Analysis of 45 candidate genes for disease modifying activity in multiple sclerosis.
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. As little is conclusively known about MS disease mechanisms, we have selected a variety of candidate genes that may influence the prognosis of the disease based on their function. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of on MS disease severity. The MS cases selected represent the prognostic best 5 % (benign MS) and worst 5 % (malignant MS) of cases in terms of clinical outcome assessed by the EDSS. Genotyping the two sets of MS patients (112 benign and 51 malignant) and a replication cohort from Sardinia provided no evidence to suggest that the genes selected have any outcome modifying activity, although small effects of these genes cannot be ruled out.


Torsion-angle molecular dynamics as a new efficient tool for NMR structure calculation.
Molecular dynamics in torsion-angle space was applied to nuclear magnetic resonance structure calculation using nuclear Overhauser effect-derived distances and J-coupling-constant-derived dihedral angle restraints. Compared to two other commonly used algorithms, molecular dynamics in Cartesian space and metric-matrix geometry combined with Cartesian molecular dynamics, the method shows increased computational efficiency and success rate for large proteins, and it shows a dramatically increased radius of convergence for DNA. The torsion-angle molecular dynamics algorithm starts from an extended strand conformation and proceeds in four stages: high-temperature torsion-angle molecular dynamics, slow-cooling torsion-angle molecular dynamics, Cartesian molecular dynamics, and minimization. Tests were carried out using experimental NMR data for protein G, interleukin-8, villin 14T, and a 12 base-pair duplex of DNA, and simulated NMR data for bovine pancreatic trypsin inhibitor. For villin 14T , a monomer consisting of 126 residues, structure determination by torsion-angle molecular dynamics has a success rate of 85%, a more than twofold improvement over other methods. In the case of the 12 base-pair DNA duplex, torsion-angle molecular dynamics had a success rate of 52% while Cartesian molecular dynamics and metric-matrix distance geometry always failed.


Results of a patient-directed survey on frequency of family history of glaucoma in 2170 patients.
To evaluate in different types of glaucoma frequency of family history of glaucoma (FHG), age at diagnosis, glaucoma risk in relatives, and acceptance rate of genetic glaucoma tests. To assess stage of visual field loss (VFL) in relation to FHG. Using standardized questions whether an ophthalmologist had found or excluded glaucoma or ocular hypertension (OH), 2170 patients with glaucoma or OH interviewed all their first and second degree relatives. One thousand three hundred thirty-eight patients had POAG, 233 primary angle closure glaucoma (PACG), 148 OH, 153 normal tension glaucoma (NTG), 50 pigmentary glaucoma (PG), and 66 pseudoexfoliation glaucoma (PEX). Frequency of FHG was 40% in POAG, without significant differences compared with NTG (P = 0.08), OH (P = 0.5), PACG (P = 0.4), and PG (P = 0.6). There were significant differences in age at diagnosis between the glaucomas (smallest between group P < 0.0001). Patients with FHG were significantly younger at diagnosis than patients without FHG in all types of glaucoma (all P values ≤ 0.03), except NTG and PEX. Patients' siblings and mothers had the highest detection probability for glaucoma in POAG and OH. There was no significant relation between stage of VFL and FHG in POAG (P = 0.6). Sixty-eight percent of patients would participate in genetic glaucoma tests. There is a similarly high genetic disposition in all types of glaucoma. Disease risk was especially high in mothers and siblings. In patients with FHG, knowledge of genetic disposition of the glaucomas may have led to earlier diagnosis. This highlights the need for glaucoma awareness campaigns.


In meso structure of the cobalamin transporter, BtuB, at 1.95 A resolution.
Crystals of the apo form of the vitamin B12 and colicin receptor, BtuB, that diffract to 1.95 A have been grown by the membrane-based in meso technique. The structure of the protein differs in several details from that of its counterpart grown by the more traditional, detergent-based (in surfo) method. Some of these differences include (i) the five N-terminal residues are resolved in meso, (ii) residues 57-62 in the hatch domain and residues 574-581 in loop 21-22 are disordered in meso and are ordered in surfo, (iii) residues 278-287 in loop 7-8 are resolved in meso, (iv) residues 324-331 in loop 9-10, 396-411 in loop 13-14, 442-458 in loop 15-16 and 526-541 in loop 19-20 have large differences in position between the two crystal forms, as have residues 86-96 in the hatch domain, and (v) the conformation of residues 6 and 7 in the Ton box (considered critical to signal transduction and substrate transport) are entirely different in the two structures. Importantly, the in meso orientation of residues 6 and 7 is similar to that of the vitamin B12-charged state. These data suggest that the "substrate-induced" 180 degrees -rotation of residues 6 and 7 reported in the literature may not be a unique signalling event. The extent to which these findings agree with structural, dynamic and functional insights gleaned from site-directed spin labelling and electron paramagnetic resonance measurements is evaluated. Packing in in meso grown crystals is dense and layered, consistent with the current model for crystallogenesis of membrane proteins in lipidic mesophases. Layered packing has been used to locate the transmembrane hydrophobic surface of the protein. Generally, this is consistent with tryptophan, tyrosine, lipid and CalphaB-factor distributions in the protein, and with predictions based on transfer free energy calculations.


Metallization and superconductivity in methane doped by beryllium at low pressure.
As one of the simplest hydrocarbons, methane (CH4) has great potential in the research of superconductors. However, the metallization of CH4 has been an issue for a long time. Here, we report the structure, metallization, and superconductivity of CH4 doped by Be at low pressures, based on first-principles calculations. The result shows that the thermodynamically stable BeCH4 with P1[combining macron] space-group can transform into a metal at ambient pressure. This ternary hydride BeCH4 exhibits a superconductivity of ∼6 K below 25.6 GPa. Interestingly, the superconducting critical temperature of BeCH4 can reach ∼30 K at 80 GPa in the form of an a-P1 space-group phase. The charge transfer from Be to CH4 molecules plays an important role in the superconductivity. Our results present a novel way to realize the metallization of methane at relative pressures and indicate that the doped methane is a potential candidate for seeking high temperature and low pressure superconductivity.


Systematic Review of Model-Based Economic Evaluations of Treatments for Alzheimer's Disease.
Numerous economic evaluations using decision-analytic models have assessed the cost effectiveness of treatments for Alzheimer's disease (AD) in the last two decades. It is important to understand the methods used in the existing models of AD and how they could impact results, as they could inform new model-based economic evaluations of treatments for AD. The aim of this systematic review was to provide a detailed description on the relevant aspects and components of existing decision-analytic models of AD, identifying areas for improvement and future development, and to conduct a quality assessment of the included studies. We performed a systematic and comprehensive review of cost-effectiveness studies of pharmacological treatments for AD published in the last decade (January 2005 to February 2015) that used decision-analytic models, also including studies considering patients with mild cognitive impairment (MCI). The background information of the included studies and specific information on the decision-analytic models, including their approach and components, assumptions, data sources, analyses, and results, were obtained from each study. A description of how the modeling approaches and assumptions differ across studies, identifying areas for improvement and future development, is provided. At the end, we present our own view of the potential future directions of decision-analytic models of AD and the challenges they might face. The included studies present a variety of different approaches, assumptions, and scope of decision-analytic models used in the economic evaluation of pharmacological treatments of AD. The major areas for improvement in future models of AD are to include domains of cognition, function, and behavior, rather than cognition alone; include a detailed description of how data used to model the natural course of disease progression were derived; state and justify the economic model selected and structural assumptions and limitations; provide a detailed (rather than high-level) description of the cost components included in the model; and report on the face-, internal-, and cross-validity of the model to strengthen the credibility and confidence in model results. The quality scores of most studies were rated as fair to good (average 87.5, range 69.5-100, in a scale of 0-100). Despite the advancements in decision-analytic models of AD, there remain several areas of improvement that are necessary to more appropriately and realistically capture the broad nature of AD and the potential benefits of treatments in future models of AD.


Management of peripheral nerve defects: external fixator-assisted primary neurorrhaphy.
Controlled joint extension followed by gradual distraction with use of an external fixator may facilitate primary repair of peripheral nerve defects by permitting end-to-end repair without tension. The hypothesis of the present study was that gradual lengthening of nerve repairs with use of incremental distraction would provide superior results compared with grafting or repair under tension. A median nerve segment measuring four times the diameter of the nerve was resected in thirty-six rabbits to create a 7-mm gap in the nerve. Neurorrhaphy was performed with use of one of three techniques. In Group 1 (cable graft), a tension-free medial antebrachial cutaneous graft was placed to allow full range of motion of the elbow postoperatively. In Group 2 (end-to-end repair without distraction), the elbow was externally fixed in hyperflexion and the nerve was repaired end-to-end. At fourteen days, the fixator was removed and unprotected elbow motion was permitted. In Group 3 (end-to-end repair with gradual distraction), the elbow was externally fixed in hyperflexion and primary neurorrhaphy was performed. At fourteen days, the elbow was extended 10 degrees every other day with use of the articulated external fixator until full extension was achieved. Median nerve amplitude, latency, and nerve-conduction velocity; flexor digitorum superficialis single-twitch force generation and maximum tetanic force generation; muscle mass; and elbow range of motion were measured at three or six months. In addition, histologic analysis of the median nerve distal to the repair site and the morphometry of the neuromuscular junction in the flexor digitorum superficialis were performed at six months. All rabbits regained full active and passive range of motion. At three months, the nerve-conduction velocities in Groups 2 and 3 were significantly greater than that in Group 1. At six months, the nerve-conduction velocities and amplitudes in Group 3 were significantly greater than those in Groups 1 and 2. At six months, the tetanic force in Group 3 was significantly greater than those in Groups 1 and 2. There were no significant differences in muscle mass among the groups. There were no significant differences in histological findings among the three groups, although there was a trend toward larger fiber size in Group 3 as compared with the other two groups. The neuromuscular junctions in Group 3 had a significantly larger surface area than did those in Group 1 (p = 0.002) and Group 2 (p = 0.034). The use of an articulated external fixator and controlled gradual distraction appears to facilitate the treatment of peripheral nerve defects.


