First Report of Laurel Oak as a Host for the Pecan Root-Knot Nematode, Meloidogyne partityla, in Florida.
Roots of laurel oak (Quercus laurifolia Michx.), member of the family Fagaceae, were found to be heavily galled by the pecan root-knot nematode, Meloidogyne partityla, in two separate home gardens between 2010 and 2012, in Alachua Co., FL. Distinct round galls were observed on secondary and tertiary roots. Internally, root-knot nematode females were clearly visible when the roots were thinly sliced and egg masses were seen protruding from the root surfaces. The nematode species identification was performed using morphology of the male stylet, selected characters of the second-stage juveniles (J2), female perineal patterns, and esterase (EST) and malate dehydrogenase (Mdh) isozyme phenotypes. Morphology of perineal patterns of females, body, stylet, and tail length of the J2 and males all matched those of the original description of M. partityla (2). A swollen deeply grooved rectum was observed in the J2. The male stylet had a blunt tip with a prominent thickening at the junction between the cone and shaft. The stylet knobs of males and females were bipartite, each incised by a deep medium longitudinal groove (2). The isozyme phenotypes (EST = Mp3; Mdh = N1a) were consistent with those previously reported for M. partityla from Florida (1). Mitochondrial DNA (mtDNA) (3) and ribosomal internal transcriber spacer (ITS) DNA (4) of females were amplified to further confirm the nematode species identification. The mtDNA amplification using the C2F3/1108 primer set (3) and the ITS amplification using a recently available M. partityla specific primer set (4) produced fragments of approximately 530 bp and 550 bp, respectively. These were consistent with those already reported for this nematode species. This first report of a plant host for the pecan root-knot nematode outside of the family Juglandaceae indicates that the nematode may have migrated from Quercus species to pecan trees during the period when orchards were being established in Florida. To our knowledge, this is the first report of the pecan root-knot nematode infecting laurel oak. References: (1) J. A. Brito et al. Nematology 10:757, 2008. (2) Kleynhans, K. P. N. Phytophylatica 18:103, 1986. (3) T. O. Powers et al., J. Nematol. 37:226, 2005. (4) R. A. Stamler. M. S. thesis, New Mexico State University, Las Cruces, 2009.


Chromatic discrimination of natural objects.
Studies of chromatic discrimination are typically based on homogeneously colored patches. Surfaces of natural objects, however, cannot be characterized by a single color. Instead, they have a chromatic texture, that is, a distribution of different chromaticities. Here we study chromatic discrimination for natural images and synthetic stimuli with a distribution of different chromaticities under various states of adaptation. Discrimination was measured at the adaptation point, where the mean chromaticity of the test stimuli was the same as the chromaticity of the adapting background, and away from the adaptation point. At the adaptation point, discrimination for natural objects resulted in threshold contours that were selectively elongated in a direction of color space matching the chromatic variation of the colors within the natural object. Similar effects occurred for synthetic stimuli. Away from the adaptation point, discrimination thresholds increased and threshold ellipses were elongated along the contrast axis connecting adapting color and test color. Away from the adaptation point, no significant differences between the different stimulus classes were found. The effect of the chromatic texture on discrimination seemed to be masked by the overall increase in discrimination thresholds. Our results show that discrimination of chromatic textures, either synthetic or natural, differs from that of simple uniform patches when the chromatic variation is centered at the adaptation point.


NADK is activated by oncogenic signaling to sustain pancreatic ductal adenocarcinoma.
Metabolic adaptations and the signaling events that control them promote the survival of pancreatic ductal adenocarcinoma (PDAC) at the fibrotic tumor site, overcoming stresses associated with nutrient and oxygen deprivation. Recently, rewiring of NADPH production has been shown to play a key role in this process. NADPH is recycled through reduction of NADP+ by several enzymatic systems in cells. However, de novo NADP+ is synthesized only through one known enzymatic reaction, catalyzed by NAD+ kinase (NADK). In this study, we show that oncogenic KRAS promotes protein kinase C (PKC)-mediated NADK phosphorylation, leading to its hyperactivation, thus sustaining both NADP+ and NADPH levels in PDAC cells. Together, our data show that increased NADK activity is an important adaptation driven by oncogenic signaling. Our findings indicate that NADK could serve as a much-needed therapeutic target for PDAC.


Co-receptor and co-stimulation blockade for mixed chimerism and tolerance without myelosuppressive conditioning.
A major challenge in the application of marrow transplantation as a route to immunological tolerance of a transplanted organ is to achieve hematopoietic stem cell (HSC) engraftment with minimal myelosuppressive treatments. We here describe a combined antibody protocol which can achieve long-term engraftment with clinically relevant doses of MHC-mismatched bone marrow, without the need for myelosuppressive drugs. Although not universally applicable in all strains, we achieved reliable engraftment in permissive strains with a two-stage strategy: involving first, treatment with anti-CD8 and anti-CD4 in advance of transplantation; and second, treatment with antibodies targeting CD4, CD8 and CD40L (CD154) at the time of marrow transplantation. Long-term mixed chimerism through co-receptor and co-stimulation blockade facilitated tolerance to donor-type skin grafts, without any evidence of donor-antigen driven regulatory T cells. We conclude that antibodies targeting co-receptor and co-stimulatory molecules synergise to enable mixed hematopoietic chimerism and central tolerance, showing that neither cytoreductive conditioning nor 'megadoses' of donor bone marrow are required for donor HSC to engraft in permissive strains.


Costs of plasticity in foraging characteristics of the clonal plant Ranunculus reptans.
In clonal plants, evolution of plastic foraging by increased lengths of leaves and internodes under unfavourable conditions may be constrained by costs and limits of plasticity. We studied costs and limits of plasticity in foraging characteristics in 102 genotypes of the stoloniferous herb Ranunculus reptans. We grew three replicates of each genotype with and three without competition by the naturally co-occuring grass Agrostis stolonifera. We used regression and correlation analyses to investigate potential costs of plasticity in lengths of leaves and stolon internodes, developmental instability costs of these traits, and a developmental range limit of these traits. We used randomization procedures to control for spurious correlations between parameters calculated from the same data. Under competition the number of rosettes, rooted rosettes, and flowers was 58%, 40%, and 61% lower, respectively, than in the absence of competition. Under competition lengths of leaves and stolon internodes were 14% and 6% smaller, respectively, than in the absence of competition. We detected significant costs of plasticity in stolon internode length in the presence of competition when fitness was measured in terms of the number of rosettes and the number of flowers (selection gradients against plasticity were 0.250 and 0.214, respectively). Within-environment variation (SD) in both foraging traits was not positively correlated with the corresponding plasticity, which indicates that there were no developmental instability costs. More plastic genotypes did not have less extreme trait values than less plastic genotypes for both foraging traits, which indicates that there was no developmental range limit. We conclude that in R. reptans costs of plasticity more strongly constrain evolution of foraging in the horizontal plane (i.e., stolon internode length) than in the vertical plane (i.e., leaf length).


A novel bioluminescent mouse model and effective therapy for adult T-cell leukemia/lymphoma.
Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor kappaB (NF-kappaB). NF-kappaB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-kappaB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1 alpha expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy.


Inhibition of oxidative drug metabolism by orphenadrine: in vitro and in vivo evidence for isozyme-specific complexation of cytochrome P-450 and inhibition kinetics.
The anti-parkinsonian agent orphenadrine has been shown to form an in vitro metabolic intermediate (MI) complex in hepatic microsomes isolated from phenobarbital (PB)-treated rats. The present study was undertaken to assess the cytochrome P-450 isozyme specificity of inhibition and MI complexation. Spectral studies with untreated and PB-induced rat hepatic microsomes confirmed earlier reports on the selectivity of P-450 complexation by orphenadrine; MI complex formation was only observed with PB-induced microsomes. Inhibition studies with the P-450 substrates androst-4-ene-3,17-dione (androstenedione) and 7-pentoxyresorufin revealed selective inhibition of P-450 PB-B/D-associated monooxygenase activity. Thus, in microsomes from untreated male rats, orphenadrine failed to significantly inhibit (less than 50% inhibition up to a concentration of 300 microM) any of the major pathways of P-450-associated androstenedione metabolism. Preincubation of these microsomal fractions with orphenadrine and NADPH was not associated with increased inhibition of androstenedione metabolism. However, in PB-induced microsomes, P-450 PB-B/D-specific androstenedione 16 beta-hydroxylase activity was significantly and selectively inhibited (IC50 = 90 microM). Preincubation of orphenadrine with NADPH-supplemented PB-induced microsomes for 2, 4, or 8 min before androstenedione addition resulted in increased inhibition toward 16 beta-hydroxylase activity, lowering the observed IC50 to 6.6, 0.47, and 0.06 microM), respectively. Preincubation did not affect the selectivity of inhibition. In the absence of preincubation, orphenadrine appeared to be a potent mixed (competitive/noncompetitive)-type inhibitor of P-450 PB-B/D-associated pentoxyresorufin O-depentylation (Ki = 3.8 microM). Preincubation of orphenadrine with NADPH-supplemented microsomal fractions for 4 min resulted in a 30-fold lowering of the apparent inhibitor constant (Ki = 0.13 microM) and a change in the apparent inhibition kinetics to noncompetitive. Treatment of rats with orphenadrine (75 mg/kg/day intraperitoneally for 3 days) was associated with a 2-fold induction of total hepatic P-450, a 5- and 2.4-fold induction of androstenedione 16 beta- and 6 beta-hydroxylase activity, respectively, and formation of an orphenadrine-P-450 MI complex. Western blots of orphenadrine-induced microsomes revealed a 20-fold increase in P-450 PB-B/D-immunoreactive protein.(ABSTRACT TRUNCATED AT 400 WORDS)


Determining the Provincial and National Burden of Influenza-Associated Severe Acute Respiratory Illness in South Africa Using a Rapid Assessment Methodology.
Local disease burden data are necessary to set national influenza vaccination policy. In 2010 the population of South Africa was 50 million and the HIV prevalence was 11%. We used a previously developed methodology to determine severe influenza burden in South Africa. Hospitalized severe acute respiratory illness (SARI) incidence was calculated, stratified by HIV status, for four age groups using data from population-based surveillance in one site situated in Gauteng Province for 2009-2011. These rates were adjusted for each of the remaining 8 provinces based on their prevalence of risk factors for pneumonia and healthcare-seeking behavior. We estimated non-hospitalized influenza-associated SARI from healthcare utilization surveys at two sites and used the percent of SARI cases positive for influenza from sentinel surveillance to derive the influenza-associated SARI rate. We applied rates of hospitalized and non-hospitalized influenza-associated SARI to census data to calculate the national number of cases. The percent of SARI cases that tested positive for influenza ranged from 7-17% depending on age group, year, province and HIV status. In 2010, there were an estimated 21,555 total severe influenza cases in HIV-uninfected individuals and 13,876 in HIV-infected individuals. In 2011, there were an estimated 29,892 total severe influenza cases in HIV-uninfected individuals and 17,289 in HIV-infected individuals. The incidence of influenza-associated SARI was highest in children <5 years and was higher in HIV-infected than HIV-uninfected persons in all age groups. Influenza virus was associated with a substantial amount of severe disease, especially in young children and HIV-infected populations in South Africa.


