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Despite the global importance of species with C4photosynthesis, there is a lack of consensus regarding C4performance under fluctuating light. Contrasting hypotheses and experimental evidence suggest that C4photosynthesis is either less, or more efficient in fixing carbon under fluctuating light than the ancestral C3form. Two main issues were identified that may underly the lack of consensus: neglect of evolutionary distance between selected C3and C4species and use of contrasting fluctuating light treatments. To circumvent these issues, we compared photosynthetic responses to fluctuating light across three independent phylogenetically controlled comparisons between C3and C4species fromAlloteropsis,Flaveria, andCleomegenera under 21% and 2% O2. Leaves were subjected to repetitive stepwise changes in light intensity (800 and 100 µmol m-2s-1PFD) with three contrasting durations: 6, 30 and 300 seconds. These experiments reconcile the opposing results found across previous studies showing that 1) stimulation of CO2assimilation in C4species during the low light phase was both stronger and more sustained than in C3species; 2) CO2assimilation patterns during the high light phase were genus-specific rather than impacted by photosynthetic pathway; and 3) the duration of each light step in the fluctuation regime can strongly influence experimental outcomes.One sentence significance statementComparing photosynthesis in three pairs of closely related C3and C4species across three fluctuating light regimes showed that C4photosynthesis has a systematic advantage under the low light phase not related to suppression of photorespiration, while the comparative efficiency under the high light phase was not determined by photosynthetic pathway.

Peer reviewed: True, INTRODUCTION: Despite their importance for the global carbon cycle and crop production, species with C4 photosynthesis are still somewhat understudied relative to C3 species. Although the benefits of the C4 carbon concentrating mechanism are readily observable under optimal steady state conditions, it is less clear how the presence of C4 affects activation of CO2 assimilation during photosynthetic induction. METHODS: In this study we aimed to characterise differences between C4 and C3 photosynthetic induction responses by analysing steady state photosynthesis and photosynthetic induction in three phylogenetically linked pairs of C3 and C4 species from Alloteropsis, Flaveria, and Cleome genera. Experiments were conducted both at 21% and 2% O2 to evaluate the role of photorespiration during photosynthetic induction. RESULTS: Our results confirm C4 species have slower activation of CO2 assimilation during photosynthetic induction than C3 species, but the apparent mechanism behind these differences varied between genera. Incomplete suppression of photorespiration was found to impact photosynthetic induction significantly in C4 Flaveria bidentis, whereas in the Cleome and Alloteropsis C4 species, delayed activation of the C3 cycle appeared to limit induction and a potentially supporting role for photorespiration was also identified. DISCUSSION: The sheer variation in photosynthetic induction responses observed in our limited sample of species highlights the importance of controlling for evolutionary distance when comparing C3 and C4 photosynthetic pathways.

Introduction: Despite their importance for the global carbon cycle and crop production, species with C4 photosynthesis are still somewhat understudied relative to C3 species. Although the benefits of the C4 carbon concentrating mechanism are readily observable under optimal steady state conditions, it is less clear how the presence of C4 affects activation of CO2 assimilation during photosynthetic induction. Methods: In this study we aimed to characterise differences between C4 and C3 photosynthetic induction responses by analysing steady state photosynthesis and photosynthetic induction in three phylogenetically linked pairs of C3 and C4 species from Alloteropsis, Flaveria, and Cleome genera. Experiments were conducted both at 21% and 2% O2 to evaluate the role of photorespiration during photosynthetic induction. Results: Our results confirm C4 species have slower activation of CO2 assimilation during photosynthetic induction than C3 species, but the apparent mechanism behind these differences varied between genera. Incomplete suppression of photorespiration was found to impact photosynthetic induction significantly in C4 Flaveria bidentis, whereas in the Cleome and Alloteropsis C4 species, delayed activation of the C3 cycle appeared to limit induction and a potentially supporting role for photorespiration was also identified. Discussion: The sheer variation in photosynthetic induction responses observed in our limited sample of species highlights the importance of controlling for evolutionary distance when comparing C3 and C4 photosynthetic pathways.

In this paper, we investigate a path-dependent American option problem and provide an efficient and implementable numerical scheme for the solution of its associated path-dependent variational inequality. We obtain the viscosity characterization of our value function and suggest a monotone, stable and consistent numerical scheme, the convergence of which is proven thanks to the uniqueness property. We further enrich our study by providing and implementing a numerical algorithm. Some numerical results are also included.

