Quantification of fossil fuel CO2 emissions on the building/street scale for a large U.S. city.
In order to advance the scientific understanding of carbon exchange with the land surface, build an effective carbon monitoring system, and contribute to quantitatively based U.S. climate change policy interests, fine spatial and temporal quantification of fossil fuel CO(2) emissions, the primary greenhouse gas, is essential. Called the "Hestia Project", this research effort is the first to use bottom-up methods to quantify all fossil fuel CO(2) emissions down to the scale of individual buildings, road segments, and industrial/electricity production facilities on an hourly basis for an entire urban landscape. Here, we describe the methods used to quantify the on-site fossil fuel CO(2) emissions across the city of Indianapolis, IN. This effort combines a series of data sets and simulation tools such as a building energy simulation model, traffic data, power production reporting, and local air pollution reporting. The system is general enough to be applied to any large U.S. city and holds tremendous potential as a key component of a carbon-monitoring system in addition to enabling efficient greenhouse gas mitigation and planning. We compare the natural gas component of our fossil fuel CO(2) emissions estimate to consumption data provided by the local gas utility. At the zip code level, we achieve a bias-adjusted Pearson r correlation value of 0.92 (p < 0.001).


Evaluation of Introduction of a Delayed Cord Clamping Protocol for Premature Neonates in a High-Volume Maternity Center.
To evaluate adherence to a delayed cord clamping protocol for preterm births in the first 2 years after its introduction, perform a quality improvement assessment, and determine neonatal outcomes associated with protocol implementation and adherence. This is a retrospective cohort study of women delivering singleton neonates at 23-32 weeks of gestation in the 2 years before (preprotocol) and 2 years after (postprotocol) introduction of a 30-second delayed cord clamping protocol at a large-volume academic center. This policy was communicated to obstetric and pediatric health care providers and nurses and reinforced with intermittent educational reviews. Barriers to receiving delayed cord clamping were assessed using χ tests and multivariable logistic regression. Neonatal outcomes then were compared between all neonates in the preprotocol period and all neonates in the postprotocol period and between all neonates in the preprotocol period and neonates receiving delayed cord clamping in the postprotocol period using multivariable linear and logistic regression analyses. Of the 427 eligible neonates, 187 were born postprotocol. Of these, 53.5% (n=100) neonates received delayed cord clamping according to the protocol. The rate of delayed cord clamping preprotocol was 0%. Protocol uptake and frequency of delayed cord clamping increased over the 2 years after its introduction. In the postprotocol period, cesarean delivery was the only factor independently associated with failing to receive delayed cord clamping (adjusted odds ratio [OR] 0.49, 95% confidence interval [CI] 0.25-0.96). In comparison with the preprotocol period, those who received delayed cord clamping in the postprotocol period had significantly higher birth hematocrit (β=2.46, P=.007) and fewer blood transfusions in the first week of life (adjusted OR 0.49, 95% CI 0.25-0.96). After introduction of an institutional delayed cord clamping protocol followed by continued health care provider education and quality feedback, the frequency of delayed cord clamping progressively increased. Compared with historical controls, performing delayed cord clamping in eligible preterm neonates was associated with improved neonatal hematologic indices, demonstrating the effectiveness of delayed cord clamping in a large-volume maternity unit.


Cytomegalovirus, aging, and HIV: a perfect storm.
The success of highly active antiretroviral therapy in preventing progression of HIV-infected individuals to AIDS has greatly reduced the burden of opportunistic infections. Individuals with HIV infection are living longer, but as a group are at greater risk to develop age-related disorders, such as certain cancers, cardiovascular disease, type II diabetes, and cognitive impairment, at earlier ages than non-HIV-infected persons. This premature susceptibility to age-related morbidities reflects a syndrome referred to as accelerated aging, wherein deleterious features associated with aging emerge decades earlier in the setting of chronic HIV infection. A prominent immunological feature of accelerated aging in HIV infection is inflation of cytomegalovirus-specific memory T-cell responses to levels associated with an immune risk phenotype. In the absence of HIV infection, immune risk phenotypes develop in cytomegalovirus-infected octogenarians and signify some degree of immune senescence and an elevated risk for all-cause mortality. Chronic inflammation is a probable factor in health risks conveyed by the immune risk phenotype and in putative relationships between cytomegalovirus infection and the same set of age-related disorders arising in chronic HIV infection. Most HIV-infected individuals are cytomegalovirus-seropositive, both HIV and cytomegalovirus are associated with inflammation-related morbidities, and HIV infection accelerates the development of cytomegalovirus-dependent immunological abnormalities. Therefore, closer investigation of the relationship between cytomegalovirus and age-related morbidities emerging in chronic HIV infection appears warranted. This review summarizes evidence that cytomegalovirus could be an important cofactor in the development of age-related morbidities in HIV infection and discusses research to address underlying mechanisms.


Detection of diarrheagenic Escherichia coli by multiplex PCR.
Diarrheagenic E.coli (DEC) are an important cause of childhood diarrhea.Identification of DEC strains needs to detect factors that determine the virulence of these organisms. There is not much data regarding the importance of DEC as a cause of diarrhea in children in India.The prevalence of DEC in children below five years with and without diarrhea was studied using two multiplex PCR assays. Two multiplex polymerase chain reaction assays were used to detect genes of five types of DEC.The targets selected for each category were eae and bfpA (bundle-forming pilus) for Enteropathogenic E.coli (EPEC), hlyA for Enterohemorrhagic E.coli (EHEC), elt and stla for Enterotoxigenic E.coli (ETEC), CVD432 for Enteroaggregative E.coli (EAEC) and ial for Enteroinvasive E.coli (EIEC). In 200 children with diarrhea 52 (26%) DEC infections were found. Among 100 controls 8 (8%) DEC infections were found. EAEC was the most common DEC by multiplex PCR both in cases (26, 13%)and controls (5,5%), followed by EPEC seen in 16% cases and 3% controls. ETEC and EIEC were found in 7 (3.5%) and 3 (1.5%) of the diarrheal cases. EIEC and ETEC were not detected in the control cases. EHEC was not isolated from either the diarrheal or control cases. DEC strains are a significant cause of diarrhea in children. The two Multiplex PCR assays can be used for the detection of DEC in routine diagnostic laboratories. These assays are specific and sensitive for the rapid detection of DEC. EAEC was the most frequent pathotype in the population under study.


From Compressed-Sensing to Artificial Intelligence-Based Cardiac MRI Reconstruction.
Cardiac magnetic resonance (CMR) imaging is an important tool for the non-invasive assessment of cardiovascular disease. However, CMR suffers from long acquisition times due to the need of obtaining images with high temporal and spatial resolution, different contrasts, and/or whole-heart coverage. In addition, both cardiac and respiratory-induced motion of the heart during the acquisition need to be accounted for, further increasing the scan time. Several undersampling reconstruction techniques have been proposed during the last decades to speed up CMR acquisition. These techniques rely on acquiring less data than needed and estimating the non-acquired data exploiting some sort of prior information. Parallel imaging and compressed sensing undersampling reconstruction techniques have revolutionized the field, enabling 2- to 3-fold scan time accelerations to become standard in clinical practice. Recent scientific advances in CMR reconstruction hinge on the thriving field of artificial intelligence. Machine learning reconstruction approaches have been recently proposed to learn the non-linear optimization process employed in CMR reconstruction. Unlike analytical methods for which the reconstruction problem is explicitly defined into the optimization process, machine learning techniques make use of large data sets to learn the key reconstruction parameters and priors. In particular, deep learning techniques promise to use deep neural networks (DNN) to learn the reconstruction process from existing datasets in advance, providing a fast and efficient reconstruction that can be applied to all newly acquired data. However, before machine learning and DNN can realize their full potentials and enter widespread clinical routine for CMR image reconstruction, there are several technical hurdles that need to be addressed. In this article, we provide an overview of the recent developments in the area of artificial intelligence for CMR image reconstruction. The underlying assumptions of established techniques such as compressed sensing and low-rank reconstruction are briefly summarized, while a greater focus is given to recent advances in dictionary learning and deep learning based CMR reconstruction. In particular, approaches that exploit neural networks as implicit or explicit priors are discussed for 2D dynamic cardiac imaging and 3D whole-heart CMR imaging. Current limitations, challenges, and potential future directions of these techniques are also discussed.


The heritability of hedonic capacity and perceived stress: a twin study evaluation of candidate depressive phenotypes.
Anhedonia and stress sensitivity have been identified as promising depressive phenotypes. Research suggests that stress-induced anhedonia is a possible mechanism underlying the association between stress and depression. The present proof-of-concept study assessed whether hedonic capacity and stress perception are heritable and whether their genetic and environmental contributions are shared. Twenty monozygotic (MZ) and 15 dizygotic (DZ) twin pairs completed a probabilistic reward task that provides an objective behavioral measure of hedonic capacity (reward responsiveness) and completed several questionnaires including the Perceived Stress Scale (PSS). Bivariate Cholesky models were used to investigate whether covariation between (1) depressive symptoms and hedonic capacity, (2) depressive symptoms and perceived stress, and (3) perceived stress and hedonic capacity resulted from shared or residual genetic and environmental factors. Additive genetic (A) and individual-specific environment (E) factors contributed to 46% and 54% of the variance in hedonic capacity, respectively. For perceived stress, 44% and 56% of the variance was accounted for by A and E factors, respectively. The genetic correlation between depression and hedonic capacity was moderate (ra=0.29), whereas the correlation between depression and stress perception was large (ra=0.67). Genetic and environmental correlations between hedonic capacity and stress perception were large (ra=0.72 and re=-0.43). The present study provides initial feasibility for using a twin approach to investigate genetic contributions of a laboratory-based anhedonic phenotype. Although these preliminary findings indicate that hedonic capacity and perceived stress are heritable, with substantial shared additive genetic contributions, replications in larger samples will be needed.