A murine inhalation model to characterize pulmonary exposure to dry Aspergillus fumigatus conidia.
Most murine models of fungal exposure are based on the delivery of uncharacterized extracts or liquid conidia suspensions using aspiration or intranasal approaches. Studies that model exposure to dry fungal aerosols using whole body inhalation have only recently been described. In this study, we aimed to characterize pulmonary immune responses following repeated inhalation of conidia utilizing an acoustical generator to deliver dry fungal aerosols to mice housed in a nose only exposure chamber. Immunocompetent female BALB/cJ mice were exposed to conidia derived from Aspergillus fumigatus wild-type (WT) or a melanin-deficient (Δalb1) strain. Conidia were aerosolized and delivered to mice at an estimated deposition dose of 1×105 twice a week for 4 weeks (8 total). Histopathological and immunological endpoints were assessed 4, 24, 48, and 72 hours after the final exposure. Histopathological analysis showed that conidia derived from both strains induced lung inflammation, especially at 24 and 48 hour time points. Immunological endpoints evaluated in bronchoalveolar lavage fluid (BALF) and the mediastinal lymph nodes showed that exposure to WT conidia led to elevated numbers of macrophages, granulocytes, and lymphocytes. Importantly, CD8+ IL17+ (Tc17) cells were significantly higher in BALF and positively correlated with germination of A. fumigatus WT spores. Germination was associated with specific IgG to intracellular proteins while Δalb1 spores elicited antibodies to cell wall hydrophobin. These data suggest that inhalation exposures may provide a more representative analysis of immune responses following exposures to environmentally and occupationally prevalent fungal contaminants.


Impact of Self-Monitoring of Blood Pressure on Processes of Hypertension Care and Long-Term Blood Pressure Control.
Background Self-monitoring of blood pressure (SMBP) improves blood pressure (BP) outcomes at 12-months, but information is lacking on how SMBP affects hypertension care processes and longer-term BP outcomes. Methods and Results We pooled individual participant data from 4 randomized clinical trials of SMBP in the United Kingdom (combined n=2590) with varying intensities of support. Multivariable random effects regression was used to estimate the probability of antihypertensive intensification at 12 months for usual care versus SMBP. Using these data, we simulated 5-year BP control rates using a validated mathematical model. Trial participants were mostly older adults (mean age 66.6 years, SD 9.5), male (53.9%), and predominantly white (95.6%); mean baseline BP was 151.8/85.0 mm Hg. Compared with usual care, the likelihood of antihypertensive intensification increased with both SMBP with feedback to patient or provider alone (odds ratio 1.8, 95% CI 1.2-2.6) and with telemonitoring or self-management (3.3, 2.5-4.2). Over 5 years, we estimated 33.4% BP control (<140/90 mm Hg) with usual care (95% uncertainty interval 27.7%-39.4%). One year of SMBP with feedback to patient or provider alone achieved 33.9% (28.3%-40.3%) BP control and SMBP with telemonitoring or self-management 39.0% (33.1%-45.2%) over 5 years. If SMBP interventions and associated BP control processes were extended to 5 years, BP control increased to 52.4% (45.4%-59.8 %) and 72.1% (66.5%-77.6%), respectively. Conclusions One year of SMBP plus telemonitoring or self-management increases the likelihood of antihypertensive intensification and could improve BP control rates at 5 years; continuing SMBP for 5 years could further improve BP control.


Heterogeneous treatment effects: what does a regression estimate?
Regressions that control for confounding factors are the workhorse of evaluation research. When treatment effects are heterogeneous, however, the workhorse regression leads to estimated treatment effects that lack behavioral interpretations even when the selection on observables assumption holds. Regressions that use propensity scores as weights and regressions based on random coefficients or hierarchical models provide alternative estimators that have clear behavioral interpretations. Assuming selection on the observables and heterogeneous treatment effects, this article (a) shows what is identified as the treatment effect in the workhorse model, (b) shows what is identified as the treatment effect by propensity score models and models based on random coefficients/ hierarchical models, and (c) provides advice for evaluators.


The liposhaver in facial plastic surgery. A multi-institutional experience.
To report a multi-institutional clinical experience with the liposhaver in facial plastic surgery. Nonrandomized, nonblinded, multi-institutional evaluation of the liposhaver in a clinical setting in patients presenting for cosmetic facial liposuction. Cosmetic facial surgery with the liposhaver was performed in 19 patients (21 procedures) who underwent submental lipectomy, facelift with defatting beneath the facelift flap, and/or correction of deep nasolabial folds. Standardized preoperative and postoperative photographs were obtained. Fat obtained from the abdomen of 1 patient was also studied histologically. This fat was excised sharply and was then liposhaved at varying oscillation speeds. Subjective evaluation by the operating surgeons. The liposhaver was used successfully in all cases. The fat was cleanly shaved and the contour results were even, without dimpling or asymmetry. Operative time was comparable to that for conventional liposuction. Preferred cannula sizes and settings were determined. There were no cases of facial nerve injury, no evidence of increased bleeding intraoperatively, and no hematomas in the immediate postoperative period. One patient developed a small hematoma on postoperative day 5 that was effectively treated with needle aspiration and a pressure dressing. Histologic evaluation of liposhaved abdominal fat showed normal fat cells and well-preserved architecture. The liposhaver offers a precise alterative to conventional liposuction. It may be less traumatic because it requires low suction pressures and does not rely on the potentially bruising, vigorous, back-and-forth motion for fat extraction typical of conventional liposuction.


Impact of bacterial mutation rate on coevolutionary dynamics between bacteria and phages.
Mutator bacteria are frequently found in natural populations of bacteria and although coevolution with parasitic viruses (phages) is thought to be one reason for their persistence, it remains unclear how the presence of mutators affects coevolutionary dynamics. We hypothesized that phages must themselves adapt more rapidly or go extinct, in the face of rapidly evolving mutator bacteria. We compared the coevolutionary dynamics of wild-type Pseudomonas fluorescens SBW25 with a lytic phage to the dynamics of an isogenic mutator of P. fluorescens SBW25 together with the same phage. At the beginning of the experiment both wild-type bacteria and mutator bacteria coevolved with phages. However, mutators rapidly evolved higher levels of sympatric resistance to phages. The phages were unable to "keep-up" with the mutator bacteria, and these rates of coevolution declined to less than the rates of coevolution between the phages and wild-type bacteria. By the end of the experiment, the sympatric resistance of the mutator bacteria was not significantly different to the sympatric resistance of the wild-type bacteria. This suggests that the importance of mutators in the coevolutionary interactions with a particular phage population is likely to be short-lived. More generally, the results demonstrate that coevolving enemies may escape from Red-Queen dynamics.


Prevalence and risk factors for post-investigation colorectal cancer ("interval cancer") after computed tomographic colonography: protocol for a systematic review.
Colorectal cancer (CRC) is a common and important disease. There are different tests for diagnosis, one of which is computed tomographic colonography (CTC). No test is perfect, and patients with normal CTC may subsequently develop CRC (either because it was overlooked originally, or because it has developed in the interim). This is termed post-investigation colorectal cancer (PICRC) or "interval cancer". How frequently this occurs after CTC is not known. The purpose of this systematic review and meta-analysis is to use the primary literature to estimate the PICRC rate after CTC, and explore associated factors. Primary studies reporting post-investigation colorectal cancer (PICRC) rates after CTC will be identified from PubMed, Embase and Cochrane Register of Controlled Trials databases. Peer-reviewed studies published after 1994 (the year CTC was introduced) will be included and the rate of PICRC within 36 months of CTC recorded. Data will be extracted from selected studies for a random effects meta-analysis. Heterogeneity, risk of bias and publication bias will be assessed, and exploratory analysis will examine factors associated with higher PICRC rates in the literature. PICRC rates are the ultimate benchmark of diagnostic quality for colonic investigations. This systematic review and meta-analysis will identify and synthesise evidence to determine PICRC rates after CTC and explore factors that may contribute to higher rates. PROSPERO (registration number CRD42016042437 ).


Cerebellar Parieto-occipital Posterior Reversible Encephalopathy Syndrome and Cerebral Metamorphopsia Associated with Asymptomatic Atrial Septum Vegetation and Renal Disease: Case Report.
BACKGROUND Posterior reversible encephalopathy syndrome (PRES) is a poorly characterized and enigmatic syndrome. Despite consistently presenting with nervous system vasogenic edema, this malady has been associated with variable triggers, neurological symptoms, and natural history. CASE REPORT The report presents a 25-year old African American female who presented with altered mental status and bilateral cortical blindness. Neuroimaging identified vasogenic edema in the cerebellum, parietal lobe, and occipital lobe. Her PRES was associated with a hypertensive emergency, renal failure, and an atrial septum vegetation (culture-negative endocarditis). All 3 contributing etiologies were addressed, upon which the patient began to recover. During recovery, the patient experienced cerebral metamorphopsia, visualizing her entire environment in the form of a cartoon. After 2 weeks of treatment she recovered to baseline state of heath, with vasogenic edema resolved on follow-up neuroimaging. CONCLUSIONS This case presents a rarely catalogued phenomena during PRES recovery, cerebral metamorphopsia, along with a new potential association (culture negative atrial septum endocarditis). The report also highlights how PRES recovery patients (with cortical blindness) should be explicitly assessed for cerebral metamorphopsia and Charles Bonnet syndrome - which may distress patients. Lastly, the atypical presentation of cerebellar vasogenic edema in our patient validates existing literature that PRES does not have a uniform picture and is not well served by its current name or proposed diagnostic criteria. Therefore, renaming the disorder to reversible vasogenic edema syndrome and derestricting the diagnostic criteria, may prevent clinicians from being discouraged when faced with diagnosing PRES in the face of atypical findings.