Recent breakthroughs in computer vision offer an exciting avenue to develop new remote, and non-intrusive patient monitoring techniques. A very challenging topic to address is the automated recognition of breathing disorders during sleep. Due to its complexity, this task has rarely been explored in the literature on real patients using such marker-free approaches. Here, we propose an approach based on deep learning architectures capable of classifying breathing disorders. The classification is performed on depth maps recorded with 3D cameras from 76 patients referred to a sleep laboratory that present a range of breathing disorders. Our system is capable of classifying individual breathing events as normal or abnormal with an accuracy of 61.8%, hence our results show that computer vision and deep learning are viable tools for assessing locally or remotely breathing quality during sleep.

The frequent occurrence of very large trees (diameter at breast height DBH ≥ 80 cm) is a typical element of both primary and secondary old-growth forests. We analyzed the characteristics of very large trees in one of the few stands of lowland old-growth beech forest in Northwestern Europe, regenerated around 1775 and left unmanaged since 1986. We examined their density, diameter range, increment, mortality rate and spatial distribution, based on repeated full dendrometric surveys. In order to evaluate the results, we compared them to original datasets from primary and secondary old-growth beech forests in Europe, and an extensive reference table, compiled from inventories and literature. In our study site, the density of very large trees increased from 31.5 to 34.3 trees ha−1 over the last 25 years, reaching a median DBH of 97 cm (mean 98.9), with the largest tree attaining a DBH of 159 cm. Although the trees were over 240 years old, they still showed an average DBH increment of 4.75 mm year−1 and a low mortality rate (0.89% year−1), indicating that they were still vital. These figures are remarkably high compared to other old-growth beech forest reference sites, where the density of very large trees generally varies between 5 and 20 trees ha−1 (median value 13.1), with a median diameter of 85–90 cm and maximum DBH for beech trees rarely exceeding 100–130 cm. The regular spatial distribution pattern of the very large trees in the studied stand clearly differed from a typical old-growth stand, in which very large trees are randomly distributed. Over the last 25 years though, because of random mortality and ingrowth, the spatial distribution gradually became more random. The extraordinary densities and sizes of the very large trees in our study site can be explained by the favorable climate and site conditions that promote high increments, in combination with the former management interventions of tending and thinning that resulted in continuous non-suppressed growth. Although derived from a very specific case with particular conditions, our observations may be relevant to other beech forests, as they tend to reset certain baseline assumptions for tree size and longevity potential of beech in Northwestern Europe.

Methionine aminopeptidase 2 (MetAP2) inhibition is a promising approach to treating diabetes, obesity, and associated metabolic disorders. Beloranib, a MetAP2 inhibitor previously investigated for treatment of Prader-Willi syndrome, was associated with venous thrombotic adverse events likely resulting from drug effects on vascular endothelial cells (ECs). Here, we report the pharmacological characterization of ZGN-1061, a novel MetAP2 inhibitor being investigated for treatment of diabetes and obesity. Four weeks of subcutaneous administration of ZGN-1061 to diet-induced obese (DIO) insulin-resistant mice produced a 25% reduction in body weight, primarily due to reduced fat mass, that was comparable to beloranib. ZGN-1061 also produced improvements in metabolic parameters, including plasma glucose and insulin, and, in HepG2 cells, initiated gene changes similar to beloranib that support observed in vivo pharmacodynamics. In vitro studies in ECs demonstrated that ZGN-1061 effects on EC proliferation and coagulation proteins were greatly attenuated, or absent, relative to beloranib, due to lower intracellular drug concentrations, shorter half-life of inhibitor-bound MetAP2 complex, and reduced cellular enzyme inhibition. In dogs, ZGN-1061 was more rapidly absorbed and cleared, with a shorter half-life than beloranib. Unlike beloranib, ZGN-1061 did not increase coagulation markers in dogs, and ZGN-1061 had a greatly improved safety profile in rats relative to beloranib. In conclusion, ZGN-1061 and beloranib demonstrated similar efficacy in a mouse model of obesity, while ZGN-1061 had a markedly improved safety profile in multiple in vitro and in vivo models. The lower duration of exposure characteristic of ZGN-1061 is expected to provide a meaningfully enhanced clinical safety profile.