Scattering matrices for large ice crystal particles.
The problem of light scattering by ice crystal particles whose sizes are essentially larger than the incident wavelength is divided into two parts. First, the scattered field is represented as a set of plane-parallel outgoing beams in the near zone of the particle. Then, in the far zone the scattered field is represented as a result of both diffraction and interference of these beams within the framework of physical optics. A proper ray-tracing algorithm for calculation of the amplitude (Jones) scattering matrix is developed and applied. For large particles, a number of reduced Mueller matrices are introduced and discussed, since the pure Mueller matrix obtained from the Jones matrix becomes a rather cumbersome and quickly oscillating value. Backscattering by hexagonal ice crystals, including polarization properties, is considered in detail.


Characterization and evaluation of detoxification functions of a nontumorigenic immortalized porcine hepatocyte cell line (HepLiu).
Primary porcine hepatocytes (PPH) are currently used in research and therapeutic applications as the biological component of extracorporeal liver assist devices to overcome the shortage of human hepatocytes. However, their finite life span and typically rapid loss of functions limit their utility. An immortalized, nontumorigenic, highly differentiated porcine hepatocyte cell line was developed in our laboratory to resolve these disadvantages. PPH were transfected with simian virus 40 (SV40) T antigen under the control of the SV40 early promoter. From the established 69 clones, 23 clones displaying hepatocyte-like morphology were screened for diazepam metabolism. One clone, HepLiu D63, has been maintained in culture for > 2 years, through more than 60 passages and 240 divisions. Albumin protein, present in early passages, was lost at later passages, but albumin transcript still was detectable in later passages. Carbamoyl phosphate synthetase, a gateway enzyme of the urea cycle, was consistently detectable in HepLiu cells. Cytokeratin 18, a characteristic marker of primary hepatocytes, was detected by both immunofluorescent staining and Western blot in HepLiu cells. Furthermore, maintenance of P450 functions in HepLiu cells was evidenced by diazepam and 7-ethoxycoumarin metabolites measured by HPLC. Phase II conjugative function was measured as acetaminophen glucuronidation. P450 dealkylase was demonstrated microscopically by the conversion of a nonfluorescent substrate to a fluorescent product. Both Northern blot analysis and immunofluorescent staining showed SV40 T antigen expression in the nuclei of HepLiu cells. No tumor formation occurred when HepLiu cells were injected into severe combined immunodeficient (SCID) mice nor was the TAI (a tumor marker) mRNA expressed, even in later passages. This immortalized, nontumorigenic, highly functional cell line may provide a valuable tool for drug/toxicological studies, liver biologic regulation studies, and artificial liver support systems.


Monte-Carlo-based phase retardation estimator for polarization sensitive optical coherence tomography.
A Monte-Carlo-based phase retardation estimator is developed to correct the systematic error in phase retardation measurement by polarization sensitive optical coherence tomography (PS-OCT). Recent research has revealed that the phase retardation measured by PS-OCT has a distribution that is neither symmetric nor centered at the true value. Hence, a standard mean estimator gives us erroneous estimations of phase retardation, and it degrades the performance of PS-OCT for quantitative assessment. In this paper, the noise property in phase retardation is investigated in detail by Monte-Carlo simulation and experiments. A distribution transform function is designed to eliminate the systematic error by using the result of the Monte-Carlo simulation. This distribution transformation is followed by a mean estimator. This process provides a significantly better estimation of phase retardation than a standard mean estimator. This method is validated both by numerical simulations and experiments. The application of this method to in vitro and in vivo biological samples is also demonstrated.


Popular intoxicants: what lessons can be learned from the last 40 years of alcohol and cannabis regulation?
In this paper we discuss the relative physical, psychological and social harms of the two most frequently used intoxicant drugs in the UK, namely cannabis and alcohol. Over the past 40 years, the use of both drugs has risen significantly with differential consequences. It is argued that increased policing of cannabis use under the current drug classification system will lead to increased criminalization of young people, but is unlikely to significantly reduce the rates of schizophrenia and psychosis. In comparison, increases in alcohol drinking are related to significant increases in liver cirrhosis hospital admissions and mortality, at a time when mortality rates from other major causes are on the decline. A recent expert-led comparison of the health and social harms to the user and to others caused by the most commonly used drugs in the UK showed alcohol to be more than twice as harmful as cannabis to users, and five times as harmful as cannabis to others. The findings underline the need for a coherent, evidence-based drugs policy that enables individuals to make informed decisions about the consequences of their drug use.


The oxidant/antioxidant network: role of melatonin.
Melatonin is now known to be a multifaceted free radical scavenger and antioxidant. It detoxifies a variety of free radicals and reactive oxygen intermediates including the hydroxyl radical, peroxynitrite anion, singlet oxygen and nitric oxide. Additionally, it reportedly stimulates several antioxidative enzymes including glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and superoxide dismutase; conversely, it inhibits a prooxidative enzyme, nitric oxide synthase. Melatonin also crosses all morphophysiological barriers, e.g., the blood-brain barrier, placenta, and distributes throughout the cell; these features increase the efficacy of melatonin as an antioxidant. Melatonin has been shown to markedly protect both membrane lipids and nuclear DNA from oxidative damage. In every experimental model in which melatonin has been tested, it has been found to resist macromolecular damage and the associated dysfunction associated with free radicals.


Male Courtship Pheromones Induce Cloacal Gaping in Female Newts (Salamandridae).
Pheromones are an important component of sexual communication in courting salamanders, but the number of species in which their use has been demonstrated with behavioral evidence remains limited. Here we developed a behavioral assay for demonstrating courtship pheromone use in the aquatically courting Iberian ribbed newt Pleurodeles waltl. By performing an in-depth study of the courtship behavior, we show that females invariably open their cloaca (cloacal gaping) before engaging in pinwheel behavior, the circling movement that is the prelude to spermatophore uptake. In contrast, cloacal gaping was not observed in failed courtships, where females escaped or displayed thanatosis. Since gaping mainly occurred during male amplexus and cloacal imposition, which is the obvious period of pheromone transfer, we next investigated whether male courtship water (i.e., water holding courtship pheromones) alone was able to induce this reaction in females. These tests showed that courtship water induced cloacal gaping significantly more than water, even in the absence of a male. Cloacal gaping thus provides a simple and robust test for demonstrating courtship pheromone use in the Iberian ribbed newt. Since opening the cloaca is an essential prerequisite for spermatophore pick-up in all internally fertilizing salamanders, we hypothesize that variations on this assay will also be useful in several other species.


Bone fractures after menopause.
Every year 30% of individuals above age 65 fall, and falls are the principal cause of bone fractures. To reduce fracture incidence requires both prevention of falls and maintenance of bone strength. PubMed searches were performed, for studies of the epidemiology of fractures, bone physiology, endocrine effects, osteoporosis measurement, genetics, prevention and effectiveness. Topic summaries were presented to the Workshop Group and omissions or disagreements were resolved by discussion. Ageing reduces bone strength in post-menopausal women because estrogen deficiency causes accelerated bone resorption. Bone mineral density (BMD) decreased more than 2.5 standard deviation below the mean of healthy young adults defines osteoporosis, a condition associated with an increased risk of fractures. Risk factors such as age and previous fracture are combined with BMD for a more accurate prediction of fracture risk. The most widely used assessment tool is FRAX™ which combines clinical risk factors and femoral neck BMD. General preventive measures include physical exercise to reduce the risk of falling and vitamin D to facilitate calcium absorption. Pharmacological interventions consist mainly in the administration of inhibitors of bone resorption. Randomized controlled trials show treatment improves BMD, and may reduce the relative fracture risk by about 50% for vertebral, 20-25% for non-vertebral and up to 40% for hip fractures although the absolute risk reductions are much lower. Although diagnosis of osteoporosis is an important step, the threshold for treatment to prevent fractures depends on additional clinical risk factors. None of the presently available treatment options provide complete fracture prevention.


Human and ecological risk assessment of a crop protection chemical: a case study with the azole fungicide epoxiconazole.
Conventional risk assessments for crop protection chemicals compare the potential for causing toxicity (hazard identification) to anticipated exposure. New regulatory approaches have been proposed that would exclude exposure assessment and just focus on hazard identification based on endocrine disruption. This review comprises a critical analysis of hazard, focusing on the relative sensitivity of endocrine and non-endocrine endpoints, using a class of crop protection chemicals, the azole fungicides. These were selected because they are widely used on important crops (e.g. grains) and thereby can contact target and non-target plants and enter the food chain of humans and wildlife. Inhibition of lanosterol 14α-demethylase (CYP51) mediates the antifungal effect. Inhibition of other CYPs, such as aromatase (CYP19), can lead to numerous toxicological effects, which are also evident from high dose human exposures to therapeutic azoles. Because of its widespread use and substantial database, epoxiconazole was selected as a representative azole fungicide. Our critical analysis concluded that anticipated human exposure to epoxiconazole would yield a margin of safety of at least three orders of magnitude for reproductive effects observed in laboratory rodent studies that are postulated to be endocrine-driven (i.e. fetal resorptions). The most sensitive ecological species is the aquatic plant Lemna (duckweed), for which the margin of safety is less protective than for human health. For humans and wildlife, endocrine disruption is not the most sensitive endpoint. It is concluded that conventional risk assessment, considering anticipated exposure levels, will be protective of both human and ecological health. Although the toxic mechanisms of other azole compounds may be similar, large differences in potency will require a case-by-case risk assessment.