Adipose-Derived Stem Cells Ameliorate Ischemia-Reperfusion Injury in a Rat Skin Free Flap Model.
Ischemia-reperfusion (I/R) injury is inevitable during free tissue transfers. When the period of ischemia exceeds the tissue tolerance, it causes necrosis and flap failure. The aim of this study was to investigate the effects of adipose-derived stem cells (ASCs) embedded in a collagen type I scaffold on the survival of free skin flaps to counteract I/R injury. Left superficial caudal epigastric skin flaps (3 × 6 cm) were performed in 28 Wistar rats that were divided into four groups. The flaps elevated in the animals of the control group did not suffer any ischemic insult, and the vascular pedicle was not cut. All other flaps were subjected to 8 hours of ischemia prior to revascularization: I/R control group (8 hours of ischemia), I/R scaffold group (8 hours of ischemia + collagen type I scaffold), and I/R scaffold-ASCs group (8 hours of ischemia + collagen type I scaffold with rat ASCs embedded). Transit-time ultrasound blood flow measurements were performed. After 7 days, the areas of flap survival were measured and tissues were stained with hematoxylin/eosin and Masson's trichrome stain for histological analysis. The mean percentage flap survival area was significantly higher in the ASCs-treated flaps (I/R scaffold-ASCs group) compared with the ischemic controls (I/R control group and I/R scaffold group). Higher vascular proliferation and lower severity of necrosis and inflammatory changes were seen histologically in the samples of the ASCs-treated group. No significant difference in blood flow was detected between groups. Subcutaneous administration of ASCs embedded on a collagen type I scaffold reduces tissue damage after I/R injury in microvascular free flaps.


Toward intelligent synthetic neural circuits: directing and accelerating neuron cell growth by self-rolled-up silicon nitride microtube array.
In neural interface platforms, cultures are often carried out on a flat, open, rigid, and opaque substrate, posing challenges to reflecting the native microenvironment of the brain and precise engagement with neurons. Here we present a neuron cell culturing platform that consists of arrays of ordered microtubes (2.7-4.4 μm in diameter), formed by strain-induced self-rolled-up nanomembrane (s-RUM) technology using ultrathin (<40 nm) silicon nitride (SiNx) film on transparent substrates. These microtubes demonstrated robust physical confinement and unprecedented guidance effect toward outgrowth of primary cortical neurons, with a coaxially confined configuration resembling that of myelin sheaths. The dynamic neural growth inside the microtube, evaluated with continuous live-cell imaging, showed a marked increase (20×) of the growth rate inside the microtube compared to regions outside the microtubes. We attribute the dramatic accelerating effect and precise guiding of the microtube array to three-dimensional (3D) adhesion and electrostatic interaction with the SiNx microtubes, respectively. This work has clear implications toward building intelligent synthetic neural circuits by arranging the size, site, and patterns of the microtube array, for potential treatment of neurological disorders.


Ochronosis of the aortic valve.
Ochronosis is the bluish-black discolouration of connective tissue, including heart valves, joints, kidney and the skin. It is due to the deposition of homogentisic acid (HGA) commonly found in alkaptonuria. Ochronosis in the aortic valve is a rare occurrence and there is limited data available on the most appropriate choice of valve prosthesis in these patients. This case involves a 72-year-old male with symptomatic aortic stenosis and on echocardiogram a severe calcific trileaflet aortic stenosis with normal ejection fraction. Intraoperative aortic cannulation was routine and uncomplicated, and bluish-black discolouration of aortic valve was noted. Thorough decalcification was undertaken and a bioprosthetic valve was chosen in accordance with patient's age and preference. There were no complications post-operatively and the patient reported being well. Ochronosis affecting the aortic valve is a rare condition and there is limited data on the recurrence rate as well as the natural history of the disease. This case reports aims to provide data to facilitate further research to better understand the natural history of aortic valve ochronosis and rates of recurrence following bioprosthetic aortic valve replacement (AVR).


HIV self-testing and STI self-collection via mobile apps: experiences from two pilot randomized controlled trials of young men who have sex with men.
Young men who have sex with men (YMSM) are disproportionately impacted by HIV and other sexually transmitted infections (STIs) in the United States (US) and have low rates of HIV/STI testing. Provision of HIV self-testing and STI self-collection can increase testing rates, and access to these kits through mobile applications (apps) could help facilitate YMSM using HIV self-testing and STI self-collection. Data for this study comes from two pilot randomized controlled trials (RCTs) of mobile apps within the Adolescent Trials Network-LYNX and MyChoices-aimed to increase HIV/STI testing among YMSM (age 15-24) who had not recently tested for HIV and were at high risk for HIV acquisition across five US cities. Both apps include the ability to order a HIV self-test with rapid results and a kit for STI self-collection and mailing of samples for syphilis, gonorrhea and chlamydia to a lab for testing. Using assessments of app users (n=80) at pre-randomization and at 3- and 6-months post-randomization and online interview data from a purposive sample of app users (n=37), we report on experiences and lessons learned with HIV self-testing and STI self-collection kits ordered via the apps. Participants were on average 20.7 years of age (SD =2.4), and 49% were non-White or multiple race/ethnicity. Sixty-three percent had a prior HIV test. Over half (58%) had a prior STI test, but only 3% had tested within the past 3 months. Nearly two-thirds ordered an HIV self-testing kit; of whom, 75% reported using at least one self-test kit over the study period. STI self-collection kit ordering rates were also high (54%); however, STI self-collection kit return rates were lower (13%), but with a high positivity rate (5.3%). Both HIV self-testing and STI self-collection kits were highly acceptable, and 87% reported that it was extremely/very helpful to be able to order these kits through the apps. The most common reason for not ordering the HIV/STI kits was preferring to test at a clinic. In interviews, participants expressed feeling empowered by being able to test at home; however, they also raised concerns around STI sample collection. HIV self-testing and STI self-collection kit ordering via mobile apps is feasible, acceptable and may show promise in increasing testing rates among YMSM. The LYNX and MyChoices apps are currently being tested in a full-scale efficacy trial, and if successful, these innovative mobile apps could be scaled up to efficiently increase HIV/STI testing among youth across the US.


Energy expenditure of walking and running: comparison with prediction equations.
This study established the published prediction equations for the energy expenditure of walking and running compared with the measured values. To make this comparison we first determined whether differences exist in energy expenditure for 1600 m of walking versus running, and whether energy expenditure differences occur due to being on the track or treadmill. Energy was measured via indirect calorimetry in 24 subjects while walking (1.41 m.s(-1)) and running (2.82 m.s(-1)) 1600 m on the treadmill. A subgroup also performed the 1600-m run/walk on the track. The measured energy expenditures were compared with published prediction equations. Running required more energy (P < 0.01) for 1600 m than walking (treadmill: running 481 +/- 20.0 kJ, walking 340 +/- 14 kJ; track: running 480 +/- 23 kJ, walking 334 +/- 14 kJ) on both the track and treadmill. Predictions using the ACSM or Leger equations for running, and the Pandolf equation for walking, were similar to the actual energy expenditures for running and walking (total error: ACSM: -20 and 14.4 kJ, respectively; Legers walking: -10.1 kJ; Pandolf walking: -10.0 kJ). An overestimation (P < 0.01) for 1600 m was found with the McArdle's table for walking and running energy expenditure and with van der Walt's prediction for walking energy expenditure, whereas the Epstein equation underestimated running energy expenditure (P < 0.01). Running has a greater energy cost than walking on both the track and treadmill. For running, the Leger equation and ACSM prediction model appear to be the most suitable for the prediction of running energy expenditure. The ACSM and Pandolf prediction equation also closely predict walking energy expenditure, whereas the McArdle's table or the equations by Epstein and van der Walt were not as strong predictors of energy expenditure.


Off-axis aberrations of a wide-angle schematic eye model.
A schematic eye model based on anatomical data, which had been previously designed to reproduce image quality on axis, has been transformed into a wide-angle model by simply adding a spherical image surface that plays the role of the retina. This model captures the main features of the wide-angle optical design of the human eye with minimum complexity: four conic optical surfaces plus a spherical image surface. Seidel aberrations (spherical aberration, coma, astigmatism, field curvature, and distortion), longitudinal and transverse chromatic aberrations, and overall monochromatic spot diagrams have been computed for this eye model and for field angles ranging from 0 degree to 60 degrees by both finite and third-order ray tracing. The modulation transfer function for each field angle has been computed as well. In each case our results have been compared with average experimental data found in the literature, showing a reasonably good agreement. The agreement between the model and experimental data is better off axis, mainly at moderate (10 degrees-40 degrees) field angles, than on axis. The model has been applied to simulate a variety of experimental methods in which image aberrations are estimated from measurements taken in the object space. Our results suggest that for some types of aberration, these methods may yield biased estimates.


Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis.
Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population. In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 μg per week for up to 2 years. The primary end point was the annualized relapse rate. Of a total of 215 patients, 107 were assigned to fingolimod and 108 to interferon beta-1a. The mean age of the patients was 15.3 years. Among all patients, there was a mean of 2.4 relapses during the preceding 2 years. The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute difference, 0.55 relapses; relative difference, 82%; P<0.001). The key secondary end point of the annualized rate of new or newly enlarged lesions on T2-weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included seizures (in 4 patients), infection (in 4 patients), and leukopenia (in 2 patients). Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient). Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events. Longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis. (Funded by Novartis Pharma; PARADIGMS ClinicalTrials.gov number, NCT01892722 .).


Misokinesia is a sensitivity to seeing others fidget that is prevalent in the general population.
Misokinesia--or the 'hatred of movements'--is a psychological phenomenon that is defined by a strong negative affective or emotional response to the sight of someone else's small and repetitive movements, such as seeing someone fidget with a hand or foot. Among those who regularly experience misokinesia sensitivity, there is a growing grass-roots recognition of the challenges that it presents as evidenced by on-line support groups. Yet surprisingly, scientific research on the topic is lacking. This article is novel in systematically examining whether misokinesia sensitivity actually exists in the general population, and if so, whether there is individual variability in the intensity or extent of what sensitivities are reported. Across three studies that included 4100 participants, we confirmed the existence of misokinesia sensitivity in both student and non-student populations, with approximately one-third of our participants self-reporting some degree of sensitivity to seeing the repetitive, fidgeting behaviors of others as encountered in their daily lives. Moreover, individual variability in the range and intensity of sensitivities reported suggest that the negative social-affective impacts associated with misokinesia sensitivities may grow with age. Our findings thus confirm that a large segment of the general population may have a visual-social sensitivity that has received little formal recognition.