OBJECTIVES: The increasing prevalence of mobile devices in clinical settings has the potential to improve both patient care and education. The benefits are particularly promising in the context of family-centered rounds in inpatient pediatric settings. We aimed to increase mobile device usage by inpatient rounding teams by 50% in 6 months. We hoped to demonstrate that use of mobile devices would improve access to patient care and educational information and to determine if use would improve efficiency and perceptions of clinical teaching. METHODS: We designed a mixed-methods study involving pre- and post-implementation surveys to residents, families, and faculty as well as direct observations of family-centered rounds. We conducted rapid cycles of continual quality improvement by using the Plan-Do-Study-Act framework involving 3 interventions. RESULTS: Pre-intervention, the mobile computing cart was used for resident education on average 3.3 times per rounding session. After cycle 3, teaching through the use of mobile devices increased by ∼79% to 5.9 times per rounding session. On the basis of survey data, we determined there was a statistically significant increase in residents’ perception of feeling prepared for rounds, receiving teaching on clinical care, and ability to teach families. Additionally, average time spent per patient on rounds decreased after implementation of mobile devices. CONCLUSIONS: Integration of mobile devices into a pediatric hospital medicine teaching service can facilitate patient care and perception of resident teaching by extending the utility of electronic medical records in care decisions and by improving access to knowledge resources.

Stigma towards people with substance use disorders is a common phenomenon with far reaching effects. This study evaluated the long-term effect of using an educational intervention on the attitudes of physician assistant students.Physician assistant students received a one-week educational intervention focused on substance abuse. Changes in student attitudes were measured one year later using the Attitude to Mental Health Questionnaire (AMIQ).Significant and sustained improvement was noted in attitudes in the AMIQ score for the opiate use disorder vignette; no significant change was noted in the alcohol use disorder vignette.The persistence of improved attitudes (although they remained negative) in study participants towards people with opiate use disorders is a cautiously encouraging finding. Educational interventions can have a sustained effect on stigma reduction, but much more work on the etiology of these implicit and explicit beliefs is needed to inform robust future interventions.

We consider a market dealer acting as a liquidity provider by continuously setting bid and ask prices for an illiquid asset in a quote-driven market. The market dealer may benefit from the bid---ask spread, but has the obligation to permanently quote both prices while satisfying some liquidity and inventory constraints. The objective is to maximize the expected utility from terminal liquidation value over a finite horizon and subject to the above constraints. We characterize the value function as the unique viscosity solution to the associated Hamilton---Jacobi---Bellman equation, and further enrich our study with numerical results. The contributions of our study concern both the modelling aspects and the dynamic structure of the control strategies. Important features and constraints characterizing market making problems are no longer ignored.

In this paper, we study the problem of determining an optimal control on the dividend and investment policy of a firm operating under uncertain environment and risk constraints. We allow the company to make investment decisions by acquiring or selling producing assets whose value is governed by a stochastic process. The firm may face liquidity costs when it decides to buy or sell assets. We formulate this problem as a multi-dimensional mixed singular and multi-switching control problem and use a viscosity solution approach. We numerically compute our optimal strategies and enrich our studies with numerical results and illustrations.

A novel but simple approach for describing stand structure in natural and managed forests driven by small-scaled disturbances is introduced. A primeval beech forest reserve in Slovakia and two beech stands in Germany with different management histories were studied, and their forest stand texture was analysed in terms of tree coordinates, stem diameter, and crown radius. Neigh-bouring trees of similar size with estimated contact of their crowns were assigned to tree groups. The study goal was to estimate the number and size of such homogeneous patches. In all cases, the number of tree groups in a particular diameter class decreased exponentially as group size increased. Single trees were predominant. Compared to simulated random tree distributions, the natural stand exhibited a more clumped distribution of small trees and more regular distribution of larger ones. The natural forest generally had smaller groups than the managed even aged stand, but the smallest group sizes were found in the uneven-aged selection forest. The simple analytical approach provided new spatial insights into neighbourhood relations of trees. The continuous scale from single trees to larger tree groups is an important achievement compared to other analytical methods applied in this field. The findings may even indicate a certain degree of self-organization in natural forests. Due to the limitations associated with each method or statistical models, a joint consideration of 1) gap dynamics, 2) forest developmental stages, and 3) size classes of homogeneous tree groups is recommended. Relevant to forest practitioners, the size class distributions enhance an understanding of the complex stand structures in natural forests and therewith support an emulation of natural forest dynamics in managed beech forests.