Unraveling the neuroprotective mechanisms of PrP (C) in excitotoxicity.
Knowledge of the natural roles of cellular prion protein (PrP (C) ) is essential to an understanding of the molecular basis of prion pathologies. This GPI-anchored protein has been described in synaptic contacts, and loss of its synaptic function in complex systems may contribute to the synaptic loss and neuronal degeneration observed in prionopathy. In addition, Prnp knockout mice show enhanced susceptibility to several excitotoxic insults, GABAA receptor-mediated fast inhibition was weakened, LTP was modified and cellular stress increased. Although little is known about how PrP (C) exerts its function at the synapse or the downstream events leading to PrP (C) -mediated neuroprotection against excitotoxic insults, PrP (C) has recently been reported to interact with two glutamate receptor subunits (NR2D and GluR6/7). In both cases the presence of PrP (C) blocks the neurotoxicity induced by NMDA and Kainate respectively. Furthermore, signals for seizure and neuronal cell death in response to Kainate in Prnp knockout mouse are associated with JNK3 activity, through enhancing the interaction of GluR6 with PSD-95. In combination with previous data, these results shed light on the molecular mechanisms behind the role of PrP (C) in excitotoxicity. Future experimental approaches are suggested and discussed.


Myocardial ischemic tolerance following heat stress is abolished by ATP-sensitive potassium channel blockade.
Heat stress is known to confer protection against ischemia, but the mechanisms involved are yet to be elucidated. Opening of ATP-sensitive potassium (K[ATP]) channels has been demonstrated to be involved in other endogenous forms of cardioprotection, in particular "classic" ischemic preconditioning and delayed preconditioning following treatment with the endotoxin derivative, monophosphoryl lipid A. We therefore speculated that there may be a role for K(ATP) channels in delayed heat stress-induced cardioprotection. This hypothesis was investigated in an in vivo rabbit model of acute myocardial infarction using two structurally dissimilar K(ATP) channel blockers, glibenclamide and sodium 5-hydroxydecanoate. Sodium pentobarbitone-anesthetized rabbits were subjected to either transient heat stress at 42 +/- 0.2 degrees C for 15 minutes or sham anesthesia. Twenty-four hours later, animals were reanesthetized ("Hypnorm" and sodium pentobarbitone) and a midline sternotomy and pericardiotomy were performed. An anterolateral branch of the circumflex coronary artery was occluded for 30 minutes and reperfused for 2 hours. The infarct-to-risk ratio was significantly limited in vehicle-treated rabbits from 41.3 +/- 4.0% in controls (n = 10) to 24.1 +/- 5.0% (n = 9; P = 0.014 by one-factor ANOVA) in heat-stressed hearts. This limitation in infarct size was abolished by 0.3 mg/kg i.v. glibenclamide or 5 mg/kg i.v. 5-hydroxydecanoate when administered 10 minutes prior to coronary occlusion (45.2 +/- 6.4%; n = 9 and 41.5 +/- 5.0%; n = 5, respectively.) The same doses of glibenclamide and 5-hydroxydecanoate in sham-anesthetized hearts had no effect (42.3 +/- 5.1%; n = 10 and 51.9 +/- 2.2%; n = 6, respectively). The adequacy of the heat stress protocol was confirmed by Western blot analysis of the inducible 72-kD heat stress protein. It is concluded, therefore, that K(ATP) channels appear to play a role in the heat stress response. The underlying mechanisms involved are, however, unclear.


Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of a novel histone deacetylase inhibitor, LAQ824, in human colon carcinoma cells and xenografts.
The aim of this work was to use phosphorus magnetic resonance spectroscopy ((31)P MRS) to investigate the pharmacodynamic effects of LAQ824, a histone deacetylase (HDAC) inhibitor. Human HT29 colon carcinoma cells were examined by (31)P MRS after treatment with LAQ824 and another HDAC inhibitor, suberoylanilide hydroxamic acid. HT29 xenografts and tumor extracts were also examined using (31)P MRS, pre- and post-LAQ824 treatment. Histone H3 acetylation was determined using Western blot analysis, and tumor microvessel density by immunohistochemical staining of CD31. Phosphocholine showed a significant increase in HT29 cells after treatment with LAQ824 and suberoylanilide hydroxamic acid. In vivo, the ratio of phosphomonoester/total phosphorus (TotP) signal was significantly increased in LAQ824-treated HT29 xenografts, and this ratio was inversely correlated with changes in tumor volume. Statistically significant decreases in intracellular pH, beta-nucleoside triphosphate (beta-NTP)/TotP, and beta-NTP/inorganic phosphate (Pi) and an increase in Pi/TotP were also seen in LAQ824-treated tumors. Tumor extracts showed many significant metabolic changes after LAQ824 treatment, in parallel with increased histone acetylation and decreased microvessel density. Treatment with LAQ824 resulted in altered phospholipid metabolism and compromised tumor bioenergetics. The phosphocholine and phosphomonoester increases may have the potential to act as pharmacodynamic markers for noninvasively monitoring tumor response after treatment with LAQ824 or other HDAC inhibitors.


Lack of attentional retraining effects in cigarette smokers attempting cessation: a proof of concept double-blind randomised controlled trial.
Observational studies have shown that attentional bias for smoking-related cues is associated with increased craving and relapse. Laboratory experiments have shown that manipulating attentional bias may change craving. Interventions to reduce attentional bias could reduce relapse in smokers seeking to quit. We report a clinical trial of attentional retraining in treatment-seeking smokers. This was a double-blind randomised controlled trial that took place in UK smoking cessation clinics. Smokers interested in quitting were randomised to five weekly sessions of attentional retraining (N=60) or placebo training (N = 58) using a modified visual probe task from one week prior to quit day. Both groups received 21 mg nicotine patches (from quit day onwards) and behavioural support. Primary outcomes included change in attentional bias reaction times four weeks after quit day on the visual probe task and craving measured weekly using the Mood and Physical Symptoms Scale. Secondary outcomes were changes in withdrawal symptoms, time to first lapse and prolonged abstinence. No attentional bias towards smoking cues was found in the sample at baseline (mean difference = 3 ms, 95% CI = -2, 9). Post-training bias was not significantly lower in the retraining group compared with the placebo group (mean difference = -9 ms, 95% CI = -20, 2). There was no difference between groups in change in craving (p = 0.89) and prolonged abstinence at four weeks (risk ratio = 1.00, 95% CI = 0.70, 1.43). Taken with one other trial, there appears to be no effect from clinic-based attentional retraining using the visual probe task. Attentional retraining conducted out of clinic may prove more effective. UK Clinical Trials ISRCTN 54375405.


MicroTools enables automated quantification of capillary density and red blood cell velocity in handheld vital microscopy.
Direct assessment of capillary perfusion has been prioritized in hemodynamic management of critically ill patients in addition to optimizing blood flow on the global scale. Sublingual handheld vital microscopy has enabled online acquisition of moving image sequences of the microcirculation, including the flow of individual red blood cells in the capillary network. However, due to inherent content complexity, manual image sequence analysis remained gold standard, introducing inter-observer variability and precluding real-time image analysis for clinical therapy guidance. Here we introduce an advanced computer vision algorithm for instantaneous analysis and quantification of morphometric and kinetic information related to capillary blood flow in the sublingual microcirculation. We evaluated this technique in a porcine model of septic shock and resuscitation and cardiac surgery patients. This development is of high clinical relevance because it enables implementation of point-of-care goal-directed resuscitation procedures based on correction of microcirculatory perfusion in critically ill and perioperative patients.


Transposon tagging in maize.
Through recent government- and industry-sponsored efforts, several forward and reverse genetic screening programs have emerged over the past few years to aid in the genetic dissection of gene function in maize. Despite a US maize crop valued at $18.4 billion last year (http://www.ncga.com/03world/main/US_crop_value_2000.html) and rich genetic history, maize has taken a back seat to Arabidopsis thaliana as the model genetic system for plants over the past decade. With a fully sequenced genome, short generation time and small size, studies of Arabidopsis have provided plant scientists with a molecular framework for hormonal, developmental and environmental signaling pathways in plants. As investigations into Arabidopsis continue, our capacity to engineer biochemical pathways and alter plant physiological responses will become increasingly sophisticated. Nevertheless, approximately 130 million years have passed since monocot and higher eudicot lineages diverged. Thus, our ability to engineer agronomically important monocot grasses such as maize, rice and wheat will become increasingly limited by our lack of understanding of the physiological and morphological differences that have evolved in the monocots and higher eudicots. The sophisticated transposon collections now being generated for maize are but one of several recent projects (http://www.nsf.gov/bio/pubs/awards/genome01.htm) to provide grass researchers with essential tools for genome analysis. Because grain crops are such a closely related group, it is hoped that many of the findings made in one grass will be directly applicable to understanding the biology of another. The goal of this review is to highlight the recent developments in maize transposon-based gene characterization programs and provide a critical examination of the advantages and disadvantages each system offers.


Fatal overdose prevention and experience with naloxone: A cross-sectional study from a community-based cohort of people who inject drugs in Baltimore, Maryland.
Overdose is a leading cause of death in the United States, especially among people who inject drugs (PWID). Improving naloxone access and carrying among PWID may offset recent increases in overdose mortality associated with the influx of synthetic opioids in the drug market. This study characterized prevalence and correlates of several naloxone outcomes among PWID. During 2018, a survey to assess experience with naloxone was administered to 915 participants in the AIDS Linked to the IntraVenous Experience (ALIVE) study, an ongoing community-based observational cohort of people who currently inject or formerly injected drugs in Baltimore, Maryland. We examined the associations of naloxone outcomes (training, supply, use, and regular possession) with socio-demographic, substance use and healthcare utilization factors among PWID in order to characterize gaps in naloxone implementation among this high-risk population. Median age was 56 years, 34% were female, 85% were African American, and 31% recently injected. In the past six months, 46% (n = 421) reported receiving training in overdose prevention, 38% (n = 346) had received a supply of naloxone, 9% (n = 85) had administered naloxone, and 9% (n = 82) reported usually carrying a supply of naloxone. Recent non-fatal overdose was not associated with any naloxone outcomes in adjusted analysis. Active opioid use (aOR = 2.10, 95% CI: 1.03, 4.28) and recent treatment of alcohol or substance use disorder (aOR = 2.01, 95% CI: 1.13, 3.56) were associated with regularly carrying naloxone. Further work is needed to encourage PWID to carry and effectively use naloxone to decrease rates of fatal opioid overdose. While accessing treatment for substance use disorder was positively associated with carrying naloxone, EMS response to 911 calls for overdose, the emergency department, and syringe services programs may be settings in which naloxone access and carrying could be encouraged among PWID.


