Optimal timing of video-assisted thoracoscopic surgery for primary spontaneous pneumothorax in children.
There is no consensus in the pediatric surgical community about when to recommend video-assisted thoracoscopic surgery (VATS) for patients with primary spontaneous pneumothorax (PSP). We aimed to identify factors that predict the likelihood of requiring VATS, and to compare recurrence rates and healthcare utilization among different management approaches to PSP. A retrospective chart review and a telephone survey were conducted on all patients 12-21years who were diagnosed with PSP from 2007 to 2015. Data were extracted on patient demographics, initial management, hospital length of stay (LOS), and subsequent admissions, procedures, and recurrences. A total of 46 patients were included with a mean age of 16.1years (+/- 1.2). Most patients were male (41, 89%) and white (16, 44%). Initial management comprised chest tube drainage alone in 28 (61%), no intervention in 8 (17%), and VATS in 10 (22%). Total LOS was 6days (IQR 4-7) and was longer in patients who underwent VATS (p<0.001). Recurrence occurred in 17 patients (37%). However, recurrence and healthcare utilization were not significantly associated with initial management approach. Among those who had initial chest tube drainage, 14 (50%) underwent VATS on that admission, and 8 (28%) had subsequent surgery. Significant predictors of ultimately requiring VATS were presence of an air leak and partial lung expansion. Most patients with PSP currently undergo chest tube placement as initial management, although most eventually require VATS. Presence of an air leak and partial lung expansion on chest radiograph within the first 48h of management should prompt earlier surgical intervention. Retrospective. III.


Relationship of Routine Inadequate Sleep Duration and Periodontitis in a Nationally Representative Sample.
Purpose. Previous research has indicated the public health impact of inadequate sleep duration on health, potentially through an immune-inflammation mechanism. This mechanism also has a role in periodontitis. The purpose of this study is to determine if there is an association of routine inadequate sleep and periodontitis. Methods. Data from merged National Health and Nutrition Examination Survey years 2009-10 and 2011-12 were the data source for the study. The key outcome was periodontitis (yes, no), and the key variable of interest was usual sleep on weekday or workday nights. Chi square and logistic regression procedures were conducted. The study included 3,740 participants who were of ages 30 years and above. Results. There were 52.7% of participants who had periodontitis. There were 35.7% who usually slept less than 7 hours on weekday or workday nights. In adjusted logistic regression the odds ratio for periodontal disease for participants who slept less than 7 hours on weekday or workday night was 1.00 [95% confidence interval: 0.83, 1.21; p = .9812]. Conclusions. The relationship of periodontitis and inadequate sleep duration in a nationally representative study of participants who were of ages 30 years and above failed to reach statistical significance in adjusted logistic regression analyses.


Acute parathyroid hormone secretory dynamics: hormone secretion from normal primate and adenomatous human tissue in response to changes in extracellular calcium concentration.
PTH secretion has been evaluated extensively using short term incubation techniques, but these methods cannot be used to adequately evaluate the early phases of PTH secretion. We developed a dispersed cell perifusion system to study these acute secretory events. Responses to low calcium conditions were studied using dispersed cells from normal primate and adenomatous human parathyroid tissue. When these cell were perifused with 1.0 mM calcium medium, PTH secretion was stable, but increased within minutes in a dose-dependent manner in response to a lowering of extracellular calcium concentrations. Similarly, PTH secretion quickly declined when cells were exposed to higher extracellular calcium concentrations. In studies of cells from 11 human adenomas, the mean maximum secretion in response to 0.25 mM calcium conditions was 587 +/- 330% (+/- SD) of that in response to 1.0 mM calcium. The magnitude of the response to low calcium stimulation was variable, and cells from two additional adenomas failed to respond to low calcium stimulation despite responses to other secretogogues. Variation in the rate of increase in stimulated PTH secretion was also found among the adenomas examined (128 +/- 95% of baseline/min), and the rate of increase in PTH release and the eventual maximum rate of release were positively correlated. In studies of cells from 4 normal primates (rhesus macaque), the maximum response to 0.25 mM Ca2+ (544 +/- 118% of baseline) and the rate of increase in PTH secretion (95 +/- 35% of baseline/min) were similar to those in adenomatous human tissue. These results indicate that 1) acute PTH secretion can be studied in vitro, and that it appears to be similar to the in vivo process; 2) there is a wide variation among adenomatous tissues in the magnitude of secretion stimulated by low calcium concentrations; 3) in addition to varied magnitude of secretion, the rate at which hormone secretion increases in response to a low calcium stimulus varied among adenomas; and 4) PTH secretion from human adenomatous tissue is similar to that from normal primate tissue in both the rate and magnitude of response.


Improving nurse care coordination with technology.
Technology offers potential solutions to the pending crisis of healthcare for older adults, while healthcare workers are in short supply. Technology can enable remote monitoring of individuals and early detection of potential problems, so that early interventions can help older adults remain as healthy and independent as possible. Research is under way with passive monitoring technology in senior housing that is finding patterns in the data that can enhance nurse care coordination through early illness detection. With early detection, interventions can be more effective and reduce hospitalization and other healthcare expenses. Case studies are presented, and implications are discussed.


Predictive factors for early aspiration in liver abscess.
To determine the predictive factors for early aspiration in liver abscess. A retrospective analysis of all patients with liver abscess from 1995 to 2004 was performed. Abscess was diagnosed as amebic in 661 (68%) patients, pyogenic in 200 (21%), indeterminate in 73 (8%) and mixed in 32 (3%). Multiple logistic regression analysis was performed to determine predictive factors for aspiration of liver abscess. A total of 966 patients, 738 (76%) male, mean age 43 +/- 17 years, were evaluated: 540 patients responded to medical therapy while adjunctive percutaneous aspiration was performed in 426 patients. Predictive factors for aspiration of liver abscess were: age > or = 55 years, size of abscess > or = 5 cm, involvement of both lobes of the liver and duration of symptoms > or = 7 d. Hospital stay in the aspiration group was relatively longer than in the non aspiration group. Twelve patients died in the aspiration group and this mortality was not statistically significant when compared to the non aspiration group. Patients with advanced age, abscess size > 5 cm, both lobes of the liver involvement and duration of symptoms > 7 d were likely to undergo aspiration of the liver abscess, regardless of etiology.


Exploiting tyrosinase expression and activity in melanocytic tumors: quercetin and the central role of p53.
Melanoma is an aggressive tumor that expresses the pigmentation enzyme tyrosinase. Tyrosinase expression increases during tumorigenesis, which could allow for selective treatment of this tumor type by strategies that use tyrosinase activity. Approaches targeting tyrosinase would involve gene transcription or signal transduction pathways mediated by p53 in a direct or indirect manner. Two pathways are proposed for exploiting tyrosinase expression: (a) a p53-dependent pathway leading to apoptosis or arrest and (b) a reactive oxygen species-mediated induction of endoplasmic reticulum stress in p53 mutant tumors. Both strategies could use tyrosinase-mediated activation of quercetin, a dietary polyphenol that induces the expression of p53 and modulates reactive oxygen species. In addition to antitumor signaling properties, activation of quercetin could complement conventional cancer therapy by the induction of phase II detoxification enzymes resulting in p53 stabilization and transduction of its downstream targets. In conclusion, recent advances in tyrosinase enzymology, prodrug chemistry, and modern chemotherapeutics present an intriguing and selective multitherapy targeting system where dietary bioflavonoids could be used to complement conventional cancer treatments.


Transient scaling and resurgence of chimera states in networks of Boolean phase oscillators.
We study networks of nonlocally coupled electronic oscillators that can be described approximately by a Kuramoto-like model. The experimental networks show long complex transients from random initial conditions on the route to network synchronization. The transients display complex behaviors, including resurgence of chimera states, which are network dynamics where order and disorder coexists. The spatial domain of the chimera state moves around the network and alternates with desynchronized dynamics. The fast time scale of our oscillators (on the order of 100ns) allows us to study the scaling of the transient time of large networks of more than a hundred nodes, which has not yet been confirmed previously in an experiment and could potentially be important in many natural networks. We find that the average transient time increases exponentially with the network size and can be modeled as a Poisson process in experiment and simulation. This exponential scaling is a result of a synchronization rate that follows a power law of the phase-space volume.


Development of a fall-risk assessment profile for community-dwelling older adults by using the National Health Interview Survey in Taiwan.
Falls represent a global health issue among older adults and cause a considerable burden on medical systems. In this study, a fall-risk assessment profile was developed for community-dwelling older adults. The data of survey participants aged > 65 years were obtained from three rounds (2005, 2009, and 2013) of the National Health Interview Survey in Taiwan. In total, 8356 older participants were included in this study. Logistic regression analyses were used to determine potential predictors associated with falls. The regression coefficients of the predictors in the final model were translated into scores (by multiplying by 5) and then summed to obtain a total risk-score for falls. A receiver operating characteristic (ROC) curve was used to evaluate the discriminative performance of the risk assessment profile. Self-reported falls within 1 year accounted for 19.1% of the total falls. The predictors that were included in the risk profile according to the logistic regression analysis results were as follows: female sex (adjusted odds ratio = 1.57; risk-score = 2), living alone (adjusted odds ratio = 1.56; risk-score = 2), urinary incontinence (adjusted odds ratio = 1.36; risk-score = 2), perceived unhealthiness (adjusted odds ratio = 1.32; risk-score = 1), perceived pain (adjusted odds ratio = 1.51; risk-score = 2), hospital admission in the past year (adjusted odds ratio = 2.42; risk-score = 4), low activity of daily living (ADL) scores (adjusted odds ratio = 1.29; risk-score = 1), and low mobility function scores (adjusted odds ratio = 1.68; risk-score = 3). At a total risk-score cutoff point of 6 (range 0-17), the model predicted falls with a sensitivity and specificity of 75.16 and 52.75%, respectively (area under the ROC curve = 0.70). The fall-risk assessment profile comprising eight predictors-female sex, living alone, incontinence, perceived unhealthiness, perceived pain, hospital admission in the past year, low ADL scores, and low mobility function scores-may serve as an assessment tool for identification of older adults with a high risk of falling, and assessment results can be used to facilitate community-based intervention.