ZGN-1061 (1061) is a methionine aminopeptidase 2 (MetAP2) inhibitor being developed to improve glycemic control in T2D. This study investigated 5 weeks (weeks) of once-daily SC treatment with a submaximal 0.3 mg/kg dose of 1061, a maximal 0.4 mg/kg dose of liraglutide (lira), 1061+lira, or vehicle (N=10/group) on body weight (BW), food intake/preference, and glycemic control in the Gubra diet-induced obese (DIO) rat model (ad libitum fed chow and highly palatable high-fat, high-sugar [HFHS] diet). Fasting (4 hour) blood glucose (FBG) was collected weekly and a semifasted (16 hour access to 50% of daily energy requirement) OGTT was performed at week 4. At week 5 (day 33), BW changed by +1.7% with vehicle vs. -6.0% with 1061, -9.1% with lira, and -16.9% with 1061+lira (all p Disclosure B.F. Burkey: Employee; Self; Zafgen. P.J. Pedersen: None. T.X. Pedersen: Employee; Self; Gubra. M. Feigh: None. J. Vath: Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen. T.E. Hughes: Board Member; Self; Zafgen. Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen.

ZGN-1061 (1061) is a methionine aminopeptidase 2 (MetAP2) inhibitor being developed to improve glycemic control in type 2 diabetes. In diet-induced obese mice, 1061 reduces fat mass and improves glycemic control, lipid metabolism, and other metabolic parameters. This study investigated 8 weeks of treatment with 1061 (0.3 mg/kg, SC, N=11) or vehicle (N=10) on metabolic parameters, hepatic pathology, and nonalcoholic fatty liver disease (NAFLD) activity score (NAS; composite measure of steatosis, inflammation, and ballooning degeneration; range 0-8) in male mice with diet-induced and biopsy-confirmed nonalcoholic steatohepatitis (DIO-NASH). At week 8, there was a vehicle corrected weight loss of 13.1% with 1061 (p Disclosure B.F. Burkey: Employee; Self; Zafgen. M. Illemann: None. S. Veidal: None. M. Feigh: None. J. Vath: Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen. T.E. Hughes: Board Member; Self; Zafgen. Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen.

Additional file 3: Figure S3. Mapping of clustering solutions of stand structural data aggregated with a bivariate normal kernel at several observational scales.

Additional file 4: Figure S4. Mapping of clustering solutions with 2 to 5 clusters of stand structural data aggregated with a bivariate normal kernel.

Additional file 1: Figure S1. Biplots of principal component analyses of stand structural data aggregated with a bivariate normal kernel.

Additional file 2: Figure S2. Between-clusters variance of stand structural data aggregated with a bivariate normal kernel.

This paper concerns with numerical resolution of an impulse control problem under state constraints arising from optimal portfolio selection under liquidity risk and price impact. We show that the value function could be obtained as the limit of an iterative procedure where each step is an optimal stopping problem and the reward function is related to the impulse operator. Given the dimension of our problem and the complexity of its solvency region, we use a numerical approximation algorithm based on quantization procedure instead of finite difference methods to calculate the value function, the transaction and no-transaction regions. We also focus on the convergence of our numerical scheme, in particular, we show that it satisfies monotonicity, stability and consistency properties. We further enrich our studies with some numerical results for the optimal transaction strategy.

Aim: To assess the efficacy, safety and tolerability of beloranib treatment for obesity. Methods: This phase II, double-blind, randomized study investigated the effects of beloranib suspension (0.6, 1.2 and 2.4mg) or placebo, administered subcutaneously, for 12weeks in 147 participants (primarily white women) with obesity. No diet or exercise advice was administered. Results: At week 12, beloranib resulted in dose-dependent progressive weight loss of -5.5±0.5, -6.9±0.6 and -10.9±1.1kg for the 0.6, 1.2 and 2.4mg beloranib doses, respectively, compared with -0.4±0.4kg with placebo (all p

Engaging residents in patient safety and quality improvement initiatives is sometimes difficult. The primary goal of the current study was to develop a standardized learning experience designed to facilitate patient safety discussions during rounds.Residents who were on inpatient rotations during a 2-month period in 2014 were exposed to patient safety discussions on rounds. Residents who were not on inpatient rotations served as a control group. Faculty received weekly text reminders with 3 questions designed to engage residents in patient safety discussions. Before and after the intervention, residents were asked to complete a modified Agency for Healthcare Research and Quality Hospital Survey on Patient Safety Culture. Faculty members were asked to complete a brief survey designed by the study investigators.Of the 160 residents who participated in the study, 49 responded to both the preintervention and postintervention surveys (31%). Residents who participated in patient safety discussions during rounds reported higher frequencies of safety events reported compared to the control group (Using weekly text reminders with 3 prompts to incorporate patient safety discussions into rounds was well received by faculty and residents and had an impact on communication and error reporting.