Use of long-term vaccination with a killed vaccine to prevent fecal shedding of Mycobacterium avium subsp paratuberculosis in dairy herds.
To determine whether vaccination with a killed vaccine prevents fecal shedding of Mycobacterium avium subsp paratuberculosis, to compare effectiveness of a culture and cull program in vaccinated and nonvaccinated herds, and to compare paratuberculosis-related preventive management in vaccinated and nonvaccinated herds. 58 commercial Dutch dairy herds. Cross-sectional study (study A) in vaccinated (n = 25) and nonvaccinated (29) herds of dairy cows. Longitudinal study (study B) in vaccinated (n = 2) and nonvaccinated (2) herds of dairy cows. In study A, fecal samples were obtained from adult cows in herds with and without a history of vaccination with a killed vaccine. Management measures were evaluated. In study B, fecal samples were obtained 4 times at 6-month intervals from cows older than 6 months. Cows that had positive test results were removed from the herd directly after the outcome of the culture. In study A, differences were not detected among the 25 herds that were vaccinated; culture results were positive for M avium subsp paratuberculosis in 4.4% of herds. In 29 herds that had not been vaccinated, culture results were positive in 6.7%. In study B, the percentage of positive results on culture decreased from 10.9% and 5.7% to 3.5% and 0%, respectively in the 2 vaccinated herds. In the 2 nonvaccinated herds, percentages decreased from 6.1% and 16.5% to 0% and 2.3%, respectively. Management practices were different between herds that were vaccinated and herds that were not; owners of herds that were not vaccinated followed more preventive management procedures and practiced less feeding of raw milk to calves. Vaccination of calves with a killed vaccine does not prevent transmission of M avium subsp paratuberculosis; therefore, hygienic practices remain essential in herd management.


Oral Miltefosine as Salvage Therapy for Refractory Acanthamoeba Keratitis.
To report a case series of patients with treatment-resistant Acanthamoeba keratitis (AK) using oral miltefosine, often as salvage therapy. Descriptive, retrospective multicenter case series. We reviewed 15 patients with AK unresponsive to therapy who were subsequently given adjuvant systemic miltefosine between 2011 and 2017. The main outcome measures were resolution of infection, final visual acuity, tolerance of miltefosine, and clinical course of disease. All patients were treated with biguanides and/or diamidines or azoles without resolution of disease before starting miltefosine. Eleven of 15 patients retained count fingers or better vision, and all were considered disease free at last follow-up. Eleven of 15 patients had worsening inflammation with miltefosine, with 10 of them improving with steroids. Six patients received multiple courses of miltefosine. Most tolerated oral miltefosine well, with mild gastrointestinal symptoms as the most common systemic side effect. Oral miltefosine is a generally well-tolerated treatment adjuvant in patients with refractory AK. The clinician should be prepared for a steroid-responsive inflammatory response frequently encountered during the treatment course.


Residual cone vision without alpha-transducin.
Behavioral experiments in humans with a rare genetic mutation that compromises the function of alpha-transducin (Galpha the alpha-subunit of the G-protein in the primary cone phototransduction cascade) reveal a residual cone response only viable at high light levels and at low temporal frequencies. It has three characteristic properties. First, it limits temporal frequency sensitivity to the equivalent of a simple first order reaction with a time constant of approximately 140 ms. Second, it delays the visual response by an amount that is also consistent with such a reaction. Third, it causes temporal acuity to be linearly related to the logarithm of the amount of bleached pigment. We suggest that these properties are consistent with the residual function depending on a sluggishly generated cone photobleaching product, which we tentatively identify as a cone metarhodopsin. By activating the transduction cascade, this bleaching product mimics the effects of real light and is therefore one of the molecular origins of "background equivalence," the long-established observation that the aftereffects of photopigment bleaches and the effects of real background lights are equivalent. Alternative explanations for the residual cone response include the possibilities that there is a secondary phototransduction mechanism that bypasses alpha-transduction, or that the truncated alpha-transduction that results from the mutation retains some minimal functionality.


Effect of viewing angle on luminance and contrast for a five-million-pixel monochrome display and a nine-million-pixel color liquid crystal display.
Digital imaging systems used in radiology rely on electronic display devices to present images to human observers. Active-matrix liquid crystal displays (AMLCDs) continue to improve and are beginning to be considered for diagnostic image display. In spite of recent progress, AMLCDs are characterized by a change in luminance and contrast response with changes in viewing direction. In this article, we characterize high pixel density AMLCDs (a five-million-pixel monochrome display and a nine-million-pixel color display) in terms of the effect of viewing angle on their luminance and contrast response. We measured angular luminance profiles using a custom-made computer-controlled goniometric instrument and a conoscopic Fourier-optics instrument. We show the angular luminance response as a function of viewing angle, as well as the departure of the measured contrast from the desired response. Our findings indicate small differences between the five-million-pixel (5 MP) and the nine-million-pixel (9 MP) AMLCDs. The 9 MP shows lower variance in contrast with changes in viewing angle, whereas the 5 MP provides a slightly better GSDF compliance for off-normal viewing.


Optimization of selection for growth in Menz sheep while minimizing inbreeding depression in fitness traits.
The genetic trends in fitness (inbreeding, fertility and survival) of a closed nucleus flock of Menz sheep under selection during ten years for increased body weight were investigated to evaluate the consequences of selection for body weight on fitness. A mate selection tool was used to optimize in retrospect the actual selection and matings conducted over the project period to assess if the observed genetic gains in body weight could have been achieved with a reduced level of inbreeding. In the actual selection, the genetic trends for yearling weight, fertility of ewes and survival of lambs were 0.81 kg, -0.00026% and 0.016% per generation. The average inbreeding coefficient remained zero for the first few generations and then tended to increase over generations. The genetic gains achieved with the optimized retrospective selection and matings were highly comparable with the observed values, the correlation between the average breeding values of lambs born from the actual and optimized matings over the years being 0.99. However, the level of inbreeding with the optimized mate selections remained zero until late in the years of selection. Our results suggest that an optimal selection strategy that considers both genetic merits and coancestry of mates should be adopted to sustain the Menz sheep breeding program.


High-molecular-weight polyethylene glycol inhibits myocardial ischemia-reperfusion injury in vivo.
Cardiac ischemia-reperfusion (I-R) injury remains a significant problem as there are no therapies available to minimize the cell death that can lead to impaired function and heart failure. We have shown that high-molecular-weight polyethylene glycol (PEG) (15-20 kD) can protect cardiac myocytes in vitro from hypoxia-reoxygenation injury. In this study, we investigated the potential protective effects of PEG in vivo. Adult rats underwent left anterior descending artery occlusion for 60 minutes followed by 48 hours or 4 weeks of reperfusion. One milliliter of 10% PEG solution or phosphate-buffered saline (PBS) control (n = 10 per group) was administered intravenously (IV) immediately before reperfusion. Fluorescein-labeled PEG was robustly visualized in the myocardium 1 hour after IV delivery. The PEG group had significant recovery of left ventricular ejection fraction at 4 weeks versus a 25% decline in the PBS group (P < .01). There was 50% less LV fibrosis in the PEG group versus PBS with smaller peri-infarct and remote territory fibrosis (P < .01). Cell survival signaling was upregulated in the PEG group with increased Akt (3-fold, P < .01) and ERK (4-fold, P < .05) phosphorylation compared to PBS controls at 48 hours. PEG also inhibited apoptosis as measured by TUNEL-positive nuclei (56% decrease, P < .02) and caspase 3 activity (55% decrease, P < .05). High-molecular-weight PEG appears to have a significant protective effect from I-R injury in the heart when administered IV immediately before reperfusion. This may have important clinical translation in the setting of acute coronary revascularization and myocardial protection in cardiac surgery.


Ankle-Brachial Index and Subsequent Risk of Severe Ischemic Leg Outcomes: The ARIC Study.
Background Ankle-brachial index (ABI) is used to identify lower-extremity peripheral artery disease (PAD). However, its association with severe ischemic leg outcomes (eg, amputation) has not been investigated in the general population. Methods and Results Among 13 735 ARIC (Atherosclerosis Risk in Communities) study participants without clinical manifestations of PAD (mean age, 54 [SD, 5.8] years; 44.4% men; and 73.6% White) at baseline (1987-1989), we quantified the prospective association between ABI and subsequent severe ischemic leg outcomes, critical limb ischemia (PAD with rest pain or tissue loss) and ischemic leg amputation (PAD requiring amputation) according to discharge diagnosis. Over a median follow-up of ≈28 years, there were 221 and 129 events of critical limb ischemia and ischemic leg amputation, respectively. After adjusting for demographics, ABI ≤0.90 versus 1.11 to 1.20 had a ≈4-fold higher risk of critical limb ischemia and ischemic leg amputation (hazard ratios, 3.85 [95% CI, 2.09-7.11] and 4.39 [95% CI, 2.08-9.27]). The magnitude of the association was modestly attenuated after multivariable adjustment (hazard ratios, 2.44 [95% CI, 1.29-4.61] and 2.72 [95% CI, 1.25-5.91], respectively). ABI 0.91 to 1.00 and 1.01 to 1.10 were also associated with these severe leg outcomes, with hazard ratios ranging from 1.7 to 2.0 after accounting for potential clinical and demographic confounders. The associations were largely consistent across various subgroups. Conclusions In a middle-aged community-based cohort, lower ABI was independently and robustly associated with increased risk of severe ischemic leg outcomes. Our results further support ABI ≤0.90 as a threshold diagnosing PAD and also suggest the importance of recognizing the prognostic value of ABI 0.91 to 1.10 for limb prognosis.


An outbreak of post-acupuncture cutaneous infection due to Mycobacterium abscessus.
Despite the increasing popularity of acupuncture, the importance of infection control is not adequately emphasized in Oriental medicine. In December 2001, an Oriental medical doctor in Seoul, South Korea, encountered several patients with persistent, culture-negative skin lesions on the trunk and extremities at the sites of prior acupuncture treatment. We identified and investigated an outbreak of Mycobacterium abscessus cutaneous infection among the patients who attended this Oriental medicine clinic. Patients were defined as clinic patients with persistent cutaneous infections at the acupuncture sites. Medical records for the previous 7 months were reviewed. Clinical specimens were obtained from the patients and an environmental investigation was performed. M. abscessus isolates, cultured from patients, were compared by pulsed-field gel electrophoresis (PFGE). Forty patients who attended the Oriental medicine clinic and experienced persistent cutaneous wound infections were identified. Cultures from five of these patients proved positive, and all other diagnoses were based on clinical and histopathologic examinations. All environmental objects tested were negative for M. abscessus, however, most were contaminated by various nosocomial pathogens. Molecular analysis using PFGE found all wound isolates to be identical. We have identified a large outbreak of rapidly growing mycobacterial infection among patients who received acupuncture at a single Oriental medicine clinic. Physicians should suspect mycobacterial infections in patients with persistent cutaneous infections following acupuncture, and infection control education including hygienic practice, should be emphasized for Oriental medical doctors practicing acupuncture.