Membrane-Disrupting Nanofibrous Peptide Hydrogels.
Self-assembled peptide nanofibers can form biomimetic hydrogels at physiological pH and ionic strength through noncovalent and reversible interactions. Inspired by natural antimicrobial peptides, we designed a class of cationic amphiphilic self-assembled peptides (CASPs) that self-assemble into thixotropic nanofibrous hydrogels. These constructs employ amphiphilicity and high terminal charge density to disrupt bacterial membranes. Here, we focus on three aspects of the self-assembly of these hydrogels: (a) the material properties of the individual self-assembled nanofibers, (b) emergence of bulk-scale elasticity in the nanofibrous hydrogel, and (c) trade-off between the desirable material properties and antimicrobial efficacy. The design of the supramolecular nanofibers allows for higher-order noncovalent ionic cross-linking of the nanofibers into a viscoelastic network. We determine the stiffness of the self-assembled nanofibers via the peak force quantitative nanomechanical atomic force microscopy and the bulk-scale rheometry. The storage moduli depend on peptide concentration, ionic strength, and concentration of multivalent ionic cross-linker. CASP nanofibers are demonstrated to be effective against Pseudomonas aeruginosa colonies. We use nanomechanical analysis and microsecond-time scale coarse-grained simulation to elucidate the interaction between the peptides and bacterial membranes. We demonstrate that the membranes stiffen, contract, and buckle after binding to peptide nanofibers, allowing disruption of osmotic equilibrium between the intracellular and extracellular matrix. This is further associated with dramatic changes in cell morphology. Our studies suggest that self-assembled peptide nanofibrils can potentially acts as membrane-disrupting antimicrobial agents, which can be formulated as injectable hydrogels with tunable material properties.


Plant-produced cottontail rabbit papillomavirus L1 protein protects against tumor challenge: a proof-of-concept study.
The native cottontail rabbit papillomavirus (CRPV) L1 capsid protein gene was expressed transgenically via Agrobacterium tumefaciens transformation and transiently via a tobacco mosaic virus (TMV) vector in Nicotiana spp. L1 protein was detected in concentrated plant extracts at concentrations up to 1.0 mg/kg in transgenic plants and up to 0.4 mg/kg in TMV-infected plants. The protein did not detectably assemble into viruslike particles; however, immunoelectron microscopy showed presumptive pentamer aggregates, and extracted protein reacted with conformation-specific and neutralizing monoclonal antibodies. Rabbits were injected with concentrated protein extract with Freund's incomplete adjuvant. All sera reacted with baculovirus-produced CRPV L1; however, they did not detectably neutralize infectivity in an in vitro assay. Vaccinated rabbits were, however, protected against wart development on subsequent challenge with live virus. This is the first evidence that a plant-derived papillomavirus vaccine is protective in an animal model and is a proof of concept for human papillomavirus vaccines produced in plants.


Traumatic injury to the immature frontal lobe: a new murine model of long-term motor impairment in the absence of psychosocial or cognitive deficits.
Traumatic brain injury in children commonly involves the frontal lobes and is associated with distinct structural and behavioral changes. Despite the clinical significance of injuries localized to this region during brain development, the mechanisms underlying secondary damage and long-term recovery are poorly understood. Here, we have characterized the first model of unilateral focal traumatic injury to the developing frontal lobe. Male C57Bl/6J mice at postnatal day (p)21, an age approximating a toddler-aged child, received a controlled cortical impact or sham surgery to the left frontal lobe and were euthanized 1 or 7 days later. A necrotic cavity and local inflammatory response were largely confined to the unilateral frontal lobe, dorsal corpus callosum and striatum anterior to the bregma. While cell death and accumulated β-amyloid precursor protein were characteristic features of the pericontusional motor cortex, corpus callosum, cingulum and dorsal striatum, underlying structures including the hippocampus showed no overt pathology. To determine the long-term functional consequences of injury at p21, two additional cohorts were subjected to a battery of behavioral tests in adolescence (p35-45) or adulthood (p70-80). In both cohorts, brain-injured mice showed normal levels of anxiety, sociability, spatial learning and memory. The signature phenotypic features were deficits in motor function and motor learning, coincident with a reduction in ipsilateral cortical brain volumes. Together, these findings demonstrate classic morphological features of a focal traumatic injury, including early cell death and axonal injury, and long-term volumetric loss of cortical volumes. The presence of deficits in sensorimotor function and coordination in the absence of abnormal findings related to anxiety, sociability and memory likely reflects several variables, including the unique location of the injury and the emergence of favorable compensatory mechanisms during subsequent brain development.


Intra-aneurysmal pressure measurements in experimental saccular aneurysms in dogs.
Intra-aneurysmal pressure was studied in an experimental model of saccular aneurysm in dogs, using a vein pouch grafted onto a common carotid arterial bifurcation. The mean and the pulse pressures were recorded simultaneously from within the aneurysm and within the common carotid artery, before and after 50% proximal carotid artery stenosis. These experiments were performed under systemic normotension, hypotension, and hypertension. Normal data suggest that mean intracarotid and intra-aneurysmal pressures are similar and relate in a nearly linear fashion to mean arterial pressure. However, after 50% stenosis, the data had a cubic relationship, the reduction of pressure occurring only in the middle range of mean arterial pressure. Both intra-aneurysmal and intracarotid pulse pressures displayed less dependence on mean arterial pressure. However, sigmoid curves also were observed with the pulse pressures after 50% proximal common carotid artery stenosis. In all cases, after 50% stenosis, the rate of increase of the pulse pressures with mean arterial pressure was greater for higher mean arterial pressures. Our preliminary data indicate that a detailed study of intra-aneurysmal pressure and blood flow in relation to systemic variables such as mean arterial pressure, cardiac output, and peripheral resistance may not only suggest improved means of managing patients with intracranial aneurysms, but also may raise the possibility that, under certain conditions, higher intra-aneurysmal pressures may be induced by downstream stenosis.


In vivo functional differences in microvascular response of 4T1 and Caki-1 tumors after treatment with OXi4503.
4T1 mouse mammary adenocarcinomas and Caki-1 human renal cell carcinomas grown in mouse dorsal window chambers were serially treated with the vascular disrupting agent (VDA) OXi4503 and their responses compared. The real-time in vivo response was assessed using spectral imaging of microvascular hemoglobin saturation. To our knowledge this is the first use of spectral imaging technology for investigation of vascular disrupting agents. Previous research showing tumor size dependence in the treatment response to VDAs suggested that for the size of tumors used in this study only a moderate response would be observed; however, the tumors unexpectedly had very different responses to treatment. Caki-1 tumors showed little permanent vessel damage and experienced transient vessel collapse with time-dependent oxygenation changes followed by recovery starting at 6 h after treatment. Caki-1 tumors did not manifest necrotic avascular regions even after repeated treatments. These results are consistent with those obtained using other imaging modalities and histology. In contrast, similarly sized 4T1 tumors showed extensive vessel disintegration, minor vascular collapse, and a drop in tumor oxygenation up to 6 h post-treatment, after which reperfusion of collapsed vessels and extensive vascular remodeling and neovascularization of the tumor rim occurred from 8-48 h. The completely disintegrated vessels did not recover and left behind avascular and apparently necrotic regions in the tumor core. Spectral imaging appears to be a useful technique for in vivo investigation of vascular disrupting agents. The differential responses of these two tumor-types suggest that further investigation of the mechanisms of action of VDAs and individual characterization of tumor VDA-responses may be needed for optimal clinical use of these agents.


Presurgical evaluation of Fontan connection options for patients with apicocaval juxtaposition using computational fluid dynamics.
Apicocaval juxtaposition (ACJ) is a rare congenital heart defect associated with single ventricle physiology where optimal positioning of the Fontan conduit for completion of total cavopulmonary connection (TCPC) is still controversial. In ACJ, the cardiac apex is ipsilateral with the inferior vena cava (IVC), risking kinking and collapse of the Fontan conduit at the apex of the heart. The purpose of this study is to evaluate two viable routes for Fontan conduit connection in patients with ACJ, using computational fluid dynamics. Internal energy loss evaluations were used to determine contribution of conduit curvature to the energy efficiency of each cavopulmonary anastomosis configuration. This percentage of energy loss contribution was found to be greater in the case of a curved extracardiac conduit connection (44%, 4.1 mW) traveling behind the ventricular apex, connecting the IVC to the left pulmonary artery, than the straighter lateral tunnel conduit (6%, 1.4 mW) installed through the ventricular apex. In contrast, net energy loss across the anastomosis was significantly lower with extracardiac TCPC (9.3 mW) in comparison with lateral tunnel TCPC (23.2 mW), highlighting that a curved Fontan conduit is favorable provided that it is traded off for a superior cavopulmonary connection efficiency. Therefore, a relatively longer and curved Fontan conduit has been demonstrated to be a suitable connection option independent of anatomical situations.


Comparison of per cent predicted and percentile values for pulmonary function test interpretation.
Pulmonary function tests (PFTs) are commonly interpreted as a fraction of predicted normal values, with an abnormal test often defined as less than 80% or greater than 120% of the predicted value. However, recommendations of the American Thoracic Society/European Respiratory Society suggest using a percentile-based approach to define an abnormal test (less than the fifth or greater than the 95th percentiles). To compare PFT values obtained by the per cent predicted method with the percentile-based method for lung function parameters. Full PFTs performed between January 2000 and July 2004, at the Health Sciences Centre (Winnipeg, Manitoba) were analyzed. Using the Crapo and Gutierrez equations, per cent predicted and percentile values were calculated. An abnormal test was defined as less than 80% or greater than 120% of predicted (per cent predicted method) or as less than the fifth or greater than the 95th percentiles (percentile method). Using the percentile method as reference standard, the diagnostic test characteristics of the per cent predicted method were calculated. The full PFTs of 2176 men and 1658 women were analyzed using the Crapo and Gutierrez equations. The mean (+/- SD) age of all subjects was 52+/-15 years. Per cent agreement between the two tests was more than 94% for all parameters except for reduced residual volume (88%). Per cent predicted methods had suboptimal sensitivity for abnormal total lung capacity (88% to 89%), increased residual volume (83% to 89%) and reduced diffusion capacity (89% with Crapo equations). Suboptimal specificity (83% to 86%) was observed for decreased residual volume. The results of the per cent predicted and percentile-based approaches for PFT interpretation were similar for the majority of lung function parameters. These two methods can be used interchangeably for spirometry. However, caution may be warranted in relying solely on per cent predicted methods for assessing lung volume or diffusion capacity.