Previous publications suggested that the precision of the new Hologic Horizon densitometer might be better than that of the previous Discovery model, but these observations were confounded by not using the same participants and technologists on both densitometers. We sought to study this issue methodically by measuring in vivo precision in both densitometers using the same patients and technologists. Precision studies for the Horizon and Discovery models were done by acquiring spine, hip, and forearm bone mineral density twice on 30 participants. The set of 4 scans on each participant (2 on the Discovery, 2 on the Horizon) was acquired by the same technologist using the same scanning mode. The pairs of data were used to calculate the least significant change according to the International Society for Clinical Densitometry guidelines. The significance of the difference between least significant changes was assessed using a Wilcoxon signed-rank test of the difference between the mean square error of the absolute value of the differences between paired measurements on the Discovery (Δ-Discovery) and the mean square error of the absolute value of the differences between paired measurements on the Horizon (Δ-Horizon). At virtually all anatomic sites, there was a nonsignificant trend for the precision to be better for the Horizon than for the Discovery. As more vertebrae were excluded from analysis, the precision deteriorated on both densitometers. The precision between densitometers was almost identical when reporting only 1 vertebral body. (1) There was a nonsignificant trend for greater precision on the new Hologic Horizon compared with the older Discovery model. (2) The difference in precision of the spine bone mineral density between the Horizon and the Discovery models decreases as fewer vertebrae are included. (3) These findings are substantially similar to previously published results which had not controlled as well for confounding from using different subjects and technologists.

BACKGROUND AND OBJECTIVE: Patient safety events are underreported by physicians. Baseline data demonstrated that physicians submitted 3% of event reports at Our Lady of the Lake Children’s Hospital. Our aim was to increase the proportion of safety reports filed by residents and faculty to 6% of all reports within a 9-month period. METHODS: We used the Model for Improvement and serial Plan, Do, Study, Act cycles to test interventions we hypothesized would improve physician recognition and reporting of patient safety events. We tracked the percentage of Our Lady of the Lake Children’s Hospital event reports entered by residents or faculty over time as the primary outcome measure. Changes to teaching team processes included “patient safety rounds” prompted by text messages, an inpatient “superintendent” rotation with core patient safety responsibilities, and a “just-in-time” faculty development program called “QI on the Fly.” RESULTS: Physician-reported events increased to a monthly average of 24% of all events reported, an improvement that has been sustained over 17 months. Resident reporting accounted for most of the increase in physician reports. Increased physician reporting was temporally associated with implementation of the “superintendent” rotation. The total number of events reported increased as a result of increased physician reporting. CONCLUSIONS: Incorporating patient safety responsibilities into a teaching team’s workflow can increase physician safety event reporting. We plan additional Plan, Do, Study, Act cycles to spread this approach to other clinical settings and investigate the impact increased reporting might have on patient care.

A high throughput LC–MS/MS method for quantification of metformin substrate uptake enables conversion of radiometric transporter inhibition assays for multidrug and toxin extrusion transporters (MATE 1 and 2) and organic cation transporter 2 (OCT2) to a nonradioactive format. Such conversion greatly simplifies assay complexity and reduces assay costs. The development of a quantitative LC–MS/MS method for metformin in support of the high throughput transporter inhibition assays faced specific challenges of achieving both adequate chromatographic retention and rapid analytical turnaround. Here we report a method that circumvents both challenges. The utilization of a porous graphitic carbon column (Hypercarb) ensured adequate retention of highly polar metformin in biological samples. The combined employment of a ballistic gradient on a 3 mm × 30 mm, 5 μm Hypercarb column, and dual staggered chromatography coupled with multiple injection chromatography acquisition, yielded a fast injection-to-injection cycle time of 30 s. The method demonstrated good accuracy, precision and excellent robustness for high throughput applications, and has been successfully implemented in the development and validation of the nonradioactive transporter inhibition assays for MATEs and OCT2.