Harnessing the unique properties of 2D materials for advanced lithium-sulfur batteries.
In the past decade, lithium-sulfur batteries have attracted tremendous attention owing to their high theoretical energy densities. The electrochemical performances of lithium-sulfur batteries are strongly dependent on the electrode materials. Among all the electrode material candidates, the application of 2D materials in lithium-sulfur batteries including a sulfur cathode, a lithium anode, a separator and/or an electrolyte has gained great success in enhancing their electrochemical performance by overcoming their intrinsic obstacles. Thus, it is necessary to summarize the relationships between the unique features of 2D materials and the electrochemical performances of lithium-sulfur batteries, guiding the development of next-generation lithium-sulfur batteries. In this review, we focus on recent advances in harnessing the unique properties of 2D materials, including their high surface area, 2D feature, high mechanical strength, plentiful active sites and functional groups to improve the electrochemical properties of sulfur cathodes, lithium anodes, electrolytes and/or separators, respectively. Finally, we propose possible directions and strategies for harnessing various properties of 2D materials to promote the development and applications of lithium-sulfur batteries.


Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine.
CD8+ cytotoxic T lymphocytes (CTLs) are critical for protection against intracellular pathogens but often have been difficult to induce by subunit vaccines in animals. DNA vaccines elicit protective CD8+ T cell responses. Malaria-naïve volunteers who were vaccinated with plasmid DNA encoding a malaria protein developed antigen-specific, genetically restricted, CD8+ T cell-dependent CTLs. Responses were directed against all 10 peptides tested and were restricted by six human lymphocyte antigen (HLA) class I alleles. This first demonstration in healthy naïve humans of the induction of CD8+ CTLs by DNA vaccines, including CTLs that were restricted by multiple HLA alleles in the same individual, provides a foundation for further human testing of this potentially revolutionary vaccine technology.


Safety and Efficacy of Intravenous Lidocaine for Pain Management in the Emergency Department: A Systematic Review.
We evaluate the safety and efficacy of intravenous lidocaine in adult patients with acute and chronic pain who are undergoing pain management in the emergency department (ED). We searched Ovid CENTRAL, Ovid EMBASE, and Ovid MEDLINE databases for randomized controlled trials and observational studies from inception to January 2017. Efficacy outcomes included reduction in pain scores from baseline to postintervention and need for rescue analgesia. Safety outcomes included incidence of serious (eg, cardiac arrest) and nonserious (eg, dizziness) adverse events. We used the Cochrane Collaboration tool and a modified Newcastle-Ottawa Scale to evaluate the risk of bias across studies. The Grading of Recommendations Assessment, Development and Evaluation approach was used to evaluate the confidence in the evidence available. From a total of 1,947 titles screened, 61 articles were selected for full-text review. Eight studies met the inclusion criteria and underwent qualitative analysis, including 536 patients. The significant clinical heterogeneity and low quality of studies precluded a meta-analysis. Among the 6 randomized controlled trials included, intravenous lidocaine had efficacy equivalent to that of active controls in 2 studies, and was better than active controls in 2 other studies. In particular, intravenous lidocaine had pain score reduction comparable to or higher than that of intravenous morphine for pain associated with renal colic and critical limb ischemia. Lidocaine did not appear to be effective for migraine headache in 2 studies. There were 20 adverse events reported by 6 studies among 225 patients who received intravenous lidocaine in the ED, 19 nonserious and 1 serious (rate 8.9%, 95% confidence interval 5.5% to 13.4% for any adverse event; and 0.4%, 95% confidence interval 0% to 2.5% for serious adverse events). The confidence in the evidence available for the outcomes evaluated was deemed to be very low because of methodological limitations, including risk of bias, inconsistency, and imprecision. There is limited current evidence to define the role of intravenous lidocaine as an analgesic for patients with acute renal colic and critical limb ischemia pain in the ED. Its efficacy for other indications has not been adequately tested. The safety of lidocaine for ED pain management has not been adequately examined.


The cutaneous rabbit illusion affects human primary sensory cortex somatotopically.
We used functional magnetic resonance imaging (fMRI) to study neural correlates of a robust somatosensory illusion that can dissociate tactile perception from physical stimulation. Repeated rapid stimulation at the wrist, then near the elbow, can create the illusion of touches at intervening locations along the arm, as if a rabbit hopped along it. We examined brain activity in humans using fMRI, with improved spatial resolution, during this version of the classic cutaneous rabbit illusion. As compared with control stimulation at the same skin sites (but in a different order that did not induce the illusion), illusory sequences activated contralateral primary somatosensory cortex, at a somatotopic location corresponding to the filled-in illusory perception on the forearm. Moreover, the amplitude of this somatosensory activation was comparable to that for veridical stimulation including the intervening position on the arm. The illusion additionally activated areas of premotor and prefrontal cortex. These results provide direct evidence that illusory somatosensory percepts can affect primary somatosensory cortex in a manner that corresponds somatotopically to the illusory percept.


Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination.
The UK was the first place to introduce meningococcal serogroup C conjugate (MCC) vaccines. From November, 1999, all people younger than 18 years, about 14 million individuals, were offered MCC immunisation. The uptake rate was more than 70% by November, 2000. We compared the carriage of meningococci in isolates we obtained from 14,064 students aged 15-17 years during vaccination in 1999, with those from 16,583 students of the same age surveyed 1 year later. Carriage of serogroup C meningococci was reduced by 66% (p=0.004). Our results show that MCC vaccines protect against carriage of meningococci that express serogroup C polysaccharide capsules.


Development and evaluation of a whole blood-based approach for flow cytometric quantification of CD154+ mould-reactive T cells.
CD154+ mould-reactive T cells were proposed as a novel biomarker in the diagnosis of invasive mycoses. As PBMC-based protocols for flow cytometric quantification of these cells are logistically challenging and susceptible to preanalytic delays, this study evaluated and optimized a whole blood-based method for the detection of mould-reactive T cells. Blood collection tubes containing costimulatory antibodies and Aspergillus fumigatus mycelial lysates were inoculated with heparinized whole blood from healthy adults, and detection rates of CD154+/CD4+A. fumigatus reactive T cells were compared with PBMC-based detection using samples from the same donors. In contrast to the PBMC-based method, double costimulation with αCD28 and αCD49d was crucial for reliable whole blood stimulation. Optimizing stimulation schemes for both matrixes, significantly higher specific T-cell detection rates were achieved by the whole blood-based method, whereas the unspecific background stimulation remained low. MHC II-dependent CD154+ upregulation was demonstrated for both matrixes. Excellent correlation and reproducible conversion factors between whole blood and PBMC-based results were observed. Using frozen ready-to-use test tubes containing costimulatory antibodies and lysates, detection rates of specific T cells were comparable to freshly prepared blood collection tubes. The optimized whole blood-based protocol was also used to detect Rhizopus arrhizus and Rhizomucor pusillus reactive T cells, resulting in 1.5- to 2.7-fold higher detection rates compared with PBMC-based measurement. In summary, the whole blood protocol is a robust, highly sensitive, and cost-effective method for mould-reactive T-cell quantification, allowing for point-of-care sample stimulation and contributing to better assay standardization in multi-centre evaluation of mould reactive T-cell quantification.


Dengue Virus Infection Triggering Thrombotic Thrombocytopenic Purpura in Pregnancy.
We report a case of thrombotic thrombocytopenic purpura (TTP) that immediately followed symptomatic dengue virus infection in a pregnant lady. The patient developed dengue fever at 16 weeks of gestation, resulting in spontaneous abortion. Subsequently, fever reappeared with persistent thrombocytopenia and jaundice. Investigations revealed microangiopathic hemolysis; there was no evidence of disseminated intravascular coagulation. The TTP episode resolved after six cycles of therapeutic plasma exchange with fresh-frozen plasma. An ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif 13 repeats) activity assay, done during convalescence, showed normal activity. The patient had an uneventful second pregnancy and has remained free of TTP recurrence for more than 2 years now. We review the pathophysiological basis of TTP in dengue infection, and suggest that jaundice with disproportionate elevation of serum aspartate aminotransferase level in a patient with dengue should arouse the suspicion of TTP.


Eighty Years of Mycopathologia: A Retrospective Analysis of Progress Made in Understanding Human and Animal Fungal Pathogens.
Mycopathologia was founded in 1938 to 'diffuse the understanding of fungal diseases in man and animals among mycologists.' This was an important mission considering that pathogenic fungi for humans and animals represent a tiny minority of the estimated 1.5-5 million fungal inhabitants on Earth. These pathogens have diverged from the usual saprotrophic lifestyles of most fungi to colonize and infect humans and animals. Medical and veterinary mycology is the subdiscipline of microbiology that dwells into the mysteries of parasitic, fungal lifestyles. Among the oldest continuing scientific publications on the subject, Mycopathologia had its share of 'classic papers' since the first issue was published in 1938. An analysis of the eight decades of notable contributions reveals many facets of host-pathogen interactions among 183 volumes comprising about 6885 articles. We have analyzed the impact and relevance of this body of work using a combination of citation tools (Google Scholar and Scopus) since no single citation metric gives an inclusive perspective. Among the highly cited Mycopathologia publications, those on experimental mycology accounted for the major part of the articles (36%), followed by diagnostic mycology (16%), ecology and epidemiology (15%), clinical mycology (14%), taxonomy and classification (10%), and veterinary mycology (9%). The first classic publication, collecting nearly 200 citations, appeared in 1957, while two articles published in 2010 received nearly 150 citations each, which is notable for a journal covering a highly specialized field of study. An empirical analysis of the publication trends suggests continuing interests in novel diagnostics, fungal pathogenesis, review of clinical diseases especially with relevance to the laboratory scientists, taxonomy and classification of fungal pathogens, fungal infections and carriage in pets and wildlife, and changing ecology and epidemiology of fungal diseases around the globe. We anticipate that emerging and re-emerging fungal pathogens will continue to cause significant health burden in the coming decades. It remains vital that scientists and physicians continue to collaborate by learning each other's language for the study of fungal diseases, and Mycopathologia will strive to be their partner in this increasingly important endeavor to its 100th anniversary in 2038 and beyond.


