest that suppression of CYP19A before and during morphological sex differentiation inhibits ovarian cavity formation in fugu. Furthermore, non-detectable limits of 17beta-estradiol and high testosterone levels by the end of the gonadal differentiation period can be ascribed to inhibition of CYP19B, suggesting that conversion of 17beta-estradiol from testosterone is plausibly regulated by CYP19B, and that this factor (CYP19B) may play an important role in AI-induced testicular development after gonadal sex differentiation through regulation of the testosterone-17beta-estradiol balance in fugu.


Family medicine residents' practice intentions: Theory of planned behaviour evaluation.
To assess residents' practice intentions since the introduction of the College of Family Physicians of Canada's Triple C curriculum, which focuses on graduating family physicians who will provide comprehensive care within traditional and newer models of family practice. A survey based on Ajzen's theory of planned behaviour was administered on 2 occasions. McMaster University in Hamilton, Ont. Residents (n = 135) who were enrolled in the Department of Family Medicine Postgraduate Residency Program at McMaster University in July 2012 and July 2013; 54 of the 60 first-year residents who completed the survey in 2012 completed it again in 2013. The survey was modeled so as to measure the respondents' intentions to practise with a comprehensive scope; determine the degree to which their attitudes, subjective norms, and perceptions of control about comprehensive practice influence those intentions; and investigate how these relationships change as residents progress through the curriculum. The survey also queried the respondents about their intentions with respect to particular medical services that underpin comprehensive practice. The responses indicate that the factors modeled by the theory of planned behaviour survey account for 60% of the variance in the residents' intentions to adopt a comprehensive scope of practice upon graduation, that there is room for curricular improvement with respect to encouraging residents to practise comprehensive care, and that targeting subjective norms about comprehensive practice might have the greatest influence on improving resident intentions. The theory of planned behaviour presents an effective approach to assessing curricular effects on resident practice intentions while also providing meaningful information for guiding further program evaluation efforts in the Department of Family Medicine at McMaster University.


Machine learning to predict early recurrence after oesophageal cancer surgery.
Early cancer recurrence after oesophagectomy is a common problem, with an incidence of 20-30 per cent despite the widespread use of neoadjuvant treatment. Quantification of this risk is difficult and existing models perform poorly. This study aimed to develop a predictive model for early recurrence after surgery for oesophageal adenocarcinoma using a large multinational cohort and machine learning approaches. Consecutive patients who underwent oesophagectomy for adenocarcinoma and had neoadjuvant treatment in one Dutch and six UK oesophagogastric units were analysed. Using clinical characteristics and postoperative histopathology, models were generated using elastic net regression (ELR) and the machine learning methods random forest (RF) and extreme gradient boosting (XGB). Finally, a combined (ensemble) model of these was generated. The relative importance of factors to outcome was calculated as a percentage contribution to the model. A total of 812 patients were included. The recurrence rate at less than 1 year was 29·1 per cent. All of the models demonstrated good discrimination. Internally validated areas under the receiver operating characteristic (ROC) curve (AUCs) were similar, with the ensemble model performing best (AUC 0·791 for ELR, 0·801 for RF, 0·804 for XGB, 0·805 for ensemble). Performance was similar when internal-external validation was used (validation across sites, AUC 0·804 for ensemble). In the final model, the most important variables were number of positive lymph nodes (25·7 per cent) and lymphovascular invasion (16·9 per cent). The model derived using machine learning approaches and an international data set provided excellent performance in quantifying the risk of early recurrence after surgery, and will be useful in prognostication for clinicians and patients.


Management Practices Promoting Sustained Implementation of the Quality Register Senior Alert for Older Adults in Municipal Care in Sweden.
Senior Alert is a national quality register aimed at supporting a standardized, structured, and systematic preventive care process for adults aged 65 and over in the areas malnutrition, pressure ulcers, falls, problems with oral health and bladder dysfunction. Therefore, the quality register is particularly suitable for older adults with multimorbidity. The aim was to describe management practices that contributed to the sustained implementation of the quality register Senior Alert in municipal elderly care in Sweden. The design of this pilot study was descriptive and inductive. The sample of n = 12 included managers (n = 7) and care staff (n = 5) at seven municipal care homes for older adults in Sweden. The study was performed between April 2014 and June 2014 using two methods: Individual interviews and nonparticipant unstructured observations. Data were analyzed using qualitative content analysis. The analysis led to the following generic categories: leading teamwork, leading a preventive care process and leading a supportive organizational structure, and to one main category: management promoting learning and quality improvement. To be sustainable, Senior Alert implementations in municipal elderly care need management. Management, by leading teamwork, a preventive care process and a supportive organizational structure, is essential for achieving learning and quality improvement.