Pediatric neurosurgeons' philosophical approaches to making intraoperative decisions when encountering an uncertainty or a complication while operating on children.
The objective of this study was to explore approaches to intraoperative decision-making in pediatric neurosurgeons when they encounter unexpected events, uncertainties, or complications while operating on children. Twenty-six pediatric neurosurgeons from 12 countries around the world were interviewed using a semistructured interview guide. The grounded theory method of data collection and analysis was used. Analysis involved line-by-line coding and was inductive, with codes and categories emerging from participants' narratives. When asked to discuss the strategies they used to make intraoperative decisions, neurosurgeons reported three distinct approaches that formed a philosophy of practice. This included the theme of professional practice-with the subthemes of preparing for uncertainty, doing no harm, being creative and adaptive, being systematic, and working on teams. The second theme pertained to patient and caregiver practices-with the subthemes of shared decision-making and seeing the whole patient. The third theme involved surgeon practice-with the subthemes of cultivating self-awareness and learning from experience. Pediatric neurosurgeons have a structured, diverse, and well-thought-out analytical philosophy and practice regarding intraoperative decision-making that encompasses a range of approaches including the following: doing no harm, cultivating self-awareness, and seeing the whole patient; and concrete practices such as preparing in advance for uncertainty, working on teams, and learning from experience. These philosophies and practices can be structured and codified in order to teach residents how to develop intraoperative judgment techniques.


Feasibility and repeatability of optical coherence tomography measurements of pre-stent thrombus burden in patients with STEMI treated with primary PCI.
Intracoronary thrombus is disrupted by stent deployment and confounded by the development of intrastent plaque prolapse. This study aims at investigating the feasibility and repeatability of thrombus quantification prior to stent implantation using optical coherence tomography (OCT) in ST-segment elevation myocardial infarction (STEMI) patients. Patients were enrolled in an OCT substudy of the TOTAL trial (a randomized trial of routine aspiration ThrOmbecTomy with PCI vs. PCI ALone in patients with STEMI undergoing primary PCI) of aspiration thrombectomy or percutaneous coronary intervention (PCI) alone in primary PCI (PPCI) of STEMI. Using OCT, thrombus burden (TB) and other measures of pre- and post-stent atherothrombus were analysed over the arterial segment defined by the final stent length. Feasibility was 86.2% (25/29 patients) for both pre- and post-stent OCT imaging. Altogether, 8111 OCT cross-sections were analysed. In Bland-Altman analyses of inter-observer variation (n = 25), the mean pre-stent TB was 8.76% for Observer 1 and 8.97% for Observer 2 (limits of agreement -2.6 to 2.2%). In Bland-Altman analyses of intra-observer variation (n = 15), the mean pre-stent TB was 8.06% for the first and 7.35% for the second round of analysis by Observer 1 (limits of agreement -1.72 to 3.15%). There was a good correlation between pre-stent TB and pre-stent quadrants with thrombus/mm (r = 0.97), but only modest correlation between pre-stent TB and post-stent atherothrombotic burden (ATB; r = 0.54). Measurement of pre-stent TB by OCT during the PPCI of STEMI is feasible and highly repeatable. Pre-stent TB is only modestly correlated with post-stent ATB, which indicates that pre-stent measurements might be of additional value when assessing the TB in STEMI.


Analysis of Plasmodium falciparum Rh2b deletion polymorphism across different transmission areas.
Despite significant progress in controlling malaria, the disease remains a global health burden. The intricate interactions the parasite Plasmodium falciparum has with its host allows it to grow and multiply in human erythrocytes. The mechanism by which P. falciparum merozoites invade human erythrocytes is complex, involving merozoite proteins as well as erythrocyte surface proteins. Members of the P. falciparum reticulocyte binding-like protein homolog (PfRh) family of proteins play a pivotal role in merozoite invasion and hence are important targets of immune responses. Domains within the PfRh2b protein have been implicated in its ability to stimulate natural protective antibodies in patients. More specifically, a 0.58 kbp deletion, at the C-terminus has been reported in high frequencies in Senegalese and Southeast Asian parasite populations, suggesting a possible role in immune evasion. We analysed 1218 P. falciparum clinical isolates, and the results show that this deletion is present in Ghanaian parasite populations (48.5% of all isolates), with Kintampo (hyper-endemic, 53.2%), followed by Accra (Hypo-endemic, 50.3%), Cape Coast (meso-endemic, 47.9%) and Sogakope (meso-endemic, 43.15%). Further analysis of parasite genomes stored in the MalariaGEN database revealed that the deletion variant was common across transmission areas globally, with an overall frequency of about 27.1%. Interestingly, some parasite isolates possessed mixed PfRh2b deletion and full-length alleles. We further showed that levels of antibodies to the domain of PfRh2 protein were similar to antibody levels of PfRh5, indicating it is less recognized by the immune system.


Metal-free phosphonation of heteroarene N-oxides with trialkyl phosphite at room temperature.
A new protocol is described for the conversion of heteroarene N-oxides to heteroarylphosphonates through in situ activation with bromotrichloromethane. The N-oxides of isoquinoline, quinoline, quinoxaline and 1,10-phenanthroline were fast transformed into the corresponding heteroarylphosphonates in up to 92% yield under mild conditions in the absence of solvent and metal catalysts. The good functional group tolerance, low cost, feasibility of scale up, and wide availability of reagents make this method a prominent complement to the Hirao coupling.


Trauma in silico: Individual-specific mathematical models and virtual clinical populations.
Trauma-induced critical illness is driven by acute inflammation, and elevated systemic interleukin-6 (IL-6) after trauma is a biomarker of adverse outcomes. We constructed a multicompartment, ordinary differential equation model that represents a virtual trauma patient. Individual-specific variants of this model reproduced both systemic inflammation and outcomes of 33 blunt trauma survivors, from which a cohort of 10,000 virtual trauma patients was generated. Model-predicted length of stay in the intensive care unit, degree of multiple organ dysfunction, and IL-6 area under the curve as a function of injury severity were in concordance with the results from a validation cohort of 147 blunt trauma patients. In a subcohort of 98 trauma patients, those with high-IL-6 single-nucleotide polymorphisms (SNPs) exhibited higher plasma IL-6 levels than those with low IL-6 SNPs, matching model predictions. Although IL-6 could drive mortality in individual virtual patients, simulated outcomes in the overall cohort were independent of the propensity to produce IL-6, a prediction verified in the 98-patient subcohort. In silico randomized clinical trials suggested a small survival benefit of IL-6 inhibition, little benefit of IL-1β inhibition, and worse survival after tumor necrosis factor-α inhibition. This study demonstrates the limitations of extrapolating from reductionist mechanisms to outcomes in individuals and populations and demonstrates the use of mechanistic simulation in complex diseases.


Application of Graph Theory to Assess Static and Dynamic Brain Connectivity: Approaches for Building Brain Graphs.
Human brain connectivity is complex. Graph theory based analysis has become a powerful and popular approach for analyzing brain imaging data, largely because of its potential to quantitatively illuminate the networks, the static architecture in structure and function, the organization of dynamic behavior over time, and disease related brain changes. The first step in creating brain graphs is to define the nodes and edges connecting them. We review a number of approaches for defining brain nodes including fixed versus data-driven nodes. Expanding the narrow view of most studies which focus on static and/or single modality brain connectivity, we also survey advanced approaches and their performances in building dynamic and multi-modal brain graphs. We show results from both simulated and real data from healthy controls and patients with mental illnesse. We outline the advantages and challenges of these various techniques. By summarizing and inspecting recent studies which analyzed brain imaging data based on graph theory, this article provides a guide for developing new powerful tools to explore complex brain networks.


The effect of development on the direction of evolution: toward a twenty-first century consensus.
One of the most important questions in evolutionary biology is: what orients the evolutionary process? That is, what causes evolution to proceed toward certain developmental trajectories, and hence phenotypes, rather than others? In particular, there has been prolonged controversy over whether the direction of evolution is determined solely by external factors or whether the nature of the ontogenetic process, and the ways in which it can be altered by mutations in developmental genes, may also play a major role. Here, I examine this issue, concentrating on the following: the possible evolutionary orienting role of "developmental bias;" the question of whether selection can and/or will break bias; the extent to which bias is already incorporated in quantitative genetic studies; and ways of approaching the possible role of bias in the origin of evolutionary novelties. Finally, I suggest that developmental bias may provide a focal point for the coming together of conceptual and practical approaches to evo-devo.


Pursuing different 'TRADDes': TRADD signaling induced by TNF-receptor 1 and the Epstein-Barr virus oncoprotein LMP1.
The pro-apoptotic tumor necrosis factor (TNF)-receptor 1-associated death domain protein (TRADD) was initially identified as the central signaling adapter molecule of TNF-receptor 1 (TNFR1). Upon stimulation with the pro-inflammatory cytokine TNFalpha, TRADD is recruited to the activated TNFR1 by direct interaction between the death domains of both molecules. TRADD mediates TNFR1 activation of NF-kappaB and c-Jun N-terminal kinase (JNK), as well as caspase-dependent apoptosis. Surprisingly, TRADD is also recruited by latent membrane protein 1 (LMP1), the major oncoprotein of the human Epstein-Barr tumor virus. By mimicking a constitutively active receptor, LMP1 is essential for B-cell transformation by the virus, activating NF-kappaB, phosphatidylinositol 3-kinase, JAK/STAT and mitogen-activated protein kinase signaling. In contrast to TNFR1, LMP1's interaction with TRADD is independent of a functional death domain. The unique structure of the LMP1-TRADD complex dictates an unusual type of TRADD-dependent NF-kappaB signaling and subverts TRADD's potential to induce apoptosis. This article provides an overview of TNFR1 and LMP1 signal transduction with a focus on TRADD's functions in apoptotic and transforming signaling, incorporating recent results from TRADD RNAi and knockout studies.