Anatomical brain connectivity and positive symptoms of schizophrenia: a diffusion tensor imaging study.
Structural brain changes in schizophrenia are well documented in the neuroimaging literature. The classical morphometric analyses of magnetic resonance imaging (MRI) data have recently been supplemented by diffusion tensor imaging (DTI), which mainly assesses changes in white matter (WM). DTI increasingly provides evidence for abnormal anatomical connectivity in schizophrenia, most often using fractional anisotropy (FA) as an indicator of the integrity of WM tracts. To better understand the clinical significance of such anatomical changes, we studied FA values in a whole-brain analysis comparing paranoid schizophrenic patients with a history of auditory hallucinations and matched healthy controls. The relationship of WM changes to psychopathology was assessed by correlating FA values with PANSS scores (positive symptoms and severity of auditory hallucinations) and with illness duration. Schizophrenic patients showed FA reductions indicating WM integrity disturbance in the prefrontal regions, external capsule, pyramidal tract, occipitofrontal fasciculus, superior and inferior longitudinal fasciculi, and corpus callosum. The arcuate fasciculus was the only tract which showed increased FA values in patients. Increased FA values in this region correlated with increased severity of auditory hallucinations and length of illness. Our results suggest that local changes in anatomical integrity of WM tracts in schizophrenia may be related to patients' clinical presentation.


Two-step evolution of endosymbiosis between hydra and algae.
In the Hydra vulgaris group, only 2 of the 25 strains in the collection of the National Institute of Genetics in Japan currently show endosymbiosis with green algae. However, whether the other non-symbiotic strains also have the potential to harbor algae remains unknown. The endosymbiotic potential of non-symbiotic strains that can harbor algae may have been acquired before or during divergence of the strains. With the aim of understanding the evolutionary process of endosymbiosis in the H. vulgaris group, we examined the endosymbiotic potential of non-symbiotic strains of the H. vulgaris group by artificially introducing endosymbiotic algae. We found that 12 of the 23 non-symbiotic strains were able to harbor the algae until reaching the grand-offspring through the asexual reproduction by budding. Moreover, a phylogenetic analysis of mitochondrial genome sequences showed that all the strains with endosymbiotic potential grouped into a single cluster (cluster γ). This cluster contained two strains (J7 and J10) that currently harbor algae; however, these strains were not the closest relatives. These results suggest that evolution of endosymbiosis occurred in two steps; first, endosymbiotic potential was gained once in the ancestor of the cluster γ lineage; second, strains J7 and J10 obtained algae independently after the divergence of the strains. By demonstrating the evolution of the endosymbiotic potential in non-symbiotic H. vulgaris group strains, we have clearly distinguished two evolutionary steps. The step-by-step evolutionary process provides significant insight into the evolution of endosymbiosis in cnidarians.


Rehabilitation of Achilles tendon ruptures: is early functional rehabilitation daily routine?
Ruptures of the Achilles tendon are the most common tendon injuries of the lower extremities. Besides the initial operative or non-operative treatment, rehabilitation of patients plays a crucial role for tendon healing and long-term outcome. As only limited evidence is available for optimized rehabilitation regimen and guidelines for the initial (e.g., first 6 weeks) rehabilitation are limited, this study investigated the current rehabilitation concepts after Achilles tendon rupture. We analyzed 213 written rehabilitation protocols that are provided by orthopedic and trauma surgery institutions throughout Germany in terms of recommendations for weight-bearing, range of motion (ROM), physiotherapy, and choice of orthosis. All protocols for operatively and non-operatively treated Achilles tendon ruptures were included. Descriptive analysis was carried out and statistical analysis applied where appropriate. Of 213 institutions, 204 offered rehabilitation protocols for Achilles tendon rupture and, therefore, 243 protocols for operative and non-operative treatment could be analyzed. While the majority of protocols allowed increased weight-bearing over time, significant differences were found for durations of fixed plantar flexion between operative (o) and non-operative (n) treatments [fixed 30° (or 20)° to 15° (or 10)°: 3.6 weeks (±0.1; o) vs 4.7 weeks (±0.3; n) (p ≤ 0.0001) and fixed 15° (or 10)° to 0°: 5.8 weeks (±0.1; o) vs 6.6 weeks (±0.2; n) (p ≤ 0.001)]. The mean time of the recommended start of physiotherapy is at 2.9 weeks (±0.2; o) vs 3.3 weeks (±0.4; n), respectively. Our study shows that a huge variability in rehabilitation after Achilles tendon rupture exists. This study shows different strategies in rehabilitation of Achilles tendon ruptures using a convertible vacuum brace system. To improve patient care, further clinical as well as biomechanical studies need to be conducted. This study might serve as basis for prospective randomized controlled trials to optimize rehabilitation for Achilles tendon ruptures.


Analysis of internal exposure associated with consumption of crops and groundwater from the high background radiation area of Mrima Hill, Kenya.
Specific concentrations of (226)Ra, (232)Th and (40)K were measured in cassava tubers, cassava leaves and groundwater obtained from the high background radiation area of Mrima hill and used in the evaluation of the ingested dose. Cassava tubers, cassava leaves and groundwater registered average (226)Ra concentrations of 60 ± 5, 141 ± 11 and 4.3 ± 0.3 Bq kg(-1), respectively. (232)Th was not detected in cassava leaves although it was present in cassava tubers as well as in groundwater in average concentrations of 35.3±61.5 and 2.0±0.1 Bq kg(-1), respectively. (40)K was present in all samples in average concentrations of 842±539 Bq kg(-1) in cassava tubers, 1708 ± 552 Bq kg(-1) in cassava leaves and 91.4 Bq kg(-1) in groundwater. The total annual effective dose due to ingestion was found to be 7.9 mSv y(-1) of which 2.4 mSv y(-1) was due to cassava tubers, 3.8 mSv y(-1) due to cassava leaves and 1.7 mSv y(-1) due to water.


Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs.
Helicobacter pylori specifically colonizes the human gastric epithelium and is the major causative agent for ulcer disease and gastric cancer development. Here, we identify members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family as receptors of H. pylori and show that HopQ is the surface-exposed adhesin that specifically binds human CEACAM1, CEACAM3, CEACAM5 and CEACAM6. HopQ-CEACAM binding is glycan-independent and targeted to the N-domain. H. pylori binding induces CEACAM1-mediated signalling, and the HopQ-CEACAM1 interaction enables translocation of the virulence factor CagA into host cells and enhances the release of pro-inflammatory mediators such as interleukin-8. Based on the crystal structure of HopQ, we found that a β-hairpin insertion (HopQ-ID) in HopQ's extracellular 3+4 helix bundle domain is important for CEACAM binding. A peptide derived from this domain competitively inhibits HopQ-mediated activation of the Cag virulence pathway, as genetic or antibody-mediated abrogation of the HopQ function shows. Together, our data suggest the HopQ-CEACAM1 interaction to be a potentially promising novel therapeutic target to combat H. pylori-associated diseases.


Prophylactic use of oxytocin in the third stage of labour.
Many maternal deaths across the world result from complications of the third stage of labour (when the placenta is delivered). To examine the effect of oxytocin given prophylactically in the third stage of labour on maternal and neonatal outcomes. Relevant trials were identified in the Cochrane Collaboration Controlled Trials Register and the Pregnancy and Childbirth Review Group's Specialised Register of Controlled Trials. Date of last search: May 2001. All acceptably randomised or quasi-randomised controlled trials including pregnant women anticipating a vaginal delivery where oxytocin was given prophylactically for the third stage of labour. Two reviewers independently assessed studies for relevance and methodological quality, and extracted data. Analysis was by intention to treat. Subgroup analyses were based on extent of selection bias, oxytocin in the context of active or expectant management of the third stage, and timing of administration. Results are presented as relative risks, and weighted mean difference, both with 95% confidence intervals using a fixed effects model. In seven trials involving over 3000 women in hospital and/or developed country settings, prophylactic oxytocin showed benefits (reduced blood loss (relative risk (RR) for blood loss > 500 ml 0.50; 95% confidence interval (CI) 0.43, 0.59) and need for therapeutic oxytocics (RR 0.50; 95% CI 0.39, 0.64).) compared to no uterotonics, although there was a non-significant trend towards more manual removal of the placenta (RR 1.17; 95% CI 0.79, 1.73) which was most marked in the expectant management subgroup, and blood transfusions (RR 1.30; 95% CI 0.50, 3.39) in the trials with more manual removals of the placenta). In six trials involving over 2800 women, there was little evidence of differential effects for oxytocin versus ergot alkaloids, except ergot alkaloids are associated with more manual removals of the placenta (RR 0.57; 95% CI 0.41, 0.79), and with the suggestion of more raised blood pressure (RR 0.53; 95% CI 0.19, 1.58) than with oxytocin. In five trials involving over 2800 women, there was little evidence of a synergistic effects of adding oxytocin to ergometrine versus ergometrine alone. For all other outcomes in the comparisons either there are no data or the number of adverse events is very small, and so definite conclusions cannot be drawn. There are strong suggestions of benefit for oxytocin in terms of postpartum haemorrhage, and the need for therapeutic oxytocics, but without sufficient information about other outcomes and side-effects it is difficult to be confident about the trade-offs for these benefits, especially if the risk of manual removal of the placenta may be increased. There seems little evidence in favour of ergot alkaloids alone compared to either oxytocin alone, or to Syntometrine, but the data are sparse. More trials are needed in domiciliary deliveries in developing countries, which shoulder most of the burden of third stage complications.


