Further characterization of the hemin-induced enhancement of primitive erythroid progenitor cell growth in vitro.
We have previously demonstrated that hemin specifically enhances the in vitro plating efficiency of primitive murine erythroid progenitors (day 7 BFUE), whereas it does not appear to affect more mature progenitors (mature BFUE or CFUE). In this report, we further characterize the effects of hemin on marrow-derived day 7 BFUE growth in vitro. BFUE were enhanced by hemin in a dose-dependent manner and to a greater extent in methyl cellulose than in plasma clot cultures. That hemin might increase the rate of cell division was suggested by the greater size of colonies grown in its presence as well as their earlier appearance in culture. In contrast, the addition of hemin to marrow cell cultures did not appear to affect the survival rate of BFUE or their progeny. While significantly augmenting the frequency of BFUE, hemin had no consistent stimulatory effect on CFUGM. Lastly, hemin was equally capable of augmenting burst growth in adherent cell-depleted as in whole marrow cell preparations. These experiments suggest that hemin augments directly and in a cell-specific manner the proliferation and/or differentiation of primitive marrow erythroid progenitors in vitro.


Leprosy, the key to another kingdom.
In India, many people affected by leprosy still live in self-established settlements, commonly referred to as leprosy colonies. Aid organisations generally attribute the social segregation of colony members to the stigma attached to leprosy. In this article, I argue that the common approach towards leprosy colonies is actually based on a limited understanding of social relations between colony members and others. The insights from this study will hopefully facilitate re-thinking current approaches to stigma reduction in leprosy. An ethnographic study conducted over a period of three months in and around a leprosy colony in India. With the help of a local research assistant, I carried out semi-structured interviews, informal conversations, and participant as well as non-participant observation. I conducted interviews with 22 colony members and 25 residents from the adjacent neighbourhoods of the colony. This study reveals that the differentiation between colony members and others derived at least as much from community membership as from stigma. Leprosy-affected people living outside the colony, for example, perceived the colony members as widely different from themselves, whilst stigma affected both groups. Programmes with the aim of reducing stigma need to approach stigma relations as embedded in various interrelated physio-emotional and socio-cultural processes, rather than approaching social aspects of leprosy by focusing exclusively on the notion of stigma.


Nectin cell adhesion molecule 4 regulates angiogenesis through Src signaling and serves as a novel therapeutic target in angiosarcoma.
Angiosarcoma is a rare, life-threatening soft tissue sarcoma with malignant endothelial cells that is mainly found in the skin. Multidisciplinary approaches are used to treat patients with unresectable metastasized lesions; considering the cellular origin of angiosarcoma, anti-angiogenic therapy has also been used recently. However, these treatments have limited efficacy, and the survival rate remains low. Thus, more effective treatments need to be developed. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in malignant tumors and promotes tumor progression. Thus, NECTIN4 is expected to be a novel therapeutic target for cancer. However, the significance of NECTIN4 in angiosarcoma remains unknown. Using immunohistochemistry, we investigated NECTIN4 expression in 74 tissue samples from angiosarcoma patients, finding variable NECTIN4 expression. In addition, we investigated NECTIN4 expression and function in human angiosarcoma cell lines. NECTIN4 expression was higher in angiosarcoma cells than normal endothelial cells, and angiosarcoma cells were sensitive to monomethyl auristatin E, the cytotoxic part of a NECTIN4-targetting antibody-drug conjugate. NECTIN4 knockdown inhibited the proliferation and angiogenesis of angiosarcoma cells, and Src kinase signaling was shown to be involved in NECTIN4 function, at least in part. NECTIN4-targeted therapy has the potential to be a novel treatment strategy for angiosarcoma.


Time course of expression of the retinoid X receptor gene and induction of imposex in the rock shell, Thais clavigera, exposed to triphenyltin chloride.
To examine the role of the retinoid X receptor (RXR) in the development of imposex in gastropods, we investigated the time course of expression of the RXR gene in various tissues (ctenidium, ovary or testis, digestive gland, penis-forming area or penis, and head ganglia) of female and male rock shells (Thais clavigera) exposed to triphenyltin (TPT) in a flow-through exposure system for 3 months. Accumulations of TPT in tissues were clearly observed in exposed individuals, whereas no accumulation of TPT was observed in the control groups. In females, 3-month exposure to TPT resulted in the development of imposex, and penis lengths in imposex-exhibiting females were significantly longer in small females (shell height <20 mm) than in large females (shell height > or = 20 mm). RXR gene expression in the ovary, penis-forming area or penis, and head ganglia of females exposed for 3 months was significantly higher than expression in control females, and the highest RXR gene expression was found in the penis-forming area or penis. Moreover, RXR gene expression in the penis-forming area or penis of each female exposed to TPT seemed to be associated with an increase in penis length. In males, the ratio of penis length to shell height was significantly larger in the exposed groups than in the controls. Although RXR gene expression in males exposed for 3 months was not significantly higher than expression in control males in any tissues, the highest gene expression was observed in the penis of exposed males. These results suggest that RXR plays an important role in the development of male genitalia (i.e., penis and vas deferens) in gastropods, although RXR might also have other physiological functions.


Spatiotemporal patterns of dengue outbreaks in Sri Lanka.
Background: Dengue occurs epidemically in Sri Lanka and every year, when the monsoon season begins, health authorities warn on rising numbers of dengue cases. The popular belief is that dengue epidemics are driven by the two monsoons which feed different parts of the country over different time periods. We analysed the time series of weekly dengue cases in all districts of Sri Lanka from 2007 to 2019 to identify the spatiotemporal patterns of dengue outbreaks and to explain how they are associated with the climatic, geographic and demographic variations around the country.Methods: We used time-series plots, statistical measures such a community-wide synchrony and Kendall-W and a time-varying graph method to understand the spatiotemporal patterns and links.Results and conclusions: The southwest wet zone and surrounding areas which receive rainfall in all four seasons usually experience two epidemic waves per year. The northern and eastern coastal region in the dry zone which receives rainfall in only two seasons experiences one epidemic wave per year. The wet zone is a highly synchronised epidemic unit while the northern and eastern districts have more independent epidemic patterns. The epidemic synchrony in the wet zone may be associated with the frequent mobility of people in and out of the wet zone hot spot Colombo. The overall epidemic pattern in Sri Lanka is not a sole outcome of the two monsoons but the regional epidemic patterns are collectively shaped by monsoon an inter-monsoon rains, human mobility, geographical proximity and other climate and topographical factors.


Concurrent locomotor adaptation and retention to visual and split-belt perturbations.
Gait asymmetry is a common symptom in groups with neurological disorders and significantly reduces gait efficiency. To develop efficient training for gait rehabilitation, we propose a novel gait rehabilitation paradigm that combines two distinct perturbation strategies: visual feedback distortion (VFD) and split-belt treadmill (SBT) walking. In SBT walking, spatiotemporal gait adaptation can be readily achieved, but it quickly fades after training. Gait adaptation to implicit VFD in an unconscious manner tends to persist longer, potentially due to a greater engagement of implicit learning during training. Thus, we investigated whether the combined strategies would lead to more effective changes in symmetric gait patterns with longer retention periods. We compared the retention of the preserved asymmetric pattern acquired by "implicit VFD+SBT walking" with "SBT-only walking" and with "SBT walking with conscious correction". In the implicit VFD+SBT walking, the speed of the two belts was gradually changed, the visual representation of gait symmetry was implicitly distorted, and no instructions were given to subjects except to watch the visual feedback. In the SBT walking with conscious correction, subjects were instructed to consciously correct their steps with the help of visual feedback while SBT walking. The SBT-only walking consisted of SBT walking with no visual feedback. After the 7-minute adaptation period, we removed the visual feedback and the split-belt perturbations, and we assessed the retention of the preserved asymmetric pattern while subjects continued walking for the 15-minute post-adaptation period. In a group of subjects who spontaneously showed visuomotor adaptation in response to the implicit VFD (16 out of 27 subjects), we found a greater retention rate during the implicit VFD+SBT walking trial than the SBT-only walking or the SBT walking with conscious correction trials. The implicit visual distortion paradigm delivered in an attention-independent (unconscious) manner can be utilized and integrated into SBT walking to improve the efficacy of symmetric gait adaptation by producing longer-lasting effects on the retention of a newly learned motor pattern.


A negative relationship between mutation pleiotropy and fitness effect in yeast.
It is generally thought that random mutations will, on average, reduce an organism's fitness because resulting phenotypic changes are likely to be maladaptive. This relationship leads to the prediction that mutations that alter more phenotypic traits, that is, are more pleiotropic, will impose larger fitness costs than mutations that affect fewer traits. Here we present a systems approach to test this expectation. Previous studies have independently estimated fitness and morphological effects of deleting all nonessential genes in Saccharomyces cerevisiae. Using datasets generated by these studies, we examined the relationship between the pleiotropic effect of each deletion mutation, measured as the number of morphological traits differing from the parental strain, and its effect on fitness. Pleiotropy explained approximately 18% of variation in fitness among the mutants even once we controlled for correlations between morphological traits. This relationship was robust to consideration of other explanatory factors, including the number of protein-protein interactions and the network position of the deleted genes. These results are consistent with pleiotropy having a direct role in affecting fitness.


Pharmacokinetics of fentanyl after intravenous and transdermal administration in goats.
To evaluate disposition of fentanyl in goats after IV and transdermal administration. 8 healthy 2-year-old goats weighing 31.8 to 53.6 kg (mean+/-SD, 40.4+/-7.5 kg). Each goat was given 2 treatments consisting of fentanyl administered IV (2.5 microg/kg of body weight) and via a transdermal patch (50 microg/h). There was a 2-month interval between treatments. Blood samples were collected at specified times and analyzed in duplicate to determine plasma fentanyl concentrations. Pharmacokinetic values were calculated, using a computerized modeling program. Administration of fentanyl was tolerated by all goats. Intravenous administration of fentanyl resulted in a transitory increase in rectal temperature that was not clinically important. Terminal elimination half-life after IV administration was 1.20+/-0.78 h, volume of distribution at steady state was 1.51+/-0.39 L/kg, and systemic clearance was 2.09+/-0.62 L/kg/h. Transdermal administration of fentanyl resulted in variable plasma concentrations, with peak plasma concentrations ranging from 1.12 to 16.69 ng/ml (mean+/-SD, 6.99+/-6.03 ng/ml) and time to peak concentration ranging from 8 to 18 hours (mean+/-SD, 13+/-4.5 hours). After removal of the transdermal patch, mean+/-SD terminal elimination half-life was 5.34+/-5.34 hours. Intravenous administration of fentanyl (2.5 microg/kg) in goats results in a relatively short half-life that will limit its use for management of pain. Transdermal administration of fentanyl (50 microg/h) in goats results in variable plasma concentrations that may exceed those anticipated on the basis of a theoretical delivery rate, but stable plasma concentrations of fentanyl may not be achieved.