We were pleased to read the response to our Journal of Teacher Education (JTE) article (Fishman et al., 2013) by Moon, Passmore, Reiser, and Michaels (2013). We believe that Moon et al. have properly identified both the value in our study and the importance of moving beyond not only our study, but similar studies, to better serve the urgent need for professional development (PD) designs that are effective in helping teachers successfully enact curricular reforms, such as the Next Generation Science Standards (NGSS; Wilson, 2013) and the Common Core State Standards in mathematics and English language arts (Common Core State Standards Initiative, 2010; Porter, McMaken, Hwang, & Yang, 2011). We agree wholeheartedly that the field would benefit from scholarship that leads to "research-based design principles to guide the ongoing development, implementation, and evaluation efforts in online PD" (Moon et al., p. 1). Below, we briefly recap our study and address the issues raised by Moon et al. in their commentary. We then expand on the ideas introduced by Moon et al. for how to take advantage of the opportunity for studying teacher learning related to the NGSS presented by the Next Generation Science Exemplar System (NGSX) PD platform. The heart of our study was the experimental comparison of PD delivered in two different media. Our study was a "media comparison" study, the value of which has been hotly debated in the field of educational technology (Clark, 1983, 1994; Kozma, 1994). We worked to make the two conditions in our study balanced with respect to opportunities to learn, while not limiting the natural affordances offered by each medium. Random assignment ensured that the teachers in each condition had equivalent characteristics. Our focus was on addressing the ongoing policy debate about how to invest in teacher PD and whether the imagined risks of online PD outweigh suggested benefits. We thus do not address the call by Dede, Ketelhut, Whitehouse, and McCloskey (2009) for a focus on theory building to articulate design principles. Perhaps most importantly, we designed our study to address a conceptual framework for studying PD that links the features of the PD to changes in teachers' knowledge and beliefs, changes in classroom practice, and changes in student learning outcomes (Desimone, 2009). Student learning might be the most policy-relevant area for study in relation to PD, and yet is perhaps the least studied, in large part because it is so difficult to identify common student learning outcomes and measures related to the PD. We were opportunistic in this respect, building our study around the adoption of a new environmental science curriculum (Edelson et al., 2005). This curriculum represented challenging inquiry-based science (Crawford, 2000), with many new techniques and tools to be learned, and our PD would be teachers' primary information source for learning how to use the new materials. Best of all, because everyone in the study was using a single curriculum, we had a common measure of learning in the curriculum-aligned test. We observed significant growth in teacher self-efficacy, classroom practice, and student learning in both conditions, but no difference between conditions. This finding was welcomed by many as a sign that it is "safe" to employ online PD, in light of concerns about what might be given up by districts in comparison with face-to-face PD (e.g., Herold, 2013). In our article, we were somewhat more conservative in our conclusions, observing that a finding of "no significant differences" indicates that we can be less concerned with media effects than with the specific needs and demands of particular contexts in which PD is needed. We absolutely agree with Moon et al. (2013) when they state that "to take [our] findings as applicable to all online PD would be an overreach" (p. 2). In fact, we were careful to make the same argument ourselves and appreciate the chance to highlight this, given its importance. …

Stigma towards people with substance use disorders is pervasive and imbedded in our US culture. Prejudicial attitudes that are part of a health care practitioner’s value system are a barrier to people accessing health care and substance use treatment. This study aimed to reduce stigmatizing attitudes of graduate health care professional students by implementing an innovative curriculum combining multiple teaching methods. Physician assistant students received a 3-h educational intervention that consisted of lecture and discussion sessions, direct interaction with a recovering substance user, viewing a film portrayal of addiction and addiction treatment, and written self-reflection. Changes in student attitudes were measured using a subscale of the Attitudes to Mental Illness Questionnaire (AMIQ) instrument and analysis of coded written reflections. A follow-up focus group resulted in additional qualitative insight into attitudes. Post-intervention scores for the “heroin” AMIQ vignette significantly improved compared to pre-test scores (p

This study employed a randomized experiment to examine differences in teacher and student learning from professional development (PD) in two modalities: online and face-to-face. The study explores whether there are differences in teacher knowledge and beliefs, teacher classroom practice, and student learning outcomes related to PD modality. Comparison of classroom practice and student learning outcomes, normally difficult to establish in PD research, is facilitated by the use of a common set of curriculum materials as the content for PD and subsequent teaching. Findings indicate that teachers and students exhibited significant gains in both conditions, and that there was no significant difference between conditions. We discuss implications for the delivery of teacher professional learning.

Objective: Evaluate the safety and tolerability of beloranib, a fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor, in obese women over 4 weeks.