Evaluating the feasibility of measuring travel to school using a wearable camera.
The school journey is often studied in relation to health outcomes in children and adolescents. Self-report is the most common measurement tool. To investigate the error on self-reported journey duration in adolescents, using a wearable digital camera (Microsoft SenseCam). During March-May 2011, participants (n=17; aged 13-15 years) from four schools wore wearable cameras to and from school for 1 week. The device automatically records time-stamped, first-person point-of-view images, without any action from the wearer. Participants also completed a researcher-administered self-report travel survey over the same period. Analysis took place in November 2011. Within- and between-subjects correlation coefficients and Bland-Altman 95% limits of agreement were derived, accounting for the multiple observations per individual. Self-report data were collected for 150 journey stages and SenseCam data for 135 (90%) of these. The within-subjects correlation coefficient for journey duration was 0.89 (95% CI=0.84, 0.93). The between-subjects correlation coefficient was 0.92 (95% CI=0.79, 0.97). The mean difference (bias) between methods at the whole sample level was small (10 seconds per journey, 95% CI= -33, 53). The wide limits of agreement (± 501 seconds, 95% CI= -491, 511) reveal large random error. Compared to direct observation from images, self-reported journey duration is accurate at the mean group level but imprecise at the level of the individual participant.


Hydroa Vacciniforme-Like Lymphoproliferative Disorder in an Adult Patient With Chronic Lymphocytic Leukemia.
Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a rare Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorder (LPD) which primarily affects children from Latin America and Asia. Typical features include vesicles and ulceration in sun-exposed areas which may be accompanied by systemic symptoms such as fever, lymphadenopathy and hepatosplenomegaly. We report a 73-year-old man diagnosed with HV-LPD in the context of zanubrutinib (oral Bruton tyrosine kinase (BTK)-inhibitor) treatment for chronic lymphocytic leukemia (CLL). The patient presented with slowly progressive peri-orbital edema and erythema non-responsive to topical therapies which eventually progressed to focal crusting and erosion. Prednisolone was subsequently introduced, which led to a good response in the patient's symptoms.


Physical properties and quantification of the ECT stimulus: I. Basic principles.
The physical properties of the electroconvulsive therapy (ECT) stimulus markedly affect both efficacy and side effects. We review basic principles in characterizing these physical properties and in quantifying the ECT stimulus. The topics discussed include the application of Ohm's law, alternative composite units of ECT dosage (energy and charge), the use of constant-current, constant-voltage, and constant-energy principles in ECT devices, the nature of current shunting in ECT and the determinants of impedance, the relations between impedance and seizure threshold, the seizure-eliciting efficiency of alternative stimulus waveforms and of stimulus parameter configurations, and the role of reactive components (capacitance and inductance) in the ECT circuit. New findings are also presented regarding several of these issues.


Association of blood arsenic levels with increased reactive oxidants and decreased antioxidant capacity in a human population of northeastern Taiwan.
Arsenic is a notorious environmental toxicant known as both a carcinogen and an atherogen in human beings, but the pathogenic mechanisms are not completely understood. In cell culture studies, trivalent arsenic enhanced oxidative stress in a variety of mammalian cells, and this association may be closely associated with the development of arsenic-related diseases. To investigate the effect of arsenic exposure on oxidative stress in humans, we conducted a population study to determine the relationships of blood arsenic to reactive oxidants and antioxidant capacity at the individual level. We recruited 64 study subjects ages 42-75 years from residents of the Lanyang Basin on the northeast coast of Taiwan, where arsenic content in well water varies from 0 to > or = 3,000 microg/L. We used a chemiluminescence method, with lucigenin as an amplifier for measuring superoxide, to measure the plasma level of reactive oxidants. We used the azino-diethyl-benzthiazoline sulphate method to determine the antioxidant capacity level in plasma of each study subject. We determined arsenic concentration in whole blood by hydride formation with an atomic absorption spectrophotometer. The average arsenic concentration in whole blood of study subjects was 9.60 +/- 9.96 microg/L (+/- SD) with a range from 0 to 46.50 microg/L. The level of arsenic concentration in whole blood of study subjects showed a positive association with the level of reactive oxidants in plasma (r = +0.41, p = 0.001) and an inverse relationship with the level of plasma antioxidant capacity (r = -0.30, p = 0.014). However, we found no significant association (p = 0.266) between levels of plasma reactive oxidants and antioxidant capacity. Our results also show that the lower the primary arsenic methylation capability, the lower the level of plasma antioxidant capacity (p = 0.029). These results suggest that ingestion of arsenic-contaminated well water may cause deleterious effects by increasing the level of reactive oxidants and decreasing the level of antioxidant capacity in plasma of individuals. Persistent oxidative stress in peripheral blood may be a mechanism underlying the carcinogenesis and atherosclerosis induced by long-term arsenic exposure.


The At Risk Child Clinic (ARCC): 3 Years of Health Activities in Support of the Most Vulnerable Children in Beira, Mozambique.
The concept of "children at risk" changes worldwide according to each specific context. Africa has a large burden of overall risk factors related to childhood health and development, most of which are of an infective or social origin. The aim of this study was to report and analyze the volumes of activities of fifteen At Risk Child Clinics (ARCCs) within the Beira District (Mozambique) over a 3 year-period in order to define the health profile of children accessing such health services. We retrospectively analyzed the data from all of the children accessing one of the 15 Beira ARCCs from January 2015 to December 2017. From this, 17,657 first consultations were registered. The motivations for accessing the services were in order of relevance: HIV exposure (n. 12,300; 69.7%), other risk conditions (n. 2542; 14.4%), Moderate Acute Malnutrition (MAM) (n. 1664; 9.4%), Severe Acute Malnutrition (SAM) (n. 772; 4.4%), and TB exposure (n. 542; 3.1%). During the first consultations, 16,865 children were screened for HIV (95.5%), and 7.89% tested HIV-positive. In our three years of experience, HIV exposure was the main indication for children to access the ARCCs in Mozambique. ARCCs could represent a strategic point to better understand health demands and to monitor the quality of care provided to this vulnerable population group, however significant effort is needed to improve the quality of the data collection.


Validating cluster size inference: random field and permutation methods.
Cluster size tests used in analyses of brain images can have more sensitivity compared to intensity based tests. The random field (RF) theory has been widely used in implementation of such tests, however the behavior of such tests is not well understood, especially when the RF assumptions are in doubt. In this paper, we carried out a simulation study of cluster size tests under varying smoothness, thresholds, and degrees of freedom, comparing RF performance to that of the permutation test, which is known to be exact. For Gaussian images, we find that the RF methods are generally conservative, especially for low smoothness and low threshold. For t images, the RF tests are found to be conservative at lower thresholds and do not perform well unless the threshold is high and images are sufficiently smooth. The permutation test performs well for any settings though the discreteness in cluster size must be accounted for. We make specific recommendations on when permutation tests are to be preferred to RF tests.


Medial patellar luxation in 16 large dogs. A retrospective study.
Unilateral medial patellar luxation was diagnosed in 10, and bilateral medial patellar luxation in six, large and giant-breed dogs (22 stifles). Lameness occurred in five dogs after trauma or surgery, and 11 dogs had no known predisposing history. The mean age at presentation was 25 months, and the mean time from initial onset of clinical signs to diagnosis was 13 weeks. All traumatic or iatrogenic luxations (five dogs) were unilateral. Luxations presumed to be congenital were unilateral in five dogs and bilateral in six. The grades of medial patellar luxation were I (1 stifle), II (11 stifles), III (9 stifles), and IV (1 stifle). Preoperative function was good (1 dog), fair (9 dogs), and poor (6 dogs). Surgical correction was performed in dogs with grades II, III, and IV luxations (21 stifles). Complications included one wound dehiscence and trochlear wedge migration, one pin loosening, and one persistent lameness caused by lymphoplasmacytic synovitis. Long-term follow-up was available in 13 dogs (18 stifles). Function was judged by owners to be excellent in seven dogs, good in five dogs, and poor in one dog. Surgical treatment of grades II and III luxations yielded good (8 stifles) and excellent (9 stifles) results, while one grade IV luxation had a poor long-term outcome.


Mother-Specific Signature in the Maternal Transcriptome Composition of Mature, Unfertilized Zebrafish Eggs.
Maternal mRNA present in mature oocytes plays an important role in the proper development of the early embryo. As the composition of the maternal transcriptome in general has been studied with pooled mature eggs, potential differences between individual eggs are unknown. Here we present a transcriptome study on individual zebrafish eggs from clutches of five mothers in which we focus on the differences in maternal mRNA abundance per gene between and within clutches. To minimize technical interference, we used mature, unfertilized eggs from siblings. About half of the number of analyzed genes was found to be expressed as maternal RNA. The expressed and non-expressed genes showed that maternal mRNA accumulation is a non-random process, as it is related to specific biological pathways and processes relevant in early embryogenesis. Moreover, it turned out that overall the composition of the maternal transcriptome is tightly regulated as about half of the expressed genes display a less than twofold expression range between the observed minimum and maximum expression values of a gene in the experiment. Even more, the maximum gene-expression difference within clutches is for 88% of the expressed genes lower than twofold. This means that expression differences observed in maternally expressed genes are primarily caused by differences between mothers, with only limited variability between eggs from the same mother. This was underlined by the fact that 99% of the expressed genes were found to be differentially expressed between any of the mothers in an ANOVA test. Furthermore, linking chromosome location, transcription factor binding sites, and miRNA target sites of the genes in clusters of distinct and unique mother-specific gene-expression, suggest biological relevance of the mother-specific signatures in the maternal transcriptome composition. Altogether, the maternal transcriptome composition of mature zebrafish oocytes seems to be tightly regulated with a distinct mother-specific signature.


Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells.
Human breast cancers are known to preferentially metastasize to skeletal sites, however, the mechanisms that mediate the skeletal preference (orthotropism) of specific types of cancers remains poorly understood. There is a significant clinical correlation between the expression of bone sialoprotein (BSP) and skeletal metastasis of breast cancers. Our laboratory, as well as others, have proposed the concept that skeletal selective metastasis and associated disease may be attributable to a mimicry of skeletal cellular phenotypes by metastasizing cancer cells. We hypothesize that breast cancer cell expression of phenotypic properties of skeletal cell types, including BSP as one component of that phenotype, is the result of ectopic expression or activity of one or more central transcriptional regulators of bone cell gene expression. To test this hypothesis, we examined the molecular mechanisms that regulate bsp expression in human breast cancer cell lines with previously characterized metastatic potentials. Our results demonstrate that the majority of the distal bsp promoter sequences act to repress BSP expression in cancer cells and that most of the promoter activity resides in the proximal -110 bp of the bsp promoter. In this region, we identified a putative Runx binding element providing a basis for a mechanism for skeletal gene activation. Our results demonstrate that Runx2 is ectopically expressed in breast cancer cells and that one isoform of Runx2 can activate bsp expression in these cells. In addition, we observe that bsp expression is additionally regulated by the homeodomain factor Msx2, another regulator of osteoblast-associated genes. Thus, this is the first report of osteoblast-related transcription factors being expressed in human breast cancer cells and provides a component of a mechanism that may explain the osteoblastic phenotype of human breast cancer cells that preferentially metastasize to bone.