Beta-arrestin-1 levels: reduced in leukocytes of patients with depression and elevated by antidepressants in rat brain.
Beta-arrestins play a pivotal role in G protein-coupled receptor desensitization. beta-Arrestins interfere in G protein receptor interaction, thus leading to desensitization of G protein-mediated receptor signaling. G protein receptor signaling and its desensitization were previously implicated in the pathophysiology of mood disorders and in the mechanism of action of antidepressant and mood-stabilizing treatments. The present study aims at quantitatively evaluating beta-arrestin-1 levels in leukocytes of patients with major depression and the effect of antidepressants on beta-arrestin-1 levels in rat brain. Beta-arrestin-1 measurements were carried out in cortical, hippocampal, and striatal brain regions of rats chronically intragastrically treated with either imipramine, desipramine, or fluvoxamine. Similar measurements were conducted in mononuclear leukocytes of 36 untreated patients with major depression and 32 healthy volunteer subjects. Beta-arrestin-1 levels were evaluated through immunoblot analyses using monoclonal antibodies to beta-arrestin-1. Beta-arrestin-1 levels were significantly elevated by all three antidepressants in rat cortex and hippocampus, while in the striatum no alterations could be detected. This process became significant within 10 days and took 2-3 weeks to reach maximal increase. Mononuclear leukocytes of patients with depression showed significantly reduced immunoreactive quantities of beta-arrestin-1. The reduction in beta-arrestin-1 levels was significantly correlated with the severity of depressive symptoms. The findings in the rat study suggest beta-arrestin-1 elevation as a biochemical mechanism for antidepressant-induced receptor down-regulation. The findings in human subjects support the implication of beta-arrestin-1 in the pathophysiology of mood disorders. Beta-arrestin-1 measurements in patients with depression may potentially serve as a biochemical marker for depression.


Intravenous procaine as a supplement to general anesthesia for carbon dioxide laser resection for carbon dioxide laser resection of laryngeal papillomas in children.
Procaine suppresses the cough reflex, decreases laryngeal irritability, and has general anesthetic properties. For these reasons, 14 pediatric patients undergoing CO2 laser resection of laryngeal papillomas were studied in which an intravenous infusion of procaine (1 mg/kg/min) was added to N2O-O2 halothane/enflurane general anesthesia immediately following endotracheal intubation. These patients were compared to nine patients receiving the same anesthesia without procaine. The mean age of both groups was 11 years. There was no difference between the groups in duration of anesthesia or surgery. Emergence, however, averaged 15 minutes in study patients compared to 36 minutes in the control group (p less than 0.01). There was no difference in anesthetic concentrations required to maintain satisfactory operative conditions in the two groups. Muscle relaxants were required intraoperatively in seven control patients but in none of the study patients. The surgeon ranked the operative conditions excellent in all study patients but poor in seven of the nine control patients. Five of the latter required postoperative treatment of laryngeal complications, including reintubation in three. Only one of the study patients had postoperative stridor. No evidence of procaine toxicity was noted in the study patients with total doses ranging from 500--3600 mg. Intravenous procaine is useful in pediatric patients having endoscopic laryngeal operations.


The presence and prognostic importance of glomerular macrophage infiltration in renal allografts.
The purpose of this study was to analyze the role of intraglomerular macrophage infiltration in human renal allografts by examining biopsies from kidney grafts that were dysfunctional after transplantation. Eighty-three patients (58 men, 25 women) of a mean age of 30.2 +/- 1.4 years were evaluated. In all cases, biopsy specimens were examined for the presence of macrophage infiltration in the glomeruli. The infiltration of these cells was evaluated immunohistochemically using monoclonal antibody CD68, which labels macrophage cytoplasm. 10 renal allograft biopsies with normal histopathology were used as control group. The CD68-positive macrophages in all glomeruli were counted and the glomerular macrophage index (GMI) was calculated. Of the 83 patients, 40 showed acute rejection (AR), 33 showed chronic rejection (CR) and 10 showed cyclosporin A (CsA) toxicity. Only the biopsies of 28 patients stained positive for CD68 in the glomeruli. Neither patients with CsA toxicity nor controls showed intraglomerular macrophages. The CD68-positive group consisted of 7/33 CR and 21/40 AR patients. We observed intraglomerular macrophages in only 6 of the 20 AR cases that responded to steroid therapy (mean GMI 0.3 +/- 0.1) and in 15 of the 20 steroid-resistant AR cases (mean GMI 1.7 +/- 1.2; p < 0.01). The outcome of grafts that contained intraglomerular macrophages was significantly worse than the outcomes of other grafts noticed during the follow-up. We conclude that the presence of glomerular macrophages can be considered a marker for rejection and is a valuable additional criterion of rejection in the histological examination of renal allograft biopsies. The presence of intraglomerular macrophages indicates that the outcome of the graft will be significantly worse than that of grafts without intraglomerular macrophage infiltration.


SIRT7-dependent deacetylation of the U3-55k protein controls pre-rRNA processing.
SIRT7 is an NAD(+)-dependent protein deacetylase with important roles in ribosome biogenesis and cell proliferation. Previous studies have established that SIRT7 is associated with RNA polymerase I, interacts with pre-ribosomal RNA (rRNA) and promotes rRNA synthesis. Here we show that SIRT7 is also associated with small nucleolar RNP (snoRNPs) that are involved in pre-rRNA processing and rRNA maturation. Knockdown of SIRT7 impairs U3 snoRNA dependent early cleavage steps that are necessary for generation of 18S rRNA. Mechanistically, SIRT7 deacetylates U3-55k, a core component of the U3 snoRNP complex, and reversible acetylation of U3-55k modulates the association of U3-55k with U3 snoRNA. Deacetylation by SIRT7 enhances U3-55k binding to U3 snoRNA, which is a prerequisite for pre-rRNA processing. Under stress conditions, SIRT7 is released from nucleoli, leading to hyperacetylation of U3-55k and attenuation of pre-rRNA processing. The results reveal a multifaceted role of SIRT7 in ribosome biogenesis, regulating both transcription and processing of rRNA.


Liraglutide-loaded PLGA/gelatin electrospun nanofibrous mats promote angiogenesis to accelerate diabetic wound healing via the modulation of miR-29b-3p.
Diabetic wounds remain a serious clinical challenge whereas current therapies have limited effects on reducing the high disability and morbidity. Impaired vascularization is closely associated with delayed healing of diabetic wounds and liraglutide (Lira), a GLP-1R receptor agonist, has been reported to promote the angiogenic ability of endothelial cells. However, its application is hindered owing to the unsustainable drug concentration. In this study, we prepared a poly (lactic-co-glycolic acid)/gelatin (PLGA/Gel) nanofibrous mat scaffold to sustain the release of Lira for skin tissue engineering through 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxy sulfosuccinimide (EDC/NHS), a green cross-linking-graft integration method. The incorporation of Lira into PLGA/Gel increased the pore size, hydrophilicity, elasticity and degradation properties of nanofibrous mats, which were advantageous to wound healing. In addition, the effects on diabetic wound healing, vascularization and its underlying mechanism were evaluated. The results revealed that PLGA/Gel/Lira remarkably improved the healing efficiency of diabetic dermal wounds characterized by shortened wound closure time, increased blood vessel density, and elevated collagen deposition and alignment. In vitro, Lira reversed the inhibitory effects on proliferation, migration, tube differentiation, and VEGF secretion of endothelial cells induced by high glucose (HG). As for the underlying mechanism, Lira specifically decreased the level of miR-29b-3p, targeting the AKT/GSK-3β/β-catenin pathway to regulate the biological function of endothelial cells. In conclusion, for the first time this study combined PLGA/Gel with Lira to take advantage of their synergistic effects to promote vascularization, a promising strategy to accelerate diabetic wound repair.


Renin-angiotensin system blocking drugs.
The two major classes of drugs that target the RAS are the angiotensin-converting enzyme (ACE) inhibitors and the selective AT1 receptor blockers (ARBs). Although both of these drug classes target angiotensin II, the differences in their mechanisms of action have implications for their effects on other pathways and receptors that may have therapeutic implications. Both ACEIs and ARBs are effective antihypertensive agents that have been shown to reduce the risk of cardiovascular and renal events. Direct inhibition of renin -the most proximal aspect of the RAS -became clinically feasible from 2007 with the introduction of aliskiren. This latter drug has been shown to be efficacious for the management of hypertension. Combined therapy of direct renin-inhibitors with ACEIs or ARBs has been tested in some clinical situations as congestive HF and proteinuria with diverse results. This article tries to offer an updated review of current knowledge on the use of RAS blocking drugs in clinical settings.


A Homoleptic KrF2 Complex, [Hg(KrF2 )8 ][AsF6 ]2 ⋅2 HF.
The reaction of Hg(AsF6 )2 with a large molar excess of KrF2 in anhydrous HF has afforded the first homoleptic KrF2 coordination complex of a metal cation, [Hg(KrF2 )8 ][AsF6 ]2 ⋅2 HF. The [Hg(KrF2 )8 ]2+ dication is well-isolated in the low-temperature crystal structure of its HF-solvated [AsF6 ]- salt, and consists of eight KrF2 molecules that are terminally coordinated to Hg2+ by means of Hg-F(KrF) bonds to form a slightly distorted, square-antiprismatic coordination sphere around mercury. The Raman spectrum of [Hg(KrF2 )8 ]2+ was assigned with the aid of calculated gas-phase vibrational frequencies. Computational studies indicate that both electrostatic and orbital interactions are important for metal-ligand bonding and provide insight into the geometry of the [Hg(KrF2 )8 ]2+ cation and the nature of noble-gas difluoride ligand bonding.