CodY-affected transcriptional gene expression of Streptococcus pyogenes during growth in human blood.
In an attempt to expand the available knowledge of pathogen-host interactions during ex vivo growth of Streptococcus pyogenes (GAS) in nonimmune whole human blood, the extents to which the expression of 51 genes including regulators with known targets, established virulence factors, physiologically important transporters and metabolic enzyme genes was differentially affected in the presence or absence of a functional codY gene were determined. The results obtained by quantitative real-time PCR using the M49 strain NZ131 showed that CodY influenced GAS gene activity in a dynamic fashion, with differential responses detected for 26 genes and occasionally characterized by discordance in the blood environment compared to laboratory medium. Degenerate derivatives of the recently discovered CodY box potentially serving as a cis-regulatory element for CodY action were identified in the upstream regions of 15 genes of the NZ131 genome, and these genes featured sequence motifs identical to the NZ131 CodY box in all completely sequenced S. pyogenes genomes. As none of these genes represented a genuine virulence factor, it seems likely, therefore, that the observed differential transcription of the majority of virulence genes was caused by indirect actions of CodY as part of a regulatory network.


Advancement of the vastus lateralis muscle for irreparable hip abductor tears: clinical and morphological results.
Outcome after advancement of the vastus lateralis muscle for irreparable disruption of the hip abductor mechanism was evaluated in 9 patients. Seven to 10 cm defects were bridged without complications. After a mean follow-up of 33 months (range: 12-60 months), the majority of patients reported a 69% satisfaction and a reduction of both pain medication and gait assists. Six out of 9 patients would undergo the same treatment again and one was undecided. On physical examination hip function was significantly improved but still poor. A significant loss of quadriceps muscle strength was the only donor site morbidity encountered. Overall, very modest but relevant improvement of hip function can be achieved with this procedure without relevant donor site morbidity and complications.


Determination of eye safety filter protection factors associated with retinal thermal hazard and blue light photochemical hazard for intense pulsed light sources.
An assessment is provided of protection factors afforded for retinal thermal hazard and blue light photochemical hazard for a range of filters used with intense pulsed light sources (IPLs). A characteristic IPL spectrum based on black body radiation at 5000 K with a low cut filter at 515 nm was identified as suitable for such estimations. Specific filters assessed included types with idealized transmission properties and also a range of types whose transmission characteristics were measured by means of a Bentham DMc150 spectroradiometer. Predicted behaviour based on these spectra is outlined which describes both the effectiveness of protection and the level of luminous transmittance afforded. The analysis showed it was possible to describe a figure of merit for a particular filter material relating the degree of protection provided and corresponding value of luminous transmittance. This consideration is important for providing users of IPL equipment with safety eyewear with adequate level of visual transmittance.


Organ localization: toward prospective patient-specific organ dosimetry in computed tomography.
With increased focus on radiation dose from medical imaging, prospective radiation dose estimates are becoming increasingly desired. Using available populations of adult and pediatric patient phantoms, radiation dose calculations can be catalogued and prospectively applied to individual patients that best match certain anatomical characteristics. In doing so, the knowledge of organ size and location is a required element. Here, the authors develop a predictive model of organ locations and volumes based on an analysis of adult and pediatric computed tomography (CT) data. Fifty eight adult and 69 pediatric CT datasets were segmented and utilized in the study. The maximum and minimum points of the organs were recorded with respect to the axial distance from the tip of the sacrum. The axial width, midpoint, and volume of each organ were calculated. Linear correlations between these three organ parameters and patient age, BMI, weight, and height were determined. No statistically significant correlations were found in adult patients between the axial width, midpoint, and volume of the organs versus the patient age or BMI. Slight, positive linear trends were found for organ midpoint versus patient weight (max r(2) = 0.382, mean r(2) = 0.236). Similar trends were found for organ midpoint versus height (max r(2) = 0.439, mean r(2) = 0.200) and for organ volume versus height (max r(2) = 0.410, mean r(2) = 0.153). Gaussian fits performed on probability density functions of the adult organs resulted in r(2)-values ranging from 0.96 to 0.996. The pediatric patients showed much stronger correlations overall. Strong correlations were observed between organ axial midpoint versus age, height, and weight (max r(2) = 0.842, mean r(2) = 0.790; max r(2) = 0.949, mean r(2) = 0.894; and max r(2) = 0.870, mean r(2) = 0.847, respectively). Moderate linear correlations were also observed for organ axial width versus height (max r(2) = 0.772, mean r(2) = 0.562) and for organ volume versus height (max r(2) = 0.781, mean r(2) = 0.601). Adult patients exhibited small variations in organ volume and location with respect to height and weight, but no meaningful correlation existed between these parameters and age or BMI. Once adulthood is reached, organ morphology and positioning seem to remain static. However, clear trends are evident between pediatric organ locations versus age, height, and weight. Such information can be incorporated into a matching methodology that may provide the highest probability of representing the anatomy of a patient undergoing a clinical exam to prospectively estimate the radiation dose.


Divergent effects of brief contemplative practices in response to an acute stressor: A randomized controlled trial of brief breath awareness, loving-kindness, gratitude or an attention control practice.
Mindfulness practices are increasingly being utilized as a method for cultivating well-being. The term mindfulness is often used as an umbrella for a variety of different practices and many mindfulness-based interventions (MBIs) contain multiple styles of practice. Despite the diversity of practices within MBIs, few studies have investigated whether constituent practices produce specific effects. We randomized 156 undergraduates to one of four brief practices: breath awareness, loving-kindness, gratitude, or to an attention control condition. We assessed practice effects on affect following brief training, and effects on affect and behavior after provocation with a stressor (i.e., Cold pressor test). Results indicate that gratitude training significantly improved positive affect compared to breath awareness (d = 0.58) and loving-kindness led to significantly greater reductions in implicit negative affect compared to the control condition (d = 0.59) immediately after brief practice. In spite of gains in positive affect, the gratitude group demonstrated increased reactivity to the stressor, reporting the CPT as significantly more aversive than the control condition (d = 0.46) and showing significantly greater increases in negative affect compared to the breath awareness, loving-kindness, and control groups (ds = 0.55, 0.60, 0.65, respectively). Greater gains in implicit positive affect following gratitude training predicted decreased post-stressor likability ratings of novel neutral faces compared to breath awareness, loving-kindness, and control groups (ds = - 0.39, -0.40, -0.33, respectively) as well. Moreover, the gratitude group was significantly less likely to donate time than the loving-kindness group in an ecologically valid opportunity to provide unrewarded support. These data suggest that different styles of contemplative practice may produce different effects in the context of brief, introductory practice and these differences may be heightened by stress. Implications for the study of contemplative practices are discussed.


N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation.
Members of the myc family of cellular oncogenes have been implicated as transcriptional regulators in pathways that govern cellular proliferation and death. In addition, N-myc and c-myc are essential for completion of murine embryonic development. However, the basis for the evolutionary conservation of myc gene family has remained unclear. To elucidate this issue, we have generated mice in which the endogenous c-myc coding sequences have been replaced with N-myc coding sequences. Strikingly, mice homozygous for this replacement mutation can survive into adulthood and reproduce. Moreover, when expressed from the c-myc locus, N-myc is similarly regulated and functionally complementary to c-myc in the context of various cellular growth and differentiation processes. Therefore, the myc gene family must have evolved, to a large extent, to facilitate differential patterns of expression.


Probabilistic modelling of chromatin code landscape reveals functional diversity of enhancer-like chromatin states.
Interpreting the functional state of chromatin from the combinatorial binding patterns of chromatin factors, that is, the chromatin codes, is crucial for decoding the epigenetic state of the cell. Here we present a systematic map of Drosophila chromatin states derived from data-driven probabilistic modelling of dependencies between chromatin factors. Our model not only recapitulates enhancer-like chromatin states as indicated by widely used enhancer marks but also divides these states into three functionally distinct groups, of which only one specific group possesses active enhancer activity. Moreover, we discover a strong association between one specific enhancer state and RNA Polymerase II pausing, linking transcription regulatory potential and chromatin organization. We also observe that with the exception of long-intron genes, chromatin state transition positions in transcriptionally active genes align with an absolute distance to their corresponding transcription start site, regardless of gene length. Using our method, we provide a resource that helps elucidate the functional and spatial organization of the chromatin code landscape.


In vivo local determination of tissue optical properties: applications to human brain.
Local and superficial near-infrared (NIR) optical-property characterization of turbid biological tissues can be achieved by measurement of spatially resolved diffuse reflectance at small source-detector separations (<1.4 mm). However, in these conditions the inverse problem, i.e., calculation of localized absorption and the reduced scattering coefficients, is necessarily sensitive to the scattering phase function. This effect can be minimized if a new parameter of the phase function gamma, which depends on the first and the second moments of the phase function, is known. If gamma is unknown, an estimation of this parameter can be obtained by the measurement, but the uncertainty of the absorption coefficient is increased. A spatially resolved reflectance probe employing multiple detector fibers (0.3-1.4 mm from the source) is described. Monte Carlo simulations are used to determine gamma, the reduced scattering and absorption coefficients from reflectance data. Probe performance is assessed by measurements on phantoms, the optical properties of which were measured by other techniques [frequency domain photon migration (FDPM) and spatially resolved transmittance]. Our results show that changes in the absorption coefficient, the reduced scattering coefficient, and gamma can be measured to within +/-0.005 mm(-1), +/-0.05 mm(-1), and +/-0.2, respectively. In vivo measurements performed intraoperatively on a human skull and brain are reported for four NIR wavelengths (674, 811, 849, 956 nm) when the spatially resolved probe and FDPM are used. The spatially resolved probe shows optimum measurement sensitivity in the measurement volume immediately beneath the probe (typically 1 mm(3) in tissues), whereas FDPM typically samples larger regions of tissues. Optical-property values for human skull, white matter, scar tissue, optic nerve, and tumors are reported that show distinct absorption and scattering differences between structures and a dependence on the phase-function parameter gamma.