The safety, acceptability, and effectiveness of acupuncture as an adjunctive treatment for acute symptoms in bipolar disorder.
There is growing interest in the utility of nonpharmacologic treatments for mood symptoms, including mood elevation and depression associated with bipolar disorders. The purpose of this research was to provide preliminary data on the safety, effectiveness, and acceptability of adjunctive acupuncture in the acute treatment of hypomania and depression associated with bipolar disorder. Two randomized trials were conducted to assess the benefits of adjunctive acupuncture for symptoms of depression and hypomania in patients with bipolar disorder (DSM-IV criteria). For 20 patients experiencing symptoms of hypomania, targeted acupuncture (points specific to symptoms) was compared to acupuncture points off the acupuncture meridian over 12 weeks (from May 2000 through May 2003). For patients experiencing symptoms of depression (n = 26), targeted acupuncture was compared to acupuncture for nonpsychiatric health concerns over 8 weeks (from November 2001 through May 2003). Preexisting psychotropic medications were maintained at stable doses throughout study participation. Regardless of acupuncture assignment or symptom pattern at entry, all patients experienced improvement over the course of study participation. There was evidence that acupuncture treatment did target the symptom dimension of interest (mood elevation in Study I, depression in Study II). There were few negative side effects and no attrition directly associated with adjunctive acupuncture. Novel methodologies are needed to assess the utility of acupuncture as adjunctive treatment of mood episodes associated with bipolar disorder. We observed similar benefits associated with "placebo" acupuncture experiences and active treatment. Further studies are warranted. TRIAL REGISTRATION (STUDY II): (ClinicalTrials.gov) Identifier: NCT00071669.


Health problems among migrant construction workers: A unique public-private partnership project.
Construction sector is a booming industry and involves many hazardous activities. Migrant labor in the industry is susceptible to various health and occupational hazards. In a unique public-private partnership project, a medical team from a public sector teaching hospital in Mumbai provided comprehensive on-site health care services to the construction workers of a private construction company. To study socio-demographic profile and morbidity pattern of construction workers. A cross-sectional study at construction site Vidyavihar (West), Mumbai, was carried out over the period of May to November 2010. A medical team provided comprehensive on-site health care services, and a Health Card was devised to maintain the record of socio-demographic, occupational details, and complete physical examination findings of the workers who participated in the study. Statistical analysis was done using SPSS 15.0. Of the 1337 workers (all males) examined, 1289 (96.4%) belonged to 15-45 years age group. The mean age of the workers was 26.25 ± 8.49 years. A third of the migrants belonged to West Bengal. The average number of health problems in the workers was 1.41. Regular consumers of tobacco and alcohol were 50.48 and 14.65%, respectively. Nearly one-fifth of the workers had febrile illness, of which 20.71% had suspected malaria; 12.6% had respiratory infections, while 3.4% were found to have hypertension. There was a statistically significant association (P < 0.05) between type of occupation and morbidity status.


Detection of polystyrene nanoplastics in biological tissues with a fluorescent molecular rotor probe.
The release of nanoplastics (NPs) from the weathering and degradation of plastics is an important environmental concern. Given their small sizes and their invasiveness in cells, methods for the detection of NPs in biological tissues are urgently needed. A simple fluorescence-based methodology for the detection of polystyrene NPs in biological tissues is proposed. The commercially available molecular rotor probe 9- (dicyanovinyl)-julolidine (DCVJ) has the properties to detect changes in hydrophobicity and microviscosity and was used to detect NPs. Increasing concentrations of 50 and 100 nm NPs in water and in tissue extracts were mixed with the DCVJ probe and the emission spectra determined between 480-800 nm at 450 nm excitation. The data revealed that NPs induces a second emission peak at 620 nm that differed from the normal spectra of the biological extract at 500 nm. A significant linear relationship was obtained for NPs of both sizes (r=0.98; P<0.001) with a theoretical limit of detection of 65 ng/mL. A simple and rapid microplate spectrofluorometric method for the semi-quantitative detection of polystyrene NPs in biological tissues is thus presented.


Translation and adaptation to Brazilian Portuguese of the Lymphedema Rating Scale in Head and Neck Cancer.
Translate to brazilian portuguese, culturally adapt and test the rating and classification scales of cervicofacial lymphedema of the MD Anderson Cancer Center Head and Neck Lymphedema Protocol (MDACC HNL) in patients undergoing treatment for head and neck cancer. The process followed international guidelines and translation stages by two head and neck surgeons, and back translation independently by two native Americans. The test of final version was based on the evaluation of 18 patients by one speech pathologist and one physical therapist who applied the scales in Portuguese. The translation of the three scales was carried out independently and the translators reached a consensus for the final version. Minor modifications were made by translating two terms into the Assessment of the Face. Versions of back-translation were similar to each other. The instrument was successfully applied to patients independently. The translation and cultural adaptation of the assessment and rating scale of the cervicofacial lymphedema of the MD Anderson Cancer Center Head and Neck Lymphedema Protocol to the Brazilian Portuguese were successful.


Update on corticosteroids for diabetic macular edema.
Diabetic macular edema (DME) remains an important cause of visual loss. Although anti-vascular endothelial growth factor (VEGF) agents are generally used as first-line treatments for patients with center-involving DME, there is an important role for corticosteroids as well. Corticosteroids may be especially useful in pseudophakic patients poorly responsive to anti-VEGF therapies, in patients wishing to reduce the number of required injections, and in pregnant patients. Intravitreal triamcinolone acetonide has been used for many years but is not approved for this indication. An extended-release bioerodable dexamethasone delivery system and an extended-release nonbioerodable fluocinolone acetonide insert have both achieved regulatory approval for the treatment of DME. All intravitreal corticosteroids are associated with risks of cataract progression, elevation of intraocular pressure, and endophthalmitis. There is no current consensus regarding the use of corticosteroids, but they are valuable for selected patients with center-involving DME.


Robust analysis of the yeast proteome under 50 kDa by molecular-mass-based fractionation and top-down mass spectrometry.
As the process of top-down mass spectrometry continues to mature, we benchmark the next installment of an improving methodology that incorporates a tube-gel electrophoresis (TGE) device to separate intact proteins by molecular mass. Top-down proteomics is accomplished in a robust fashion to yield the identification of hundreds of unique proteins, many of which correspond to multiple protein forms. The TGE platform separates 0-50 kDa proteins extracted from the yeast proteome into 12 fractions prior to automated nanocapillary LC-MS/MS in technical triplicate. The process may be completed in less than 72 h. From this study, 530 unique proteins and 1103 distinct protein species were identified and characterized, thus representing the highest coverage to date of the Saccharomyces cerevisiae proteome using top-down proteomics. The work signifies a significant step in the maturation of proteomics based on direct measurement and fragmentation of intact proteins.


Attenuation of wild-type yellow fever virus by passage in HeLa cells.
During the 1960s three different research groups reported that passage of wild-type yellow fever (YF) virus [strain Asibi (YF-Asibi)] in HeLa cells resulted in attenuation of the virus for monkeys so that the virus no longer caused viscerotropic disease. We have repeated and extended this observation to analyse the process of attenuation of YF virus during cell culture passage. A large plaque (LP) variant of YF-Asibi virus became attenuated for both monkeys and mice following six serial subcultures in HeLa cells (YF-Asibi-LP HeLa p6). Thus, attenuation was probably due to a genetic change in the virus population rather than to selective enrichment of a pre-existing variant of YF-Asibi-LP virus. No evidence was obtained to implicate defective interfering particles in the attenuation process. Comparison of the YF-Asibi-LP viruses before and after passage in HeLa cells, using a panel of envelope protein-reactive monoclonal antibodies (MAbs), showed that MAbs which specifically neutralize YF-Asibi-LP virus, and not YF 17D-204 vaccine virus, also neutralized YF-Asibi-LP HeLa p6. This indicated that the epitopes involved in the biological process of neutralization were not altered during attenuation. However, two MAbs that recognize envelope protein epitopes did distinguish between HeLa- and non-HeLa-passaged YF-Asibi-LP virus. One of these (MAb 117) which is YF wild-type-specific, recognized YF-Asibi-LP virus but not YF-Asibi-LP HeLa p6 virus, whereas the other (MAb411), which is YF vaccine-specific, recognized YF-Asibi-LP HeLa p6 virus but not YF-Asibi-LP virus. These results suggest that antigenic changes in the viral envelope protein may determine the relative virulence or attenuation of YF virus.


Evaluation of structural equation mixture models Parameter estimates and correct class assignment.
Structural Equation Mixture Models(SEMMs) are latent class models that permit the estimation of a structural equation model within each class. Fitting SEMMs is illustrated using data from one wave of the Notre Dame Longitudinal Study of Aging. Based on the model used in the illustration, SEMM parameter estimation and correct class assignment are investigated in a large scale simulation study. Design factors of the simulation study are (im)balanced class proportions, (im)balanced factor variances, sample size, and class separation. We compare the fit of models with correct and misspecified within-class structural relations. In addition, we investigate the potential to fit SEMMs with binary indicators. The structure of within-class distributions can be recovered under a wide variety of conditions, indicating the general potential and flexibility of SEMMs to test complex within-class models. Correct class assignment is limited.