The Tharsis mantle source of depleted shergottites revealed by 90 million impact craters.
The only martian rock samples on Earth are meteorites ejected from the surface of Mars by asteroid impacts. The locations and geological contexts of the launch sites are currently unknown. Determining the impact locations is essential to unravel the relations between the evolution of the martian interior and its surface. Here we adapt a Crater Detection Algorithm that compile a database of 90 million impact craters, allowing to determine the potential launch position of these meteorites through the observation of secondary crater fields. We show that Tooting and 09-000015 craters, both located in the Tharsis volcanic province, are the most likely source of the depleted shergottites ejected 1.1 million year ago. This implies that a major thermal anomaly deeply rooted in the mantle under Tharsis was active over most of the geological history of the planet, and has sampled a depleted mantle, that has retained until recently geochemical signatures of Mars' early history.


Increased numbers of CCR5+ interferon-gamma- and tumor necrosis factor-alpha-secreting T lymphocytes in multiple sclerosis patients.
To determine the frequency of in vivo activated T(H)1 lymphocytes, T-cell subsets of 9 multiple sclerosis patients with active disease and 17 healthy controls were analyzed by immunostaining for CCR5, CD26, and their expression of interleukin-2, interferon-gamma, and tumor necrosis factor-alpha. The numbers of CCR5+ interferon-gamma- and tumor necrosis factor-alpha-producing T cells were significantly increased in the peripheral blood of multiple sclerosis patients. CCR5 expression may be a useful marker to identify effector cells in multiple sclerosis and could be used as a tool for monitoring disease activity.


How Coiled-Coil Assemblies Accommodate Multiple Aromatic Residues.
Rational protein design requires understanding the contribution of each amino acid to a targeted protein fold. For a subset of protein structures, namely, α-helical coiled coils (CCs), knowledge is sufficiently advanced to allow the rational de novo design of many structures, including entirely new protein folds. Current CC design rules center on using aliphatic hydrophobic residues predominantly to drive the folding and assembly of amphipathic α helices. The consequences of using aromatic residues-which would be useful for introducing structural probes, and binding and catalytic functionalities-into these interfaces are not understood. There are specific examples of designed CCs containing such aromatic residues, e.g., phenylalanine-rich sequences, and the use of polar aromatic residues to make buried hydrogen-bond networks. However, it is not known generally if sequences rich in tyrosine can form CCs, or what CC assemblies these would lead to. Here, we explore tyrosine-rich sequences in a general CC-forming background and resolve new CC structures. In one of these, an antiparallel tetramer, the tyrosine residues are solvent accessible and pack at the interface between the core and the surface. In another more complex structure, the residues are buried and form an extended hydrogen-bond network.


Adequacy of laboratory simulation of in-line skater falls.
Currently most laboratory simulation of distal radius fractures and wrist injuries has been with axial limb loading or vertical drop technique. To better assess the contribution of horizontal velocity in momentum in the development of wrist injury and wrist fracture we have compared forces and fracture patterns for fall simulations involving strictly vertical impacts with those that incorporated horizontal momentum in fresh-frozen upper extremities. The premise for testing was based on a forward fall onto the palmar surface of an outstretched arm. A 45 degrees-incline impact device was used to model the horizontal and vertical velocity components of a skater fall at a representative speed. Sled mass was 26.2 kg. A 45.5-kg vertical impact system furnished contrasting data and represented prior state-of-the-art technology. Drop heights were adjusted to compensate for discrepancy in sled mass. Measurements from either impact system included vertical and horizontal forces and kinetic energy at impact. Fracture patterns were assessed radiographically. Nine trials were conducted with the incline device and 11 trials were conducted with the vertical impact system. The fracture rate was substantially higher for vertical impacts versus incline impacts (82% vs 33%). The rate of carpal fractures also was higher. Vertical and horizontal forces were similar statistically although slightly greater for vertical impacts. Kinetic energy, however, was 3 times greater for incline impacts than for vertical impacts. These kinetic parameters support the argument that the incline impacts should have resulted in far greater injury. The data suggest horizontal momentum changes limb loading. We submit that published methods for modeling skater falls have failed to provide a true simulation of the event in question.


Models of female orgasm.
Self-report instruments concerning personality and subjective responses to sexual orgasm were filled out by 281 female university undergraduates. Exploratory and confirmatory factor analyses were used to evaluate the dimensionality of women's subjective responsiveness to orgasm. The results did not support the concept of a unidimensional orgasm process; separate coital and masturbatory factors of orgasmic experience were obtained. Highly internally consistent scales were developed to assess the two factors, and both scales were found to be significantly correlated with indices of extraversion, attitudes toward masturbation, and sexual experience. A path-analytic model was developed which is consistent with the hypothesis that heterosexual and monosexual behaviors act as mediators between extraversion, neuroticism, and attitudes toward masturbation, on the one hand, and subjective coital or masturbatory orgasmic responsiveness, on the other. It appears that attitudes toward masturbation may also have a direct influence on masturbatory responsiveness. Various therapeutic implications of the path model are described. Replications and extensions of the study with older, more experienced populations are necessary.


Antigenic profile of tumor progression stages in human melanocytic nevi and melanomas.
Sixteen monoclonal antibodies that were obtained after immunization of BALB/c mice with intact melanoma cells or extracts of melanoma cells were tested for reactivity with normal and malignant melanocytic cells in situ, using an immunoperoxidase technique on frozen tissue sections. Sections representing six histopathologically defined stages of tumor progression, ranging from normal melanocytes to highly malignant metastatic lesions, were used. Thirteen monoclonal antibodies (MAbs) did not stain normal melanocytes in situ, whereas three MAbs weakly stained between 1 and 12.5% of melanocytes in 6-22% of the skin sections examined. MAb B 73.1, which was produced by immunization of mice with human natural killer cells and which binds to the Fc receptor of natural killer cells and granulocytes, reacted exclusively with malignant cells that represent the last two stages of tumor progression, vertical growth phase (VGP) primary melanoma and metastatic melanoma. All other antibodies showed variable reactivity with benign proliferative lesions or radial growth phase (RGP), an early stage of primary melanoma. Staining by MAbs that were reactive with gangliosides, unknown antigens, receptors, and two proteins (120/94 kDa protein and 250 kDa glycoprotein) showed a gradual increase in subsequent stages of tumor progression. Two steps in tumor progression were characterized by significant quantitative changes in the expression of antigens detected by the MAbs used in this study. First, mature nevus cells showed significantly higher reactivity with a panel of six MAbs, when compared to normal melanocytes. Second, a separate panel of six MAbs discriminated between RGP and VGP primary melanoma cells. No significant differences in antigen expression were found between dysplastic nevus cells and RGP melanoma, except that some antigens (nerve growth factor receptor and GD2/GD3 gangliosides) appear to be expressed at lower levels in RGP lesions, nor did VGP primary and metastatic melanomas show significant differences in antigen expression. These results suggest that (a) tumor progression of melanocytic cells in vivo is accompanied by significant quantitative differences in the expression of antigens, (b) some of the antigens examined here are associated with biologically aggressive malignant lesions but not normal or premalignant melanocytic cells, and (c) RGP primary melanoma cells are antigenically more similar to nevus cells than to VGP primary melanoma cells.


Barriers to evidence-based practice implementation in physiotherapy: a systematic review and meta-analysis.
To review and meta-analyse the evidence about the prevalence of barriers to evidence-based practice (EBP) reported in physiotherapy. Two independent investigators conducted an extensive electronic search in EMBASE, PubMed, Scopus, Web of Science and CINAHL databases from their inception to July 2020 and included the retrieved articles if they investigated barriers to EBP among physiotherapy professionals. Subsequently, they extracted data and assessed the methodological quality using a scale described in a similar previous study. The outcome for meta-analysis was frequency of each reported barrier. Sub-analyses were performed grouping studies based on countries where surveys were performed, classified as either developed or developing countries. Twenty-nine articles were included in the systematic reviews and meta-analysis. Risk of bias assessment of included studies showed a median score: 4 points (interquartile range: 3-4). The findings of meta-analysis revealed that lack of time was the most frequently reported barrier (53.0% [95% confidence interval, 95%CI, 44.0-62.0]), followed by language (36.0% [95%CI 16.0-62.0]), lack of access (34.0% [95%CI 23.0.27]) and lack of statistical skills (31.0% [95%CI 20.0-44.0]). Lack of skills and lack of generalizability were declared as barriers by 27.0% [95%CI 18.0-38.0] and 23.0% [95%CI 15.0-33.0] of responders, respectively. Lack of support and lack of interest are less frequent, with 16.0% [95%CI 11.0-24.0] and 9.0% [95%CI 6.0-15.0] of responses, respectively. Barriers reported in investigations performed in developed countries were less frequent when compared to those performed in developing countries. Organizational issues and methodological skills seem key issues to allow the implementation of EBP, suggesting the need to adopt or enhance organizational and training strategies to facilitate the implementation of the EBP. Quantitative synthesis showed high heterogeneity for all analyses, and therefore, pooled data should be interpreted with caution.


Accessory ossicles in the elbow.
Accessory ossicles in the elbow are often diagnosed as osteochondritis dissecans or chondromatosis, but no terminologic agreements seem to exist in the literature. Our study of 5 patients suggests that accessory ossicles in the fossa olecrani or coronoidea may represent anatomic variants, perhaps best described as os supratrochleare anterius and posterius, respectively.


Endoscopic stenting for benign upper gastrointestinal strictures and leaks.
Self-expandable metal stents (SEMS) and self-expandable plastic stents (SEPS) maybe used for the treatment of benign upper gastrointestinal (GI) leaks and strictures. This study reviewed our experience with stent insertions in patients with benign upper GI conditions. Patients who underwent stent placement for benign upper GI strictures and leaks between March 2007 and April 2011 at a tertiary referral academic center were studied using an endoscopic database and electronic patient records. The technical success, complications, and clinical improvement after stent removal were compared according to type of stent. The outcomes measured were clinical response, adverse events, and predictors of stent migration. Thirty-eight patients (50 % male, mean age = 54 years, range = 12-82) underwent 121 endoscopic procedures. Twenty patients had stents placed for strictures, and 18 had stents placed for leaks. Stent placement was technically successful in all patients. The average duration of stent placement was 54 days (range = 18-118). Clinical improvement immediately after stent placement was seen in 29 of the 38 patients (76.3 %). Immediate post-procedure adverse events occurred in 8 patients. Late adverse events were seen in 18 patients. Evidence of stent migration occurred in 16 patients and was seen in 42 of the 118 successfully placed stents (35.5 %). Migration was more frequent with fully covered SEMS (p = 0.002). After stent removal, 27 patients were evaluable for long-term success (median follow-up time of 283 days, IQR 38-762). Resolution of strictures or leaks was seen in 11 patients (40.7 %). Predictors for long-term success included increasing age and if the stent did not cross the GE junction. Placement of SEPS and SEMS for benign refractory strictures and fistulas has modest long-term clinical efficacy and is limited by a significant migration rate. Stent migration is common and frequent with fully covered SEMS compared to other types of stents, regardless of indication or location.