RATIONALE Multiplexed liquid chromatography (LC) coupled with multiple-injection-chromatogram acquisition has emerged as the method of choice for high-speed discovery bioanalysis, because it significantly reduces injection-to-injection cycle time while maintaining the chromatography quality. Historically, systems utilizing this approach had been custom built, and therefore relied on custom software tools to communicate with multiple vendor software for system control, which lacked transferability, flexibility and robustness. METHODS In this study, we refined a multiplexed bioanalytical system previously reported, by implementing open-deck auto-sampler manifold and multiple-injection-chromatogram acquisition, all on a commercially available system with single software control. RESULTS As a result of these improvements, the developed LC/tandem mass spectrometry (MS/MS) method on the system was nearly three times faster than the previous method, while demonstrating comparable analytical accuracy, precision and robustness. This system has been evaluated for in vitro ADME screening assays including metabolic stability, CYP inhibition and Caco-2. The biological data generated on the developed system displayed good correlation with those from the previous LC/MS/MS approaches. CONCLUSIONS The developed platform demonstrated applicability to the in vitro screening assays evaluated and has been successfully implemented to support the high-throughput metabolic stability assay, with a significantly improved bioanalytical throughput, capacity and data turnaround. Copyright © 2013 John Wiley & Sons, Ltd.

The 2013 closure of a public hospital in Baton Rouge, LA transformed graduate medical education (GME) at Our Lady of the Lake Regional Medical Center (OLOL). Administrators were tasked with incorporating residents into patient safety and quality improvement initiatives to fulfill regulatory obligations. This report outlines our experiences as we built these patient safety and quality improvement initiatives in a rapidly expanding independent academic medical center.We joined the Alliance of Independent Academic Medical Centers (AIAMC) to meet and learn from national peers. To fulfill the scholarly activity requirement of the AIAMC's National Initiative IV, we formed a multidisciplinary team to develop a patient safety education project. Prioritized monthly team meetings allowed for project successes to be celebrated and circulated within the organization.The public-private partnership that more than quadrupled the historic size of GME at OLOL has, in the past 2 years, led to the development of an interdisciplinary team. This team has expanded to accommodate residency program leadership from across the campus. Our National Initiative IV project won a national award and inspired several follow-up initiatives. In addition, this work led to the formation of a Patient Safety and Clinical Quality Improvement fellowship that matched its first fellow in 2015.Through the commitment and support of hospital and medical education leaders, as well as a focus on promoting cultural change through scholarly activity, we were able to greatly expand patient safety and quality improvement efforts in our institution.

As teacher professional development research includes more experimental designs, new challenges arise. We examine the threat of participant attrition as an example of the types of problems researchers face. Counter-intuitively, higher levels of recruitment effort were related to higher dropout rates among teachers. We also found that teachers left because of changes in teaching assignments, institutional challenges, and personal challenges. Finally, the majority of teachers in urban schools dropped out, while the majority of teachers in rural or suburban schools remained. We conclude with recommendations for future teacher learning experiments.

Medical professionals' negative attitudes toward patients with mental illness and substance abuse disorders can have negative consequences, and these attitudes are not rare. In surveys, patients have reported discrimination in mental health settings in the 16% to 44% range and 17% to 31% in physical health settings.1 More concerning than the perceived stigma experienced by patients is the potential for bias in medical decision making. For example, health care providers are less likely to refer people with mental illnesses for a mammogram, less likely to admit them for hospitalization after a diabetic crisis, and less likely to perform a cardiac catheterization.2 Stigmatizing beliefs also affect clinical decisions through diagnostic overshadowing, attributing physical symptoms to the mental condition and consequently not investigating or treating them.3 Although evidence suggests that patients with mental illnesses are no less likely to be adherent to treatment recommendations than others, health care professionals who endorsed more stigmatizing attitudes about mental illness were more likely to be pessimistic about the likelihood of patients adhering to treatment, and this contributed to impaired decision making.4

Persistent nasal carriage of Staphylococcus aureus is the primary reservoir for this pathogen and a risk factor for infection. The nares of 12 to 30% of healthy individuals are persistently colonized with staphylococci. Elucidating the yet enigmatic determinants of this phenomenon is of major public health interest. We hypothesized that differences in the levels of antimicrobial peptides (AMPs) that are found in human skin and have pronounced antistaphylococcal activity may contribute to this phenomenon. We compared constitutive and induced mRNA levels of RNase 7 and human β-defensin 3 (HBD-3) in healthy and experimentally wounded gluteal skin of 60 volunteers after ascertaining their carrier status through repeated nasal cultures. We found that levels of HBD-3 expression in skin of persistent nasal carriers of S. aureus were lower: induced levels in carriers were 63% (95% confidence interval, 43 to 94%; P = 0.02) and constitutive levels were 76% (95% confidence interval, 52 to 110%; P = 0.14) of those found in noncarriers. No such associations were present for RNase 7. In conjunction with existing knowledge, these findings suggest that healthy individuals with deficient HBD-3 expression in keratinocytes are more prone to persistent nasal colonization with S. aureus .