Resistance of Malus domestica fruit to Botrytis cinerea depends on endogenous ethylene biosynthesis.
The plant hormone ethylene regulates fruit ripening, other developmental processes, and a subset of defense responses. Here, we show that 1-aminocyclopropane-1-carboxylic acid synthase (ACS)-silenced apple (Malus domestica) fruit that express a sense construct of ACS were more susceptible to Botrytis cinerea than untransformed apple, demonstrating that ethylene strengthens fruit resistance to B. cinerea infection. Because ethylene response factors (ERFs) are known to contribute to resistance against B. cinerea via the ethylene-signaling pathway, we cloned four ERF cDNAs from fruit of M. domestica: MdERF3, -4, -5, and -6. Expression of all four MdERF mRNAs was ethylene dependent and induced by wounding or by B. cinerea infection. B. cinerea infection suppressed rapid induction of wound-related MdERF expression. MdERF3 was the only mRNA induced by wounding and B. cinerea infection in ACS-suppressed apple fruit, although its induction was reduced compared with wild-type apple. Promoter regions of all four MdERF genes were cloned and putative cis-elements were identified in each promoter. Transient expression of MdERF3 in tobacco increased expression of the GCC-box containing gene chitinase 48.


Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors.
We have previously reported a series of cyclopropyl urea derivatives as potent orally available soluble epoxide hydrolase (sEH) inhibitors. Here, we designed and synthesized three substituted cyclopropane derivatives that occupy all available pockets of sEH catalytic domain. Compound 14 with a diphenyl substituted cyclopropyl moiety showed good sEH inhibitory activity. Co-crystal structure of this compound and human sEH hydrolase catalytic domain revealed enzyme pockets occupied by the phenoxypiperidine part and the diphenyl cyclopropyl moiety. Furthermore, investigation of the phenoxypiperidine part of compound 14 resulted in the discovery of compound 19, which showed potent sEH inhibitory activity (sub-nM sEH IC50 values).


Nicotinic acetylcholine receptor beta2 subunit gene implicated in a systems-based candidate gene study of smoking cessation.
Although the efficacy of pharmacotherapy for tobacco dependence has been previously demonstrated, there is substantial variability among individuals in treatment response. We performed a systems-based candidate gene study of 1295 single nucleotide polymorphisms (SNPs) in 58 genes within the neuronal nicotinic receptor and dopamine systems to investigate their role in smoking cessation in a bupropion placebo-controlled randomized clinical trial. Putative functional variants were supplemented with tagSNPs within each gene. We used global tests of main effects and treatment interactions, adjusting the P-values for multiple correlated tests. An SNP (rs2072661) in the 3' UTR region of the beta2 nicotinic acetylcholine receptor subunit (CHRNB2) has an impact on abstinence rates at the end of treatment (adjusted P = 0.01) and after a 6-month follow-up period (adjusted P = 0.0002). This latter P-value is also significant with adjustment for the number of genes tested. Independent of treatment at 6-month follow-up, individuals carrying the minor allele have substantially decreased the odds of quitting (OR = 0.31; 95% CI 0.18-0.55). Effect of estimates indicate that the treatment is more effective for individuals with the wild-type (OR = 2.14, 95% CI 1.20-3.81) compared with individuals carrying the minor allele (OR = 0.83, 95% CI 0.32-2.19), although this difference is only suggestive (P = 0.10). Furthermore, this SNP demonstrated a role in the time to relapse (P = 0.0002) and an impact on withdrawal symptoms at target quit date (TQD) (P = 0.0009). Overall, while our results indicate strong evidence for CHRNB2 in ability to quit smoking, these results require replication in an independent sample.


Non-protein amino acids in Australian acacia seed: implications for food security and recommended processing methods to reduce djenkolic acid.
Seed of Australian acacia species, Acacia colei, Acacia elecantha, Acacia torulosa, Acacia turmida and Acacia saligna, were analysed for the presence of toxic non-protein amino acids and the levels of essential amino acids. Amines were derivatised with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate before analysis using liquid chromatography electrospray ionisation triple quadrupole mass spectrometry (LC-ESI-QQQ-MS). Multiple reaction monitoring (MRM) with optimised transitions and collision energies for each analyte were employed. The known nephrotoxic compound djenkolic acid was found to be present at elevated levels in all species tested. The lowest levels were in A. colei (0.49% w/w) and the highest in A. saligna (1.85% w/w). Observed levels of djenkolic acid are comparable to measured and reported levels found in the djenkol bean. Subsequent testing of seed processing methods showed djenkolic acid levels can be significantly reduced by over 90% by dry roasting at 180 °C rendering the seed safe for human consumption.


Analysis of Incidence-Severity Relationships for Strawberry Powdery Mildew as Influenced by Cultivar, Cultivar Type, and Production Systems.
The relationships between strawberry powdery mildew incidence (I) and severity (S) were investigated for various cultivars, for June-bearing and day-neutral cultivars, and for production systems (open-field and plastic-tunnel) with the objective of deriving a simple relationship for predicting severity (proportion of leaf area diseased [PLAD]) from incidence (proportion of diseased leaves). Data were collected from 2006 to 2011 at 11 commercial and experimental sites, for a total of 2,326 observations (n). For the cultivars grown in open fields, higher severity was observed on 'Seascape', with mean PLAD of 0.299 (n = 427); followed by 'Chambly', with 0.133 (n = 334); 'Cavendish', with 0.115 (n = 250); 'Darselect', with 0.111 (n = 321); and 'Jewel', with 0.105 (n = 276). In general, mean severity was higher when the strawberry plants were grown in plastic tunnels, with PLAD of 0.204, 0.199, and 0.181 for Chambly (n = 204), Darselect (n = 261), and Jewel (n = 253), respectively. A linear model based on complementary log-log transformation of I and S provided a good fit of the data (coefficient of determination [R2] adjusted for degrees of freedom from 0.82 to 0.96). A covariance analysis indicated that the sampling year and site of sampling did not significantly influence the estimated slope of the I-S relationship, nor did the specific cultivar among the June-bearing ones, whereas the production system (open-field versus plastic-tunnel) and the cultivar type (June-bearing versus day-neutral) significantly influenced the estimated slope. From this analysis, we were able to develop three specific models for open-field-grown June-bearing cultivars (R2 = 0.90), for the open-field-grown day-neutral cultivar (Seascape, R2= 0.91), and for June-bearing cultivars grown in plastic tunnels (R2 = 0.92). From these results, it was concluded that strawberry powdery mildew leaf severity can be accurately estimated from incidence of diseased leaves. The I-S relationships developed in the present study may be used in making practical disease management decisions, especially for management programs that use information on disease level in the field to initiate fungicide spraying programs or to time the interval between sprays.


A genetic comparison of two alleged subspecies of Philippine cynomolgus macaques.
Two subspecies of cynomolgus macaques (Macaca fascicularis) are alleged to co-exist in the Philippines, M. f. philippensis in the north and M. f. fascicularis in the south. However, genetic differences between the cynomolgus macaques in the two regions have never been studied to document the propriety of their subspecies status. We genotyped samples of cynomolgus macaques from Batangas in southwestern Luzon and Zamboanga in southwestern Mindanao for 15 short tandem repeat (STR) loci and sequenced an 835 bp fragment of the mtDNA of these animals. The STR genotypes were compared with those of cynomolgus macaques from southern Sumatra, Singapore, Mauritius and Cambodia, and the mtDNA sequences of both Philippine populations were compared with those of cynomolgus macaques from southern Sumatra, Indonesia and Sarawak, Malaysia. We conducted STRUCTURE and PCA analyses based on the STRs and constructed a median joining network based on the mtDNA sequences. The Philippine population from Batangas exhibited much less genetic diversity and greater genetic divergence from all other populations, including the Philippine population from Zamboanga. Sequences from both Batangas and Zamboanga were most closely related to two different mtDNA haplotypes from Sarawak from which they are apparently derived. Those from Zamboanga were more recently derived than those from Batangas, consistent with their later arrival in the Philippines. However, clustering analyses do not support a sufficient genetic distinction of cynomolgus macaques from Batangas from other regional populations assigned to subspecies M. f. fascicularis to warrant the subspecies distinction M. f. philippensis.


Ecosystem warming extends vegetation activity but heightens vulnerability to cold temperatures.
Shifts in vegetation phenology are a key example of the biological effects of climate change1-3. However, there is substantial uncertainty about whether these temperature-driven trends will continue, or whether other factors-for example, photoperiod-will become more important as warming exceeds the bounds of historical variability4,5. Here we use phenological transition dates derived from digital repeat photography6 to show that experimental whole-ecosystem warming treatments7 of up to +9 °C linearly correlate with a delayed autumn green-down and advanced spring green-up of the dominant woody species in a boreal Picea-Sphagnum bog. Results were confirmed by direct observation of both vegetative and reproductive phenology of these and other bog plant species, and by multiple years of observations. There was little evidence that the observed responses were constrained by photoperiod. Our results indicate a likely extension of the period of vegetation activity by 1-2 weeks under a 'CO2 stabilization' climate scenario (+2.6 ± 0.7 °C), and 3-6 weeks under a 'high-CO2 emission' scenario (+5.9 ± 1.1 °C), by the end of the twenty-first century. We also observed severe tissue mortality in the warmest enclosures after a severe spring frost event. Failure to cue to photoperiod resulted in precocious green-up and a premature loss of frost hardiness8, which suggests that vulnerability to spring frost damage will increase in a warmer world9,10. Vegetation strategies that have evolved to balance tradeoffs associated with phenological temperature tracking may be optimal under historical climates, but these strategies may not be optimized for future climate regimes. These in situ experimental results are of particular importance because boreal forests have both a circumpolar distribution and a key role in the global carbon cycle11.