Hydrogen gas distribution in organs after inhalation: Real-time monitoring of tissue hydrogen concentration in rat.
Hydrogen has therapeutic and preventive effects against various diseases. Although animal and clinical studies have reported promising results, hydrogen distribution in organs after administration remains unclear. Herein, the sequential changes in hydrogen concentration in tissues over time were monitored using a highly sensitive glass microsensor and continuous inhalation of 3% hydrogen gas. The hydrogen concentration was measured in the brain, liver, kidney, mesentery fat and thigh muscle of rats. The maximum concentration, time to saturation, and other measurements representing the dynamics of distribution were obtained from the concentration curves, and the results obtained for different organs were compared. The time to saturation was significantly longer (20.2 vs 6.3-9.4 min. P = 0.004 in all cases) and increased more gradually in muscle than in the other organs. The maximum concentration was the highest in liver and the lowest in the kidney (29.0 ± 2.6 vs 18.0 ± 2.2 μmol/L; P = 0.03 in all cases). The concentration varied significantly depending on the organ (P = 0.03). These results provide the fundamentals for elucidating the mechanisms underlying the in vivo favourable effects of hydrogen gas in mammalian systems.


Urban residential tree canopy and perceived stress among pregnant women.
To examine the association of urban residential tree canopy cover with perceived stress in a cohort of pregnant women in Philadelphia, PA, and explore whether this association differed among participants with a history of anxiety and depression. We performed a secondary analysis of 1294 participants of the Motherhood & Microbiome (M&M) pregnancy cohort who lived in Philadelphia, with first visit perceived stress (Cohen's Perceived Stress Scale, PSS-14), and key covariate data. Tree canopy cover was calculated as percent cover within 100 and 500 m radii buffers around participants' homes. We performed multilevel mixed effects linear regression models, with perceived stress as the dependent variable. The main independent variable was tree canopy coverage. Individual-level covariates included season of last menstrual period, history of depression or anxiety, race/ethnicity, insurance, parity, and age. Census tract neighborhood deprivation index was used to account for area-level socioeconomic confounding variables. We also examined whether a history of anxiety or depression, modified the association between tree canopy coverage and perceived stress. Most participants were non-Hispanic Black (70.6%, n = 913), on Medicaid or uninsured (60.4%, n = 781), and 15.8% (n = 204) of participants had a prior history of depression or anxiety. We did not detect associations between tree canopy coverage and perceived stress overall. However, we detected effect modification; among participants with a history of depression or anxiety, each standard deviation increase in tree canopy cover was associated with lower PSS-14 in 100 m buffers (β -1.0, 95% CI -1.8, -0.2), but not among participants with no histories of depression or anxiety (β 0.2, 95% CI -0.3, 0.7) (interaction P = 0.007). Results were similar in directionality but not statistically significant within 500 m buffers. Residential tree canopy coverage was associated with reduced perceived stress among urban-dwelling pregnant women with history of anxiety or depression. Future studies of the effects of greenness and other stress-reducing efforts should consider underlying mental health conditions as effect modifiers.


Protein kinase C activity in developing rat brain cells exposed to 2.45 GHz radiation.
There is growing concern by the public regarding the potential human health hazard due to exposure to microwave frequencies. 2.45 GHz radiation widespread use in industry, research, and medicine, and leakage into the environment is possible. In order to quantitate this, experiments were performed on developing rat brain. Male Wistar 35-day-old rats (n = 6) were used for this study. Animals were exposed to 2.45 GHz radiation for 2 h/day for a period of 35 days at a power density of 0.344 mW/cm(2) (SAR 0.11 W/kg). The control group was sham irradiated. After 35 days these rats were sacrificed and whole brain tissue was isolated for protein kinase C (PKC) assay. For morphological study the forebrain was isolated from the whole brain and PKC activity was measured using P(32) labeled ATP. Our study reveals a statistically significant (p < 0.05) decrease in PKC activity in hippocampus as compared to the remaining portion of the whole brain and the control group. A similar experiment conducted on hippocampus and the whole brain gave a similar result. Electron microscopic study shows an increase in the glial cell population in the exposed group as compared to the control group. This present study is indicative of a significant change after exposure to the above-mentioned field intensity. This suggests that chronic exposures may affect brain growth and development.


Investigating the cellular effects of isolated radiation tracks using microbeam techniques.
Studies of the effects of radiation at the cellular level have generally been carried out by exposing cells randomly to the charged-particle tracks of a radiation beam. Recently, a number of laboratories have developed techniques for microbeam irradiation of individual cells. These approaches are designed to remove much of the randomness of conventional methods and allow the nature of the targets and pathways involved in a range of radiation effects to be studied with greater selectivity. Another advantage is that the responses of individual cells can be followed in a time-lapse fashion and, for example, processes such as "bystander" effects can be studied clearly. The microbeam approach is of particular importance in mechanistic studies related to the risks associated with exposure to low fluences of charged particles. This is because it is now possible to determine the actions of strictly single particle tracks and thereby mimic, under in vitro conditions, exposures at low radiation dose that are significant for protection levels, especially those involving medium- to high-LET radiations. Overall, microbeam methods provide a new dimension in exploring mechanisms of radiation effect at the cellular level. Microbeam methods and their application to the study of the cellular effects of single charged-particle traversals are described.


Abnormalities in metabolic network activity precede the onset of motor symptoms in Parkinson's disease.
Imaging studies show that Parkinson's disease (PD) alters the activity of motor- and cognition-related metabolic brain networks. However, it is not known whether the network changes appear at or before symptom onset. In this study, we examined 15 hemiparkinsonian patients who underwent serial metabolic imaging with [(18)F]-fluorodeoxyglucose (FDG) PET at baseline and again 2.1 +/- 0.6 (mean +/- SD) and 3.9 +/- 0.7 years later. We assessed longitudinal changes in network activity in each cerebral hemisphere, focusing specifically on the "presymptomatic" hemisphere--ipsilateral to the initially involved body side. At the network level, the activity of the PD motor-related pattern (PDRP) increased symmetrically in both hemispheres over time (p < 0.001), with significant bilateral elevations at each of the three time points. Hemispheric expression of the PD cognition-related pattern likewise increased symmetrically (p < 0.001), although significant elevations were not evident on either side until 4 years. At the regional level, putamen metabolism contralateral to the initially affected body side was elevated at all three time points, without longitudinal change. In contrast, in the initially presymptomatic hemisphere, putamen metabolic activity increased steadily over time, reaching abnormal levels only at 4 years. Metabolic activity in the contralateral precuneus fell to subnormal levels by the final time point. These findings suggest that abnormal PDRP activity antecedes the appearance of motor signs by approximately 2 years. The timing and laterality of symptom onset relates to focal asymmetric metabolic changes at the putamenal node of this network.


Stanniocalcin-1 regulates endothelial gene expression and modulates transendothelial migration of leukocytes.
The mammalian counterpart of the fish calcium-regulating hormone stanniocalcin-1 (STC1) inhibits monocyte chemotactic protein-1- and stromal-derived factor-1alpha (SDF-1alpha)-mediated chemotaxis and diminishes chemokinesis in macrophage-like RAW264.7 and U937 cells in a manner that may involve attenuation of the intracellular calcium signal. STC1 is strongly induced in the kidney following obstructive injury. We hypothesized that STC1 may serve to attenuate the influx of inflammatory cells to the site of tissue injury. In this study, we examined the effect of STC1 on the migration of freshly isolated human macrophages, neutrophils, and T and B lymphocytes through quiescent or IL-1beta-treated human umbilical vein endothelial cell (HUVEC) monolayers. STC1 inhibited transmigration of macrophages and T lymphocytes through quiescent or IL-1beta-activated HUVECs but did not attenuate the transmigration of neutrophils and B lymphocytes. STC1 regulates gene expression in cultured endothelial cells and is detected on the apical surface of endothelial cells in vivo. The data suggest that STC1 plays a critical role in transendothelial migration of inflammatory cells and is involved in the regulation of numerous aspects of endothelial function.


Predicting the clinical outcome of stimulant medication in pediatric attention-deficit/hyperactivity disorder: data from quantitative electroencephalography, event-related potentials, and a go/no-go test.
We searched for predictors of the clinical outcome of stimulant medication in pediatric attention-deficit/hyperactivity disorder (ADHD), emphasizing variables from quantitative electroencephalography, event-related potentials (ERPs), and behavioral data from a visual go/no-go test. Nineteen-channel electroencephalography (EEG) was recorded during the resting state in eyes-open and eyes-closed conditions and during performance of the cued go/no-go task in 98 medication-naïve ADHD patients aged 7-17 years and in 90 controls with the same age and sex distribution as the patients. For patients, the recording was followed by a systematic trial on stimulant medication lasting at least 4 weeks. Based on data from rating scales and interviews, two psychologists who were blind to the electrophysiological results independently rated the patients as responders (REs) (N=74) or non-responders (non-REs) (N=24). Using a logistic regression model, comparisons were made between REs and non-REs on the EEG spectra, ERPs (cue P3, contingent negative variation, and P3 no-go of the ERP waves and independent components [ICs] extracted from these waves), reaction time, reaction time variability, number of commission and omission errors, intelligence quotient, age, sex, ADHD subtype, and comorbidities. The two groups differed significantly on eight of the variables, with effect sizes (Cohen's d) ranging from 0.49 to 0.76. In the multivariate logistic regression analysis, only three of these variables were significantly associated with clinical outcome. The amplitude of the IC cue P3, which has a parietal-occipital distribution, was normal in REs but significantly smaller in non-REs, whereas the centrally distributed IC P3 no-go early was smaller in REs than in non-REs and controls. In addition, the REs had more power in the EEG theta band. A quartile-based index was calculated using these three variables. The group with the lowest scores comprised only 36% REs; response rates in the three other groups were 83%, 86%, and 89%. The clinical outcome of stimulant medication was best predicted by electrophysiological parameters. The brain dysfunctions of the REs appear to be primarily associated with prefrontal lobe hypoactivation. The non-REs were deviant from the controls in parietal-occipital functions.