Genetic Affinities among Southern Africa Hunter-Gatherers and the Impact of Admixing Farmer and Herder Populations.
Southern African indigenous groups, traditionally hunter-gatherers (San) and herders (Khoekhoe), are commonly referred to as "Khoe-San" populations and have a long history in southern Africa. Their ancestors were largely isolated up until ∼2,000 years ago before the arrival of pastoralists and farmers in southern Africa. Assessing relationships among regional Khoe-San groups has been challenging due to admixture with immigrant populations that obscure past population affinities and gene flow among these autochthonous communities. We re-evaluate a combined genome-wide data set of previously published southern Africa Khoe-San populations in conjunction with novel data from Khoe-San individuals collected in Xade (Central Kalahari Game Reserve, Botswana) prior to their resettlement outside the reserve. After excluding regions in the genome that trace their ancestry to recent migrant groups, the genetic diversity of 20 Khoe-San groups fitted an isolation-by-distance model. Even though isolation-by-distance explained most genetic affinities between the different autochthonous groups, additional signals of contact between Khoe-San groups could be detected. For instance, we found stronger genetic affinities, than what would be explained by isolation-by-distance gene flow, between the two geographically separated Khoe-San groups, who speak branches of the Kx'a-language family (ǂHoan and Ju). We also scanned the genome-wide data for signals of adaptive gene flow from farmers/herders into Khoe-San groups and identified a number of genomic regions potentially introduced by the arrival of the new groups. This study provides a comprehensive picture of affinities among Khoe-San groups, prior to the arrival of recent migrants, and found that these affinities are primarily determined by the geographic landscape.


Microarray analysis of juvenile hormone response in Drosophila melanogaster S2 cells.
A microchip array encompassing probes for 14,010 genes of Drosophila melanogaster was used to analyze the effect of juvenile hormone (JH) on genome-wide gene expression. JH is a member of a group of insect hormones involved in regulating larval development and adult reproductive processes. Total RNA was isolated from Drosophila S2 cells after 4 hours treatment with 250 ng/ml (10R) JH III or 250 ng/ml methyl linoleate. A collection of 32 known or putative genes demonstrated a significant change with JH III treatment (r > 2.0, P <or= 0.005). Of these, the abundance of 13 transcripts was significantly increased and 19 decreased. The expression of a subset of these loci was analyzed by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Three loci that exhibited constant expression in the presence and absence of JH III (RP49 [FBgn0002626], FBgn0023529, and FBgn0034354) were evaluated and found to be reliable invariant reference transcripts for real-time RT-qPCR analysis using BestKeeper and geNorm software. Increased expression in presence of JH III was confirmed by real-time RTqPCR analysis. However, only one of five loci that exhibited reduced expression on microarrays could be confirmed as significantly reduced (P <or= 0.05). Among the confirmed JH III up-regulated genes were two loci of unknown function (FBgn0040887 and FBgn0037057) and Epac, an exchange protein directly activated by cyclic AMP, a guanine nucleotide exchange factor for Rap1 small GTPase.


Caregiver behavior change for child survival and development in low- and middle-income countries: an examination of the evidence.
In June of 2012, representatives from more than 80 countries promulgated a Child Survival Call to Action, which called for reducing child mortality to 20 or fewer child deaths per 1,000 live births in every country by 2035. To address the problem of ending preventable child deaths, the U.S. Agency for International Development and the United Nations Children's Fund convened, on June 3-4, 2013, an Evidence Summit on Enhancing Child Survival and Development in Lower- and Middle-Income Countries by Achieving Population-Level Behavior Change. Six evidence review teams were established on different topics related to child survival and healthy development to identify the relevant evidence-based interventions and to prepare reports. This article was developed by the evidence review team responsible for identifying the research literature on caregiver change for child survival and development. This article is organized into childhood developmental periods and cross-cutting issues that affect child survival and healthy early development across all these periods. On the basis of this review, the authors present evidence-based recommendations for programs focused on caregivers to increase child survival and promote healthy development. Last, promising directions for future research to change caregivers' behaviors are given.


Development of a virtual classroom for pre-analytical phase of laboratory medicine for undergraduate medical students using the Delphi technique.
Amongst the pre-analytical, analytical, and post-analytical phase of laboratory testing, pre-analytical phase is the most error-prone. Knowledge gaps in understanding of pre-analytical factors are identified in the clinical years amongst undergraduate students due to lack of formal teaching modules on the pre-analytical phase. This study was conducted to seek experts' consensus in Clinical Chemistry on learning objectives and contents using the Delphi technique with an aim to develop an asynchronous virtual classroom for teaching pre-analytical factors of laboratory testing. A mixed method study was conducted at the Aga Khan University. A questionnaire comprising of 16 learning objectives and their associated triggers was developed on Google Docs for developing the case vignettes. A four-point Likert Scale, which included strongly agree, agree, disagree and strongly disagree, was utilized for the learning objectives. An open-ended question was included for experts to suggest new items for inclusion. A cut off of at least 75% agreement was set to establish consensus on each item. A total of 17 Chemical Pathology faculty from 13 institutions across Pakistan were invited to participate in the first round of Delphi. Similar method of response was used in round two to establish consensus on the newly identified items suggested by the faculty in round 1. Later, the agreed-upon objectives and triggers were used to develop interactive scenarios over Moodle to concurrently test and teach medical students in a nonchalant manner. A total of 17 responses were received in Round 1 of the Delphi process (response rate = 100%), while 12 responses were received in Round 2 (response rate = 71%). In round 1, all 16 learning objectives reached the required consensus (≥ 75%) with no additional learning objectives suggested by the experts. Out of 75 triggers in round 1, 61 (81.3%) reached the consensus to be included while 39 were additionally suggested. In 2nd round, 17 out of 39 newly suggested triggers met the desired consensus. 14 triggers did not reach the consensus after two rounds, and were therefore eliminated. The virtual classroom developed using the agreed-upon learning objectives and triggers consisted of 20 items with a total score of 31 marks. The questions included multiple choice questions, fill in the blanks, drag and drop sequences and read-and-answer comprehensions. Specific learning points were included after each item and graphs and pictures were included for a vibrant experience. We developed an effective and interactive virtual session with expert consensus on the pre-analytical phase of laboratory testing for undergraduate medical students which can be used for medical technologist, graduate students and fellows in Chemical Pathology.