Effectiveness of a rural longitudinal integrated clerkship in preparing medical students for internship.
We interviewed graduates from the first two cohorts of a postgraduate medical program that had a senior year longitudinal integrated clerkship (LIC) in a practice setting in rural New South Wales, Australia to determine how well their training prepared them to be junior doctors (3-4 years after graduation), and what aspects of that training they thought were particularly useful. In-depth interviews. Fourteen junior doctors were interviewed. Participants reported feeling well prepared in ability to develop close relationships with clinical supervisors, good clinical and procedural skills, ability to work autonomously and work in teams, knowledge of health systems, ability to ensure self-care, and professionalism. Consensus view was that a rural placement was an excellent way to learn medicine for a variety of reasons including relationships with clinicians, less competition for access to patients, and opportunities to extend their clinical skills and act up to intern level. The advantages we found in the training these junior doctors received which prepared them well for internship were integral both to the longitudinal, unstructured placement, and to the fact that it was carried out in a rural area. The two aspects of these placements appear to act synergistically, reinforcing the learning experience.


Differential behavioural and neurochemical effects of para-methoxyamphetamine and 3,4-methylenedioxymethamphetamine in the rat.
1. This study was prompted by recent deaths that have occurred after recreational administration of the substituted amphetamine para-methoxyamphetamine (PMA). Because relatively little is known regarding its mechanism(s) of action, its effects on physiological, behavioural and neurochemical parameters were compared with the well known effects of 3,4-methylenedioxymethamphetamine (MDMA). 2. Equivalent doses of PMA (5-20 mg/kg) produced greater hypothermia than MDMA at an ambient temperature of 20 degrees C. At 30 degrees C, PMA continued to evoke hypothermia except the highest dose where hyperthermia ensued. MDMA altered body temperature only at the highest dose where hyperthermia also resulted. 3. At both 20 and 30 degrees C, MDMA stimulated locomotor activity whereas PMA had modest effects and then, only at high doses. 4. In vivo chronoamperometry was used to measure the effect of MDMA and PMA on release, and inhibition of uptake, of serotonin (5-HT) and dopamine (DA) in the dorsal striatum of anaesthetised rats. As expected, MDMA evoked release of DA and inhibited uptake of both DA and 5-HT. By contrast, PMA was a relatively weak releasing agent and did not inhibit DA uptake. However, PMA potently inhibited uptake of 5-HT. 5. Taken together these data suggest that the acute adverse effects of PMA are more likely to be associated with alterations in serotonergic rather than dopaminergic neurotransmission.


Understanding Positive Youth Development in Sport Through the Voices of Indigenous Youth.
This study aimed to understand how positive youth development through sport and physical activity is understood and experienced by urban indigenous youth. Research in positive youth development claims that structured physical activities are critical for development. The 5 Cs (i.e., confidence, competence, character, connection, caring) are a gold standard when discussing positive outcomes and are important characteristics for youth to possess to attain the sixth C-contribution. Indigenous leaders recognize the value of sport for indigenous children and youth. Recent works in sport psychology have called for research to understand youth sport and physical activity from diverse cultural perspectives. The current study used a community-based participatory framework, and 43 youth from across 3 Canadian settings were recruited. Talking circles were used to collect the data. Results point to some unique understandings of the 5 Cs by the participants-namely, the inclusion of the self within each C.


Emotion, olfaction, and the human amygdala: amygdala activation during aversive olfactory stimulation.
Electrophysiologic and lesion studies of animals increasingly implicate the amygdala in aspects of emotional processing. Yet, the functions of the human amygdala remain poorly understood. To examine the contributions of the amygdala and other limbic and paralimbic regions to emotional processing, we exposed healthy subjects to aversive olfactory stimuli while measuring regional cerebral blood flow (rCBF) with positron emission tomography. Exposure to a highly aversive odorant produced strong rCBF increases in both amygdalae and in the left orbitofrontal cortex. Exposure to less aversive odorants produced rCBF increases in the orbitofrontal cortex but not in the amygdala. Change of rCBF within the left amygdala and the left OFC was highly intercorrelated, indicating a strong functional interaction between these brain regions. Furthermore, the activity within the left amygdala was associated significantly with subjective ratings of perceived aversiveness. These findings provide evidence that the human amygdala participates in the hedonic or emotional processing of olfactory stimuli.


Systematic quality assurance of the BSD2000-3D MR-compatible hyperthermia applicator performance using MR temperature imaging.
Radiofrequency (RF) mild hyperthermia (40 °C-44 °C for 60 minutes) is an effective adjuvant treatment for several types of cancer. To ensure treatment efficacy, quality assurance (QA) is necessary. This study presents the first systematic 3D characterisation of the heating performance of the commonly used Pyrexar BSD2000-3D MR-compatible hyperthermia applicator using magnetic resonance temperature imaging (MRTI). A reproducibly positioned phantom was heated with a power of 1000 watts during the 12.4 min needed to measure eight temperature distributions using MRTI. The target heating location was systematically varied between experiments. We analysed focus shape characteristics, steering accuracy, focus deformation due to steering, presence of off-target heating and reproducibility. The mean maximum temperature increase was 5.9 ± 0.4 °C. The mean full width half maximum (FWHM) was 14.4 ± 0.5 cm in the XY plane and 24.5 ± 0.8 cm in Z-direction. The mean steering error was 0.4 ± 0.2 cm. The focus shape slightly varied between experiments, depending on steering distance in Y-direction. Off-target heating was not detected. Reproducibility of the focus amplitude and shape was determined by comparing the mean deviation from the mean temperature in the central slice was 0.3 ± 0.2 °C. The Pyrexar BSD2000-3D MR-compatible applicator provides robust and reproducible heating. The upper boundary of the 95% confidence interval of the spatial steering accuracy is 0.9 cm, i.e. sufficient to fulfil the criterion of ≤0.2 °C temperature variation due to positioning errors as defined by Canters et al.


Electromechanical coupling between the atria and mitral valve.
Anterior leaflet (AL) stiffening during isovolumic contraction (IVC) may aid mitral valve closure. We tested the hypothesis that AL stiffening requires atrial depolarization. Ten sheep had radioopaque-marker arrays implanted in the left ventricle, mitral annulus, AL, and papillary muscle tips. Four-dimensional marker coordinates (x, y, z, and t) were obtained from biplane videofluoroscopy at baseline (control, CTRL) and during basal interventricular-septal pacing (no atrial contraction, NAC; 110-117 beats/min) to generate ventricular depolarization not preceded by atrial depolarization. Circumferential and radial stiffness values, reflecting force generation in three leaflet regions (annular, belly, and free-edge), were obtained from finite-element analysis of AL displacements in response to transleaflet pressure changes during both IVC and isovolumic relaxation (IVR). In CTRL, IVC circumferential and radial stiffness was 46 ± 6% greater than IVR stiffness in all regions (P < 0.001). In NAC, AL annular IVC stiffness decreased by 25% (P = 0.004) in the circumferential and 31% (P = 0.005) in the radial directions relative to CTRL, without affecting edge stiffness. Thus AL annular stiffening during IVC was abolished when atrial depolarization did not precede ventricular systole, in support of the hypothesis. The likely mechanism underlying AL annular stiffening during IVC is contraction of cardiac muscle that extends into the leaflet and requires atrial excitation. The AL edge has no cardiac muscle, and thus IVC AL edge stiffness was not affected by loss of atrial depolarization. These findings suggest one reason why heart block, atrial dysrhythmias, or ventricular pacing may be accompanied by mitral regurgitation or may worsen regurgitation when already present.


Erythroid differentiation in CGL cells from a patient with blast crisis.
A 60-year-old patient with Ph1 + ve CGL presented with blast crisis. The leukaemic blast cells resembled erythroblasts and had 51 chromosomes with two Ph1. Cells obtained from peripheral blood, marrow and a pleural effusion were cultured under a variety of conditions. After 2-3 weeks in culture, the model 51-chromosome line persisted but many of the cells displayed erythroid morphology and differentiated to resemble mature normoblasts, strongly positive on o-tolidine +ve staining. Haemoglobin analysis by starch gel and globin synthesis studies demonstrated only fetal haemoglobin (HbF) synthesis in the cultured cells whilst the patient's reticulocytes synthesized very little HbF. Restriction enzyme mapping of DNA from the cultured cells showed that beta-globin genes were still present in these cells even though they were not expressed.


Selection of Native Tree Species for Subtropical Forest Restoration in Southwest China.
The use of native species in forest restoration has been increasingly recognized as an effective means of restoring ecosystem functions and biodiversity to degraded areas across the world. However, successful selection of species adapted to local conditions requires specific knowledge which is often lacking, especially in developing countries. In order to scale up forest restoration, experimental data on the responses of native species to propagation and restoration treatments across a range of local conditions are required. In this study, the restoration potential of 34 native tree species was evaluated based on nursery research and field planting experiments at a highly degraded site in a subtropical area of southwest China. We examined species performance in terms of germination rates as well as survival rates and growth over 2 years after planting. Of the 34 species examined, 25 had a germination percentage greater than 50%. Survivorship ranged from 0 to 97% across species and was greater than 50% for 20 species. Mean monthly growth increments varied between species. Pioneer species performed well, and 14 mid- and late-successional species performed reasonably well to very well in this study. However, the remaining 16 mid- and late-successional species performed poorly. These results indicate that carefully selected mid- and late-successional species can be effectively incorporated into mixed species plantings. This data can be used to inform restoration planning, helping to identify suitable species and so enhance the biodiversity and resilience of restored forests.