A model for colour pattern formation in the butterfly wing of Papilio dardanus.
The butterfly Papilio dardanus is well known for the spectacular phenotypic polymorphism in the female of the species. We show that numerical simulations of a reaction diffusion model on a geometrically accurate wing domain produce spatial patterns that are consistent with many of those observed on the butterfly. Our results suggest that the wing coloration is due to a simple underlying stripe-like pattern of some pigment-inducing morphogen. We focus on the effect of key factors such as parameter values for mode selection, threshold values which determine colour, wing shape and boundary conditions. The generality of our approach should allow us to investigate other butterfly species. The relationship between these key factors and gene activities is discussed in the context of recent biological advances.


Infusional cyclophosphamide, doxorubicin, and etoposide in relapsed and resistant non-Hodgkin's lymphoma: evidence for a schedule-dependent effect favoring infusional administration of chemotherapy.
This study attempted to determine the efficacy of cyclophosphamide (C), doxorubicin (D), and etoposide (E) administered as a continuous intravenous (IV) infusion (infusional CDE) over 4 days in patients with relapsed or resistant non-Hodgkin's lymphoma (rNHL) and in patients with previously untreated (uNHL) who had poor prognostic features. Fifty-eight patients with rNHL and 10 patients with uNHL received infusional CDE every 28 or more days; all but one had intermediate- to high-grade histology. The cumulative doses of C, D, and E administered per treatment cycle were 750 mg/m2, 50 mg/m2, and 240 mg/m2, respectively. In the rNHL group, all patients had previously received C, most (81%) had received D, and a minority (16%) had received E. Objective response occurred in 30 patients with rNHL (52%; 95% confidence interval, 39% to 65%); 10 patients had a complete response (CR) (17%; 95% confidence interval, 7% to 27%). Eleven patients (19%) remain progression-free (median follow-up, 22 months; range, 10+ to 38+), and six patients (10%) are disease-free (median follow-up, 25 months; range, 10+ to 38+). Among 10 patients with uNHL, eight (80%) had a CR, and none have relapsed (median follow-up, 11 months; range, 9+ to 24+). Toxicity was primarily hematologic. Two treatment-related deaths (3%) occurred, both attributable to infection in the relapsed or resistant group. Infusional CDE produced a CR in substantial proportion of patients who had previously been exposed to at least two of the agents administered as an IV bolus, suggesting a schedule-dependent effect in favor of the infusional administration of certain cytotoxic agents in patients with lymphoid neoplasms. In addition, infusional CDE was effective and tolerable in patients with poor-prognosis NHL when used as initial therapy, and merits further study in that setting.


More Unnecessary Imaginary Worlds - Part 2: The ICER Evidence Report on Modeling Oral Semaglutide for Type 2 Diabetes.
On 9 December2019, the Institute for Clinical and Economic Review (ICER) released its final evidence report to establish the value of oral semaglutide (Novo Nordisk) for Type 2 diabetes (T2DM). A key element in this report was the development of a lifetime cost effectiveness microsimulation model based on a small sample of NHANES diabetes respondents. The model contrasted oral semaglutide added to current antihyperglycemic treatment for T2DM. The purpose of the model was to estimate outcomes that included life years (LYs) gained, an estimate of equal value life years gained (evLYGs), QALYs gained, clinical events, cost per major adverse cardiovascular events (MACE) avoided and total costs for each intervention over a lifetime time horizon. Previous commentaries in INNOVATTIONS in Pharmacy have provided detailed critiques of the ICER modeling framework. While this model differs from previous ICER models, the result is still a framework that constructs a so-called evidence base that fails the demarcation test. It is best described as pseudoscience. The model creates, by assumption, an imaginary world. The claims made for oral semaglutide by ICER should not be taken seriously by health care decision makers. The purpose of this commentary is to point to the limitations of the model with particular reference to the utility metrics employed, the resulting claims for quality adjusted life years (QALYs) and consequent recommendations for price discounting and affordability.


A predictive integrated framework based on the radial basis function for the modelling of the flow of pharmaceutical powders.
This study presents a modelling framework to predict the flowability of various commonly used pharmaceutical powders and their blends. The flowability models were trained and validated on 86 samples including single components and binary mixtures. Two modelling paradigms based on artificial intelligence (AI) namely, a radial basis function (RBF) and an integrated network were employed to model the flowability represented by the flow function coefficient (FFC) and the bulk density (RHOB). Both approaches were utilized to map the input parameters (i.e. particle size, shape descriptors and material type) to the flow properties. The input parameters of the blends were determined from the particle size, shape and material type properties of the single components. The results clearly indicated that the integrated network outperformed the single RBF network in terms of the predictive performance and the generalization capabilities. For the integrated network, the coefficient of determination of the testing data set (not used for training the model) for FFC was R2=0.93, reflecting an acceptable predictive power of this model. Since the flowability of the blends can be predicted from single component size and shape descriptors, the integrated network can assist formulators in selecting excipients and their blend concentrations to improve flowability with minimal experimental effort and material resulting in the (i) minimization of the time required, (ii) exploration and examination of the design space, and (iii) minimization of material waste.


Arterial dermatan sulfate proteoglycan structure in pigeons susceptible to atherosclerosis.
Arterial dermatan sulfate proteoglycans (DS-PG) were isolated from randomly bred White Carneau (RBWC) pigeons and a line of White Carneau pigeons (WC-2) genetically selected for increased atherosclerosis susceptibility. To characterize the basic proteoglycan (PG) structure and to identify structural differences that may relate to a specific arterial phenotype, embryos were labeled with radioactive sulfate in ovo and PG were isolated from aortas with 4.0 M GdnHCl. DS-PG were separated from chondroitin sulfate PG by gel chromatography and further purified by CsCl buoyant density ultracentrifugation and ion-exchange of chromatography. The DS-PG monomers from the two genetic lines of pigeons eluted at different positions on two high pressure liquid chromatography (HPLC) gel permeation systems, which suggested a structural difference between the two monomers. Analysis of the monomer components showed a similar protein core molecular weight of 50,000 for each and a similar amino acid composition. Glycosaminoglycans (GAG) molecular weights were estimated to be 15,000 for WC-2 and 18,000 for RBWC. The findings suggest a basic difference in post-translational processing of PG in the two pigeon types which may reflect distinct functional properties associated with resistance or susceptibility to atherosclerosis.


Pharmacy, social media, and health: Opportunity for impact.
To discuss opportunities and challenges for pharmacists' use of social media to affect health care. Not applicable. Evolutions in social media (e.g., Facebook, Twitter, YouTube) are beginning to alter the way society communicates. These new applications promote openness, user-generated content, social networking, and collaboration. The technologies, along with patient behaviors and desires, are stimulating a move toward more open and transparent access to health information. Although social media applications can reach large audiences, they offer message-tailoring capabilities that can effectively target specific populations. Another powerful aspect of social media is that they facilitate the organization of people and distribution of content-two necessary components of public health services. Although implementing health interventions via social media poses challenges, several examples exist that display the potential for pharmacists to use social media in health initiatives. Pharmacists have long played a role in educating patients on matters influencing health care. Social media offer several unique features that may be used to advance the role of pharmacy in health care initiatives. Public familiarity with social media, the economical nature of using social media, and the ability to disseminate information rapidly through social media make these new applications ideal for pharmacists wanting to provide innovative health care on both an individual and public level.


Plant GRAS and metazoan STATs: one family?
GRAS is a recently discovered family of plant-specific proteins that play important regulatory roles in diverse aspects of plant development. Several of the motifs present in the GRAS proteins suggest that they function as transcription factors, although homology-searching programs have revealed no significant similarity to any non-plant proteins. Here we propose that the GRAS proteins are related to the Signal Transducers and Activators of Transcription (STAT) family of proteins. STATs are known in many non-plant species, and act as intracellular intermediaries between extracellular ligands and the transcription and activation of genes. Our hypothesis is that the GRAS proteins perform this function in plants, with mechanisms similar to those of the animal STATs. If true, this hypothesis has important implications for the evolution of phosphotyrosine based signal transduction systems in eukaryotic organisms. BioEssays 22:573-577, 2000.


Dry season determinants of malaria disease and net use in Benin, West Africa.
To achieve malaria eradication, control efforts have to be sustained even when the incidence of malaria cases becomes low during the dry season. In this work, malaria incidence and its determinants including bed net use were investigated in children of under 5 years of age in 28 villages in southern Benin during the dry season. Mean malaria clinical incidence was measured in children aged 0-5 years by active case detection in 28 villages of the Ouidah-Kpomasse-Tori Bossito sanitary district between November 2007 and March 2008. Using Poisson mixed-effect models, malaria incidence was assessed according to the level of transmission by different vector species, and Long-Lasting Insecticide-treated mosquito Nets (LLIN) use and ownership. Then, a Binomial mixed-effect model was developed to assess whether nighttime temperature (derived from MODIS remote sensing data), biting nuisance and LLIN ownership are good predictors of LLIN use >60%. Results suggested that Anopheles funestus (Incidence Rates Ratio (IRR) = 3.38 [IC95 1.91-6]) rather than An. gambiae s.s. is responsible for malaria transmission. A rate of LLIN use >60% was associated with a lower risk of malaria (IRR = 0.6 [IC95 0.37-0.99]). Low nocturnal temperature and high biting nuisance were good predictors of LLIN use >60%. As recommended by the Malaria Eradication (MalERA) Consultative Group on Modelling, there is a need to understand better the effects of seasonality on malaria morbidity. This study highlights the need to take into account the specificity of malaria epidemiology during the dry-hot season and get a better understanding of the factors that influence malaria incidence and net use. These findings should help National Malaria Control Programmes to implement more effective and sustainable malaria control strategies in Africa.