Anticoagulation therapy in atrial fibrillation in combination with acute myocardial infarction influences long-term outcome: a prospective cohort study from the Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA).
The American and European guidelines do not agree with regard to antithrombotic treatment in patients with atrial fibrillation (AF) and acute myocardial infarction (AMI), thus causing uncertainty among physicians. We investigated the prescription of oral anticoagulation (OAC) in patients discharged alive with AF after an AMI and the influence of OAC treatment on 1-year mortality. This was a prospective cohort study using data from the Register of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA) on patients admitted to the coronary care units of 72 Swedish hospitals from 1995 to 2002. A total of 6182 patients discharged alive with first registry-recorded AMI and AF on discharge ECG were included. One-year mortality data were obtained from the Swedish National Cause of Death Register. Only 30% (n=1848) of the 6182 patients with AF were prescribed OAC. At 1 year, the unadjusted mortality was 31% (1183 deaths) in the platelet-inhibitors only group and 22% (414 deaths) in the OAC-treated group. In Cox regression analysis with adjustment for confounding factors, OAC treatment was associated with a reduction in 1-year mortality (relative risk 0.73; 95% CI 0.62 to 0.86; P<0.001) in hospital survivors of AMI with AF. The reduction in mortality appeared to be caused primarily by a lower rate of ischemic heart death (55.6% versus 62.0%) and fatal stroke (5.7% versus 7.5%) in the OAC group. This reduction of mortality was similar among most subgroups based on age, sex, baseline characteristics, previous disease manifestations, and medications. In daily clinical practice, OAC was only given to a minority (30%) of AMI patients with AF, despite the fact that OAC was associated with a 29% relative and 7% absolute reduction in 1-year mortality after adjustment for confounding variables. The results emphasize the importance of OAC treatment for AF after AMI.


Matched cascade of bandgap-shift and frequency-conversion using stimulated Raman scattering in a tapered hollow-core photonic crystal fibre.
We report on a novel means which lifts the restriction of the limited optical bandwidth of photonic bandgap hollow-core photonic crystal fiber on generating high order stimulated Raman scattering in gaseous media. This is based on H(2)-filled tapered HC-PCF in which the taper slope is matched with the effective length of Raman process. Raman orders outside the input-bandwidth of the HC-PCF are observed with more than 80% quantum-conversion using a compact, low-power 1064 nm microchip laser. The technique opens prospects for efficient sources in spectral regions that are poorly covered by currently existing lasers such as mid-IR.


Predictors of type-2 diabetes remission following bariatric surgery after a two-year follow-up.
Bariatric surgery is evolving as a successful tool for managing morbid obesity and T2DM. This study aimed to identify predictors of diabetes remission after two types of bariatric procedures. This prospective study enrolled 172 patients with morbid obesity associated with T2DM scheduled for bariatric surgery. Two laparoscopic bariatric procedures were done; single anastomosis gastric bypass (SAGB, n = 83) and sleeve gastrectomy (LSG, n = 68). Lipid accumulation product index (LAP) and quantitative insulin sensitivity check index (QUICKI) were used to evaluate lipid profile and insulin sensitivity. Two years after surgery condition of DM was evaluated as complete remission (CR), partial remission (PR), or improvement. The primary outcome measure was predictors of diabetes remission. Two years after surgery, 151 patients were available for evaluation, where 75 patients (49.7%) achieved CR, while PR was found in 36 (23.8%). CR was significantly associated with younger age, shorter duration of DM (p < 0.001, for both), higher C-peptide and GLP-1 levels (p < 0.001 and p = 0.002, respectively), and bypass surgery (p = 0.027). On multivariate analysis, shorter duration of DM, lower BMI, and higher C-peptide levels were the independent factors predicting CR. Complete remission of T2DM can be achieved in nearly half of the patients two years after SG or SAGB. The duration of diabetes and preoperative BMI and C-peptide levels are the independent factors predicting complete remissions.


Cost-Sensitive Feature Selection by Optimizing F-Measures.
Feature selection is beneficial for improving the performance of general machine learning tasks by extracting an informative subset from the high-dimensional features. Conventional feature selection methods usually ignore the class imbalance problem, thus the selected features will be biased towards the majority class. Considering that F-measure is a more reasonable performance measure than accuracy for imbalanced data, this paper presents an effective feature selection algorithm that explores the class imbalance issue by optimizing F-measures. Since F-measure optimization can be decomposed into a series of cost-sensitive classification problems, we investigate the cost-sensitive feature selection by generating and assigning different costs to each class with rigorous theory guidance. After solving a series of cost-sensitive feature selection problems, features corresponding to the best F-measure will be selected. In this way, the selected features will fully represent the properties of all classes. Experimental results on popular benchmarks and challenging real-world data sets demonstrate the significance of cost-sensitive feature selection for the imbalanced data setting and validate the effectiveness of the proposed method.


Time use among individuals with persistent mental illness: identifying risk factors for imbalance in daily activities.
The aim of this study was to investigate associations between time use in daily activities and sociodemographic and clinical factors in order to identify individuals with persistent mental illness at risk of having an imbalance in daily activities, as reflected in their time use and daily rhythm. Participants (n = 103) were selected from a psychiatric outpatient unit using a randomized stratified selection procedure. The main findings indicated that time spent in daily activities increased with age, and that older individuals more often had a beneficial daily rhythm. Women and individuals living with children spent more time on self-care/self-maintenance than men and individuals living without children. Individuals with a diagnosis of psychosis spent less total time in daily activities than individuals with non-psychosis. In conclusion, general psychiatric symptoms, such as self-blame, anxiety, and difficulties in cooperating with others, explained most of the risk of spending little time in work/education as well as the risk of spending long periods asleep and having an adverse daily rhythm. A diagnosis of psychosis and high levels of general symptoms together explained most of the risk of having low total time use in activity. Factors such as age and living with children or not seemed to be important factors in relation to time use and daily rhythm.


Angiogenic Factor Profiles in Pregnant Women With a History of Early-Onset Severe Preeclampsia Receiving Low-Molecular-Weight Heparin Prophylaxis.
To evaluate whether daily low-molecular-weight (LMW) heparin prophylaxis during pregnancy alters profile of circulating angiogenic factors that have been linked with the pathogenesis of preeclampsia and fetal growth restriction. This is a planned ancillary study of the Heparin-Preeclampsia trial, a randomized trial in pregnant women with a history of severe early-onset preeclampsia (less than 34 weeks of gestation). In the parent study, all women were treated with aspirin and then randomized to receive LMW heparin or aspirin alone. In this study, we measured serum levels of circulating angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin by immunoassay) at the following gestational windows: 10-13 6/7 weeks, 14-17 6/7 weeks, 18-21 6/7 weeks, 22-25 6/7 weeks, 26-29 6/7 weeks, 30-33 6/7 weeks, and 34-37 6/7 weeks. Samples were available from 185 patients: LMW heparin+aspirin (n=92) and aspirin alone (n=93). The two groups had comparable baseline characteristics and had similar adverse composite outcomes (35/92 [38.0%] compared with 36/93 [38.7%]; P=.92). There were no significant differences in serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin in the participants who received LMW heparin and aspirin compared with those who received aspirin alone regardless of gestational age period. Finally, women who developed an adverse composite outcome at less than 34 weeks of gestation demonstrated significant alterations in serum angiogenic profile as early as 10-13 6/7 weeks that was most dramatic 6-8 weeks preceding delivery. Prophylactic LMW heparin therapy when beginning from before 14 weeks of gestation with aspirin during pregnancy is not associated with an improved angiogenic profile. This may provide a molecular explanation for the lack of clinical benefit noted in recent trials. ClinicalTrials.gov, NCT00986765.


Involvement of target gene polymorphisms in 5-Fluorouracil toxicity: a case report.
Personalized medicine is becoming an important tool in oncology, both in preventing disease and in optimizing the treatment of existing cancers. Here we describe the cases of 2 patients with relevant systemic toxicity following 5-fluorouracil (5-FU) therapy and we study the more frequent polymorphisms in the target genes, in particular: (1) the variability in the number of 28-base repetitions present in the 5'-untranslated sequence of the thymidine synthase gene; (2) the presence of single-nucleotide polymorphisms in the methylene tetrahydrofolate reductase gene, and (3) the presence of mRNA splicing in intron 14 of the hepatic enzyme dihydropyrimidine dehydrogenase. The 5-FU gene profile of our patients strongly suggested that the polymorphisms expressed may contribute to the adverse effects seen during the therapy. To what extent these polymorphisms induced adverse effects cannot be established at present; however, our results strengthen the relevance of the 5-FU-related pharmacogenomic profile to predict the response outcome and the chemotherapy toxicity.


Relationships among performance scores of four diagnostic decision support systems.
To examine the relationships among different performance scores for each of four diagnostic decision support systems (DDSSs). Intercorrelations among seven performance scores on a set of 105 cases for each of four DDSSs (DXplain, Iliad, Meditel, QMR) were computed. The performance scores for each case reflected: 1) presence or absence of the case diagnosis in the DDSS knowledge base; 2) presence or absence of the correct diagnosis anywhere on the DDSS diagnosis list; 3) presence or absence of the correct diagnosis in the top ten diagnoses; 4) relevance of the DDSS diagnosis list; 5) comprehensiveness of the DDSS diagnosis list; 6) whether the DDSS suggested additional diagnoses to the experts' list; and 7) the length of the DDSS diagnosis list. For all DDSSs, the two Correct Diagnosis scores (top ten and total list) were significantly related: 1) to the presence of the correct diagnosis in the knowledge base; 2) to the Comprehensiveness score; and 3) to each other. There were significant differences among the four DDSSs on the magnitude and/or direction of the relationships between: 1) the two Correct Diagnosis scores; 2) the Relevance and Length scores; and 3) the Relevance and Additional Diagnoses scores. The production of a correct diagnosis for a given case is not related to the number of diagnoses suggested by the DDSS and, across different DDSSs, is not consistently related to other measures of performance. These data indicate that multiple measures are needed to fully describe the performance of a DDSS.