Effects of bilateral salpingo-oophorectomy at the time of hysterectomy on pelvic organ prolapse: results from the Women's Health Initiative trial.
This study aims to estimate the effects of bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy and estrogen therapy on vaginal prolapse. A retrospective analysis of the Women's Health Initiative estrogen-alone trial was performed. Women who retained their ovaries were compared with women who had BSO at the time of hysterectomy for the presence of cystocele or rectocele at entry into the study. Based on BSO and hormone therapy (HT) status, participants were categorized into groups. We hypothesized that BSO and prolonged hypoestrogenemia may be associated with an increased risk of prolapse. Univariate and multivariate analyses were used to determine the effects of BSO and HT status on cystocele and rectocele. Of 10,739 participants in the estrogen-alone trial, 8,879 women were included in the analysis. Older age, higher parity, higher body mass index, higher waist-to-hip ratio, and non-African-American race/ethnicity were associated with increased odds of developing cystocele or rectocele. Women who retained their ovaries had higher rates of cystocele or rectocele at screening (39%) compared with all women who had BSO (31-36%; odds ratio, 1.18; 95% CI, 1.04-1.33). After controlling for multiple variables, our analysis showed that women who retained their ovaries had higher odds of developing cystocele or rectocele compared with women who had BSO and no subsequent HT (odds ratio, 1.23; 95% CI, 1.07-1.41). All other comparisons were nonsignificant. BSO at the time of hysterectomy is not associated with increased risk of cystocele or rectocele. BSO and no subsequent HT may even have a protective effect against cystocele or rectocele.


Comparing zonal and CFD model predictions of isothermal indoor airflows to experimental data.
It is inappropriate to use the assumption of instantaneously well-mixed zones to model airflows and pollutant transport in large indoor spaces. We investigate two approaches for describing the details of airflows in large indoor spaces, for accuracy and suitability for integration with multi-zone infiltration models. One approach, called the zonal method, was developed over the last 15 years to provide an improvement over the well-mixed assumption. The second approach is the use of a computational fluid dynamics simulation using a coarse grid model of the large indoor space. We compare velocity predictions from different formulations of zonal methods and coarse-grid k-epsilon computational fluid dynamics (CFD) models, to measurements, in a 2D mechanically ventilated isothermal room. Our results suggest that, when airflow details are required, coarse-grid CFD is a better-suited method to predict airflows in large indoor spaces coupled with complex multi-zone buildings, than are the zonal methods. Based on the comparison of pressure predictions from different models, we offer guidance regarding the coupling of a model of detailed airflow in large spaces to algebraic multi-zone infiltration models.


Ligand-dependent ubiquitination of Smad3 is regulated by casein kinase 1 gamma 2, an inhibitor of TGF-beta signaling.
Transforming growth factor-beta (TGF-beta) elicits a variety of cellular activities primarily through a signaling cascade mediated by two key transcription factors, Smad2 and Smad3. Numerous regulatory mechanisms exist to control the activity of Smad3, thereby modulating the strength and specificity of TGF-beta responses. In search for potential regulators of Smad3 through a yeast two-hybrid screen, we identified casein kinase 1 gamma 2 (CKIgamma2) as a novel Smad3-interacting protein. In mammalian cells, CKIgamma2 selectively and constitutively binds Smad3 but not Smad1, -2 or -4. Functionally, CKIgamma2 inhibits Smad3-mediated TGF-beta responses including induction of target genes and cell growth arrest, and this inhibition is dependent on CKIgamma2 kinase activity. Mechanistically, CKIgamma2 does not affect the basal levels of Smad proteins or activity of the receptors. Rather, CKIgamma2 preferentially promotes the ubiquitination and degradation of activated Smad3 through direct phosphorylation of its MH2 domain at Ser418. Importantly, mutation of Ser418 to alanine or aspartic acid causes an increase or decrease of Smad3 activity, respectively, in the presence of TGF-beta. CKIgamma2 is the first kinase known to mark activated Smad3 for destruction. Given its negative function in TGF-beta signaling and its reported overexpression in human cancers, CKIgamma2 may act as an oncoprotein during tumorigenesis.