Exosomes separated based on the "STOP" criteria for tumor-targeted drug delivery.
Exosomes, a class of natural nanoparticles, have recently been used for drug delivery. To move from bench to bedside, exosomes should meet the "STOP" criteria: (1) high Safety; (2) good Targeting ability; (3) rapid Obtainment; and (4) high Purity. To the best of our knowledge, however, no studies on exosomes that can satisfy all the abovementioned criteria have been reported to date. In this study, an optimized superparamagnetic nanoparticle cluster (SMNC)-based method was used to easily achieve the abovementioned objective. Multiple superparamagnetic nanoparticles (SPMNs) labeled by holo-transferrin with PEG spacers anchor onto an exosome to form an upgraded exosome-based superparamagnetic nanoparticle cluster (denoted SMNC-EXO-PLUS). SMNC-EXO-PLUSs separated exosomes from healthy animal blood to ensure high safety, and their formation based on the specific binding of SPMNs to exosomes endowed exosomes with high purity. In addition, SMNC-EXO-PLUSs possessed strong magnetic response, realizing their rapid obtainment and good targeting ability. The results demonstrated that the cell viability was maintained as high as 88% in a 1000 μg mL-1 SMNC-EXO-PLUS solution, and the time interval from the extraction of blood to the acquisition of purified exosomes could be reduced to 3.5 h. Furthermore, the effects of in vivo tumor inhibition of drug-loaded SMNC-EXO-PLUSs (denoted as D-SMNC-EXO-PLUSs) were pronounced. Based on the "STOP" criteria, we exploited a new exosome-related drug delivery vehicle, dramatically promoting the clinical translation of exosomes.


Honey-based mixtures used in home medicine by nonindigenous population of misiones, Argentina.
Honey-based mixtures used in home medicine by nonindigenous population of Misiones, Argentina. Medicinal mixtures are an underinvestigated issue in ethnomedical literature concerning Misiones, one of the most bioculturally diverse province of Argentina. The new culturally sensitive politics of the Provincial Health System is a response to cultural practices based on the medicinal use of plant and animal products in the home medicine of the local population. Honey-based medicinal formulas were investigated through interviews with 39 farmers of mixed cultural (Criollos) and Polish origins in northern Misiones. Fifty plant species and 8 animal products are employed in honey-based medicines. Plants are the most dominant and variable elements of mixtures. Most of the mixtures are food medicines. The role of honey in more than 90% of formulas is perceived as therapeutic. The ecological distribution of taxa and the cultural aspects of mixtures are discussed, particularly the European and American influences that have shaped the character of multispecies medicinal recipes.


E-HOSPITAL - A Digital Workbench for Hospital Operations and Services Planning Using Information Technology and Algebraic Languages.
In this paper, we describe the development of a unified framework and a digital workbench for the strategic, tactical and operational hospital management plan driven by information technology and analytics. The workbench can be used not only by multiple stakeholders in the healthcare delivery setting, but also for pedagogical purposes on topics such as healthcare analytics, services management, and information systems. This tool combines the three classical hierarchical decision-making levels in one integrated environment. At each level, several decision problems can be chosen. Extensions of mathematical models from the literature are presented and incorporated into the digital platform. In a case study using real-world data, we demonstrate how we used the workbench to inform strategic capacity planning decisions in a multi-hospital, multi-stakeholder setting in the United Kingdom.


Modulation of circulating angiogenic factors and tumor biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy.
Aerobic exercise training (AET) is an effective adjunct therapy to attenuate the adverse side-effects of adjuvant chemotherapy in women with early breast cancer. Whether AET interacts with the antitumor efficacy of chemotherapy has received scant attention. We carried out a pilot study to explore the effects of AET in combination with neoadjuvant doxorubicin-cyclophosphamide (AC+AET), relative to AC alone, on: (i) host physiology [exercise capacity (VO2 peak), brachial artery flow-mediated dilation (BA-FMD)], (ii) host-related circulating factors [circulating endothelial progenitor cells (CEP) cytokines and angiogenic factors (CAF)], and (iii) tumor phenotype [tumor blood flow ((15)O-water PET), tissue markers (hypoxia and proliferation), and gene expression] in 20 women with operable breast cancer. AET consisted of three supervised cycle ergometry sessions/week at 60% to 100% of VO2 peak, 30 to 45 min/session, for 12 weeks. There was significant time × group interactions for VO2 peak and BA-FMD, favoring the AC+AET group (P < 0.001 and P = 0.07, respectively). These changes were accompanied by significant time × group interactions in CEPs and select CAFs [placenta growth factor, interleukin (IL)-1β, and IL-2], also favoring the AC+AET group (P < 0.05). (15)O-water positron emission tomography (PET) imaging revealed a 38% decrease in tumor blood flow in the AC+AET group. There were no differences in any tumor tissue markers (P > 0.05). Whole-genome microarray tumor analysis revealed significant differential modulation of 57 pathways (P < 0.01), including many that converge on NF-κB. Data from this exploratory study provide initial evidence that AET can modulate several host- and tumor-related pathways during standard chemotherapy. The biologic and clinical implications remain to be determined.


Handwriting analysis indicates spontaneous dyskinesias in neuroleptic naïve adolescents at high risk for psychosis.
Growing evidence suggests that movement abnormalities are a core feature of psychosis. One marker of movement abnormality, dyskinesia, is a result of impaired neuromodulation of dopamine in fronto-striatal pathways. The traditional methods for identifying movement abnormalities include observer-based reports and force stability gauges. The drawbacks of these methods are long training times for raters, experimenter bias, large site differences in instrumental apparatus, and suboptimal reliability. Taking these drawbacks into account has guided the development of better standardized and more efficient procedures to examine movement abnormalities through handwriting analysis software and tablet. Individuals at risk for psychosis showed significantly more dysfluent pen movements (a proximal measure for dyskinesia) in a handwriting task. Handwriting kinematics offers a great advance over previous methods of assessing dyskinesia, which could clearly be beneficial for understanding the etiology of psychosis.


Turmeric extract may improve irritable bowel syndrome symptomology in otherwise healthy adults: a pilot study.
To assess the effects of turmeric (Curcuma longa) extract on irritable bowel syndrome (IBS) symptomology in otherwise healthy adults. Partially blinded, randomized, two-dose, pilot study. Five hundred (500) volunteers were screened for IBS using the Rome II criteria. Two hundred and seven (207) suitable volunteers were randomized. One or two tablets of a standardized turmeric extract taken daily for 8 weeks. IBS prevalence, symptom-related quality of life (IBSQOL) and self-reported effectiveness. IBS prevalence decreased significantly in both groups between screening and baseline (41% and 57%), with a further significant drop of 53% and 60% between baseline and after treatment, in the one- and two-tablet groups respectively (p < 0.001). A post-study analysis revealed abdominal pain/discomfort score reduced significantly by 22% and 25% in the one- and two-tablet group respectively, the difference tending toward significance (p = 0.071). There were significant improvements in all bar one of the IBSQOL scales of between 5% and 36% in both groups, approximately two thirds of all subjects reported an improvement in symptoms after treatment, and there was a favorable shift in self-reported bowel pattern. There were no significant differences between groups. Turmeric may help reduce IBS symptomology. Placebo controlled trials are now warranted to confirm these findings.


Establishment of a multidisciplinary hepatocellular carcinoma clinic is associated with improved clinical outcome.
To evaluate differences in overall survival in patients with hepatocellular carcinoma (HCC) after the establishment of a multidisciplinary clinic (MDC) for HCC. Patient demographic and tumor characteristics of 355 patients diagnosed with HCC were collected between October 2006 and September 2011. Patients diagnosed after the initiation of the HCC MDC on October 1, 2010, were compared to patients diagnosed in the 4 years before. Patient demographics, tumor characteristics, treatment regimens, and overall survival were analyzed between the groups. A total of 105 patients were diagnosed in the time period after HCC MDC initiation compared to 250 patients in the previous 4 years. Patients diagnosed with HCC after the HCC MDC had fewer symptoms at presentation (64 vs. 78 %, p = 0.01) and earlier stage of tumor presentation [Barcelona Clinic for Liver Cancer (BCLC) A stage, 44 vs. 26 %, p = 0.0003; tumor, node, metastasis classification system stage 1, 44 vs. 30 %, p = 0.003) compared with patients diagnosed before MDC formation. The median time to treatment after diagnosis in the later period was significantly shorter than in the earlier time period (2.3 vs. 5.3 months, p = 0.002). On multivariate analysis, being seen in the HCC MDC remained independently associated with better overall survival (hazard ratio 2.5, 95 % confidence interval 2-3), after adjusting for BCLC stage and recipient of curative treatment. Patients diagnosed after HCC MDC initiation had a median survival of 13.2 months compared to the 4.8 months observed in patients diagnosed before MDC formation (p = 0.005). The implementation of a MDC for the evaluation and treatment of patients with HCC is associated with improved overall survival.


Physical activity in paid work time for desk-based employees: a qualitative study of employers' and employees' perspectives.
Poor physical and mental health of employees create significant problems in the workplace. Physical activity (PA) has been shown as an effective strategy for preventing and treating numerous physical and mental health issues as well as work performance outcomes. However, there are many barriers to taking part in PA (such as lack of time) with participation rates typically low. Providing PA in paid work time might be a way to overcome these issues, yet employers' and employees' opinions of this concept are unknown. The aim of this study was to explore employee and employer perspectives of PA in paid work time. Workplaces were recruited through existing contacts on the research team. Focus groups and interviews were conducted with employees and managers at one University and two executive non-departmental public bodies in central Scotland with mainly desk-based employees. Both managers and employees were involved to gain perspectives throughout the organisational hierarchy and were interviewed separately to reduce social desirability bias. All discussions were digitally recorded and transcribed verbatim. Data were analysed thematically for both managers and employees but due to significant overlap in themes between the groups, these are reported together in the results. Three out of five organisations approached took part in this qualitative study. Two individual interviews were held with strategic managers, five focus groups with middle managers (n = 16) and nine with employees (n = 45). Benefits were anticipated by managers and employees for both employees themselves and the organisation and included improved mental health, productivity and more favourable perceptions of the employer. Despite these widely acknowledged benefits, significant barriers were identified and included the structure and nature of the working day (high workload, front line job requirements), workplace culture and norms (resentment from colleagues, no break culture) and organisational concerns (cost of lost time, public perceptions). This study suggests that there are significant barriers to PA in paid work time. Whilst numerous anticipated benefits were conveyed by both employees and managers, PA in paid work time is unlikely to become common place until changes in attitudes and the culture towards movement at work occur.