Crystal structure of tris-(N-methyl-salicyl-aldiminato-κ(2) N,O)chromium(III).
The crystal structure of the title compound, [Cr(C8H8NO)3], is isotypic with the vanadium(III) analogue. The asymmetric unit consists of one Cr(3+) cation and three N-methyl-salicylaldiminate anions. The metal cation is octa-hedrally coordinated by three N,O-chelating N-methyl-salicylaldiminate ligands, leading to discrete and neutral complexes. In the crystal, neighbouring complexes are linked via C-H⋯O hydrogen-bonding inter-actions into chains propagating parallel to the c axis.


Efflux of hydraulically lifted water from mycorrhizal fungal hyphae during imposed drought.
Apart from improving plant and soil water status during drought, it has been suggested that hydraulic lift (HL) could enhance plant nutrient capture through the flow of mineral nutrients directly from the soil to plant roots, or by maintaining the functioning of mycorrhizal fungi. We evaluated the extent to which the diel cycle of water availability created by HL covaries with the efflux of HL water from the tips of extramatrical (external) mycorrhizal hyphae, and the possible effects on biogeochemical processes. Phenotypic mycorrhizal fungal variables, such as total and live hyphal lengths, were positively correlated with HL efflux from hyphae, soil water potential (dawn), and plant response variables (foliar (15)N). The efflux of HL water from hyphae was also correlated with bacterial abundance and soil enzyme activity (P), and the moistening of soil organic matter. Such findings indicate that the efflux of HL water from the external mycorrhizal mycelia may be a complementary explanation for plant nutrient acquisition and survival during drought.


A multilaboratory evaluation of a commercial enzyme-linked immunosorbent assay test for the detection of antibodies against Mycobacterium avium subsp. paratuberculosis in cattle.
Five laboratories participated in a study to evaluate sources of variation in results from an enzyme-linked immunosorbent assay (ELISA) for antibodies against Mycobacterium avium subsp. paratuberculosis. Each laboratory repeatedly tested duplicates of a negative, positive (P), and high-positive (HP) serum sample, which were supplied by the United States Department of Agriculture: Animal and Plant Health Inspection Service: Veterinary Services, National Veterinary Services Laboratories, Ames, IA, on all 96-well microtiter plates when routinely testing other samples for M. avium subsp. paratuberculosis antibodies. These 3 sera were aliquoted and sent to the 5 participating laboratories. This study focused on variation in test results because of assay reagents and laboratory techniques and did not account for biologic variability associated with the time course of infection in cattle. Overall, results from 868 microtiter plates were used in the study. For each sample a sample-to-positive (S/P) ratio was calculated according to the manufacturer's directions. The S/ P ratio for the P sample ranged from 0.06 to 1.039 (mean = 0.466 and 0.484 for wells 1 and 2, respectively) and those for the HP sample ranged from 2.446 to 8.727 (mean = 4.027 and 3.980 for wells 1 and 2, respectively). The majority of the variation in S/P ratio for the P sample was attributed to kit lot (37.5%), followed by random (unexplained) error (27.0%), laboratory (18.3%), and kit lot by laboratory (11.9%). By eliminating plates in which the separation between negative and positive control ODs was less than 0.4, the proportion of variation attributed to laboratory was reduced markedly. These results confirm that there is variability in M. avium subsp. paratuberculosis ELISA results and that several sources contribute to the observed variability. The study gives a relative estimate of the contribution of various sources to the overall variability observed in the M. avium subsp. paratuberculosis ELISA results with kit lot being a primary contributor. Similar data for other ELISA tests for antibodies to M. avium subsp. paratuberculosis or other antigens also should be developed.


Reduced Maximum Pitch Elevation Predicts Silent Aspiration of Small Liquid Volumes in Stroke Patients.
Preliminary evidence has shown that reduced ability to maximally raise vocal pitch correlates with the occurrence of aspiration (i.e., airway invasion by food or liquid). However, it is unclear if this simple task can be used as a reliable predictor of aspiration in stroke patients. Our aim was to examine whether maximum vocal pitch elevation predicted airway invasion and dysphagia in stroke. Forty-five consecutive stroke patients (<1 month poststroke) at a rehabilitation setting participated in a videofluoroscopic swallow study and two maximum vocal pitch elevation tasks. Maximum pitch was evaluated acoustically [maximum fundamental frequency (max F0)] and perceptually. Swallowing safety was rated using the Penetration/Aspiration Scale and swallowing performance was assessed using components of the Modified Barium Swallow Impairment Profile (MBSImPTM©). Data were analyzed using simple regression and receiver operating characteristics curves to test the sensitivity and specificity of max F0 in predicting aspiration. Correlations between max F0 and MBSImP variables were also examined. Max F0 predicted silent aspiration of small liquid volumes with 80% sensitivity and 65% specificity (p = 0.023; area under the curve: 0.815; cutoff value of 359.03 Hz). Max F0 did not predict non-silent aspiration or penetration in this sample and did not significantly correlate with MBSImP variables. Furthermore, all participants who aspirated silently on small liquid volumes (11% of sample) had suffered cortical or subcortical lesions. In stroke patients (<1 month poststroke), reduced maximum pitch elevation predicts silent aspiration of small liquid volumes with high sensitivity and moderate specificity. Future large-scale studies focusing on further validating this finding and exploring the value of this simple and non-invasive tool as part of a dysphagia screening are warranted.


C4A gene deletion: association with Graves' disease.
The association of HLA class I and class II antigens, particularly HLA-B8,DR3, with a variety of autoimmune diseases has been well documented. The C4A*Q0 (non-expressed C4A) allele which is in linkage disequilibrium with HLA-B8,DR3 has also been reported to be associated with systemic lupus erythematosus, insulin-dependent diabetes mellitus and Graves' disease. However, the number of studies has been limited by the requirement of family data for the assignment of the C4A*Q0 allele based on C4 protein typing. Recently, with the availability of a C4 cDNA probe, a C4A gene deletion associated with HLA-B8,DR3 has been reported in normal individuals. We have tried to resolve the problem of assigning the C4A*Q0 allele by using both phenotypic and genotypic approaches and have determined the significance of the C4A*Q0 allele in 80 unrelated patients with Graves' disease and in 50 normal control subjects. Our results demonstrate a strong association of the C4A*Q0 allele with Graves' disease (56 versus 26%; P less than 0.002, relative risk = 3.7) and in particular in association with HLA-B8 and/or DR3 (92 versus 70.6%; P less than 0.04) when compared with normal controls. All the C4A*Q0 alleles that were associated with HLA-B8 and/or DR3 were due to a C4A gene deletion. Of the C4A*Q0 alleles, in Graves' disease, 94% (compared with 82% in the control group) could be detected by C4 DNA analysis using either TaqI or EcoRI restriction endonucleases. It is suggested that a combination of C4 protein typing with C4 DNA analysis is the best approach for the determination of the C4A*Q0 allele in unrelated individuals without access to family data.


Non-alcoholic steatohepatitis (NASH): where are we now and where are we going?
Although non-alcoholic steatohepatitis (NASH) was considered relatively uncommon prior to the middle of the last decade, over the past three years there has been an explosion of studies on various aspects of NASH with one study reporting that after hepatitis C, NASH was the most common diagnosis in patients presenting largely with persistent abnormalities of liver function tests. The field of NASH has come a long way in a relatively short space of time. This article considers advances in knowledge that have arisen as a result of these studies and highlights areas for further work.


Preparation of organotypic brain slice cultures for the study of Alzheimer's disease.
Alzheimer's disease, the most common cause of dementia, is a progressive neurodegenerative disorder characterised by amyloid-beta deposits in extracellular plaques, intracellular neurofibrillary tangles of aggregated tau, synaptic dysfunction and neuronal death. There are no cures for AD and current medications only alleviate some disease symptoms. Transgenic rodent models to study Alzheimer's mimic features of human disease such as age-dependent accumulation of abnormal beta-amyloid and tau, synaptic dysfunction, cognitive deficits and neurodegeneration. These models have proven vital for improving our understanding of the molecular mechanisms underlying AD and for identifying promising therapeutic approaches. However, modelling neurodegenerative disease in animals commonly involves aging animals until they develop harmful phenotypes, often coupled with invasive procedures. In vivo studies are also resource, labour, time and cost intensive. We have developed a novel organotypic brain slice culture model to study Alzheimer' disease which brings the potential of substantially reducing the number of rodents used in dementia research from an estimated 20,000 per year. We obtain 36 brain slices from each mouse pup, considerably reducing the numbers of animals required to investigate multiple stages of disease. This tractable model also allows the opportunity to modulate multiple pathways in tissues from a single animal. We believe that this model will most benefit dementia researchers in the academic and drug discovery sectors. We validated the slice culture model against aged mice, showing that the molecular phenotype closely mimics that displayed in vivo, albeit in an accelerated timescale. We showed beneficial outcomes following treatment of slices with agents previously shown to have therapeutic effects in vivo, and we also identified new mechanisms of action of other compounds. Thus, organotypic brain slice cultures from transgenic mouse models expressing Alzheimer's disease-related genes may provide a valid and sensitive replacement for in vivo studies that do not involve behavioural analysis.


[Distribution of 4-methylphenol in warm blooded animals].
The distribution of 4-methylphenol in warm-blooded animals (rabbits) was studied after intragastric administration of the toxin. 4-methylphenol (free or bound) is present largely in the urine, liver and kidney tissues.


The use of breastfeeding pillow to reduce discomfort for breastfeeding mothers.
The process of breastfeeding for newborns in the special care room often experiences obstacles due to diverse factors, such as environmental factors, hospitalization impact, and maternal discomfort during breastfeeding. The aim of this study was to determine whether breastfeeding pillows decrease maternal discomfort during breastfeeding. This research employed a randomized control trial (RCT) design involving 70 participants who were divided into an intervention (n=35) and a control group (n=35) based on the inclusion criteria. The intervention group used a breastfeeding pillow while breastfeeding the baby, and the control group provided ASI (breast milk) as recommended in the treatment room. The data measurement instruments were an observation sheet and the body part discomfort scale (BPDS). The BPDS comprised 4 assessments: the initial assessment, day I assessment, day II assessment, and the final assessment. The results of the GLM-RM analysis showed a significant reduction in maternal discomfort among participants using breastfeeding pillows (P<0.05). Supporting facilities such as breastfeeding pillows are needed to improve maternal comfort to increase the breastfeeding period and ensure optimal nutrition.