Ghost Factors of Laboratory Carbonate Chemistry Are Haunting Our Experiments.
AbstractFor many historical and contemporary experimental studies in marine biology, seawater carbonate chemistry remains a ghost factor, an uncontrolled, unmeasured, and often dynamic variable affecting experimental organisms or the treatments to which investigators subject them. We highlight how environmental variability, such as seasonal upwelling and biological respiration, drive variation in seawater carbonate chemistry that can influence laboratory experiments in unintended ways and introduce a signal consistent with ocean acidification. As the impacts of carbonate chemistry on biochemical pathways that underlie growth, development, reproduction, and behavior become better understood, the hidden effects of this previously overlooked variable need to be acknowledged. Here we bring this emerging challenge to the attention of the wider community of experimental biologists who rely on access to organisms and water from marine and estuarine laboratories and who may benefit from explicit considerations of a growing literature on the pervasive effects of aquatic carbonate chemistry changes.


Early Life Adversity and Adult Social Behavior: Focus on Arginine Vasopressin and Oxytocin as Potential Mediators.
Exposure to stress during the early postnatal period (i.e., early life stress, ES) can impact brain physiology and modify individual variability in adult social behavior. Arginine vasopressin (AVP) and oxytocin (OXT) are two centrally released neuropeptides that are involved in shaping essential social behaviors, like aggression, social recognition, and social motivation. AVP and OXT modulate activity in brain regions important for the establishment of social behavior, and may be particularly sensitive to ES. In this review, we discuss whether ES alters the characteristics of the AVP- and OXT- systems in rodents, and whether these changes are associated with later alterations in aggression, social recognition, and social motivation. We have integrated causal studies indicating that (1) ES affects AVP/OXT, and (2) that changing AVP/OXT in affected regions alters social behavior. Although there is encouraging evidence that ES causes AVP- and OXT-system changes, and that these may mediate social behavior, a comprehensive understanding of the exact nature of AVP- and OXT changes and whether they are causal in establishing these behavioral disturbances needs further investigation. As there are indications that ES alters AVP- and OXT characteristics in humans as well, and that these may interact with adult predisposition to psychopathology with social dysfunction, future rodent studies may lay ground for a better understanding of such changes in humans. Ultimately, this may assist in developing therapeutic strategies to target ES effects on social behavior.


Ankle flexibility and injury patterns in dancers.
Lower-extremity injuries are common among dancers and cause significant absences from rehearsals and performances. For this study of lower-extremity injuries in 101 ballet and 47 modern dance students, injuries requiring medical attention sustained over 1 academic year were associated with the following data obtained at the beginning of the school year: ankle flexibility, sex, dance discipline, previous injury, body mass index, and years of training. Eighty-three of the 148 students (age range, 12 to 28 years) reported prior lower-limb injuries, the most common being ankle sprains (28% of all dancers). Previous leg injuries correlated significantly with lower dorsiflexion measurements and with more new injuries. Female students had greater ankle and first metatarsophalangeal flexibility. Modern dancers had greater ankle inversion. Ninety-four students sustained 177 injuries during the study, including 75 sprains or strains and 71 cases of tendinitis. Thirty-nine percent (N = 69) were ankle injuries; 18% (N = 33) were knee injuries; 23% (N = 40) were foot injuries; and 20% (N = 35) were either hip or thigh injuries. Sixty-seven percent (N = 78) of the injured students were ballet dancers. Age, years of training, body mass index, sex, and ankle range of motion measurement had no predictive value for injury; previous injury and dance discipline both correlated with increased risk of injury.


Crucial steps in the structure determination of a coronavirus spike glycoprotein using cryo-electron microscopy.
The tremendous pandemic potential of coronaviruses was demonstrated twice in the last 15 years by two global outbreaks of deadly pneumonia. Entry of coronaviruses into cells is mediated by the transmembrane spike glycoprotein S, which forms a trimer carrying receptor-binding and membrane fusion functions. Despite their biomedical importance, coronavirus S glycoproteins have proven difficult targets for structural characterization, precluding high-resolution studies of the biologically relevant trimer. Recent technological developments in single particle cryo-electron microscopy allowed us to determine the first structure of a coronavirus S glycoprotein trimer which provided a framework to understand the mechanisms of viral entry and suggested potential inhibition strategies for this family of viruses. Here, we describe the key factors that enabled this breakthrough.