Feature selection for gene expression using model-based entropy.
Gene expression data usually contain a large number of genes but a small number of samples. Feature selection for gene expression data aims at finding a set of genes that best discriminate biological samples of different types. Using machine learning techniques, traditional gene selection based on empirical mutual information suffers the data sparseness issue due to the small number of samples. To overcome the sparseness issue, we propose a model-based approach to estimate the entropy of class variables on the model, instead of on the data themselves. Here, we use multivariate normal distributions to fit the data, because multivariate normal distributions have maximum entropy among all real-valued distributions with a specified mean and standard deviation and are widely used to approximate various distributions. Given that the data follow a multivariate normal distribution, since the conditional distribution of class variables given the selected features is a normal distribution, its entropy can be computed with the log-determinant of its covariance matrix. Because of the large number of genes, the computation of all possible log-determinants is not efficient. We propose several algorithms to largely reduce the computational cost. The experiments on seven gene data sets and the comparison with other five approaches show the accuracy of the multivariate Gaussian generative model for feature selection, and the efficiency of our algorithms.


Gender differences in substrate for endurance exercise.
The effects of gender on substrate utilization during prolonged submaximal exercise were studied in six males and six equally trained females. After 3 days on a controlled diet (so that the proportions of carbohydrate, protein, and fat were identical), subjects ran on a treadmill at a velocity requiring an O2 consumption of approximately 65% of maximal. They ran a total "distance" of 15.5 km with a range in performance time of 90-101 min. Plasma glycerol, glucose, free fatty acids, and selected hormones (catecholamines, growth hormone, insulin, and glucagon) were measured throughout and after the run by sampling from an indwelling venous catheter, and glycogen utilization was calculated from pre- and postexercise needle biopsies of vastus lateralis. Exercise protein catabolism was estimated from 24-h urinary urea nitrogen excretion over the test day and a nonexercise day. The males were found to have significantly higher respiratory exchange ratios (mean 0.94 vs. 0.87), greater muscle glycogen utilization (by 25%), and greater urea nitrogen excretion (by 30%) than the females. No gender differences were evident in the hormonal response to the exercise with the exception of a lower insulin concentration and a higher epinephrine concentration in the males. We conclude that, during moderate-intensity long-duration exercise, females demonstrate greater lipid utilization and less carbohydrate and protein metabolism than equally trained and nourished males.


Can laparoscopy be performed safely early after laparotomy?
Early subsequent laparotomy has high morbidity and mortality rates. The majority of these procedures, such as control of intraabdominal bleeding, management of intraabdominal sepsis, assessment of bowel viability, or anastomotic suture line, which are performed during early subsequent laparotomy, can be managed safely by laparoscopy, with resultant decreased mortality and morbidity rates. However, fear of dehiscence and ventral hernia prevents widespread use of laparoscopy. The aim of this experimental study was to compare the deleterious effects of subsequent laparotomy with laparoscopy in abdominal wounds during the early postceliotomy period. A 4-cm median laparotomy was performed in 120 Wistar-Albino rats that were classified into three groups. The control group (1) did not receive additional treatment. On the third postoperative day, early subsequent laparotomy and pneumoperitoneum were performed in group 2 and group 3 rats, respectively. Ten rats from each group were selected randomly and killed after 5 days, 1 week, 2 weeks, and 4 weeks. Bursting pressure and tensile strength of the abdominal wound were assessed. Results of the study showed impaired abdominal wound healing in subsequent laparotomy group rats (group 2) (P < 0.05). Pneumoperitoneum did not cause statistical differences in wound healing parameters when compared with control group rats (P > 0.05). In conclusion, pneumoperitoneum does not affect abdominal wound healing adversely, but early subsequent laparotomy impairs wound healing severely. Laparoscopy would be an alternative to high-risk early subsequent relaparotomy.


Advantages of a mixed diet: feeding on several foliar age classes increases the performance of a specialist insect herbivore.
Two field studies were carried out to determine the influence of Abies balsamea foliage age on the preference and performance of larvae of Neodiprion abietis, a specialist Diprionid sawfly. Preference was determined by examining N. abietis defoliation on all age classes of foliage. Performance was estimated using larval survival, cocoon weights and the percentage of adults that were females. Neodiprion abietis preference for, and performance on, current-year foliage was very low, peaked on 2 or 3-year-old foliage, and declined on older foliage. Thus, sawfly feeding preference was adaptive. However, survival and cocoon weight were highest when sawflies were allowed to feed on all age classes of foliage, demonstrating that an insect specialist may perform better when feeding on several age classes of foliage from a single host plant species. These results indicate that either different larval instars have different nutritional requirements, or that food mixing provides the best diet, permitting the herbivore to obtain needed nutrients while avoiding ingestion of toxic doses of secondary metabolites. In addition, our results suggest that limited availability of varied foliage has more negative consequences for N. abietis females than for males, as the percentage of survivors that were females decreased when juvenile mortality was high. Our results emphasize the importance of considering non-linear changes in foliar quality as leaves age on herbivore preference and performance, and demonstrate how a herbivore can use this variability to maximize its fitness.


Reversibility of brain tissue loss in anorexia nervosa assessed with a computerized Talairach 3-D proportional grid.
We describe the results of our follow-up magnetic resonance imaging (MRI) study of underweight patients with anorexia nervosa, using rigorous methodology to control for head position across time. All subjects first underwent an initial scan and rescan to verify that our computerized three-dimensional co-planar grid method for volume measurement was reliable and accurate, regardless of head positioning. After a period of several months, subjects had a follow-up scan to assess for changes that may have occurred following significant weight gain. Ventricular and total brain volume measurements from the initial scans were compared with the scans from an age- and sex-matched normal control group to determine whether we could replicate previous findings of ventricular enlargement compared with controls and whether brain volume is reduced compared with controls. Anorexic subjects had significantly larger ventricles when compared with normal controls but did not differ significantly in total brain volume. Using a repeated measures analysis of variance, a priori contrasts compared the initial/rescan pair volumes with each other and the initial/rescan pair volumes with the follow-up volume. These analyses showed that ventricular and total brain volumes derived from the initial/rescan pair were nearly identical, but that at follow-up ventricular volume decreased significantly and total brain volume increased significantly after weight gain.


Sociodemographic and clinical characteristics associated with vitamin D status in newly diagnosed pediatric cancer patients.
Vitamin D deficiency and insufficiency are associated with serious sequelae in childhood cancer survivors. However, data on vitamin D deficiency in children with newly diagnosed cancer are scarce and the role of sociodemographic factors and vitamin D supplementation is largely unknown. We assessed vitamin D status and its socio-demographic and clinical correlates in 163 children with newly diagnosed cancer, using 25-hydroxy vitamin D (25(OH)D) concentrations and assessed longitudinal changes following vitamin D supplementation. Sixty-five percent of the patients with newly diagnosed cancer had low 25(OH)D concentrations. Fifty-two patients (32%) were vitamin D deficient (≤20 ng/mL 25(OH)D concentration), and 53(33%) were insufficient (21-29 ng/mL 25(OH)D concentration). Age over 10 (P = 0.019), Hispanic ethnicity (P = 0.002), and female sex (P = 0.008) were significantly associated with lower 25(OH)D concentration at diagnosis. Vitamin D supplementation resulted in significant increase in 25(OH)D concentrations (P < 0.001). However, following supplementation in the longitudinal analysis, this increase was less pronounced in Hispanic patients vs. non-Hispanic (P = 0.007), and in children with solid tumors vs. hematological malignancies (P = 0.003). Vitamin D deficiency and insufficiency are common in children with newly diagnosed cancer. Hispanic patients, females and older children were at higher risk for vitamin D deficiency and insufficiency. Although supplementation appeared to increase 25(OH)D concentrations over time, this increase was not as pronounced in certain subsets of patients. Prospective trials of the effects of vitamin D supplementation on bone health in children with newly diagnosed cancer are warranted, particularly in Hispanics and patients with solid tumors.


Maternal and perinatal outcomes by mode of delivery in senegal and mali: a cross-sectional epidemiological survey.
In the context of rapid changes regarding practices related to delivery in Africa, we assessed maternal and perinatal adverse outcomes associated with the mode of delivery in 41 referral hospitals of Mali and Senegal. Cross-sectional survey nested in a randomised cluster trial (1/10/2007-1/10/2008). The associations between intended mode of delivery and (i) in-hospital maternal mortality, (ii) maternal morbidity (transfusion or hysterectomy), (iii) stillbirth or neonatal death before Day 1 and (iv) neonatal death between 24 hours after birth and hospital discharge were examined. We excluded women with immediate life threatening maternal or fetal complication to avoid indication bias. The analyses were performed using hierarchical logistic mixed models with random intercept and were adjusted for women's, newborn's and hospitals' characteristics. Among the 78,166 included women, 2.2% had a pre-labor cesarean section (CS) and 97.8% had a trial of labor. Among women with a trial of labor, 87.5% delivered vaginally and 12.5% had intrapartum CS. Pre-labor CS was associated with a marked reduction in the risk of stillbirth or neonatal death before Day 1 as compared with trial of labor (OR = 0.2 [0.16-0.36]), though we did not show that maternal mortality (OR = 0.3 [0.07-1.32]) and neonatal mortality after Day 1 (OR = 1.3 (0.66-2.72]) differed significantly between groups. Among women with trial of labor, intrapartum CS and operative vaginal delivery were associated with higher risks of maternal mortality and morbidity, and neonatal mortality after Day 1, as compared with spontaneous vaginal delivery. In referral hospitals of Mali and Senegal, pre-labor CS is a safe procedure although intrapartum CS and operative vaginal delivery are associated with increased risks in mothers and infants. Further research is needed to determine what aspects of obstetric care contribute to a delay in the provision of intrapartum interventions so that practices may be made safer when they are needed.


FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer's disease.
Amyloid-β (Aβ) induces neuronal loss and cognitive deficits and is believed to be a prominent cause of Alzheimer's disease (AD); however, the cellular pathology of the disease is not fully understood. Here, we report that IgG Fcγ receptor II-b (FcγRIIb) mediates Aβ neurotoxicity and neurodegeneration. We found that FcγRIIb is significantly upregulated in the hippocampus of AD brains and neuronal cells exposed to synthetic Aβ. Neuronal FcγRIIb activated ER stress and caspase-12, and Fcgr2b KO primary neurons were resistant to synthetic Aβ-induced cell death in vitro. Fcgr2b deficiency ameliorated Aβ-induced inhibition of long-term potentiation and inhibited the reduction of synaptic density by naturally secreted Aβ. Moreover, genetic depletion of Fcgr2b rescued memory impairments in an AD mouse model. To determine the mechanism of action of FcγRIIb in Aβ neurotoxicity, we demonstrated that soluble Aβ oligomers interact with FcγRIIb in vitro and in AD brains, and that inhibition of their interaction blocks synthetic Aβ neurotoxicity. We conclude that FcγRIIb has an aberrant, but essential, role in Aβ-mediated neuronal dysfunction.


FREL: A Stable Feature Selection Algorithm.
Two factors characterize a good feature selection algorithm: its accuracy and stability. This paper aims at introducing a new approach to stable feature selection algorithms. The innovation of this paper centers on a class of stable feature selection algorithms called feature weighting as regularized energy-based learning (FREL). Stability properties of FREL using L1 or L2 regularization are investigated. In addition, as a commonly adopted implementation strategy for enhanced stability, an ensemble FREL is proposed. A stability bound for the ensemble FREL is also presented. Our experiments using open source real microarray data, which are challenging high dimensionality small sample size problems demonstrate that our proposed ensemble FREL is not only stable but also achieves better or comparable accuracy than some other popular stable feature weighting methods.


Antimicrobial properties of honey.
Honey has been widely accepted as food and medicine by all generations, traditions, and civilizations, both ancient and modern. For at least 2700 years, honey has been used by humans to treat a variety of ailments through topical application, but only recently have the antiseptic and antimicrobial properties of honey been discovered. Honey has been reported to be effective in a number of human pathologies. Clinical studies have demonstrated that application of honey to severely infected cutaneous wounds rapidly clears infection from the wound and improves tissue healing. A large number of in vitro and limited clinical studies have confirmed the broad-spectrum antimicrobial (antibacterial, antifungal, antiviral, and antimycobacterial) properties of honey, which may be attributed to the acidity (low pH), osmotic effect, high sugar concentration, presence of bacteriostatic and bactericidal factors (hydrogen peroxide, antioxidants, lysozyme, polyphenols, phenolic acids, flavonoids, methylglyoxal, and bee peptides), and increase in cytokine release, and to immune modulating and anti-inflammatory properties of honey; the antimicrobial action involves several mechanisms. Despite a large amount of data confirming the antimicrobial activity of honey, there are no studies that support the systemic use of honey as an antibacterial agent.


Perfusion imaging with compensation for asymmetric magnetization transfer effects.
The effects of off-resonance radio-frequency irradiation on the intensity of the MR signal from water protons in the cat brain are asymmetric around the chemical shift of the water signal. This asymmetry, which could arise from a shift in the magnetization transfer spectrum approximately 1.5 ppm upfield from the solvent water signal, must be taken into account to compensate for magnetization transfer effects inherent in arterial spin tagging approaches that use a single radio-frequency coil. Two approaches that either correct for, or circumvent, the apparent upfield shift of the magnetization transfer spectrum are presented, and a perfusion image of the cat brain, using flow-induced adiabatic inversion of arterial water protons, is presented. Other problems in obtaining quantitative cerebral blood flow values using the arterial spin tagging approach are discussed.


Gender-specific effects of brain-derived neurotrophic factor Val66Met polymorphism and childhood maltreatment on anxiety.
Although the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is thought to play an important role in the pathophysiology of anxiety, studies on the association between the BDNF polymorphism and anxiety have reported inconsistent results. As possible confounders in determining anxiety, childhood maltreatment and gender as well as their interactions with BDNF polymorphism have been suggested. This study examined the effect of BDNF genotype, childhood maltreatment, and their interaction on anxiety levels by gender. A total of 206 unrelated Korean healthy young adults (108 were male and the mean age was 23.1 ± 3.2 years) were genotyped for the BDNFVal66Met polymorphism. Measures for anxiety and childhood maltreatment were completed. The main and interaction effects of BDNF polymorphism and childhood maltreatment on anxiety were analyzed by general linear models in all subjects and then in gender-stratified groups. Gender-specific analyses revealed that the interaction effect was significant only in males (p = 0.014). Interestingly, male subjects with the Val/Met genotype tended to be resilient against the increased anxiety after childhood maltreatment. In females, the main effects of both BDNF genotype and childhood maltreatment were significant (p = 0.024 and p = 0.009, respectively) and post-hoc analysis revealed that the Val/Val genotype was associated with a higher anxiety than the Met/Met genotype (p = 0.004). Our results support the interaction effect between the BDNFVal66Met polymorphism and childhood maltreatment in determining anxiety and further emphasize the possible moderating role of gender in this gene-environment interaction.


Soluble α-klotho: a novel serum biomarker for the activity of GH-producing pituitary adenomas.
Klotho is a lifespan-influencing gene expressed mainly in the kidneys. Soluble α-Klotho (αKL) is released into the circulation. In this study, we present baseline αKL serum levels of patients with acromegaly compared with controls with other pituitary adenomas and assess changes following transsphenoidal surgery. Prospective controlled study. We measured soluble αKL (sandwich ELISA) and IGF1 (RIA) in sera of 14 patients (eight females and six males) with active acromegaly and in 22 control patients (13 females and nine males) operated for non-GH-producing pituitary adenomas. Immunohistochemical staining for Klotho was performed in resected adenomas and in normal pituitary tissue samples. Soluble αKL was high in the acromegaly group preoperatively (median 4217 pg/ml, interquartile range (IQR) 1812-6623 pg/ml) and declined after surgery during early follow-up (2-6 days; median 645 pg/ml, IQR 550-1303 pg/ml) (P<0.001) and during late follow-up (2-3 months post-operatively; median 902 pg/ml, IQR 497-1340 pg/ml; P<0.001). In controls, preoperative soluble αKL was significantly lower than in acromegalics, 532 pg/ml (400-677 pg/ml; P<0.001). Following surgery, soluble αKL remained low during early and late follow-up - changes over time within the control group were not statistically significant. These results were independent of age, sex and kidney function. Klotho staining was equal or slightly decreased in GH-positive adenomas compared with controls. High soluble αKL serum levels were specific to GH-producing adenomas and decreased rapidly following adenoma removal. Thus, soluble αKL appears to be a new specific and sensitive biomarker reflecting disease activity in acromegaly. Similar Klotho staining patterns in controls and acromegalics suggest that the rise in serum αKL is caused by systemic actions of pituitary GH rather than due to increased expression of Klotho by the pituitary (adenoma).


Unmute the Organization Through Serious Play.
In this article, we sketch up an action research process designed to give voice to those who traditionally have not had a voice in organizations. In particular, the research process was structured around "serious play" and designed as a talk show, where researchers played parts, including a talk show host, and where questions pertaining to organizational life were discussed in depth. The structure of the discussion was construed based on reflective teams, i.e., two actors performing a dialogue (talk show host and guest) and a silent group (audience) as listeners. The key research question concerns in what ways such an action research process is replicable? Applying a critical lens, we argue that even if strong claims of replicability are not met, as in being able to reproduce results and/or generalize them, this is outside the point. Rather, as we set out to apply a qualitative research design to achieve cogenerative learning effects, we advance an understanding of replicability-as-recoverability. This entails giving explicit grounds for our epistemic anchoring in critical realism and sketching out a research design which is sufficiently clear and transparent to undergo critical scrutiny.


Clinical features of COVID-19 mortality: development and validation of a clinical prediction model.
The COVID-19 pandemic has affected millions of individuals and caused hundreds of thousands of deaths worldwide. Predicting mortality among patients with COVID-19 who present with a spectrum of complications is very difficult, hindering the prognostication and management of the disease. We aimed to develop an accurate prediction model of COVID-19 mortality using unbiased computational methods, and identify the clinical features most predictive of this outcome. In this prediction model development and validation study, we applied machine learning techniques to clinical data from a large cohort of patients with COVID-19 treated at the Mount Sinai Health System in New York City, NY, USA, to predict mortality. We analysed patient-level data captured in the Mount Sinai Data Warehouse database for individuals with a confirmed diagnosis of COVID-19 who had a health system encounter between March 9 and April 6, 2020. For initial analyses, we used patient data from March 9 to April 5, and randomly assigned (80:20) the patients to the development dataset or test dataset 1 (retrospective). Patient data for those with encounters on April 6, 2020, were used in test dataset 2 (prospective). We designed prediction models based on clinical features and patient characteristics during health system encounters to predict mortality using the development dataset. We assessed the resultant models in terms of the area under the receiver operating characteristic curve (AUC) score in the test datasets. Using the development dataset (n=3841) and a systematic machine learning framework, we developed a COVID-19 mortality prediction model that showed high accuracy (AUC=0·91) when applied to test datasets of retrospective (n=961) and prospective (n=249) patients. This model was based on three clinical features: patient's age, minimum oxygen saturation over the course of their medical encounter, and type of patient encounter (inpatient vs outpatient and telehealth visits). An accurate and parsimonious COVID-19 mortality prediction model based on three features might have utility in clinical settings to guide the management and prognostication of patients affected by this disease. External validation of this prediction model in other populations is needed. National Institutes of Health.