A population-based cytogenetic study of adults with acute lymphoblastic leukemia.
Chromosomal abnormalities are increasingly used to risk stratify adults with acute lymphoblastic leukemia. Published data describing the age-specific incidence of chromosomal abnormalities and their prognostic relevance are largely derived from clinical trials. Trials frequently have age restrictions and low recruitment rates. Thus we investigated these factors in a population-based cohort of 349 patients diagnosed during the course of 19 years in the northern part of England. The incidence of most chromosomal abnormalities varied significantly with age. The incidence of t(9;22)(q34;q11) increased in each successive decade, up to 24% among 40- to 49-year-old subjects. Thereafter the incidence reached a plateau. t(4;11)(q21;q23) and t(1;19)(q23;p13) were a rare occurrence among patients older than 60 years of age. In contrast, the frequency of t(8;14)(q24;q32) and t(14;18)(q32;q21) increased with age. High hyperdiploidy occurred in 13% of patients younger than 20 years of age but in only 5% of older patients. The incidence of low hypodiploidy/near-triploidy and complex karyotype increased with age from 4% (15-29 years) to 16% (>or= 60 years). Overall survival varied significantly by age and cytogenetics. Older patients and those with t(9;22), t(4;11), low hypodiploidy/near-triploidy, or complex karyotype had a significantly inferior outcome. These population-based results demonstrate the cytogenetic heterogeneity of adult acute lymphoblastic leukemia. These data will inform the delivery of routine clinical services and the design of new age-focused clinical trials.


InfoColorizer: Interactive Recommendation of Color Palettes for Infographics.
When designing infographics, general users usually struggle with getting desired color palettes using existing infographic authoring tools, which sometimes sacrifice customizability, require design expertise, or neglect the influence of elements' spatial arrangement. We propose a data-driven method that provides flexibility by considering users' preferences, lowers the expertise barrier via automation, and tailors suggested palettes to the spatial layout of elements. We build a recommendation engine by utilizing deep learning techniques to characterize good color design practices from data, and further develop InfoColorizer, a tool that allows users to obtain color palettes for their infographics in an interactive and dynamic manner. To validate our method, we conducted a comprehensive four-part evaluation, including case studies, a controlled user study, a survey study, and an interview study. The results indicate that InfoColorizer can provide compelling palette recommendations with adequate flexibility, allowing users to effectively obtain high-quality color design for input infographics with low effort.


A prospective observational study of predictors of difficult intubation in Indian patients.
During routine preoperative assessment of patients one of the commonest practices is predicting difficulty of intubation. The present study was undertaken to evaluate parameters associated with difficult intubation and to test on new set of patients. At the end, to form simple predictive rule to decreased the number of false alarms. In initial series of 483 Indian population patients we measured age, sex, weight, height, interincisor gap, mandibular length, neck movement, neck circumference, subluxation of mandible, sternocricoid distance, and identified factors associated with difficult intubation. These were applied on next 480 patients of prospective series and simple predictive rule in form of risk sum score was developed. After analyzing initial series data we found that weight (P = 0.033), height (P = 0.034), interincisor gap (P = 0.005), subluxation (P < 0.001), neck movement (P < 0.001), and sternocricoid distance (P = 0.020) were significantly associated with difficult intubation. These six factors were applied on next set of 480 patients to found accuracy of predicting difficult intubation of weight (51.7%), height (83.8%), interincisor gap (80.2%), subluxation (77.7%), neck movement (82.7%), and sternocricoid distance (79.2). Total score greater than 2 predicted 92.8% of difficult laryngoscopies correctly as against 33.9% would be falsely labeled as difficult. Interincisor gap and sternocricoid distance are the two most sensitive factors predicting difficult intubation in Indian patients. However, risk sum score of more than 6 may lead to better anticipation of truly difficult intubations.


Influence of a cell-wall-associated protease on production of alpha-amylase by Bacillus subtilis.
AmyL, an extracellular alpha-amylase from Bacillus licheniformis, is resistant to extracellular proteases secreted by Bacillus subtilis during growth. Nevertheless, when AmyL is produced and secreted by B. subtilis, it is subject to considerable cell-associated proteolysis. Cell-wall-bound proteins CWBP52 and CWBP23 are the processed products of the B. subtilis wprA gene. Although no activity has been ascribed to CWBP23, CWBP52 exhibits serine protease activity. Using a strain encoding an inducible wprA gene, we show that a product of wprA, most likely CWBP52, is involved in the posttranslocational stability of AmyL. A construct in which wprA is not expressed exhibits an increased yield of alpha-amylase. The potential role of wprA in protein secretion is discussed, together with implications for the use of B. subtilis and related bacteria as hosts for the secretion of heterologous proteins.


Acupuncture for osteoarthritis of the knee.
About 10% of people aged over 55 years in the UK report having some restriction of daily activity because of knee osteoarthritis, around 25% of whom are severely disabled. Every year, symptomatic knee osteoarthritis accounts for about 0.5% of all primary care consultations in those over 55 years, rising to 1% in those over 70 years. Acupuncture is increasingly being used within the NHS, particularly for painful conditions such as osteoarthritis, but its place within mainstream healthcare remains controversial. Here we examine what, if anything, acupuncture offers in the management of patients with osteoarthritis of the knee.


Relationship of venom effects to venom antigen and antivenom serum concentrations in a patient with Crotalus atrox envenomation treated with a Fab antivenom.
To describe the association among venom antigenemia, serum antivenom concentrations, and venom effects in a 53-year-old woman who was bitten by a Western Diamondback rattlesnake (Crotalus atrox). The patient was enrolled in a multicenter trial of an investigational Fab antivenom. Her clinical condition and coagulation parameters were monitored for 2 weeks after the bite. After antivenom administration, the progression of the venom's effects was arrested. The antivenom reversed some local venom effects, caused venom antigens to disappear from the blood, and resolved the patient's profound thrombocytopenia (before antivenom, 12,000/mm3; 1 hour after antivenom, 227,000/mm3). Local venom effects recurred twice in the 24 hours after antivenom administration but were easily managed with additional Fab antivenom. Venom antigenemia was detected on days 5 and 8 after the initial treatment and was accompanied in one instance by the new onset of hypofibrinogenemia (119 mg/L) that resolved spontaneously and in both instances by renewed profound thrombocytopenia. Repeat Fab antivenom does no days 6 and 9 were followed by increases in platelet count (from 16,000 to 40,000/mm3 and from 11,000 to 20,000/mm3, respectively) and by the reduction or disappearance of venom antigenemia. The patient sustained no significant bleeding complications, and all laboratory values had returned to normal 2 weeks after the bite. Initial control of local symptoms and coagulopathy was prompt after the administration of Fab antivenom. Repeat doses during the 24 to 36 hours after a bite may be necessary for local control. Recrudescence of coagulopathy was likely due in part to renewed venom antigenemia after clearance of Fab antivenom. The role of Fab antivenom in the treatment of recurrent coagulopathy requires further study.


Identification of candidate circulating cisplatin-resistant biomarkers from epithelial ovarian carcinoma cell secretomes.
The majority of patients diagnosed with advanced epithelial ovarian carcinoma (EOC) relapse with resistant disease, and there are no biomarkers that possess clinical utility to identify or monitor these patients. This study aimed to identify secreted proteins ('secretome') collected from human EOC cell lines that differ in their inherent platinum sensitivity. Secreted proteins collected from conditioned medium from ovarian cancer cell lines that vary in their sensitivity to cisplatin were digested with trypsin and analysed by liquid chromatography-tandem mass spectrometry for peptide identification. Of the 1688 proteins identified, 16 possessed significant differential abundances (P<0.05) between the platinum-resistant and -sensitive cell lines. A number of these were verified by immunoblot, including COL11A1, which was also found to be associated with worse progression-free survival (PFS; N=723) and overall survival (OS; N=1183) as assessed from publicly available transcript expression data from ovarian cancer tumour specimens. Secretome proteomics of EOC cells resulted in the identification of a novel candidate biomarker, COL11A1. The expression level of COL11A1 correlates to worse PFS and OS, and is predicted to reside in peripheral circulation making this an attractive candidate for validation in sera as a biomarker of cisplatin resistance and poor outcome.


Genomics-assisted breeding in fruit trees.
Recent advancements in genomic analysis technologies have opened up new avenues to promote the efficiency of plant breeding. Novel genomics-based approaches for plant breeding and genetics research, such as genome-wide association studies (GWAS) and genomic selection (GS), are useful, especially in fruit tree breeding. The breeding of fruit trees is hindered by their long generation time, large plant size, long juvenile phase, and the necessity to wait for the physiological maturity of the plant to assess the marketable product (fruit). In this article, we describe the potential of genomics-assisted breeding, which uses these novel genomics-based approaches, to break through these barriers in conventional fruit tree breeding. We first introduce the molecular marker systems and whole-genome sequence data that are available for fruit tree breeding. Next we introduce the statistical methods for biparental linkage and quantitative trait locus (QTL) mapping as well as GWAS and GS. We then review QTL mapping, GWAS, and GS studies conducted on fruit trees. We also review novel technologies for rapid generation advancement. Finally, we note the future prospects of genomics-assisted fruit tree breeding and problems that need to be overcome in the breeding.


Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery.
The PREVENT III study was a prospective, randomized, double-blinded, multicenter phase III trial of a novel molecular therapy (edifoligide; E2F decoy) for the prevention of vein graft failure in patients undergoing infrainguinal revascularization for critical limb ischemia (CLI). From November 2001 through October 2003, 1404 patients with CLI were randomized to a single intraoperative ex vivo vein graft treatment with edifoligide or placebo. After surgery, patients underwent graft surveillance by duplex ultrasonography and were followed up for index graft and limb end points to 1 year. A blinded Clinical Events Classification committee reviewed all index graft end points. The primary study end point was the time to nontechnical index graft reintervention or major amputation due to index graft failure. Secondary end points included all-cause graft failure, clinically significant graft stenosis (>70% by angiography or severe stenosis by ultrasonography), amputation/reintervention-free survival, and nontechnical primary graft patency. Event rates were based on Kaplan-Meier estimates. Time-to-event end points were compared by using the log-rank test. Demographics, comorbidities, and procedural details reflected a population with CLI and diffuse atherosclerosis. Tissue loss was the presenting symptom in 75% of patients. High-risk conduits were used in 24% of cases, including an alternative vein in 20% (15% spliced vein and 5% non-great saphenous vein) and 6% less than 3 mm in diameter; 14% of the cases were reoperative bypass grafts. Most (65%) grafts were placed to infrapopliteal targets. Perioperative (30-day) mortality occurred in 2.7% of patients. Major morbidity included myocardial infarction in 4.7% and early graft occlusion in 5.2% of patients. Ex vivo treatment with edifoligide was well tolerated. There was no significant difference between the treatment groups in the primary or secondary trial end points, primary graft patency, or limb salvage. A statistically significant improvement was observed in secondary graft patency (estimated Kaplan-Meier rates were 83% edifoligide and 78% placebo; P = .016) within 1 year. The reduction in secondary patency events was manifest within 30 days of surgery (the relative risk for a 30-day event for edifoligide was 0.45; 95% confidence interval, 0.27-0.76; P = .005). For the overall cohort at 1 year, the estimated Kaplan-Meier rate for survival was 84%, that for primary patency was 61%, that for primary assisted patency was 77%, that for secondary patency was 80%, and that for limb salvage was 88%. In this prospective, randomized, placebo-controlled clinical trial, ex vivo treatment of lower extremity vein grafts with edifoligide did not confer protection from reintervention for graft failure.


Antibodies to junctional sarcoplasmic reticulum proteins: probes for the Ca2+-release channel.
The junctional face membrane plays a key role in excitation-contraction coupling in skeletal muscle. A protein of 350 kDa, tentatively identified as a component of the junctional feet, connects transverse tubules to terminal cisternae of sarcoplasmic reticulum [Kawamoto, Brunschwig, Kim & Caswell (1986) J. Cell Biol. 103, 1405-1414]. The membrane topology and protein composition of sarcoplasmic reticulum Ca2+-release channels of rabbit skeletal muscle were investigated using an immunological approach, with anti-(junctional face membrane) and anti-(350 kDa protein) polyclonal antibodies. Upon preincubation of the terminal cisternae with anti-(junctional face membrane) antibodies, Ca2+-ATPase and Ca2+-loading activities were not affected, whereas anti-(350 kDa protein) antibodies stimulated Ca2+-ATPase activity by 25% and inhibited Ca2+-loading activity by 50% (at an antibody/terminal cisternae protein ratio of 1:1). Specific photolabelling of terminal cisternae proteins with [14C]doxorubicin was prevented by both anti-(junctional face membrane) and anti-(350 kDa protein) antibodies. Stimulation of Ca2+ release by doxorubicin was prevented by both anti-(junctional face membrane) and anti-(350 kDa protein) antibodies. Half-maximal inhibition was obtained at an antibody/terminal cisternae protein ratio of 1:1. Kinetic measurements of Ca2+ release indicated that anti-(350 kDa protein) antibodies prevented Ca2+-induced Ca2+ release, whereas the ATP-stimulation and the inhibition by Mg2+ were not affected. These results suggest that: (i) Ca2+- and doxorubicin-induced Ca2+ release is mediated by Ca2+ channels which are selectively localized in the junctional face membrane; (ii) the 350 kDa protein is a component of the Ca2+-release channel in native terminal cisternae vesicles; and (iii) the Ca2+-activating site of the channel is separate from other allosteric sites.


Long-term immunogenicity of preservative-free hepatitis B vaccine formulations in adults.
Vaccination with recombinant hepatitis B vaccines is highly effective in preventing hepatitis B infection. Recently, a preservative-free (PF) formulation of hepatitis B vaccine [GlaxoSmithKline (GSK) Biologicals, Rixensart, Belgium] has been licensed. The immunogenicity of the PF hepatitis B vaccine and antibody persistence 6 years later was assessed in this study. This formulation was compared with the preservative- containing (PC) formulation of the vaccine and a low-preservative (LP) content formulation. Five hundred forty-one healthy adult subjects were evaluated in the primary study. Over 94% of the subjects in the three study groups had seroprotective anti-HBs antibody concentrations (>or=10 mIU/ml) 1 month after completing primary vaccination. Antibody measurements in 242 healthy adults who returned for the follow-up study and who had received primary vaccination 6 years earlier showed that over 81% of subjects in the three study groups still had anti-HBs antibody concentrations >or=10 mIU/ml. No apparent differences in antibody decline or distribution between the study groups were observed. These results indicate that the removal of preservatives from the hepatitis B vaccine does not affect adversely its immunogenicity both in the short and in the longer term.


Source of funding and results of studies of health effects of mobile phone use: systematic review of experimental studies.
There is concern regarding the possible health effects of cellular telephone use. We examined whether the source of funding of studies of the effects of low-level radiofrequency radiation is associated with the results of studies. We conducted a systematic review of studies of controlled exposure to radiofrequency radiation with health-related outcomes (electroencephalogram, cognitive or cardiovascular function, hormone levels, symptoms, and subjective well-being). We searched EMBASE, Medline, and a specialist database in February 2005 and scrutinized reference lists from relevant publications. Data on the source of funding, study design, methodologic quality, and other study characteristics were extracted. The primary outcome was the reporting of at least one statistically significant association between the exposure and a health-related outcome. Data were analyzed using logistic regression models. Of 59 studies, 12 (20%) were funded exclusively by the telecommunications industry, 11 (19%) were funded by public agencies or charities, 14 (24%) had mixed funding (including industry), and in 22 (37%) the source of funding was not reported. Studies funded exclusively by industry reported the largest number of outcomes, but were least likely to report a statistically significant result: The odds ratio was 0.11 (95% confidence interval, 0.02-0.78), compared with studies funded by public agencies or charities. This finding was not materially altered in analyses adjusted for the number of outcomes reported, study quality, and other factors. The interpretation of results from studies of health effects of radiofrequency radiation should take sponsorship into account.


The UK EndoVascular Aneurysm Repair (EVAR) trials: randomised trials of EVAR versus standard therapy.
To assess the efficacy of endovascular aneurysm repair (EVAR) against standard alternative management in patients with large abdominal aortic aneurysm (AAA). Two national, multicentre randomised trials - EVAR trials 1 and 2. Patients were recruited from 38 out of 41 eligible UK hospitals. Men and women aged at least 60 years, with an AAA measuring at least 5.5 cm on a computerised tomography scan that was regarded as anatomically suitable for EVAR, were assessed for fitness for open repair. Patients considered fit were randomised to EVAR or open repair in EVAR trial 1 and patients considered unfit were randomised to EVAR or no intervention in EVAR trial 2. EVAR, open repair or no intervention. The primary outcome was mortality (operative, all-cause and AAA related). Patients were flagged at the UK Office for National Statistics with centrally coded death certificates assessed by an Endpoints Committee. Power calculations based upon mortality indicated that 900 and 280 patients were required for EVAR trials 1 and 2, respectively. Secondary outcomes were graft-related complications and reinterventions, adverse events, renal function, health-related quality of life and costs. Cost-effectiveness analyses were performed for both trials. Recruitment occurred between 1 September 1999 and 31 August 2004, with targets exceeded in both trials: 1252 randomised into EVAR trial 1 (626 to EVAR) and 404 randomised into EVAR trial 2 (197 to EVAR). Follow-up closed in December 2009 with very little loss to follow-up (1%). In EVAR trial 1, 30-day operative mortalities were 1.8% and 4.3% in the EVAR and open-repair groups, respectively: adjusted odds ratio 0.39 [95% confidence interval (CI) 0.18 to 0.87], p = 0.02. During a total of 6904 person-years of follow-up, 524 deaths occurred (76 AAA related). Overall, there was no significant difference between the groups in terms of all-cause mortality: adjusted hazard ratio (HR) 1.03 (95% CI 0.86 to 1.23), p = 0.72. The EVAR group did demonstrate an early advantage in terms of AAA-related mortality, which was sustained for the first few years, but lost by the end of the study, primarily due to fatal endograft ruptures: adjusted HR 0.92 (95% CI 0.57 to 1.49), p = 0.73. The EVAR procedure was more expensive than open repair (mean difference £1177) and not found to be cost-effective, but the model was sensitive to alternative assumptions. In EVAR trial 2, during a total of 1413 person-years of follow-up, a total of 305 deaths occurred (78 AAA related). The 30-day operative mortality was 7.3% in the EVAR group. However, this group later demonstrated a significant advantage in terms of AAA-related mortality, but this became apparent only after 4 years: overall adjusted HR 0.53 (95% CI 0.32 to 0.89), p = 0.02. Sadly, this advantage did not result in any benefit in terms of all-cause mortality: adjusted HR 0.99 (95% CI 0.78 to 1.27), p = 0.97. Overall, EVAR was more expensive than no intervention (mean difference £10,222) and not found to be cost-effective. EVAR offers a clear operative mortality benefit over open repair in patients fit for both procedures, but this early benefit is not translated into a long-term survival advantage. Among patients unfit for open repair, EVAR is associated with a significant long-term reduction in AAA-related mortality but this does not appear to influence all-cause mortality. Current Controlled Trials ISRCTN 55703451. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 9. See the HTA programme website for further project information.


Impact of the COVID-19 Public Health Crisis and a Structured COVID Unit on Physician Behaviors in Code Status Ordering.
Purpose: Code status orders are standard practice impacting end-of-life care for individuals. This study reviews the impact of a COVID unit on physician behaviors towards goal-concordant end-of-life care at an urban academic tertiary-care hospital. Methods: We conducted a retrospective cohort study of code status ordering on adult inpatients comparing the pre-pandemic period to patients who tested positive, negative and were not tested during the pandemic from January 1, 2019, to December 31, 2020. Results: We analyzed 59,471 unique patient encounters (n = 35,317 pre-pandemic and n = 24,154 during). 1,631 cases of COVID-19 were seen. The rate of code status orders among all inpatients increased from 22% pre-pandemic to 29% during the pandemic (P < .001). Code status orders increased for both patients who were COVID-negative (32% P < .001) and COVID-positive (65% P < .001). Being in a cohorted COVID unit increased code status ordering by an odds of 4.79 (P < .001). Compared to the pre-pandemic cohort, the COVID-positive cohort is less female (50% to 56% P < .001), more Black (66% to 61% P < .001), more Hispanic (6.5% to 5%) and less white (26% to 30% P < .001). Compared to Black patients, white patients had lower odds (.86) of code status ordering (P < .001). Other race/ethnicity categories were not significant. Conclusions: Code status ordering remains low. Compared to pre-pandemic rates, the frequency of orders placed significantly increased for all patients during the pandemic. The largest increase occurred in patients with COVID-19. This increase likely occurred due to protocols in the COVID unit and disease uncertainty.