Ashkenazi Jewish centenarians do not demonstrate enrichment in mitochondrial haplogroup J.
Association of mitochondrial haplogroup J with longevity has been reported in several population subgroups. While studies from northern Italy and Finland, have described a higher frequency of haplogroup J among centenarians in comparison to non-centenarian, several other studies could not replicate these results and suggested various explanations for the discrepancy. We have evaluated haplogroup frequencies among Ashkenazi Jewish centenarians using two different sets of matched controls. No difference was observed in the haplogroup J frequencies between the centenarians or either matched control group, despite adequate statistical power to detect such a difference. Furthermore, the lack of association was robust to population substructure in the Ashkenazi Jewish population. Given this discrepancy with the previous reported associations in the northern Italian and the Finnish populations, we conducted re-analysis of these previously published data, which supported one of several possible explanations: i) inadequate matching of cases and controls; ii) inadequate adjustment for multiple comparison testing; iii) cryptic population stratification. There does not exist a universal association of mitochondrial haplogroup J with longevity across all population groups. Reported associations in specialized populations may reflect genetic or other interactions specific to those populations or else cryptic confounding influences, such as inadequate matching attributable to population substructure, which are of general relevance to all studies of the possible association of mitochondrial DNA haplogroups with common complex phenotypes.


One haploid parent contributes 100% of the gene pool for a widespread species in northwest North America.
The monoicous peatmoss Sphagnum subnitens has a tripartite distribution that includes disjunct population systems in Europe (including the Azores), northwestern North America and New Zealand. Regional genetic diversity was highest in European S. subnitens but in northwestern North America, a single microsatellite-based multilocus haploid genotype was detected across 16 sites ranging from Coos County, Oregon, to Kavalga Island in the Western Aleutians (a distance of some 4115 km). Two multilocus haploid genotypes were detected across 14 sites on South Island, New Zealand. The microsatellite-based regional genetic diversity detected in New Zealand and North American S. subnitens is the lowest reported for any Sphagnum. The low genetic diversity detected in both of these regions most likely resulted from a founder event associated with vegetative propagation and complete selfing, with one founding haploid plant in northwest North America and two in New Zealand. Thus, one plant appears to have contributed 100% of the gene pool for the population systems of S. subnitens occurring in northwest North America, and this is arguably the most genetically uniform group of plants having a widespread distribution yet detected. Although having a distribution spanning 12.5° of latitude and 56° of longitude, there was no evidence of any genetic diversification in S. subnitens in northwest North America. No genetic structure was detected among the three regions, and it appears that European plants of S. subnitens provided the source for New Zealand and northwest North American populations.


Experiences of care planning in England: interviews with patients with long term conditions.
The prevalence and impact of long term conditions continues to rise. Care planning for people with long term conditions has been a policy priority in England for chronic disease management. However, it is not clear how care planning is currently understood, translated and implemented in primary care. This study explores experience of care planning in patients with long term conditions in three areas in England. We conducted semi-structured interviews with 23 predominantly elderly patients with multiple long term conditions. The interviews were designed to explore variations in and emergent experiences of care planning. Qualitative analysis of interview transcripts involved reflexively coding and re-coding data into categories and themes. No participants reported experiencing explicit care planning discussions or receiving written documentation setting out a negotiated care plan and they were unfamiliar with the term 'care planning'. However, most described some components of care planning which occurred over a number of contacts with health care professionals which we term "reactive" care planning. Here, key elements of care planning including goal setting and action planning were rare. Additionally, poor continuity and coordination of care, lack of time in consultations, and patient concerns about what was legitimate to discuss with the doctor were described. Amongst this population, elements of care planning were present in their accounts, but a structured, comprehensive process and consequent written record (as outlined in English Department of Health policy) was not evident. Further research needs to explore the advantages and disadvantages of different approaches to care planning for different patient groups.


When passion makes the heart grow colder: the role of passion in alternative goal suppression.
Quality of goal engagement and alternative goal suppression were investigated in this research. Integrating the dualistic model of passion (Vallerand et al., 2003) with goal-systems theory (Kruglanski et al., 2002), we hypothesized that obsessive passion--associated with recurrent goal-conflicts--would predict greater alternative goal suppression (i.e., goal-shielding) than would harmonious passion--characterized by effective synthesis of the passionate activity with other life domains. Results from 5 laboratory studies supported these hypotheses. In Study 1, participants' dispositional measures of harmonious and obsessive passion were correlated with an implicit measure of goal-shielding. Obsessive (but not harmonious) passion predicted the suppression of alternative goals and the progressive inhibition of unfamiliar goals. In Study 2, we extended these findings by demonstrating the interrelation between quality of goal engagement and goal-commitment such that goal-shielding effects were enhanced, but only for goals in conflict with other life domains (vs. well-integrated goals). In Study 3, the causal influence of passion on goal-shielding was supported via an experimental manipulation of passion. In Study 4, we replicated and extended Studies 1 and 3 by experimentally demonstrating that obsessive (but not harmonious) passion is a mindset conducive to the development of inhibitory links with alternative goals. Study 5 explored the psychological costs associated with repeated unconscious goal suppression by examining its effects on the depletion of self-regulatory resources. Collectively, the present results suggest that the qualitative distinction between obsessive and harmonious passion has implications for the goal-shielding effect and for subsequent self-regulatory behavior.


Endovascular repair for abdominal aortic aneurysms: the first hundred cases.
To evaluate the early and mid-term results of the first 100 elective endovascular repairs for abdominal aortic aneurysms. Retrospective analysis of prospectively collected data. University teaching hospital, Hong Kong. The first 100 patients with infrarenal abdominal aortic aneurysms who underwent elective endovascular repair. Peri-operative data, mortality and morbidities as well as the follow-up details were recorded. Cumulative data on endoleaks, clinical failures, secondary procedures, and survival were evaluated with Kaplan-Meier analyses. There were 85 men and 15 women, with a mean age of 75 (range, 50-90) years. Failed implantations due to access difficulty occurred in two patients during the same period, giving a technical success rate of 98%. The mean aneurysm diameter was 6.2 cm. Access site injury requiring repair occurred in four (4%) of the patients, while wound problems were the most common complications (11%). The median hospital stay was 6 days, and there were two hospital deaths, giving a hospital mortality rate of 2%. During a mean follow-up of 36 (standard deviation, 24) months, there were three aneurysmal ruptures and four elective open conversions, with only one aneurysm-related death after hospital discharge. At 3 years, the cumulative rates of freedom from any endoleak, freedom from primary failure, freedom from secondary failure, freedom from secondary procedures, and survival were 60%, 84%, 89%, 88%, and 78%, respectively. The early and mid-term results of elective endovascular repair for abdominal aortic aneurysms appear promising. The procedure is effective in preventing aneurysm-related death in the mid-term. Nevertheless, the importance of constant surveillance cannot be over-emphasised, as clinical failures and ruptures are still a concern.


Cell cycle independent interaction of CDC2 with the centrosome, which is associated with the nuclear matrix-intermediate filament scaffold.
The cell cycle regulating Cdc2 protein kinase helps orchestrate cell cycle dependent changes in cell structure and function. This report shows that Cdc2 is localized to the centrosome region and is tightly bound to the nuclear matrix-intermediate filament scaffold. Antibodies to Cdc2 and to the centrosome-specific protein, pericentrin, label the centrosome in an apparently cell cycle independent manner. Isolated centrosomes also label similarly with both antibodies. Essentially, all cells show Cdc2 labeling of the centrosomes, implying an independence of the stage in the cell cycle, a conclusion supported by studies of synchronized cells. In contrast to the labeling of every cell with the Cdc2 monoclonal antibody, fewer centrosomes were labeled with an antibody to the PSTAIRE domain of Cdc2. Embedment-free, immunogold electron micrographs of extracted cell whole mounts show the centrioles and a pericentriolar network of filaments. Both Cdc2 and pericentrin antibodies decorate the amorphous pericentriolar material, while the Cdc2 antibodies also decorate the centrioles themselves. The constitutive presence of Cdc2 at the centrosome suggests a continuing role in the dynamics of centrosome function throughout the cell cycle.


Altered structural connectivity and trait anhedonia in patients with schizophrenia.
This study tested association between anhedonia scores and white matter integrity in order to investigate the neural basis of trait anhedonia in schizophrenia. A total of 31 patients with schizophrenia and 33 healthy controls underwent diffusion weighted imaging and scoring of trait anhedonia using the Physical Anhedonia Scale. Using tract-based spatial statistics, we found that fractional anisotropy values of some white matter regions were differently correlated with Physical Anhedonia Scale scores between the two groups. The white matter regions that were more significantly correlated with trait anhedonia in patients than in controls included the left side of the cingulum, splenium of the corpus callosum, inferior longitudinal fasciculus, superior longitudinal fasciculus I and II, anterior thalamic radiation, and optic radiation. Of these regions, fractional anisotropy values in the cingulum and superior longitudinal fasciculus II were positively correlated with trait anhedonia in patients with schizophrenia. These findings suggest that alterations in structural connectivity within large-scale brain networks, including the default mode and central executive networks, may contribute to the development of trait anhedonia in patients with schizophrenia.


Inbreeding avoidance by recognition of close kin in the pea aphid, Acyrthosiphon pisum.
Inbreeding depression has detrimental effects on many organisms, but its effects are potentially greater in organisms that have at least one asexually reproducing life stage. Here, the existence of severe inbreeding depression upon selfing (r = 1) in the cyclic parthenogenetic aphid Acyrthosiphon pisum (Harris) (Hemiptera: Aphididae) is documented. Egg hatching success and offspring survival of inbred mating pairs are significantly lower than that of outbred mating pairs. Two possible mechanisms for avoiding selfing are examined: avoidance of partners of identical genetic makeup and avoidance of partners of the same body color (as a proxy for genetic similarity). Mating between males and females of the same color was as successful as mating between partners of different colors. In contrast, the success of mating between close kin was consistently reduced compared to that of mating between genetically unrelated partners. Interestingly, mating between close kin proceeded normally until the very last stage of the mating process. Thus, inbreeding avoidance appears to take place sometime between copulation and sperm transfer, suggesting that cryptic female choice may play a role in the process.