Endovascular detachable balloon embolization therapy of cavernous carotid artery aneurysms: results in 87 cases.
Interventional neurovascular techniques for treating patients with intracranial aneurysms are now being performed in selected cases. In certain anatomical locations that are difficult to reach surgically, such as the cavernous portion of the internal carotid artery (ICA), this technique may be especially useful. The procedure is performed from a transfemoral approach, using local anesthesia, thus permitting continuous neurological monitoring. Between 1981 and 1989, 87 patients diagnosed as having an intracavernous aneurysm were treated with endovascular detachable balloon embolization techniques. The patients ranged in age from 11 to 84 years. The presenting symptom was mass effect in 69 cases (79.3%), rupture of a preexisting aneurysm resulting in a carotid-cavernous sinus fistula in eight cases (9.2%), trauma resulting in a cavernous pseudoaneurysm in seven cases (8.0%), and hemorrhage in three cases (3.4%). Therapeutic occlusion of the ICA across or just proximal to the aneurysm neck was performed in 68 patients (78.2%). Since 1984, with the development of a permanent solidifying agent (2-hydroxyethyl methacrylate) to fill the balloon, it is now feasible in some cases to guide the balloon directly into the aneurysm and preserve the parent artery; this was achieved in 19 cases (22%). Follow-up examination has demonstrated complete thrombosis with partial or total alleviation of symptoms in all patients with therapeutic occlusion of the parent vessel. Of the 19 patients with preservation of the parent artery, follow-up studies have demonstrated total exclusion in 12 cases (63%) and subtotal occlusion of greater than 85% in seven cases (37%), with clinical improvement in all cases. Complications from therapy included transient cerebral ischemia during or after therapy requiring volume expansion in seven cases, embolic symptoms requiring antiplatelet medication in two cases, and stroke in four cases; there were no deaths. Detachable balloon embolization therapy, particularly for large and giant symptomatic aneurysms of the cavernous ICA, can be an effective mode of treatment.


Compact two-mode (de)multiplexer based on symmetric Y-junction and multimode interference waveguides.
A compact two-mode (de)multiplexer [(DE)MUX] based on symmetric Y-junction and multimode interference (MMI) waveguides was designed by 3D beam propagation method (BPM). The phase evolution in the structure was discussed in detail. Simulations show that the optical bandwidth is as large as 100 nm (1500 nm ~1600 nm). The two-mode (DE)MUX is very compact compared with the other kind of mode (DE)MUX. The length of the structure is only 48.8 μm. Simulation also shows the fabrication tolerance is as large as ± 75 nm.


Quantitative quality-control metrics for in vivo oximetry in small vessels by visible light optical coherence tomography angiography.
Biological functions rely on local microvasculature to deliver oxygen and nutrients and carry away metabolic waste. Alterations to local oxygenation levels are manifested in diseases including cancer, diabetes mellitus, etc. The ability to quantify oxygen saturation (sO2) within microvasculature in vivo to assess local tissue oxygenation and metabolic function is highly sought after. Visible light optical coherence tomography (vis-OCT) angiography has shown promise in reaching this goal. However, achieving reliable measurements in small vessels can be challenging due to the reduced contrast and requires data averaging to improve the spectral data quality. Therefore, a method for quality-control of the vis-OCT data from small vessels becomes essential to reject unreliable readings. In this work, we present a quantitative metrics to evaluate the spectral data for a reliable measurement of sO2, including angiography signal to noise ratio (SNR), spectral anomaly detection and discard, and theory-experiment correlation analysis. The thresholds for each quantity can be flexibly adjusted according to different applications and system performance. We used these metrics to measure sO2 of C57BL/6J mouse lower extremity microvasculature and validated it by introducing hyperoxia for expected sO2 changes. After validation, we applied this protocol on C57BL/6J mouse ear microvasculature to conduct in vivo small blood vessel OCT oximetry. This work seeks to standardize the data processing method for in vivo oximetry in small vessels by vis-OCT.


Cigarette Smoking Progression Among Young Adults Diagnosed With ADHD in Childhood: A 16-year Longitudinal Study of Children With and Without ADHD.
Children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for smoking cigarettes, but there is little longitudinal research on the array of smoking characteristics known to be prognostic of long-term smoking outcomes into adulthood. These variables were studied into early adulthood in a multisite sample diagnosed with ADHD combined type at ages 7-9.9 and followed prospectively alongside an age- and sex-matched local normative comparison group (LNCG). Cigarette smoking quantity, quit attempts, dependence, and other characteristics were assessed in the longitudinal Multimodal Treatment Study of Children with ADHD (MTA) eight times to a mean age of 24.9 years: ADHD n = 469; LNCG n = 240. In adulthood, the ADHD group had higher rates of daily cigarette smoking, one or more quit attempts, shorter time to first cigarette of the day, and more severe withdrawal than the LNCG. The ADHD group did not appear to have better smoking cessation rates despite a higher proportion quitting at least once. Smoking quantity and nicotine dependence did not differ between groups. The ADHD group reported younger daily smoking onset and faster progression from smoking initiation to daily smoking across assessments. Finally, ADHD symptom severity in later adolescence and adulthood was associated with higher risk for daily smoking across assessments in the ADHD sample. This study shows that ADHD-related smoking risk begins at a young age, progresses rapidly, and becomes resistant to cessation attempts by adulthood. Prevention efforts should acknowledge the speed of uptake; treatments should target the higher relapse risk in this vulnerable population. Although childhood ADHD predicts later smoking, longitudinal studies of this population have yet to fully characterize smoking behaviors into adulthood that are known to be prognostic of long-term smoking outcome. The current study demonstrates earlier and faster progression to daily smoking among those with a childhood ADHD diagnosis, as well as greater risk for failed quit attempts. Prevention efforts should address speed of smoking uptake, while treatments are needed that address smoking relapse risk. The current study also demonstrates ADHD symptom severity over development increases daily smoking risk, implicating the need for continuous ADHD symptom management.


Measurement of cytokine release at the single cell level using the ELISPOT assay.
The enzyme-linked immunospot (ELISPOT) assay took its design concept from traditional ELISA techniques and evolved over the years from a method for detecting antibodies secreted from B cells to a method for detecting cytokines or other soluble mediators secreted from a variety of different cell types. The ELISPOT assay allows the quantitative measurement of frequency of cytokine secreting cells at the single cell level directly ex vivo without elaborate in vitro expansion or manipulation of cell populations. The function of cells can be inferred from the pattern of cytokines secreted by cells in response to diverse antigenic stimuli and thus the ELISPOT assay has become a powerful method for monitoring immune responses in health and disease. The ELISPOT assay like the ELISA assay is relatively easy to perform and it has the promise of robustness, reliability, and reproducibility of performance for use as a diagnostic tool. The history, applications, validation process, and future challenges of the ELISPOT assay are discussed in this chapter.


Digital operation of an ytterbium-doped two-mode fiber interferometric optical intensity switch.
Digital operation of an all-optical intensity switch is demonstrated in a two-mode interferometer constructed from ytterbium-doped fiber. We clamp the resonantly enhanced phase shift responsible for the switching by allowing the fiber to lase, resulting in a bistable, digital response. The degree of phase shift at the clamping point can be controlled by adjustment of the laser threshold, and for complete switching (phase shift of pi) the power length product PL(pi) was estimated to be 1.3 mW m . Isolation of 11 dB was observed, with switching speed limited by the relaxation time of ytterbium.


Honey supplementation in spontaneously hypertensive rats elicits antihypertensive effect via amelioration of renal oxidative stress.
Oxidative stress is implicated in the pathogenesis and/or maintenance of elevated blood pressure in hypertension. This study investigated the effect of honey on elevated systolic blood pressure (SBP) in spontaneously hypertensive rats (SHR). It also evaluated the effect of honey on the amelioration of oxidative stress in the kidney of SHR as a possible mechanism of its antihypertensive effect. SHR and Wistar Kyoto (WKY) rats were randomly divided into 2 groups and administered distilled water or honey by oral gavage once daily for 12 weeks. The control SHR had significantly higher SBP and renal malondialdehyde (MDA) levels than did control WKY. The mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione S-transferase (GST) were significantly downregulated while total antioxidant status (TAS) and activities of GST and catalase (CAT) were higher in the kidney of control SHR. Honey supplementation significantly reduced SBP and MDA levels in SHR. Honey significantly reduced the activities of GST and CAT while it moderately but insignificantly upregulated the Nrf2 mRNA expression level in the kidney of SHR. These results indicate that Nrf2 expression is impaired in the kidney of SHR. Honey supplementation considerably reduces elevated SBP via amelioration of oxidative stress in the kidney of SHR.


Students' perceptions of their learning experiences: A repeat regional survey of healthcare students.
Student experience is an international concern and recent research has focused on initiatives to improve students' learning experiences and ultimately reduce attrition levels. To determine similarities and differences between students' perceptions of their learning experiences between 2011 and 2015 in relation to campus-based learning, placement-based learning and personal circumstances. A repeat online survey in 2011 and 2015; using a questionnaire developed from thematic analysis of narrative interviews with a subsample of the target population. Nine universities in the North West of England. A total of 1080 students completed the survey in 2011 and 1983 students in 2015 from a target population of all students studying on commissioned pre-registration healthcare education programmes. An online survey was made available to all undergraduate students studying on Health Education funded programmes within the region and survey respondents were invited to give demographic information and rate their agreement to statements on four-point Likert-type responses. Responses to a repeat survey of healthcare studying in the North West of England in 2015 were strikingly similar overall to those of an original 2011 survey. Although the students were positive overall about their experiences, a number were dissatisfied with some aspects of their experiences - particularly in relation to initial support on campus and whilst studying on placement. Four years on from the original survey, despite a considerable investment in improving students' experiences across the region, there appears to be little change in students' perceptions of their learning experiences CONCLUSION: In the short-term monitoring of student experience needs to be continued; and links to attrition (potential or actual) noted and acted upon. However, given that attrition from these courses has been a long-term problem and the complexity of its resolution a recurrent finding in the literature; new ways of framing and resolving the problem need to be considered.