Progression of Primary Angle Closure Suspect to Primary Angle Closure and Associated Risk Factors: The Handan Eye Study.
To investigate the progression of angle closure from primary angle closure suspect (PACS) and associated risk factors over five years in rural Chinese adults. In this population-based cohort study, subjects aged ≥30 years old with unilateral or bilateral PACS at baseline of the Handan Eye Study who participated in the follow-up and had undergone baseline and follow-up gonioscopic examinations were included. The progression of angle closure was defined as the presence of primary angle closure (PAC)/primary angle-closure glaucoma (PACG) during the follow-up in subjects with PACS at baseline. Ocular data from the right eye were used for cases with bilateral PACS and unilateral PACS in the right eye at baseline. For those with unilateral PACS in the left eye at baseline, ocular data from the left eye were used. Demographic information, ocular conditions, personal history, and systemic comorbidities were compared between the progression and nonprogression groups. Univariate and multivariate logistic regression was performed to identify the baseline risk factors for progression of angle closure. In total, 526 subjects (111 male, 415 female) with baseline PACS were finally enrolled. The overall progression of PACS to angle closure was 32 cases (31 PAC, 1 PACG). Logistic regression analysis identified narrower mean angle width (P < 0.001) to be associated with the progression. We report the progression from baseline PACS to PAC/PACG after five years. And baseline mean angle width was determined to be independent predictive risk factor for the progression of angle closure.


Rapid diversification and hybridization have shaped the dynamic history of the genus Elaenia.
Multi-locus data have proven invaluable in phylogenetic reconstruction and species delimitation. However, the mixed genetic signal from different loci can make inference of evolutionary history challenging and may produce incongruences depending on analytical and marker choice. Aside from incomplete lineage sorting (ILS) following diversification events that have had little time for deep differentiation, the most common causes of incongruent phylogenies are genetic introgression confounding a bifurcating evolutionary trajectory. In this study, we used multi-locus analytical approaches on sequence data of nine loci from 80 individuals of over 20 Neotropical Elaenia flycatcher species to examine the systematics, molecular phylogeny and species limits of this complex genus. Our results provide a robust phylogeny and estimates of species limits within Elaenia, but point to important cases of incongruences among phylogenies based on different analytical approaches. Simulations and estimates of divergence times provide reasonable explanations for the incongruent placement of some Elaenia taxa, pointing to multiple cases of both ILS and introgression within the genus. Molecular dating of major evolutionary events revealed intensive diversification during the Pleistocene, suggesting a central role of climate oscillations in the evolution of Elaenia flycatchers.


Oocyte competence is independent of the ovulation trigger adopted: a large observational study in a setting that entails vitrified-warmed single euploid blastocyst transfer.
To assess whether the GnRH-agonist or urinary-hCG ovulation triggers affect oocyte competence in a setting entailing vitrified-warmed euploid blastocyst transfer. Observational study (April 2013-July 2018) including 2104 patients (1015 and 1089 in the GnRH-a and u-hCG group, respectively) collecting ≥1 cumulus-oocyte-complex (COC) and undergoing ICSI with ejaculated sperm, blastocyst culture, trophectoderm biopsy, comprehensive-chromosome-testing, and vitrified-warmed transfers at a private clinic. The primary outcome measure was the euploid-blastocyst-rate per inseminated oocytes. The secondary outcome measure was the maturation-rate per COCs. Also, the live-birth-rate (LBR) per transfer and the cumulative-live-birth-delivery-rate (CLBdR) among completed cycles were investigated. All data were adjusted for confounders. The generalized-linear-model adjusted for maternal age highlighted no difference in the mean euploid-blastocyst-rate per inseminated oocytes in either group. The LBR per transfer was similar: 44% (n=403/915) and 46% (n=280/608) in GnRH-a and hCG, respectively. On the other hand, a difference was reported regarding the CLBdR per oocyte retrieval among completed cycles, with 42% (n=374/898) and 25% (n=258/1034) in the GnRh-a and u-hCG groups, respectively. Nevertheless, this variance was due to a lower maternal age and higher number of inseminated oocytes in the GnRH-a group, and not imputable to the ovulation trigger itself (multivariate-OR=1.3, 95%CI: 0.9-1.6, adjusted p-value=0.1). GnRH-a trigger is a valid alternative to u-hCG in freeze-all cycles, not only for patients at high risk for OHSS. Such strategy might increase the safety and flexibility of controlled-ovarian-stimulation with no impact on oocyte competence and IVF efficacy.


All-cause mortality for cohabiting spouses of stroke survivors: Evidence from Swedish national registries.
Spousal concordance for cardiovascular risk factors and lifestyle behaviors may affect prevalence rates of diabetes, hypertension, and stroke. Spouses of stroke survivors, therefore, would be expected to have elevated mortality rates, but this has not been established. Thus, the aim of this study was to investigate whether cohabitant spouses of stroke survivors have higher mortality rates compared to a matched reference cohort. Data for this population-based cohort study were extracted from Swedish national registries from 2010 to 2016. The national sample consisted of 13,049 spouses of first ever stroke survivors and a reference cohort of 51,685 cohabitant individuals from the general population matched by age, gender, and place of residence. Effects on mortality were analyzed using Cox proportional hazard survival analyses. Female and male spouses of stroke survivors were found to have 5-year hazard ratios of death of 1.26 (95% confidence interval 1.17, 1.36) and 1.24 (95% confidence interval 1.16, 1.33), respectively, when compared to the reference cohort. Both female and male spouses had higher mortality from diseases in the circulatory system compared to the reference cohort. Spouses of stroke survivors have higher mortality rates than a matched reference population that persist for a minimum of 5 years. Policy-makers should acknowledge and address the health status of spouses when evaluating and planning the health and social care of stroke survivors.


Peptide-Based Optical/Electronic Materials: Assembly and Recent Applications in Biomedicine, Sensing, and Energy Storage.
The unique optical and electronic properties of living systems are impressive. Peptide-based supramolecular self-assembly systems attempt to mimic these properties by preparation optical/electronic function materials with specific structure through simple building blocks, rational molecular design, and specific kinetic stimulation. From the perspective of building blocks and assembly strategies, the unique optical and electronic properties of peptide-based nanostructures, including peptides self-assembly and peptides regulate the assembly of external function subunits, are systematically reviewed. Additionally, their applications in biomedicine, sensing, and energy storage are also highlighted. This bioinspired peptide-based function material is one of the hot candidates for the new generation of green intellect materials, with many advantages such as biocompatibility, environmental friendliness, and adjustable morphology.


Eradicating BVD, reviewing Irish programme data and model predictions to support prospective decision making.
Bovine Viral Diarrhoea is an infectious production disease of major importance in many cattle sectors of the world. The infection is predominantly transmitted by animal contact. Postnatal infections are transient, leading to immunologically protected cattle. However, for a certain window of pregnancy, in utero infection of the foetus results in persistently infected (PI) calves being the major risk of BVD spread, but also an efficient target for controlling the infection. There are two acknowledged strategies to identify PI animals for removal: tissue tag testing (direct; also known as the Swiss model) and serological screening (indirect by interpreting the serological status of the herd; the Scandinavian model). Both strategies are effective in reducing PI prevalence and herd incidence. During the first four years of the Irish national BVD eradication programme (2013-16), it has been mandatory for all newborn calves to be tested using tissue tag testing. During this period, PI incidence has substantially declined. In recent times, there has been interest among stakeholders in a change to an indirect testing strategy, with potential benefit to the overall programme, particularly with respect to cost to farmers. Advice was sought on the usefulness of implementing the necessary changes. Here we review available data from the national eradication programme and strategy performance predictions from an expert system model to quantify expected benefits of the strategy change from strategic, budgetary and implementation points of view. Key findings from our work include (i) drawbacks associated with changes to programme implementation, in particular the loss of epidemiological information to allow real-time monitoring of eradication progress or to reliably predict time to eradication, (ii) the fact that only 25% of the herds in the Irish cattle sector (14% beef, 78% dairy herds) would benefit financially from a change to serosurveillance, with half of these participants benefiting by less than EUR 75 per annum at herd level or an average of EUR 1.22 per cow, and (iii) opportunities to enhance the effectiveness of the current programme, particularly in terms of time to eradication, through enforced compliance with PI removal as currently outlined in programme recommendations. The assembled information provides scientific arguments, contributing to an informed debate of the pros and cons of a change in eradication strategy in Ireland.


Long-term effective population sizes, temporal stability of genetic composition and potential for local adaptation in anadromous brown trout (Salmo trutta) populations.
We examined the long-term temporal (1910s to 1990s) genetic variation at eight microsatellite DNA loci in brown trout (Salmo trutta L) collected from five anadromous populations in Denmark to assess the long-term stability of genetic composition and to estimate effective population sizes (Ne). Contemporary and historical samples consisted of tissue and archived scales, respectively. Pairwise thetaST estimates, a hierarchical analysis of molecular variance (amova) and multidimensional scaling analysis of pairwise genetic distances between samples revealed much closer genetic relationships among temporal samples from the same populations than among samples from different populations. Estimates of Ne, using a likelihood-based implementation of the temporal method, revealed Ne >or= 500 in two of three populations for which we have historical data. A third population in a small (3 km) river showed Ne >or= 300. Assuming a stepping-stone model of gene flow we considered the relative roles of gene flow, random genetic drift and selection to assess the possibilities for local adaptation. The requirements for local adaptation were fulfilled, but only adaptations resulting from strong selection were expected to occur at the level of individual populations. Adaptations resulting from weak selection were more likely to occur on a regional basis, i.e. encompassing several populations. Ne appears to have declined recently in at least one of the studied populations, and the documented recent declines of many other anadromous brown trout populations may affect the persistence of local adaptation.