Integrated Bloch-Siegert B₁ mapping and multislice imaging of hyperpolarized ¹³C pyruvate and bicarbonate in the heart.
Hyperpolarization of (13) C labeled substrates via dynamic nuclear polarization has been used as a method to noninvasively study real-time metabolic processes occurring in vivo. In these studies, proper calibration of radiofrequency transmit power is required to efficiently observe rapidly decaying magnetization. Conventional transmit radiofrequency field (B₁⁺) mapping methods rely on placing magnetization in a fixed, known state prior to imaging, making them unsuitable for imaging of hyperpolarized magnetization. Recently, a phase-based B(1) mapping method based on the Bloch-Siegert shift has been reported. This method uses a B(1) -dependent shift in the resonance frequency of nuclei in the presence of an off-resonance radiofrequency pulse. In this article, we investigate the feasibility of Bloch-Siegert B(1) mapping and observation of metabolism of hyperpolarized [1-¹³C] pyruvate in vivo, in a single injection. The technique is demonstrated with phantom experiments, and in normal rat and pigs in vivo. This method is anticipated to improve quantitative measurements of hyperpolarized (13) C metabolism in vivo by enabling accurate flip-angle corrections. This work demonstrates the use of Bloch-Siegert B(1) mapping under challenging out-of-equilibrium imaging conditions.


Vaginal ring adherence in sub-Saharan Africa: expulsion, removal, and perfect use.
In sub-Saharan Africa, HIV incidence and prevalence remain disproportionately high among women. Vaginal rings (VRs) have been formulated for the delivery of antiretroviral-based microbicides, and their favorable safety and tolerability profiles reported in clinical studies. Although the concept of drug release through a VR has existed since 1970, and VRs have been marketed since 1992 for contraceptive or hormone replacement purposes, VR use as a microbicide delivery system is a novel application. This is the first study to evaluate VR adherence among African women in the context of its potential use as an HIV prevention method, to examine predictors of adherence, and to describe clinical or contextual reasons for VR removals or nonadherence. This was a randomized trial of the safety and acceptability of a placebo VR worn for 12 weeks in 170 HIV-negative, African women aged 18-35 in four clinic sites in South Africa and Tanzania. The findings suggest that adherence to VR use in the context of HIV prevention trials in these communities should be high, thereby enabling more accurate assessment of an active microbicide safety and efficacy.


Effects of single- and biventricular pacing on temporal and spatial dynamics of ventricular contraction.
Resynchronization is frequently used for the treatment of heart failure, but the mechanism for improvement is not entirely clear. In the present study, the temporal synchrony and spatiotemporal distribution of left ventricular (LV) contraction was investigated in eight dogs during right atrial (RA), right ventricular apex (RVa), and biventricular (BiV) pacing using tagged magnetic resonance imaging. Mechanical activation (MA; the onset of circumferential shortening) was calculated from the images throughout the left ventricle for each pacing protocol. MA width (time for 20-90% of the left ventricle to contract) was significantly shorter during RA (43.6 +/- 17.1 ms) than BiV and RVa pacing (67.4 +/- 15.2 and 77.6 +/- 16.4 ms, respectively). The activation delay vector (net delay in MA from one side of the left ventricle to the other) was significantly shorter during RA (18.9 +/- 8.1 ms) and BiV (34.2 +/- 18.3 ms) than during RVa (73.8 +/- 16.3 ms) pacing. Rate of LV pressure increase was significantly lower during RVa than RA pacing (1,070 +/- 370 vs. 1,560 +/- 300 mmHg/s) with intermediate values for BiV pacing (1,310 +/- 220 mmHg/s). BiV pacing has a greater impact on correcting the spatial distribution of LV contraction than on improving the temporal synchronization of contraction. Spatiotemporal distribution of contraction may be an important determinant of ventricular function.


Third-order aberrations of the thin refractive tunable-focus lens.
We present an approach to the problem of the calculation of basic paraxial parameters and the third-order aberration coefficients of thin refractive tunable-focus lenses. It is shown that aberration coefficients of the third order of the thin refractive tunable-focus lens can be completely characterized by three functions that depend only on refractive indices of fluids forming the tunable-focus lens and do not depend on the position and size of the object and the position of the entrance pupil.


Specific roles of G(i) protein family members revealed by dissecting SST5 coupling in human pituitary cells.
Despite intensive investigation over the past 20 years, the specific role played by individual G(i) protein family members in mediating complex cellular effects is still largely unclear. Therefore, we investigated the role of specific G(i) proteins in mediating somatostatin (SS) effects in somatotroph cells. Because our previous data showed that SS receptor type 5 (SST5) carrying a spontaneous R240W mutation in the third intracellular loop had a similar ability to inhibit intracellular cAMP levels to the wild-type protein but failed to mediate inhibition of growth hormone (GH) release and cell proliferation, we used this model to check specific receptor-G-protein coupling by a bioluminescent resonance energy transfer analysis. In HEK293 cells, wild-type SST5 stimulated the activation of Gα(i1-3) and Gα(oA), B, whereas R240W SST5 maintained the ability to activate Gα(i1-3) and Gα(oB), but failed to activate the splicing variant Gα(oA). To investigate the role of the selective deficit in Gα(oA) coupling, we co-transfected human adenomatous somatotrophs with SST5 and a pertussis toxin (PTX)-resistant Gα(oA) (Gα(oA(PTX-r))) protein. In PTX-treated cells, Gα(oA(PTX-r)) rescued the ability of the selective SST5 analog BIM23206 to inhibit extracellular signal-related kinase 1/2 (ERK1/2) phosphorylation, GH secretion and intracellular cAMP levels. Moreover, we demonstrated that silencing of Gα(oA) completely abolished SST5-mediated inhibitory effects on GH secretion and ERK1/2 phosphorylation, but not on cAMP levels. In conclusion, by analysing the coupling specificity of human SST5 to individual Gα(i) and Gα(o) subunits, we identified a crucial role for Gα(oA) signalling in human pituitary cells.


A comprehensive substance flow analysis of a municipal wastewater and sludge treatment plant.
The fate of total organic carbon, 32 elements (Al, Ag, As, Ba, Be, Br, Ca, Cd, Cl, Co, Cr, Cu, Fe, Hg, K, Li, Mg, Mn, Mo, N, Na, Ni, P, Pb, S, Sb, Se, Sn, Sr, Ti, V, and Zn) and 4 groups of organic pollutants (linear alkylbenzene sulfonates, bis(2-ethylhexyl)phthalate, polychlorinated biphenyl and polycyclic aromatic hydrocarbons) in a conventional wastewater treatment plant were assessed. Mass balances showed reasonable closures for most of the elements. However, gaseous emissions were accompanied by large uncertainties and show the limitation of mass balance based substance flow analysis. Based on the assessment, it is evident that both inorganic and organic elements accumulated in the sewage sludge, with the exception of elements that are highly soluble or degradable by wastewater and sludge treatment processes. The majority of metals and metalloids were further accumulated in the incineration ash, while the organic pollutants were effectively destroyed by both biological and thermal processes. Side streams from the sludge treatment process (dewatering and incineration) back to the wastewater treatment represented less than 1% of the total volume entering the wastewater treatment processes, but represented significant substance flows. In contrast, the contribution by spent water from the flue gas treatment process was almost negligible. Screening of human and eco-toxicity by applying the consensus-based environmental impact assessment method USEtox addressing 15 inorganic constituents showed that removal of inorganic constituents by the wastewater treatment plant reduced the toxic impact potential by 87-92%.


CBD Suppression of EAE Is Correlated with Early Inhibition of Splenic IFN-γ + CD8+ T Cells and Modest Inhibition of Neuroinflammation.
In this study cannabidiol (CBD) was administered orally to determine its effects and mechanisms in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). We hypothesized that 75 mg/kg of oral CBD given for 5 days after initiation of disease would reduce EAE severity through suppression of either the early peripheral immune or late neuroimmune response. EAE was induced in C57BL/6 mice at two different magnitudes, and peripheral inflammatory and neuroinflammatory responses were measured at days 3, 10, and 18. Th1, Th17, Tc1, Tc17, Tregs, and myeloid derived suppressor cells (MDSC) were identified from the lymph nodes and spleens of each mouse to determine if CBD altered the suppressor cell or inflammatory cell populations in secondary lymphoid tissues. Additionally, neuroinflammation was identified in brain and spinal cord tissues using various immunohistochemical techniques and flow cytometry. Early treatment of EAE with oral CBD reduced clinical disease at the day 18 timepoint which correlated with a significant decrease in the percentage of MOG35-55 specific IFN-γ producing CD8+ T cells in the spleen at day 10. Analysis of both T cell infiltration and lesion size within the spinal cord also showed a moderate reduction in neuroinflammation within the central nervous system (CNS). These results provide evidence that oral CBD suppressed the peripheral immune response that precedes neuroinflammation; however, analysis of the neuroinflammatory endpoints also suggest that the modest reduction in neuroinflammation was only partially responsible for CBD's neuroprotective capability. Graphical Abstract CBD was administered orally for the first 5 days following initiation of EAE. CBD attenuated clinical disease, and we found that CBD suppressed IFN-γ producing CD8+ T cells in the spleen at day 10. There was also modest suppression of neuroinflammation. Together these data demonstrate that early, oral administration of CBD protected mice from disease, but the modest effects on neuroinflammation suggest other mechanisms participate in CBD's neuroprotective effect in EAE.


Process evaluation of serial screening criteria to identify injured patients that benefit from brief intervention: practical implications.
The aim of the current study is to evaluate the effectiveness of serial screening methods for the identification of injured patients at risk for alcohol problems and are most likely to benefit from brief interventions. We hypothesize that blood alcohol concentration (BAC) alone is not sufficient to effectively identify at-risk drinkers in the trauma care setting. During a 2-year period, patients admitted to an urban Level I trauma center for treatment of an injury were screened for alcohol problems. Screening consisted of four serial screening criteria: (1) clinical indication of acute intoxication including positive BAC; (2) self-reported drinking 6 hours before injury; (3) at-risk drinking as defined by National Institutes on Alcohol Abuse and Alcoholism or (4) by responding yes to one or more items on the CAGE within the last year. In all, 11,028 patients were seen. Fifty-eight percent were eligible for screening and 90% of eligible patients were screened. Of screened patients, 41% screened positive for an alcohol-related injury. Of patients that did not have a BAC drawn, 39% (n = 935) went on to screen positive using serial screening procedures. Additionally, 36% (n = 339) of patients with a negative BAC went on to screen positive using serial screening procedures. This evaluation clearly suggests that BAC alone is not sufficient to identify patients who are most likely to benefit from brief alcohol interventions. Self-reported drinking in conjunction with BAC facilitates identification and intervention of injured patients with alcohol problems.