Weight change trajectory in women with breast cancer receiving chemotherapy and the effect of different regimens.
To investigate the trajectory of weight change in Taiwanese women with breast cancer after starting chemotherapy and the impact of chemotherapy regimens on weight change while controlling for age, menopausal status, body mass index, lymph node involvement and changes in habits of dietary fat intake and exercise. Weight gain after adjuvant chemotherapy in women with breast cancer has negative impact on health outcomes. Longitudinal, clinical observational study. Weights were repeatedly measured in 147 women with breast cancer stages I-III. Hierarchical linear modelling was used to analyse these longitudinal data. The overall pattern of weight change was a cubic form beginning with a mean of 56·9 kg before chemotherapy. It gradually increased to 59·4 kg at 8·5 months after the first chemotherapy followed by a decrease to 58·5 kg at 21·5 months. During the last 2·5 months, weight increased slightly and never returned to the initial level. After controlling for confounders, steeper weight change was observed among women receiving cyclophosphamide, methotrexate and fluorouracil. The highest weight gain in the cyclophosphamide, methotrexate and fluorouracil group was 2·9 kg (5%) vs. 0·9 kg (1%) in the anthracycline-based group. The trajectory of body weight change within two years after chemotherapy shows a trend of gradual ascent, followed by a small decline and a slight increase in the last 2·5 months. The chemotherapy regimen can predict the trend after controlling for other confounders; women on cyclophosphamide, methotrexate and fluorouracil have a steeper weight change. Nurses can inform women with breast cancer about the expected changes in body weight after chemotherapy to reduce their uncertainty. Future studies on effective interventions to minimise chemotherapy-induced weight gain are needed.


Ethanol extract of Piper longum L. attenuates gentamicin-induced hair cell loss in neonatal cochlea cultures.
Piper longum L. (PL), also as known as long pepper, a well-known spice and traditional medicine in Asia and Pacific islands, has been reported to exhibit wide spectrum activity including antioxidant activity. However, little information is available on its protective effect on gentamicin (GM) induced ototoxicity which is commonly regarded as being mediated by reactive oxygen species and reactive nitrogen species. This study was undertaken to investigate the protective effect of PL ethanol extract on gentamicin-induced hair cell loss in neonatal cochlea cultures. Cochlea cultures from postnatal day 2-3 mice were used for analysis of the protective effects of PL against gentamicin-induced hair cell loss by phalloidin staining. E. coil cultures were used to determine whether PL interferes with the antibiotic activity of GM. Nitric oxide (NO)-scavenging activity of PL was also measured in vitro. GM induced significant dose-dependent hair cell loss in cochlea cultures. However, without interfering with the antibiotic activity of GM, PL showed a significant and concentration-dependent protective effect against GM-induced hair cell loss, and hair cells retained their stereocilia well. In addition, PL expressed direct scavenging activity toward NO radical liberated within solution of sodium nitroprusside. These findings demonstrate the protective effect of PL on GM-induced hair cell loss in neonatal cochlea cultures, and suggest that it might be of therapeutic benefit for treatment of GM-induced ototoxicity.


Vascular endothelial growth factor, lipoporotein-associated phospholipase A2, sP-selectin and antiphospholipid antibodies, biological markers with prognostic value in pulmonary hypertension associated with chronic obstructive pulmonary disease and systemic lupus erithematosus.
Pulmonary arterial hypertension (PH) is a progressive disease with a poor prognosis that ultimately leads to right ventricular failure and death. The pathogenesis of severe PH seems to be related to inflammatory responses and coagulation disturbances. Many diseases can develop PH in their course, thus aggravating their outcome. The objective was to investigate the values of vascular endothelial growth factor (VEGF), sP-selectin, lipoprotein-associated phospholipase A2 (PLA2-LDL), antiphospholipid antibodies (APLA) and their relation with PH, in systemic lupus erythematosus (SLE) and chronic obstructive pulmonary disease (COPD), two conditions in which the occurrence of PH is frequent. Prospective clinical study. A University Department of Internal Medicine, a National Institute of Research. 30 SLE patients (15 patients without PH (group I) and 15 patients with PH group II)), 30 patients with COPD (15 patients without PH (group III) and 15 patients with PH (group IV)) and 10 healthy controls, selected by clinical, immunological, echocardiographical criteria and pulmonary functional tests. VEGF, sP-selectin and PLA2-LDL level in plasma and presence of antiphospholipids antibodies (lupus anticoagulant, anticardiolipin and anti beta2 GPI) in plasma. - In patients with PH, the values of VEGF were significantly increased [group II (1023.1) and IV (904.3)] compared with group I (744.2), III (356.4), and controls (330.3). The values of sP-selectin in group II (9.7), and IV (10.4) were also increased compared with controls (6). APLA were present in all patients in group II (100%), and in 8 patients in group IV (53%), while in the other groups the frequency was low (33% group I and 13% group III). PLA2-LDL activity was higher in group II (429.1) and group IV (394.5) than in group I (317.8), group III (343.2) and controls (256.3). PH is a severe complication in COPD and SLE. The increased values of VEGF, PLA2-LDL and P-selectin in patients with long standing PH are related to severe endothelial dysfunction and may have prognostic values. APLA may have pathogenic value in SLE patients with PH. APLA are possibly implicated in the pathogenesis of PH in these diseases. VEGF, APLA and sP-selectin may constitute new therapeutic targets for PH.


A review of evidence-based traffic engineering measures designed to reduce pedestrian-motor vehicle crashes.
We provide a brief critical review and assessment of engineering modifications to the built environment that can reduce the risk of pedestrian injuries. In our review, we used the Transportation Research Information Services database to conduct a search for studies on engineering countermeasures documented in the scientific literature. We classified countermeasures into 3 categories-speed control, separation of pedestrians from vehicles, and measures that increase the visibility and conspicuity of pedestrians. We determined the measures and settings with the greatest potential for crash prevention. Our review, which emphasized inclusion of studies with adequate methodological designs, showed that modification of the built environment can substantially reduce the risk of pedestrian-vehicle crashes.


Multi-View Broad Learning System for Primate Oculomotor Decision Decoding.
Multi-view learning improves the learning performance by utilizing multi-view data: data collected from multiple sources, or feature sets extracted from the same data source. This approach is suitable for primate brain state decoding using cortical neural signals. This is because the complementary components of simultaneously recorded neural signals, local field potentials (LFPs) and action potentials (spikes), can be treated as two views. In this paper, we extended broad learning system (BLS), a recently proposed wide neural network architecture, from single-view learning to multi-view learning, and validated its performance in decoding monkeys' oculomotor decision from medial frontal LFPs and spikes. We demonstrated that medial frontal LFPs and spikes in non-human primate do contain complementary information about the oculomotor decision, and that the proposed multi-view BLS is a more effective approach for decoding the oculomotor decision than several classical and state-of-the-art single-view and multi-view learning approaches.


Absence of lipoprotein lipase in cultured human adipose stromal cells.
To develop a system for studying the regulation of adipose tissue lipoprotein lipase (LPL) in human cells, we isolated cells from the stromalvascular fraction of human adipose tissue and propagated them in tissue culture. These cells were cultured in medium containing fetal bovine, horse, or human sera in the absence or presence of aminoglycoside antibiotics. After the cells had been at confluence for at least 1 week, they were exposed to medium containing insulin, 3-isobutyl-l-methylxanthine (IBMX), and dexamethasone, in an attempt to induce differentiation into cells which produce LPL. Stromal cells in 62 cultures from 20 subjects were monitored for any LPL activity secreted into the culture medium. In addition, cultures were assayed for activity releasable with heparin, and extractable from cell digests in nonionic detergent. Upon reaching confluence, the human adipose tissue stromal cells began to accumulate lipid droplets. However, no consistent LPL activity was measured in the culture medium or after exposure to heparin. Five cultures contained a minimal amount of detergent extractable hydrolytic activity. In contrast, cultures of rat stromal cells not exposed to insulin, IBMX, and dexamethasone, contained assayable LPL in the culture medium (3.3 +/- 1.6 nEq/min/ml) and in the heparin-releasable fraction (1.7 +/- 0.5 nEq/min/10(6)cells). Thus, human adipose tissue stromal cells do not represent a useful system for studying the regulation of LPL. Although these cells accumulate some lipid, the absence of measurable LPL suggests that complete differentiation has not yet occurred.


High gain, wide field of view concentrator for optical communications.
The field of view and gain of optical concentrators used within free space optical communications systems are constrained by conservation of etendue. In this Letter, consideration of the processes in a fluorescent concentrator leads to a simple design strategy for these concentrators for this application. Significantly, because fluorescent concentrators do not conserve etendue, this can lead to concentrators with wider fields of view and higher gains. A model of a fluorescent concentrator containing a quantum dot material suggests that it could have a gain 50 times higher than an etendue conserving concentrator with the same field of view.


Acidification and γ-aminobutyric acid independently alter kairomone-induced behaviour.
Exposure to high pCO2 or low pH alters sensation and behaviour in many marine animals. We show that crab larvae lose their ability to detect and/or process predator kairomones after exposure to low pH over a time scale relevant to diel pH cycles in coastal environments. Previous work suggests that acidification affects sensation and behaviour through altered neural function, specifically the action of γ-aminobutyric acid (GABA), because a GABA antagonist, gabazine, restores the original behaviour. Here, however, gabazine resulted in a loss of kairomone detection/processing, regardless of pH. Our results also suggest that GABAergic signalling is necessary for kairomone identification in these larvae. Hence, the mechanism for the observed pH effect varies from the original GABA hypothesis. Furthermore, we suggest that this pH effect is adaptive under diel-cycling pH.


A single nucleotide polymorphism in the MDM2 gene: from a molecular and cellular explanation to clinical effect.
In a recent article, a candidate pathway approach was taken to try to identify single nucleotide polymorphisms (SNP) that make up the genetic variation, which underlies the phenotypic variation seen between individuals in their susceptibility to cancer and the progression of their disease. The p53 stress response pathway was chosen given its well-documented importance in tumor suppression. A SNP was found which associates with the attenuation of the p53 pathway and the acceleration of tumor formation in humans and data was presented which describe a molecular mechanism for these phenotypes.


Mining metabolic pathways through gene expression.
An observed metabolic response is the result of the coordinated activation and interaction between multiple genetic pathways. However, the complex structure of metabolism has meant that a compete understanding of which pathways are required to produce an observed metabolic response is not fully understood. In this article, we propose an approach that can identify the genetic pathways which dictate the response of metabolic network to specific experimental conditions. Our approach is a combination of probabilistic models for pathway ranking, clustering and classification. First, we use a non-parametric pathway extraction method to identify the most highly correlated paths through the metabolic network. We then extract the defining structure within these top-ranked pathways using both Markov clustering and classification algorithms. Furthermore, we define detailed node and edge annotations, which enable us to track each pathway, not only with respect to its genetic dependencies, but also allow for an analysis of the interacting reactions, compounds and KEGG sub-networks. We show that our approach identifies biologically meaningful pathways within two microarray expression datasets using entire KEGG metabolic networks. An R package containing a full implementation of our proposed method is currently available from http://www.bic.kyoto-u.ac.jp/pathway/timhancock.