Reduction in biogenic amines in douchi fermented by probiotic bacteria.
Ecology studies showed that esophageal and gastric cancers are directly correlated with the consumption of processed foods. The carcinogenicity of traditional Chinese fermented foods such as douchi (fermented black beans or fermented black soybeans) is due to the presence of carcinogenic N-nitroso compounds, which are derived from biogenic amines. Among the various biogenic amines that can act as precursors of N-nitroso compounds, histamine and tyramine are considered to be the most toxic and are of public health concern when present in food. We have examined some douchi products on the market, and significant amounts of histamine and tyramine were found. The use of fermentation starters generated by subculturing fermented products with unknown microbiota would induce the risk of biogenic amines. As the microbiota used in fermentation is a crucial factor in determining the biogenic amines of fermented food, it is hypothesized that the possible harmful effects of douchi can be minimized through the use of fermentation starters composed of probiotic bacteria. This is the first study to investigate the potential of using probiotic bacteria in manufacturing douchi. Lactobacillus rhamnosus GG (LGG), Lactobacillus casei Shirota (LcS) and Escherichia coli Nissle 1917 (EcN) were used to ferment black beans in this study, and no tyramine was detected in black bean samples incubated with these three strains anaerobically at 37°C or 20°C. The starter culture strains, temperature and presence of oxygen during the incubation period were found to be critical to the generation of biogenic amines. The findings of this study can provide evidence-based insights and warrant further investigations on the potential of reducing the harmful compounds in food fermented with probiotic bacteria as well as the sensory evaluation of douchi fermented with probiotic bacteria.


Evidence-based intervention to reduce avoidable hospital admissions in care home residents (the Better Health in Residents in Care Homes (BHiRCH) study): protocol for a pilot cluster randomised trial.
Acute hospital admission is distressing for care home residents. Ambulatory care sensitive conditions, such as respiratory and urinary tract infections, are conditions that can cause unplanned hospital admission but may have been avoidable with timely detection and intervention in the community. The Better Health in Residents in Care Homes (BHiRCH) programme has feasibility tested and will pilot a multicomponent intervention to reduce these avoidable hospital admissions. The BHiRCH intervention comprises an early warning tool for noting changes in resident health, a care pathway (clinical guidance and decision support system) and a structured method for communicating with primary care, adapted for use in the care home. We use practice development champions to support implementation and embed changes in care. Cluster randomised pilot trial to test study procedures and indicate whether a further definitive trial is warranted. Fourteen care homes with nursing (nursing homes) will be randomly allocated to intervention (delivered at nursing home level) or control groups. Two nurses from each home become Practice Development Champions trained to implement the intervention, supported by a practice development support group. Data will be collected for 3 months preintervention, monthly during the 12-month intervention and 1 month after. Individual-level data includes resident, care partner and staff demographics, resident functional status, service use and quality of life (for health economic analysis) and the extent to which staff perceive the organisation supports person centred care. System-level data includes primary and secondary health services contacts (ie, general practitioner and hospital admissions). Process evaluation assesses intervention acceptability, feasibility, fidelity, ease of implementation in practice and study procedures (ie, consent and recruitment rates). Approved by Research Ethics Committee and the UK Health Research Authority. Findings will be disseminated via academic and policy conferences, peer-reviewed publications and social media (eg, Twitter). ISRCTN74109734; Pre-results.


Impact of a malaria intervention package in schools on Plasmodium infection, anaemia and cognitive function in schoolchildren in Mali: a pragmatic cluster-randomised trial.
School-aged children are rarely targeted by malaria control programmes, yet the prevalence of Plasmodium infection in primary school children often exceeds that seen in younger children and could affect haemoglobin concentration and school performance. A cluster-randomised trial was carried out in 80 primary schools in southern Mali to evaluate the impact of a school-based malaria intervention package. Intervention schools received two interventions sequentially: (1) teacher-led participatory malaria prevention education, combined with distribution of long-lasting insecticidal nets (LLINs), followed 7 months later at the end of the transmission season by (2) mass delivery of artesunate and sulfadoxine-pyrimethamine administered by teachers, termed intermittent parasite clearance in schools (IPCs). Control schools received LLINs as part of the national universal net distribution programme. The impact of the interventions on malaria and anaemia was evaluated over 20 months using cross-sectional surveys in a random subset of 38 schools(all classes), with a range of cognitive measures (sustained attention, visual search, numeracy, vocabulary and writing) assessed in a longitudinal cohort of children aged 9-12 years in all 80 schools. Delivery of a single round of IPCs was associated with dramatic reductions in malaria parasitaemia (OR 0.005, 95% CI 0.002 to 0.011, p<0.001) and gametocyte carriage (OR 0.02, 95% CI 0.00 to 0.17, p<0.001) in intervention compared with control schools. This effect was sustained for 6 months until the beginning of the next transmission season. IPCs was also associated with a significant decrease in anaemia (OR 0.56, 95% CI 0.40 to 0.78, p=0.001), and increase in sustained attention (difference +0.23, 95% CI 0.10 to 0.36, p<0.001). There was no evidence of impact on other cognitive measures. The combination of malaria prevention education, LLINs and IPCs can reduce anaemia and improve sustained attention of school children in areas of highly seasonal transmission. These findings highlight the impact of asymptomatic malaria infection on cognitive performance in schoolchildren and the benefit of IPCs in reducing this burden. Additionally, malaria control in schools can help diminish the infectious reservoir that sustains Plasmodium transmission.


Sequence motifs recognized by the casposon integrase of Aciduliprofundum boonei.
Casposons are a group of bacterial and archaeal DNA transposons encoding a specific integrase, termed casposase, which is homologous to the Cas1 enzyme responsible for the integration of new spacers into CRISPR loci. Here, we characterized the sequence motifs recognized by the casposase from a thermophilic archaeon Aciduliprofundum boonei. We identified a stretch of residues, located in the leader region upstream of the actual integration site, whose deletion or mutagenesis impaired the concerted integration reaction. However, deletions of two-thirds of the target site were fully functional. Various single-stranded 6-FAM-labelled oligonucleotides derived from casposon terminal inverted repeats were as efficiently incorporated as duplexes into the target site. This result suggests that, as in the case of spacer insertion by the CRISPR Cas1-Cas2 integrase, casposon integration involves splaying of the casposon termini, with single-stranded ends being the actual substrates. The sequence critical for incorporation was limited to the five terminal residues derived from the 3' end of the casposon. Furthermore, we characterize the casposase from Nitrosopumilus koreensis, a marine member of the phylum Thaumarchaeota, and show that it shares similar properties with the A. boonei enzyme, despite belonging to a different family. These findings further reinforce the mechanistic similarities and evolutionary connection between the casposons and the adaptation module of the CRISPR-Cas systems.


A bifactor model of the Beck Depression Inventory and its association with medical prognosis after myocardial infarction.
Evidence suggests that depression is associated with adverse outcomes in patients with myocardial infarction (MI). Some of the symptoms of depression may also be symptoms of somatic illness and these may confound the association between depression and prognosis. We investigated whether depression following MI is associated with medical prognosis independent of these somatic symptoms. The database of an individual patient data meta-analysis was used. Endpoints were all-cause mortality and cardiovascular events. Nine studies were included. Bifactor factor analysis included 13,100 participants and 7,595 participants were included in survival models. Dimensions were generated from the Beck Depression Inventory using factor analyses. The prognostic association was assessed using mixed-effects Cox regression analysis. A bifactor model, consisting of a general factor and 2 general depression-free subgroup factors (a somatic/affective and a cognitive/affective), provided the best fit. There was a significant association between the general depression factor and all-cause mortality (hazard ratio [HR] = 1.25; 95% confidence interval [CI] [1.17, 1.34], p < .001) and cardiovascular events (HR = 1.18; 95% CI [1.13, 1.23], p < .001). After adjustment for demographics, measures of cardiac disease severity, and health-related variables, the association between the general depression factor and all-cause mortality (HR = 1.14; 95% CI [1.04, 1.25], p = .003) and cardiovascular events (HR = 1.16; 95% CI [1.10, 1.23], p = .014) attenuated. Additionally, the general depression-free somatic/affective factor was significantly associated with the endpoints, while the general depression-free cognitive/affective was not. A general depression factor is associated with adverse medical prognosis following MI independent of somatic/affective symptoms that may be partly attributable to somatic illness. (PsycINFO Database Record


Differentiation of Aspergillus parasiticus from Aspergillus sojae by random amplification of polymorphic DNA.
Aspergillus parasiticus and Aspergillus sojae are two morphologically similar species belonging to the Aspergillus section flavi. A new method to distinguish the two species, the aflatoxin producer A. parasiticus and the koji mold A. sojae, was developed. Single primers with arbitrary sequences were used to generate random amplified polymorphic DNA (RAPD) markers from strains of these two species. Three decamers, OPA-04, OPB-10, and OPR-01, allowed adequate discrimination between strains of A. parasiticus and A. sojae in RAPD analyses. A. sojae was further separated into group I and group II with the three primers. On the other hand, A. parasiticus was divided into group A and group B when amplified with OPA-04 and OPR-10 primers. The previously misidentified stain CCRC 32423 and the misclassified strain CCRC 30227 were identified as Aspergillus flavus and A. sojae, respectively, on the basis of RAPD patterns and morphological characteristics. We suggest that the RAPD technique is a rapid and reliable tool to distinguish A. parasiticus from A. sojae.


Preventive effect of pretreatment with intravenous nicorandil on contrast-induced nephropathy in patients with renal dysfunction undergoing coronary angiography (PRINCIPLE Study).
To investigate the effect of pretreatment with intravenous nicorandil on the incidence of contrast-induced nephropathy (CIN) in patients with renal dysfunction undergoing coronary angiography. This randomized controlled multicenter study enrolled a total of 166 patients (nicorandil n=81; control n=85) with an estimated glomerular filtration rate <60 mL/min. Nicorandil 12 mg dissolved in 100 mL of 0.9% saline was administered intravenously for 30 minutes just prior to coronary angiography in the nicorandil group. The same volume of only saline was given to the control group. The primary endpoint was the incidence of CIN, defined as >0.5 mg/dL increase or >25% rise in serum creatinine (SCr) concentration within 48 hours of contrast exposure compared to baseline. The final analysis included 149 patients (nicorandil n=73; control n=76). The baseline characteristics and the total volume of the used contrast (Iodixanol, 125.6±69.1 mL vs. 126.9±74.6 mL, p=0.916) were similar between the two groups. The incidence of CIN also did not differ between the nicorandil and control groups (6.8% vs. 6.6%, p=0.794). There was no difference between the two groups in the relative change in SCr from baseline to peak level within 48 hours after coronary angiography (-1.58±24.07% vs. 0.96±17.49%, p=0.464), although the nicorandil group showed less absolute change in SCr than the control group (-0.01±0.43 mg/mL vs. 0.02±0.31 mg/mL, p=0.005). Prophylactic intravenous infusion of nicorandil did not decrease the incidence of CIN in patients with renal dysfunction undergoing coronary angiography.


Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury.
Astroglial scars surround damaged tissue after trauma, stroke, infection, or autoimmune inflammation in the CNS. They are essential for wound repair, but also interfere with axonal regrowth. A better understanding of the cellular mechanisms, regulation, and functions of astroglial scar formation is fundamental to developing safe interventions for many CNS disorders. We used wild-type and transgenic mice to quantify and dissect these parameters. Adjacent to crush spinal cord injury (SCI), reactive astrocytes exhibited heterogeneous phenotypes as regards proliferation, morphology, and chemistry, which all varied with distance from lesions. Mature scar borders at 14 d after SCI consisted primarily of newly proliferated astroglia with elongated cell processes that surrounded large and small clusters of inflammatory, fibrotic, and other cells. During scar formation from 5 to 14 d after SCI, cell processes deriving from different astroglia associated into overlapping bundles that quantifiably reoriented and organized into dense mesh-like arrangements. Selective deletion of STAT3 from astroglia quantifiably disrupted the organization of elongated astroglia into scar borders, and caused a failure of astroglia to surround inflammatory cells, resulting in increased spread of these cells and neuronal loss. In cocultures, wild-type astroglia spontaneously corralled inflammatory or fibromeningeal cells into segregated clusters, whereas STAT3-deficient astroglia failed to do so. These findings demonstrate heterogeneity of reactive astroglia and show that scar borders are formed by newly proliferated, elongated astroglia, which organize via STAT3-dependent mechanisms to corral inflammatory and fibrotic cells into discrete areas separated from adjacent tissue that contains viable neurons.


Molecular evidence for a new bacteriophage of Borrelia burgdorferi.
We have recovered a DNase-protected, chloroform-resistant molecule of DNA from the cell-free supernatant of a Borrelia burgdorferi culture. The DNA is a 32-kb double-stranded linear molecule that is derived from the 32-kb circular plasmids (cp32s) of the B. burgdorferi genome. Electron microscopy of samples from which the 32-kb DNA molecule was purified revealed bacteriophage particles. The bacteriophage has a polyhedral head with a diameter of 55 nm and appears to have a simple 100-nm-long tail. The phage is produced constitutively at low levels from growing cultures of some B. burgdorferi strains and is inducible to higher levels with 10 microg of 1-methyl-3-nitroso-nitroguanidine (MNNG) ml(-1). In addition, the prophage can be induced with MNNG from some Borrelia isolates that do not naturally produce phage. We have isolated and partially characterized the phage associated with B. burgdorferi CA-11.2A. To our knowledge, this is the first molecular characterization of a bacteriophage of B. burgdorferi.


Angiographic perfusion score: an angiographic variable that integrates both epicardial and tissue level perfusion before and after facilitated percutaneous coronary intervention in acute myocardial infarction.
Both epicardial and myocardial perfusion have been associated with clinical outcomes in the setting of ST elevation myocardial infarction (STEMI), and the performance of adjunctive/rescue percutaneous coronary intervention (PCI) may further improve clinical outcomes after fibrinolytic administration. The goal was to develop a simple, broadly applicable angiographic metric that takes into account indices of epicardial and myocardial perfusion both before and after PCI to arrive at a single perfusion grade in patients undergoing cardiac catheterization after fibrinolysis. The angiographic perfusion score (APS) is the sum of the Thrombolysis in Myocardial Infarction (TIMI) flow grade (TFG; 0-3) added to the TIMI myocardial perfusion grade (TMPG; 0-3) before and after PCI (total possible grade, 0-12). Failed perfusion was defined as an APS of 0 to 3, partial perfusion was defined as an APS of 4 to 9, and full perfusion was defined as an APS of 10 to 12. The APS was evaluated in patients from the Double-blind, Placebo-contolled, Multicenter Angiographic Trial of Rhumab CD18 in Acute Myocardial Infarction (LIMIT-AMI; n = 394) and Enoxaparin as Adjunctive Antithrombin Therapy for ST-Elevation Myocardial Infarction-Thrombolysis In Myocardial Infarction (ENTIRE-TIMI) 23 trials (n = 483), and infarct size (120-216 hours after AMI SPECT Technetium-99m Sestamibi data) was assessed in the LIMIT-AMI trial. The APS was associated with the incidence of death or myocardial infarction (failed, 16.7% [n = 18]; partial, 2.5% [n = 155]; full, 2.4% [n = 82]; P =.039 for trend) and larger SPECT infarct sizes (failed, median 39% [n = 10]; partial, 12% [n = 79]; and full, 8% [n = 35]; P =.002). No patient with full APS died, whereas the mortality rate was 11.1% in patients with a failed APS (P =.03). The APS combines grades of epicardial and tissue level perfusion before and after PCI or at the end of diagnostic cardiac catheterization to arrive at a single angiographic variable that is associated with infarct size and the rates of 30-day death or MI. Partial or full angiographic perfusion scores are associated with a halving of infarct size, and no patients with full angiographic perfusion died.


Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer.
Purpose: Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCSs).Experimental Design: TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived, and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt's electronic health database (BioVU) and the CALGB 90401 trial.Results: Eight sensory items formed a subscale with good internal consistency (Cronbach α = 0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year, 1.06; P = 2 × 10-9), smoking (OR, 1.54; P = 0.004), excess drinking (OR, 1.83; P = 0.007), and hypertension (OR, 1.61; P = 0.03). CisIPN was correlated with lower self-reported health (OR, 0.56; P = 2.6 × 10-9) and weight gain adjusted for years since treatment (OR per Δkg/m2, 1.05; P = 0.004). PrediXcan identified lower expressions of MIDN and RPRD1B, and higher THEM5 expression as associated with CisIPN (P value for each < 5 × 10-6) with replication of RPRD1B meeting significance criteria (Fisher combined P = 0.0089).Conclusions: CisIPN is associated with age, modifiable risk factors, and genetically determined expression level of RPRD1B Further study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN. Clin Cancer Res; 23(19); 5757-68. ©2017 AACR.


Central sensitization and changes in conditioned pain modulation in people with chronic nonspecific low back pain: a case-control study.
Quantitative sensory testing is widely used in human research to investigate the state of the peripheral and central nervous system contributions in pain processing. It is a valuable tool to help identify central sensitization and may be important in the treatment of low back pain. The aim of this study was to evaluate changes in local and segmental hypersensitivity and endogenous pain inhibition in people with chronic nonspecific low back pain. Thirty patients with chronic low back pain and thirty healthy subjects were studied. Pressure pain thresholds (PPTs) were measured from the lumbar region and over the tibialis anterior muscle (TA). A cold pressor test was used to assess the activation of conditioned pain modulation (CPM), and PPTs in the lumbar region were recorded 30 s after immersion of participant's foot in a bucket with cold water. People with chronic low back pain have significantly lower PPT than controls at both the lumbar region [89.5 kPa (mean difference) 95 % CI 40.9-131.1 kPa] and TA [59.45 kPa (mean difference) 95 % CI 13.49-105.42 kPa]. During CPM, people with chronic low back pain have significantly lower PPT than controls in lumbar region [118.6 kPa (mean difference) 95 % CI 77.9-159.2 kPa]. Women had significantly lower PPTs than men in both lumbar region [101.7 kPa (mean difference) 95 % CI 37.9-165.7 kPa] and over the TA [189.7 kPa (mean difference) 95 % CI 14.2-145.2 kPa]. There was no significant difference in PPTs in men between healthy controls and those with low back pain, suggesting the significant differences are mediated primarily by difference between women.


CYP2B6*6 Genotype Specific Differences in Artemether-Lumefantrine Disposition in Healthy Volunteers.
Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of the antimalarial drugs artemether and lumefantrine. Here we investigated the effect of CYP2B6*6 on the plasma pharmacokinetics of artemether, lumefantrine, and their metabolites in healthy volunteers. Thirty healthy and previously genotyped adult volunteers-15 noncarriers (CYP2B6*1/*1) and 15 homozygote carriers (CYP2B6*6/*6)-selected from a cohort of 150 subjects from the Ilorin metropolitan area were administered the complete 3-day course of artemether and lumefantrine (80 and 480 mg twice daily, respectively). Intensive pharmacokinetic sampling was conducted at different time points before and after the last dose. Plasma concentrations of artemether, lumefantrine, dihydroartemisinin, and desbutyllumefantrine were quantified using validated liquid chromatography-mass spectrometric methods. Pharmacokinetic parameters were evaluated using noncompartmental analysis. Artemether clearance of CYP2B6*6/*6 volunteers was nonsignificantly lower by 26% (ratios of geometric mean [90% CI]; 0.74 [0.52-1.05]), and total exposure (the area under the plasma concentration-time curve from time 0 to infinity [AUC0-∞ ]) was greater by 35% (1.35 [0.95-1.93]) when compared with those of *1/*1 volunteers. Similarly, assuming complete bioconversion from artemether, the dihydroartemisinin AUC0-∞ was 22% lower. On the contrary, artemether-to-dihydroartemisinin AUC0-∞ ratio was 73% significantly higher (1.73 [1.27-2.37]). Comparison of lumefantrine exposure and lumefantrine-to-desbutyllumefantrine metabolic ratio of *6/*6 with corresponding data from *1/*1 volunteers showed no differences. The increased artemether-to-dihydroartemisinin metabolic ratio of *6/*6 volunteers is unlikely to result in differences in artemether-lumefantrine efficacy and treatment outcomes. This is the first study in humans to associate CYP2B6*6 genotype with artemether disposition.