Investigating the association of ventral and dorsal striatal dysfunction during reward anticipation with negative symptoms in patients with schizophrenia and healthy individuals.
Negative symptoms are a core feature of schizophrenia and also found in healthy individuals in subclinical forms. According to the current literature the two negative symptom domains, apathy and diminished expression may have different underlying neural mechanisms. Previous observations suggest that striatal dysfunction is associated with apathy in schizophrenia. However, it is unclear whether apathy is specifically related to ventral or dorsal striatal alterations. Here, we investigated striatal dysfunction during reward anticipation in patients with schizophrenia and a non-clinical population, to determine whether it is associated with apathy. Chronic schizophrenia patients (n = 16) and healthy controls (n = 23) underwent an event- related functional MRI, while performing a variant of the Monetary Incentive Delay Task. The two negative symptom domains were assessed in both groups using the Brief Negative Symptoms Scale. In schizophrenia patients, we saw a strong negative correlation between apathy and ventral and dorsal striatal activation during reward anticipation. In contrast, there was no correlation with diminished expression. In healthy controls, apathy was not correlated with ventral or dorsal striatal activation during reward anticipation. This study replicates our previous findings of a correlation between ventral striatal activity and apathy but not diminished expression in chronic schizophrenia patients. The association between apathy and reduced dorsal striatal activity during reward anticipation suggests that impaired action-outcome selection is involved in the pathophysiology of motivational deficits in schizophrenia.


Depletion effects in smectic phases of hard-rod-hard-sphere mixtures.
It is known that when hard spheres are added to a pure system of hard rods the stability of the smectic phase may be greatly enhanced, and that this effect can be rationalised in terms of depletion forces. In the present paper we first study the effect of orientational order on depletion forces in this particular binary system, comparing our results with those obtained adopting the usual approximation of considering the rods parallel and their orientations frozen. We consider mixtures with rods of different aspect ratios and spheres of different diameters, and we treat them within Onsager theory. Our results indicate that depletion effects, and consequently smectic stability, decrease significantly as a result of orientational disorder in the smectic phase when compared with corresponding data based on the frozen-orientation approximation. These results are discussed in terms of the tau parameter, which has been proposed as a convenient measure of depletion strength. We present closed expressions for tau, and show that it is intimately connected with the depletion potential. We then analyse the effect of particle geometry by comparing results pertaining to systems of parallel rods of different shapes (spherocylinders, cylinders and parallelepipeds). We finally provide results based on the Zwanzig approximation of a fundamental-measure density-functional theory applied to mixtures of parallelepipeds and cubes of different sizes. In this case, we show that the tau parameter exhibits a linear asymptotic behaviour in the limit of large values of the hard-rod aspect ratio, in conformity with Onsager theory, as well as in the limit of large values of the ratio of rod breadth to cube side length, d, in contrast to Onsager approximation, which predicts tau approximately d (3). Based on both this result and the Percus-Yevick approximation for the direct correlation function for a hard-sphere binary mixture in the same limit of infinite asymmetry, we speculate that, for spherocylinders and spheres, the tau parameter should be of order unity as d tends to infinity.


Expanding and optimizing 3D bioprinting capabilities using complementary network bioinks.
A major challenge in three-dimensional (3D) bioprinting is the limited number of bioinks that fulfill the physicochemical requirements of printing while also providing a desirable environment for encapsulated cells. Here, we address this limitation by temporarily stabilizing bioinks with a complementary thermo-reversible gelatin network. This strategy enables the effective printing of biomaterials that would typically not meet printing requirements, with instrument parameters and structural output largely independent of the base biomaterial. This approach is demonstrated across a library of photocrosslinkable bioinks derived from natural and synthetic polymers, including gelatin, hyaluronic acid, chondroitin sulfate, dextran, alginate, chitosan, heparin, and poly(ethylene glycol). A range of complex and heterogeneous structures are printed, including soft hydrogel constructs supporting the 3D culture of astrocytes. This highly generalizable methodology expands the palette of available bioinks, allowing the biofabrication of constructs optimized to meet the biological requirements of cell culture and tissue engineering.


Germline mutations of BRCA1 gene exon 11 are not associated with platinum response neither with survival advantage in patients with primary ovarian cancer: understanding the clinical importance of one of the biggest human exons. A study of the Tumor Bank Ovarian Cancer (TOC) Consortium.
Germline mutations in BRCA1 gene have been reported in up to 20 % of epithelial ovarian cancer (EOC) patients. Distinct clinical characteristics have been attributed to this special EOC population. We hypothesized that mutations in different BRCA1 gene exons may differently affect the clinical course of the disease. The aim of this study was to analyze, in a large cohort of primary EOCs, the clinical impact of mutations in BRCA1 gene exon 11, the largest exon of the gene sequence encoding the 60 % of BRCA1 protein. Two hundred sixty-three primary EOC patients, treated between 2000 and 2008 at Charité University Hospital of Berlin, were included. Patients' blood samples were obtained from the Tumor Ovarian Cancer (TOC) Network ( www.toc-network.de ). Direct sequencing of BRCA1 gene exon 11 was performed for each patient to detect mutations. Based on their BRCA1 exon 11 mutational status, patients were compared regarding clinico-pathological variables and survival. Mutations in BRCA1 exon 11 were found in 18 out of 263 patients (6.8 %). Further 10/263 (3.8 %) cases showed variants of uncertain significance (VUS). All exon 11 BRCA1-positive tumors (100 %) were Type 2 ovarian carcinomas (p = 0.05). Age at diagnosis was significantly younger in Type 2 exon 11 mutated patients (p = 0.01). On multivariate analysis, BRCA1 exon 11 mutational status was not found to be an independent predictive factor for optimal cytoreduction, platinum response, or survival. Mutations in BRCA1 gene exon 11 seem to predispose women to exclusively develop a Type 2 ovarian cancer at younger age. Exon 11 BRCA1-mutated EOC patients showed distinct clinico-pathological features but similar clinical outcome with respect to sporadic EOC patients.


Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults With Community-Acquired Bacterial Pneumonia: The LEAP 2 Randomized Clinical Trial.
New antibacterials are needed to treat community-acquired bacterial pneumonia (CABP) because of growing antibacterial resistance and safety concerns with standard care. To evaluate the efficacy and adverse events of a 5-day oral lefamulin regimen in patients with CABP. A phase 3, noninferiority randomized clinical trial conducted at 99 sites in 19 countries that included adults aged 18 years or older with a Pneumonia Outcomes Research Team (PORT) risk class of II, III, or IV; radiographically documented pneumonia; acute illness; 3 or more CABP symptoms; and 2 or more vital sign abnormalities. The first patient visit was on August 30, 2016, and patients were followed up for 30 days; the final follow-up visit was on January 2, 2018. Patients were randomized 1:1 to receive oral lefamulin (600 mg every 12 hours for 5 days; n = 370) or moxifloxacin (400 mg every 24 hours for 7 days; n = 368). The US Food and Drug Administration (FDA) primary end point was early clinical response at 96 hours (within a 24-hour window) after the first dose of either study drug in the intent-to-treat (ITT) population (all randomized patients). Responders were defined as alive, showing improvement in 2 or more of the 4 CABP symptoms, having no worsening of any CABP symptoms, and not receiving any nonstudy antibacterial drug for current CABP episode. The European Medicines Agency coprimary end points (FDA secondary end points) were investigator assessment of clinical response at test of cure (5-10 days after last dose) in the modified ITT population and in the clinically evaluable population. The noninferiority margin was 10% for early clinical response and investigator assessment of clinical response. Among 738 randomized patients (mean age, 57.5 years; 351 women [47.6%]; 360 had a PORT risk class of III or IV [48.8%]), 707 (95.8%) completed the trial. Early clinical response rates were 90.8% with lefamulin and 90.8% with moxifloxacin (difference, 0.1% [1-sided 97.5% CI, -4.4% to ∞]). Rates of investigator assessment of clinical response success were 87.5% with lefamulin and 89.1% with moxifloxacin in the modified ITT population (difference, -1.6% [1-sided 97.5% CI, -6.3% to ∞]) and 89.7% and 93.6%, respectively, in the clinically evaluable population (difference, -3.9% [1-sided 97.5% CI, -8.2% to ∞]) at test of cure. The most frequently reported treatment-emergent adverse events were gastrointestinal (diarrhea: 45/368 [12.2%] in lefamulin group and 4/368 [1.1%] in moxifloxacin group; nausea: 19/368 [5.2%] in lefamulin group and 7/368 [1.9%] in moxifloxacin group). Among patients with CABP, 5-day oral lefamulin was noninferior to 7-day oral moxifloxacin with respect to early clinical response at 96 hours after first dose. ClinicalTrials.gov Identifier: NCT02813694; European Clinical Trials Identifier: 2015-004782-92.


Magnetoelectric effect and phase transitions in CuO in external magnetic fields.
Apart from being so far the only known binary multiferroic compound, CuO has a much higher transition temperature into the multiferroic state, 230 K, than any other known material in which the electric polarization is induced by spontaneous magnetic order, typically lower than 100 K. Although the magnetically induced ferroelectricity of CuO is firmly established, no magnetoelectric effect has been observed so far as direct crosstalk between bulk magnetization and electric polarization counterparts. Here we demonstrate that high magnetic fields of ≈ 50 T are able to suppress the helical modulation of the spins in the multiferroic phase and dramatically affect the electric polarization. Furthermore, just below the spontaneous transition from commensurate (paraelectric) to incommensurate (ferroelectric) structures at 213 K, even modest magnetic fields induce a transition into the incommensurate structure and then suppress it at higher field. Thus, remarkable hidden magnetoelectric features are uncovered, establishing CuO as prototype multiferroic with abundance of competitive magnetic interactions.