Body mass-to-waist ratio strongly correlates with skeletal muscle volume in children.
We hypothesized that body mass-to-waist ratio is strongly associated with the total-body skeletal muscle volume (SMV) in children. The purpose of the present study was to examine this hypothesis. By using magnetic resonance imaging, total-body SMV (SMVMRI) was determined in 70 boys and 53 girls aged 6 to 12 years. Waist was measured at each of the level of umbilicus (Wumb) and the minimum circumference (Wmin), and the ratio of body mass to each of the two measured values was calculated (BM/Wumb and BM/Wmin, respectively). A single regression analysis was used to examine the relationships between SMVMRI and either BM/Wumb or BM/Wmin. On the basis of the obtained regression equations, SMVMRI was estimated and referred to as SMVBM/Wumb or SMVBM/Wmin. In both boys and girls, SMVMRI was highly correlated to BM/Wumb (r = 0.937 for boys and r = 0.939 for girls, P < 0.0001) and BM/Wmin (r = 0.915 and 0.942, P < 0.0001). R2 and the standard error of estimate for SMVBM/Wumb were 0.878 and 706.2 cm3, respectively, in boys and 0.882 and 825.3 cm3, respectively, in girls, and those for SMVBM/Wmin were 0.837 and 814.0 cm3, respectively, in boys and 0.888 and 804.1 cm3, respectively, in girls. In both boys and girls, there were no significant differences between SMVMRI and either SMVBM/Wumb or SMVBM/Wmin, without systematic errors in Band-Altman plots. There was no significant effect of model on the absolute values of the residuals in both boys and girls. The current results indicate that body mass-to-waist ratio can be a convenient outcome measure for assessing the total-body skeletal muscle volume in children.


Stopping and restarting PrEP and loss to follow-up among PrEP-taking men who have sex with men and transgender women at risk of HIV-1 participating in a prospective cohort study in Kenya.
To assess frequency and predictors of switching between being on and off PrEP and being lost to follow-up (LTFU) among men who have sex with men (MSM) and transgender women (TGW) with access to PrEP services in Sub-Saharan Africa. This was a prospective cohort study of MSM and TGW from coastal Kenya who initiated daily oral PrEP from June 2017 to June 2019. Participants were followed monthly for HIV-1 testing, PrEP refill, risk assessment and risk reduction counselling. Follow-up was censored at the last visit before 30 June 2019, or the last HIV-1-negative visit (for those with HIV-1 seroconversion), whichever occurred first. We estimated transition intensities (TI) and predictors of switching: (i) between being off and on PrEP; and (ii) from either PrEP state and being LTFU (i.e. not returning to the clinic for > 90 days) using a multi-state Markov model. In all, 134 participants starting PrEP were followed for a median of 20.3 months [interquartile range (IQR): 7.7-22.1]. A total of 49 (36.6%) people stopped PrEP 73 times [TI = 0.6/person-year (PY), 95% confidence interval (CI): 0.5-0.7] and, of these, 25 (51.0%) restarted PrEP 38 times (TI = 1.2/PY, 95% CI: 0.9-1.7). In multivariable analysis, stopping PrEP was related to anal sex ≤ 3 months, substance-use disorder and travelling. Restarting PrEP was related to non-Christian or non-Muslim religion and travelling. A total of 54 participants were LTFU: on PrEP (n = 47, TI = 0.3/PY, 95% CI: 0.3-0.5) and off PrEP (n = 7, TI = 0.2/PY, 95% CI: 0.1-0.4). In multivariable analysis, becoming LTFU while on PrEP was associated with secondary education or higher, living in the area for ≤ 1 year, residence outside the immediate clinic area and alcohol-use disorder. Switching between being on and off PrEP or becoming LTFU while on PrEP was frequent among individuals at risk of HIV-1 acquisition. Alternative PrEP options (e.g. event-driven PrEP) may need to be considered for MSM and TGW with PrEP-taking challenges, while improved engagement with care is needed for all MSM and TGW regardless of PrEP regimen.


House dust mites on skin, clothes, and bedding of atopic dermatitis patients.
Atopic dermatitis is a common allergic condition in children, often associated with a positive skin reaction to house dust mite allergens. To determine the presence of house dust mites on the skin, clothes, and bedding of patients with atopic dermatitis. Nineteen patients with atopic dermatitis were examined during a 2-year period. Samples from affected and healthy skin surfaces were obtained with adhesive tape, and dust samples from bedding and clothes were collected with a vacuum cleaner at the start of the study and 3-6 weeks later, and examined for the presence of house dust mites. The findings were compared with those of 21 healthy controls. The most common mite species on skin were Dermatophagoides pteronyssinus and Dermatophagoides farinae, which were found in nine patients and three controls. The patient group showed a significantly larger percentage of samples with mites than did the control group (34.9% and 7.9%, respectively) (P < 0.001), and a significantly larger percentage of individuals with at least one positive sample (84.2% and 14.2%, respectively) (P < 0.0001). No correlation was found between the number of mites on the skin and clothes/bedding of patients, or between patients and controls with regard to the number of mites on the clothes and bedding. Patients with atopic dermatitis showed a higher prevalence of mites on their skin than did healthy individuals, which could be involved in allergic sensitization and disease exacerbation.


Virtual gait training for children with cerebral palsy using the Lokomat gait orthosis.
The Lokomat gait orthosis was developed in the Spinal Cord Injury Center at the University Hospital Balgrist Zurich and provides automatic gait training for patients with neurological gait impairments, such as Cerebral Palsy (CP). Each patient undergoes a task-oriented Lokomat rehabilitation training program via a virtual reality setup. In four virtual scenarios, the patient is able to exercise tasks such as wading through water, playing soccer, overstepping obstacles or training in a street scenario, each task offering varying levels of difficulty. Patients provided positive feedback in reference to the utilized haptic method, specifically addressing the sufficient degree of realism. In a single case study, we verified the task difficulty.


The relationship between scoring systems and cytokine levels in neonatal sepsis.
In this study, 20 newborn infants with sepsis were evaluated and scored according to the criteria of Töllner and Rodwell and associates. Leukocyte count, serum C-reactive protein (CRP), tumour necrosis factor (TNF)-alpha and interluekin (IL)-6 levels were also studied in all infants. The aim of this study was to determine if a relationship exists between the scoring systems and the cytokine levels in neonatal sepsis. The infants were divided into two groups as blood culture positive and negative. Blood culture was positive in 12 (60%) infants. We did not find a significant difference for leukocyte count, cytokine levels and scoring systems between the blood culture positive and negative groups. However, we found a positive correlation between the scoring systems and serum CRP and TNF-alpha levels (P < 0.05), but no correlation with IL-6. In conclusion, we suggest that only serum CRP level without performing scoring and studying serum TNF-alpha concentration may be used in early diagnosis of neonatal sepsis. However, further studies are necessary to define this because of the small sample size of our pilot study.


Foraging profiles of sympatric lowland gorillas and chimpanzees in the Lopé Reserve, Gabon.
Comparison of the diets of sympatric gorillas and chimpanzees allows an analysis of niche separation between these two closely related species. Qualitatively, their diets are similar, being dominated by an equally diverse array of fruit species complemented with vegetative plant parts, seeds and insects. Gorillas eat more vegetative plant parts than do chimpanzees, but niche separation is most obvious in periods of fruit scarcity when the two species show different strategies that reduce competition for food. Their abilities to overcome mechanical and physical plant defences appear to differ, as gorillas are able to subsist entirely on abundant vegetative foods. Chimpanzees show social adjustment, foraging alone or in small groups, to reduce intra-specific competition for scarce fruit resources. Thus it seems that subtle physiological differences have far-reaching repercussions, defining potential evolutionary pathways for social organization and allowing sufficient niche separation between species.


Low-intensity blue-enriched white light (750 lux) and standard bright light (10,000 lux) are equally effective in treating SAD. A randomized controlled study.
Photoreceptor cells containing melanopsin play a role in the phase-shifting effects of short-wavelength light. In a previous study, we compared the standard light treatment (SLT) of SAD with treatment using short-wavelength blue-enriched white light (BLT). Both treatments used the same illuminance (10,000 lux) and were equally highly effective. It is still possible, however, that neither the newly-discovered photoreceptor cells, nor the biological clock play a major role in the therapeutic effects of light on SAD. Alternatively, these effects may at least be partly mediated by these receptor cells, which may have become saturated as a result of the high illuminances used in the therapy. This randomized controlled study compares the effects of low-intensity BLT to those of high-intensity SLT. In a 22-day design, 22 patients suffering from a major depression with a seasonal pattern (SAD) were given light treatment (10,000 lux) for two weeks on workdays. Subjects were randomly assigned to either of the two conditions, with gender and age evenly distributed over the groups. Light treatment either consisted of 30 minutes SLT (5000 °K) with the EnergyLight® (Philips, Consumer Lifestyle) with a vertical illuminance of 10,000 lux at eye position or BLT (17,000 °K) with a vertical illuminance of 750 lux using a prototype of the EnergyLight® which emitted a higher proportion of short-wavelengths. All participants completed questionnaires concerning mood, activation and sleep quality on a daily basis. Mood and energy levels were also assessed on a weekly basis by means of the SIGH-SAD and other assessment tools. On day 22, SIGH-SAD ratings were significantly lower than on day 1 (SLT 65.2% and BLT 76.4%). On the basis of all assessments no statistically significant differences were found between the two conditions. With sample size being small, conclusions can only be preliminary. Both treatment conditions were found to be highly effective. The therapeutic effects of low-intensity blue-enriched light were comparable to those of the standard light treatment. Saturation effects may play a role, even with a light intensity of 750 lux. The therapeutic effects of blue-enriched white light in the treatment of SAD at illuminances as low as 750 lux help bring light treatment for SAD within reach of standard workplace and educational lighting systems.