Micrometastasis: detection methods and clinical importance.
Metastatic disease is the most important determinant in the clinical management of patients with cancer. Disseminated tumor cells are regarded as a surrogate for early metastatic spread of disease. These cells can be detected in bone marrow aspirates, lymph nodes and peripheral blood, where we refer to them as circulating tumor cells. Detection of disseminated tumor cells represents a great technical challenge, and many different technologies have been developed to enhance the sensitivity and specificity of the testing for these rare events. Different characteristics of tumor cells have been used to establish enrichment methods, including the differential expression of tumor-specific markers on the surface of the cells, the size-based selection of the cells, and other physical properties. Despite technical obstacles, the detection of circulating tumor cells in particular have emerged in recent years as a biomarker with outstanding predictive and prognostic capacity in a number of malignancies including breast, prostate, lung and colorectal cancer. In this text, we provide a comprehensive review of different approaches for enrichment of disseminated and circulating tumor cells and elucidate additional molecular methods for their detection. Further, the clinical significance of disseminated tumor cells detected in various compartments is discussed. Based on recent findings on the biology and heterogeneity of tumor cells, along with development of robust enrichment techniques, we believe that future research will focus less on pure detection but more importantly on detailed molecular characterization of these rare events with the potential impact on design of novel therapeutics.


Mitomycin C augmented glaucoma surgery: evolution of filtering bleb avascularity, transconjunctival oozing, and leaks.
To prospectively study the evolution of possible high risk features of conjunctival filtration blebs like avascularity, transconjunctival oozing (TCO), and leaks after mitomycin C (MMC) enhanced glaucoma surgery. Single observer, 2 year prospective study on bleb characteristics of 125 eyes of 125 consecutive patients who had MMC augmented glaucoma surgery with initially successful filtration. MMC (0.2 mg/ml for 2 minutes in most cases) was applied on the area of the scleral flap before dissection. Glaucoma surgeries included were trabeculectomy, deep sclerectomy, and combined procedures. A dry fluorescein strip was applied on the avascular part of the bleb and observed for aqueous egress with flow (point leak, PL) or without (TCO). The mean time (95% CI) for observing bleb avascularity, TCO, and bleb leaks were 106 days (69 to 143), 208 days (155 to 261), and 609 days (559 to 659), respectively. Bleb leaks were observed in 17 eyes (13.6%)-15 (24.6%) in the trabeculectomy group and two (3.1%) in the deep sclerectomy group (p = 0.003). Kaplan-Meier survival analyses showed that the probability of observing bleb avascularity at sixth, 12th, and 24th month after surgery was 56%, 71%, and 73%, respectively. In eyes with avascular blebs, the probability of developing TCO and leaks was 77% and 1% at 6 months, 81% and 12% at 12 months, and 95% and 26% at 24 months, respectively. Cox's regression analyses and log rank tests showed that eyes with larger avascular blebs (>4 mm) were more likely to develop TCO (hazard ratio 3.77, p = 0.001) and delayed bleb leaks were more likely to be seen in eyes of the trabeculectomy group rather than the deep sclerectomy group (hazard ratio 0.06, p = 0.0006). MMC application over the area of scleral flap dissection during glaucoma surgery is associated with a high incidence of bleb avascularity, TCO, and delayed bleb leaks. Most eyes developed bleb avascularity within the first year after surgery. TCO will eventually be seen in all eyes with avascular blebs and the incidence of leaks gradually increases with time. This study shows that patients with eyes undergoing glaucoma surgery with MMC and avascular blebs should be monitored indefinitely.


Activation of archaeal transcription mediated by recruitment of transcription factor B.
Archaeal promoters consist of a TATA box and a purine-rich adjacent upstream sequence (transcription factor B (TFB)-responsive element (BRE)), which are bound by the transcription factors TATA box-binding protein (TBP) and TFB. Currently, only a few activators of archaeal transcription have been experimentally characterized. The best studied activator, Ptr2, mediates activation by recruitment of TBP. Here, we present a detailed biochemical analysis of an archaeal transcriptional activator, PF1088, which was identified in Pyrococcus furiosus by a bioinformatic approach. Operon predictions suggested that an upstream gene, pf1089, is polycistronically transcribed with pf1088. We demonstrate that PF1088 stimulates in vitro transcription by up to 7-fold when the pf1089 promoter is used as a template. By DNase I and hydroxyl radical footprinting experiments, we show that the binding site of PF1088 is located directly upstream of the BRE of pf1089. Mutational analysis indicated that activation requires the presence of the binding site for PF1088. Furthermore, we show that activation of transcription by PF1088 is dependent upon the presence of an imperfect BRE and is abolished when the pf1089 BRE is replaced with a BRE from a strong archaeal promoter. Gel shift experiments showed that TFB recruitment to the pf1089 operon is stimulated by PF1088, and TFB seems to stabilize PF1088 operator binding even in the absence of TBP. Taken together, these results represent the first biochemical evidence for a transcriptional activator working as a TFB recruitment factor in Archaea, for which the designation TFB-RF1 is suggested.


The critical role of the research question, inclusion criteria, and transparency in meta-analyses of integrity test research: a reply to Harris et al. (2012) and Ones, Viswesvaran, and Schmidt (2012).
We clear up a number of misconceptions from the critiques of our meta-analysis (Van Iddekinge, Roth, Raymark, & Odle-Dusseau, 2012). We reiterate that our research question focused on the criterion-related validity of integrity tests for predicting individual work behavior and that our inclusion criteria flowed from this question. We also reviewed the primary studies we could access from Ones, Viswesvaran, and Schmidt's (1993) meta-analysis of integrity tests and found that only about 30% of the studies met our inclusion criteria. Further, analyses of some of the types of studies we had to exclude revealed potentially inflated validity estimates (e.g., corrected validities as high as .80 for polygraph studies). We also discuss our experience trying to obtain primary studies and other information from authors of Harris et al. (2012) and Ones, Viswesvaran, and Schmidt (2012). In addition, we address concerns raised about certain decisions we made and values we used, and we demonstrate how such concerns would have little or no effect on our results or conclusions. Finally, we discuss some other misconceptions about our meta-analysis, as well as some divergent views about the integrity test literature in general. Overall, we stand by our research question, methods, and results, which suggest that the validity of integrity tests for criteria such as job performance and counterproductive work behavior is weaker than the authors of the critiques appear to believe.


Comparison of therapies between fixed-dose telmisartan/hydrochlorothiazide and losartan/hydrochlorothiazide in patients with mild to moderate hypertension.
Among angiotensin receptor blockers (ARBs), telmisartan is suggested to function as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR gamma) and to improve lipid and glucose metabolism. Clinical benefits of telmisartan over other ARBs may be apparent in combination with diuretics, which have harmful influences on lipid and glucose metabolism. In the present study, 21 patients treated with mild to moderate hypertension (13 women and 8 men aged 63.1 +/- 11.6 years) underwent a 24-week treatment period with telmisartan 40 mg and HCTZ 12.5 mg once daily, or a 24-week treatment period with losartan 50 mg and HCTZ 12.5 mg once daily, without a wash-out period, in a quasi-randomized cross-over manner. Their ambulatory blood pressure and metabolic parameters were measured after the 2 treatment periods. Ambulatory systolic and diastolic blood pressures did not differ significantly between the 2 treatment periods during 24 hours, daytime, night-time, and early-morning hours (06:00-08:00). Serum uric acid was insignificantly higher in the treatment period with telmisartan/HCTZ than in the treatment period with losartan/HCTZ (P = 0.086). Although serum total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol did not differ significantly, serum triglycerides were slightly higher in the treatment period with telmisartan/HCTZ than in the treatment period with losartan/HCTZ (P = 0.060). Parameters of glucose metabolism did not differ significantly between the 2 treatment periods. In conclusion, antihypertensive efficacy was similar between the 2 regimens throughout 24 hours, despite different elimination half-lives of telmisartan and losartan. Although telmisartan is suggested to function as a partial agonist of PPARgamma, no clinical benefit was found in combination with HCTZ with respect to lipid and glucose metabolism.


A time study of staff and student activities in a level II fieldwork program.
A study was conducted to determine the cost and benefits of the occupational therapy Level II fieldwork program at University of Michigan Hospitals in order to complete annual contractual agreements between academic and clinical education agencies. A tally sheet consisting of 34 tasks was used by all staff members (therapists, assistants, and clerical support personnel) to record time spent daily on the student program (cost). Students recorded independent treatment provided (benefit). The cost and benefit of the program was equated to a full-time equivalent staff position. Results showed the following: the time staff devoted to the student program was equivalent to 1.33 of a full-time employee's workload and the treatments provided by students were equivalent to 1.35 of an employee's production. The findings of this study support the accepted assumption that the cost of a clinical program for occupational therapy students is at least balanced by the benefits derived from student production. However, the quality of student efforts may be less than that of staff efforts.


The Usefulness of the Glycosylated Hemoglobin Level for the Diagnosis of Gestational Diabetes Mellitus in the Korean Population.
An oral glucose tolerance test (OGTT) is the current method used for screening and diagnosis of gestational diabetes mellitus (GDM). OGTT is a relatively complicated procedure and is expensive. Thus, new strategies that do not require fasting or more than a single blood draw may improve the diagnosis of GDM and increase the rate of GDM testing. We investigated the utility of monitoring glycosylated hemoglobin (HbA1c) levels for the diagnosis of GDM. The data from 992 pregnant women with estimated gestational ages ranging from 24 to 28 weeks were retrospectively reviewed. There were 367 women with plasma glucose levels ≥140 mg/dL 1 hour after a 50-g OGTT. GDM was diagnosed according to the Carpenter-Coustan criteria for a 3-hour 100 g OGTT. A HbA1c assessment was performed at the same time. We enrolled 343 women in this study, and there were 109 women with GDM. The area under the curve the receiver operating characteristic curve for HbA1c detection of GDM was 0.852 (95% confidence interval, 0.808 to 0.897). A HbA1c cutoff value ≥5.35% had maximal points on the Youden index (0.581). The sensitivity was 87.2% and the specificity was 70.9% for diagnosing GDM. A threshold value ≥5.35% indicated that 163 patients had GDM and that 68 (41.7%) were false positive. The positive predictive value was 58.3% at this threshold value. Despite substantial progress in methodology, HbA1c values cannot replace OGTT for the diagnosis of GDM.