Foliar Abscisic Acid-To-Ethylene Accumulation and Response Regulate Shoot Growth Sensitivity to Mild Drought in Wheat.
Although, plant hormones play an important role in adjusting growth in response to environmental perturbation, the relative contributions of abscisic acid (ABA) and ethylene remain elusive. Using six spring wheat genotypes differing for stress tolerance, we show that young seedlings of the drought-tolerant (DT) group maintained or increased shoot dry weight (SDW) while the drought-susceptible (DS) group decreased SDW in response to mild drought. Both the DT and DS groups increased endogenous ABA and ethylene concentrations under mild drought compared to control. The DT and DS groups exhibited different SDW response trends, whereby the DS group decreased while the DT group increased SDW, to increased concentrations of ABA and ethylene under mild drought, although both groups decreased ABA/ethylene ratio under mild drought albeit at different levels. We concluded that SDW of the DT and DS groups might be distinctly regulated by specific ABA:ethylene ratio. Further, a foliar-spray of low concentrations (0.1 μM) of ABA increased shoot relative growth rate (RGR) in the DS group while ACC (1-aminocyclopropane-1-carboxylic acid, ethylene precursor) spray increased RGR in both groups compared to control. Furthermore, the DT group accumulated a significantly higher galactose while a significantly lower maltose in the shoot compared to the DS group. Taken all together, these results suggest an impact of ABA, ethylene, and ABA:ethylene ratio on SDW of wheat seedlings that may partly underlie a genotypic variability of different shoot growth sensitivities to drought among crop species under field conditions. We propose that phenotyping based on hormone accumulation, response and hormonal ratio would be a viable, rapid, and an early-stage selection tool aiding genotype selection for stress tolerance.


Booster clips for giant and thick-based aneurysms.
The authors describe their experience using booster clips to secure the closure of primary clips in the repair of giant and other thick-walled aneurysms. These clips were used for 21 aneurysms in 20 patients, comprising 12% of all aneurysms operated on during the 15-month period of the report, but representing about 50% of all giant aneurysms operated on during the same time frame. These clips are designed to encircle the primary clip and have fixation "shoes" to close upon the jaws of the primary clip. All aneurysms were opened for decompression and thrombectomy when necessary following temporary major vessel occlusion before placement of the primary clip. Cerebral blood flow measurements and continuous electroencephalographic monitoring were utilized to predict the brain's tolerance to temporary ligation of the internal carotid artery (ICA) in those cases with a giant aneurysm arising from that vessel. There were no complications attributable to the periods of intracranial or cervical ICA occlusion; these periods varied but did not exceed 8 minutes for the former nor the tolerance period for the latter, which was calculated as from 5 to 30 minutes. It was necessary to reoperate on two patients and reposition clips because of stenoses or occlusions identified on immediate postoperative angiography. Fifteen patients had normal neurological function at the time of discharge. Three patients had minor deficits which did not prevent employment; two of these were related to a preoperative deficit and one was a complication of delayed ischemia. There were two deaths: one from bleeding complications and probable damage to perforating vessels in a patient operated on under profound hypothermia (the only case in the series so managed), and one from respiratory complications in a patient with severe pulmonary problems.


Effects of reducing sedentary time on glucose metabolism in immigrant Pakistani men.
This study aimed to examine the association between changes in objectively measured overall physical activity (PA) and changes in fasting and postprandial plasma insulin, C-peptide, and glucose concentrations in type 2 diabetes-prone immigrant Pakistani men living in Norway and to examine whether this association is explained by changes in moderate and vigorous PA (MVPA) or changes in sedentary time. The current study is a secondary cohort analysis on data collected from the Physical Activity and Minority Health study, a randomized controlled trial aimed at increasing the PA level, and not sedentary time per se, in a group of sedentary immigrant Pakistani men (n = 150). For the present analyses, the two groups were merged and a cohort analysis was performed. Overall PA (counts per minute) and its subcomponents, sedentary time and MVPA, were measured with accelerometry. Outcome variables were measured after a 2-h standardized glucose tolerance test. Change in overall PA was significantly associated with postprandial log-transformed plasma insulin (β = -0.002; 95% confidence interval (CI), -0.003 to 0.000; P = 0.008), C-peptide (β = -2.7; 95% CI, -4.9 to -0.5; P = 0.01), and glucose concentration (β = -0.006; 95% CI, -0.01 to -0.002; P = 0.002). Change in sedentary time was significantly and beneficially associated with changes in postprandial log-transformed plasma insulin (β = 0.002; 95% CI, 0.001-0.003; P = 0.001), C-peptide (β = 3.7; 95% CI, 1.5-6.0; P = 0.001), and glucose concentration (β = 0.006; 95% CI, 0.002-0.1; P = 0.002), independent of changes in MVPA, waist circumference, and other confounders. Increasing overall PA by reducing sedentary time seems as important as increasing time spent at MVPA in relation to postprandial plasma insulin and glucose levels in diabetes-prone immigrant men.