Minimal representations, geometric quantization, and unitarity.
In the framework of geometric quantization we explicitly construct, in a uniform fashion, a unitary minimal representation pio of every simply-connected real Lie group Go such that the maximal compact subgroup of Go has finite center and Go admits some minimal representation. We obtain algebraic and analytic results about pio. We give several results on the algebraic and symplectic geometry of the minimal nilpotent orbits and then "quantize" these results to obtain the corresponding representations. We assume (Lie Go)C is simple.


Infant-directed input and literacy effects on phonological processing: Non-word repetition scores among the Tsimane'.
Language input in childhood and literacy (and/or schooling) have been described as two key experiences impacting phonological processing. In this study, we assess phonological processing via a non-word repetition (NWR) group game, in adults and children living in two villages of an ethnic group where infants are rarely spoken to, and where literacy is variable. We found lower NWR scores than in previous work for both children (N = 17; aged 1-12 years) and adults (N = 13; aged 18-60 years), which is consistent with the hypothesis that there would be long-term effects on phonological processing of experiencing low levels of directed input in infancy. Additionally, we found some evidence that literacy and/or schooling increases NWR scores, although results should be interpreted with caution given the small sample size. These findings invite further investigations in similar communities, as current results are most compatible with phonological processing being influenced by aspects of language experience that vary greatly between and within populations.


Chloral hydrate for sedation of children with asthma during dental treatment.
We hypothesised that chloral hydrate is safe and effective for sedation during dental treatments for children with mild asthma. We evaluated the safety and efficacy of chloral hydrate by measuring changes in heart rate (HR), transcutaneous oxygen saturation, (SpO2), asthma score, behaviour, types and frequency of adverse reactions associated with chloral hydrate were assessed throughout treatment. Children (<10 years old) with mild asthma undergoing dental treatments received a single 65 mg/kg oral dose of chloral hydrate liquid 1 hour prior to treatment in an open label trial. Heart rate (HR), SpO2, asthma score, behaviour, types and frequency of adverse reactions associated with chloral hydrate were assessed throughout treatment. Asthma score was obtained before and after treatment. Thirty minutes after treatment, SpO2, HR, and level of consciousness was assessed. Twenty four children were enrolled and 92% (22/24) recovered from sedation without respiratory depression. Two experienced mild respiratory depression related to chloral hydrate. Asthma was not a contributing factor as they did not experience wheezing, cough, tachypnoea, or retractions. Inhaled nitrous oxide supplemented chloral hydrate sedation in 63% (15/24) children to achieve effective cooperation. Three children had a SpO2 <95% (2 during treatment, 1 during recovery). Chloral hydrate 65 mg/kg administered a as single oral dose appears to be safe with respect to disease exacerbation for children with mild asthma undergoing dental treatment. Due to ineffective sedation and mild respiratory depression associated with chloral hydrate, newer, easily titrated medications, such as midazolam, may offer advantages.


Challenges in the Development of e-Quit worRx: An iPad App for Smoking Cessation Counseling and Shared Decision Making in Primary Care.
Smoking is the leading preventable cause of morbidity and mortality in the United States, killing more than 450,000 Americans. Primary care physicians (PCPs) have a unique opportunity to discuss smoking cessation evidence in a way that enhances patient-initiated change and quit attempts. Patients today are better equipped with technology such as mobile devices than ever before. The aim of this study was to evaluate the challenges in developing a tablet-based, evidence-based smoking cessation app to optimize interaction for shared decision making between PCPs and their patients who smoke. A group of interprofessional experts developed content and a graphical user interface for the decision aid and reviewed these with several focus groups to determine acceptability and usability in a small population. Using a storyboard methodology and subject matter experts, a mobile app, e-Quit worRx, was developed through an iterative process. This iterative process helped finalize the content and ergonomics of the app and provided valuable feedback from both patients and provider teams. Once the app was made available, other technical and programmatic challenges arose. Subject matter experts, although generally amenable to one another's disciplines, are often challenged with effective interactions, including language, scope, clinical understanding, technology awareness, and expectations. The successful development of this app and its evaluation in a clinical setting highlighted those challenges and reinforced the need for effective communications and team building.


Structural and vibrational study of primidone based on monomer and dimer calculations.
Primidone (Mysoline), with the chemical formula 5-ethyl-5-phenyl-hexahydropyrimidine- 4,6-dione (C12H14N2O2), has been a valuable drug in the treatment of epilepsy. In the present work, the experimental IR and Raman spectra of solid phase primidone were recorded, and the results were compared with theoretical wavenumber values of monomer and dimer forms of the title molecule. Vibrational spectral simulations in the dimer form were carried out to improve the assignment of the bands in the solid phase experimental spectra. The possible stable conformers of free molecule were searched by means of torsion potential energy surfaces scan studies through two dihedral angles. The molecular geometries of the monomer and dimer forms of title molecule were optimized using DFT method at B3LYP/6-31++G(d,p) level of theory. Using PEDs determined the contributions of internal (stretching, bending, etc.) coordinates to each normal mode of vibration. Further, HOMO-LUMO energy gap and NBO properties of the investigated molecule in monomer and dimer forms were also calculated.


Glucose intolerance, insulin resistance, and pathological features of Alzheimer disease in the Baltimore Longitudinal Study of Aging.
Peripheral glucose homeostasis has been implicated in the pathogenesis of Alzheimer disease (AD). The relationship among diabetes mellitus, insulin, and AD is an important area of investigation. However, whether cognitive impairment seen in those with diabetes is mediated by excess pathological features of AD or other related abnormalities, such as vascular disease, remains unclear. To investigate the association between serial measures of glucose intolerance and insulin resistance and in vivo brain β-amyloid burden, measured with carbon 11–labeled Pittsburgh Compound B (11C-PiB), and AD pathology at autopsy. Scores calculated from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) and Braak criteria were correlated with measures of hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance in 197 participants who underwent autopsy after death and who had undergone 2 or more oral glucose tolerance tests (OGTT) using grouped analyses and a continuous mixed-models analysis. The same measures of glucose intolerance and insulin resistance were also correlated with brain 11C-PiB retention in an additional 53 living subjects from the Baltimore Longitudinal Study of Aging neuroimaging study. Prospective, serially assessed cohort of community-dwelling subjects. Cohort 1 consisted of 197 participants enrolled in the Baltimore Longitudinal Study of Aging who had 2 or more OGTTs during life and a complete brain autopsy after death. Cohort 2 consisted of 53 living subjects who had 2 or more OGTTs and underwent brain 11C-PiB positron emission tomography. Autopsy and 11C-PiB positron emission tomography. The correlation of brain markers of AD, including CERAD score, Braak score, and 11C-PiB retention, with serum markers of glucose homeostasis using grouped and continuous mixed-models analyses. We found no significant correlations between measures of brain AD pathology or 11C-PiB β-amyloid load and glucose intolerance or insulin resistance in subjects who had a mean (SD) of 6.4 (3.2) OGTTs during 22.1 (8.0) years of follow-up. Thirty subjects with frank diabetes mellitus who received medications also had AD pathology scores that were similar to those of the cohort as a whole. In this prospective cohort with multiple assessments of glucose intolerance and insulin resistance, measures of glucose and insulin homeostasis are not associated with AD pathology and likely play little role in AD pathogenesis. Long-term therapeutic trials are important to elucidate this issue.


Semiparametric modeling of the spatial distribution of occupational accident risk in the casual labor market, Piracicaba, southeast Brazil.
The objective of this study was to estimate the spatial distribution of work accident risk in the informal work market in the urban zone of an industrialized city in southeast Brazil and to examine concomitant effects of age, gender, and type of occupation after controlling for spatial risk variation. The basic methodology adopted was that of a population-based case-control study with particular interest focused on the spatial location of work. Cases were all casual workers in the city suffering work accidents during a one-year period; controls were selected from the source population of casual laborers by systematic random sampling of urban homes. The spatial distribution of work accidents was estimated via a semiparametric generalized additive model with a nonparametric bidimensional spline of the geographical coordinates of cases and controls as the nonlinear spatial component, and including age, gender, and occupation as linear predictive variables in the parametric component. We analyzed 1,918 cases and 2,245 controls between 1/11/2003 and 31/10/2004 in Piracicaba, Brazil. Areas of significantly high and low accident risk were identified in relation to mean risk in the study region (p < 0.01). Work accident risk for informal workers varied significantly in the study area. Significant age, gender, and occupational group effects on accident risk were identified after correcting for this spatial variation. A good understanding of high-risk groups and high-risk regions underpins the formulation of hypotheses concerning accident causality and the development of effective public accident prevention policies.


Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary.
Numerous studies have tested the association between TP53 mutations in ovarian cancer and prognosis but these have been consistently confounded by limitations in study design, methodology, and/or heterogeneity in the sample cohort. High-grade serous (HGS) carcinoma is the most clinically important histological subtype of ovarian cancer. As these tumours may arise from the ovary, Fallopian tube or peritoneum, they are collectively referred to as high-grade pelvic serous carcinoma (HGPSC). To identify the true prevalence of TP53 mutations in HGPSC, we sequenced exons 2-11 and intron-exon boundaries in tumour DNA from 145 patients. HGPSC cases were defined as having histological grade 2 or 3 and FIGO stage III or IV. Surprisingly, pathogenic TP53 mutations were identified in 96.7% (n = 119/123) of HGPSC cases. Molecular and pathological review of mutation-negative cases showed evidence of p53 dysfunction associated with copy number gain of MDM2 or MDM4, or indicated the exclusion of samples as being low-grade serous tumours or carcinoma of uncertain primary site. Overall, p53 dysfunction rate approached 100% of confirmed HGPSCs. No association between TP53 mutation and progression-free or overall survival was found. From this first comprehensive mapping of TP53 mutation rate in a homogeneous group of HGPSC patients, we conclude that mutant TP53 is a driver mutation in the pathogenesis of HGPSC cancers. Because TP53 mutation is almost invariably present in HGPSC, it is not of substantial prognostic or predictive significance.