[Serum mesothelin dosages in follow-up of previously exposed workers].
High dosages of Serum Mesothelin have been demonstrated to be significantly associated to Pleural Malignant Mesothelioma. We recently demonstrated that Serum Mesothelin may be clinically helpful both for diagnostic and prognostic purposes, with the best cut-off corresponding to 1 nM. We also discovered that high levels of Serum Mesothelin are significantly associated to Lung Cancer. The usefulness of this marker in secondary prevention has been suggested, though never demonstrated. We therefore started a long-term prospective cohort study including previously asbestos-exposed workers. These subjects periodically underwent both radiological tests and serum mesothelin dosages. As a mid-term goal of this longitudinal study we decided to check the variability of mesothelin dosages, comparing baseline and follow-up values, as well as the possible correlation with age, duration of exposure, smoking, any abnormality of respiratory functional tests (RFT) and/or radiological tests. At baseline, Mesothelin mean value was 0.66 +/- 0.4 (range 0.08-2.2 nM). Both age (p = 0.04) and abnormal thoracic TC (p = 0.04) were significantly correlated with increased serum mesothelin levels and increasing age. No association was found between baseline mesothelin levels and duration of asbestos exposure (p = 0.5), smoking habits (p = 0.2), abnormal RFT, DLCO (carbon monoxide diffusing capacity) or thoracic X-ray. No significant variation was observed between mesothelin values at baseline and at follow-up (p = 0.2).


A Deep Learning Approach to Antibiotic Discovery.
Due to the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover new antibiotics. To address this challenge, we trained a deep neural network capable of predicting molecules with antibacterial activity. We performed predictions on multiple chemical libraries and discovered a molecule from the Drug Repurposing Hub-halicin-that is structurally divergent from conventional antibiotics and displays bactericidal activity against a wide phylogenetic spectrum of pathogens including Mycobacterium tuberculosis and carbapenem-resistant Enterobacteriaceae. Halicin also effectively treated Clostridioides difficile and pan-resistant Acinetobacter baumannii infections in murine models. Additionally, from a discrete set of 23 empirically tested predictions from >107 million molecules curated from the ZINC15 database, our model identified eight antibacterial compounds that are structurally distant from known antibiotics. This work highlights the utility of deep learning approaches to expand our antibiotic arsenal through the discovery of structurally distinct antibacterial molecules.


PSA doubling time predicts the outcome after active surveillance in screening-detected prostate cancer: results from the European randomized study of screening for prostate cancer, Sweden section.
This study reports the outcome of active surveillance in men with PSA screening-detected prostate cancer (PC), and PSA doubling time (PSADT) was evaluated as a predictor of selecting patients to active treatment or surveillance. On December 31, 1994, 10,000 men were randomized to biennial PSA testing. Through to December 2004, a total of 660 men were diagnosed with PC, of whom 270 managed with initial surveillance. Of these 270 patients, 104 (39%) received active treatment during follow-up, 70 radical prostatectomy, 24 radiation and 10 endocrine treatment. Those who received active treatment during follow-up (mean 63 months) were significantly younger (62.6 vs. 65.5 years, p < 0.0001) and had a shorter PSADT (3.7 vs. 12 years, p < 0.0001). PSA relapse was observed in 9 of 70 patients who received RRP during a mean follow-up of 37 months. Seven of these nine PSA relapses were in the patients with preoperative PSADT < 2 years. None of the 37 operated patients with a PSADT > 4 years had a PSA relapse. In a Cox regression analysis adjusted for PSA, ratio-free PSA and amount of cancer in biopsy, only the preoperative PSADT was statistically significant predictor of PSA relapse in p = 0.031. The optimal candidate for surveillance is a man with early, low-grade, low-stage PC and a PSADT > 4 years. In younger men with a PSADT of less than 4 years, surveillance does not seem to be a justified alternative, and patient should be informed about the risk with such an approach.


Characterization of rhodopsin P23H-induced retinal degeneration in a Xenopus laevis model of retinitis pigmentosa.
To investigate the pathogenic mechanisms that underlie retinal degeneration induced by the rhodopsin mutation P23H in a Xenopus laevis model of RP. Transgenic X. laevis were generated that expressed the rhodopsin mutants rhoP23H and rhoP23H/K29R (a variant incapable of transducin activation). Using quantitative dot blot assay, transgenic rhodopsin levels and the extent of retinal degeneration were determined. The contribution of rhodopsin signal transduction to cell death was assessed by comparison of rhoP23H and rhoP23H/K296R effects and by dark rearing of rhoP23H tadpoles. Intracellular localization and the oligomeric state of rhoP23H were determined by confocal immunofluorescence microscopy and Western blot analysis. RhoP23H induced retinal degeneration in a dose-dependent manner whereas expression of a control rhodopsin did not, indicating that rod photoreceptor death was specific to the P23H mutation and was not caused by the overexpression of rhodopsin. Neither abolishment of rhoP23H photosensitivity and ability to activate transducin nor dark rearing rescued rod viability. RhoP23H was localized primarily to the endoplasmic reticulum (ER) of inner segments. Western blot analysis of transgenic retinas showed that rhoP23H was prone to form dimers and higher molecular weight oligomers. However, aggresomes were not observed in rhoP23H transgenic retinal sections, despite their being reported in cultured cells expressing rhoP23H. These results support a role for rhoP23H misfolding and inner segment accumulation in rod death, possibly by ER overload or other cellular stress pathways rather than by altered rhodopsin signal transduction or aggresome formation.