The continuous push for smaller bump pitch interconnection in line with smaller Cu/low-k technology nodes demands the substrate technology to support finer interconnection. However, the conventional organic buildup substrate is facing a bottleneck in fine-pitch wiring due to its technology limitation, and the cost of fabricating finer pitch organic substrate is higher. To address these needs, Si interposer with through silicon via (TSV) has emerged as a good solution to provide high wiring density interconnection, and at the same time to minimize coefficient of thermal expansion mismatch to the Cu/low-k chip that is vulnerable to thermal-mechanical stress and improve electrical performance due to shorter interconnection from the chip to the substrate. This paper presents the development of TSV interposer technology for a 21 × 21 mm Cu/low-k test chip on flip chip ball grid array (FCBGA) package. The Cu/low-k chip is a 65-nm nine-metal layer chip with 150-μm SnAg bump pitch of total 11 000 I/O, with via chain and daisy chain for interconnect integrity monitoring and reliability testing. The TSV interposer size is 25 × 25 × 0.3 mm with CuNiAu as under bump metallization on the top side and SnAgCu bumps on the underside. The conventional bismaleimide triazine substrate size is 45 × 45 mm with BGA pad pitch of 1 mm and core thickness of 0.8 mm. Mechanical and thermal modeling and simulation for the FCBGA package with TSV interposer have been performed. TSV interposer fabrication processes and assembly process of the large die mounted on TSV interposer with Pb-free solder bumps and underfill have been set up. The FCBGA samples have passed moisture sensitivity test and thermal cycling reliability testing without failures in underfill delamination and daisy chain resistance measurements.

The semiconductor industry has maintained an average 15% cost down per year over the range of products it offers. Continued cost reduction will be difficult to achieve based on current practices and raw material prices. The need to remain competitive has compelled integrated device manufacturers and subcontractors to look at alternative material types, most notably copper wire. A recent survey of the industry has revealed that there remain very widespread concerns on migrating away from the use of gold. It is important that the cost of using gold wire is minimized without compromising on product reliability and quality. We present a critical review of the wire bonding process focusing on various practices, procedures, and material choices. Such analyses indicate, for example, that a reduction of the FAB ratio in a 32 I/O QFN with 38 wires from 2 to 1.4, would save 1 km per 1,100 strips.

This paper presents the findings of work performed on 20-μm diameter copper wire of five different wire types from three suppliers. Gold wire is the control. The test die was mounted on BT (B (Bismaleimide) and T (Triazine)) resin substrates. The bonding parameters were optimized for each wire used. Part of the optimization process involved monitoring the flatness of the bonded ball and the amount of aluminum remaining under the bond. The crystal structure of each type of interconnect was examined using composite imaging techniques. Visual data such as ball size, thickness, and shape were collected. First and second bonds were subjected to destructive testing, such as ball shear and wire pull, throughout the preparation process. The samples were then subjected to an industry-standard, high temperature stress test to determine the long-term stability of the interface of each wire type. Data for all read points are presented on all tests performed and provide useful information on the material and process set best suited for long term reliability.

Quantification of small molecules using liquid chromatography/tandem mass spectrometry (LC/MS/MS) on a triple quadrupole mass spectrometer has become a common practice in bioanalytical support of in vitro adsorption, distribution, metabolism and excretion (ADME) screening. The bioanalysis process involves primarily three indispensable steps: MS/MS optimization for a large number of new chemical compounds undergoing various screening assays in early drug discovery, high-throughput sample analysis with LC/MS/MS for those chemically diverse compounds using the optimized MS/MS conditions, and post-acquisition data review and reporting. To improve overall efficiency of ADME bioanalysis, an integrated system was proposed featuring an automated and unattended MS/MS optimization, a staggered parallel LC/MS/MS for high-throughput sample analysis, and a sophisticated software tool for LC/MS/MS raw data review as well as biological data calculation and reporting. The integrated platform has been used in bioanalytical support of a serum protein binding screening assay with high speed, high capacity, and good robustness. In this new platform, a unique sample dilution scheme was also introduced. With this dilution design, the total number of analytical samples was reduced; therefore, the total operation time was reduced and the overall throughput was further improved. The performance of the protein binding screening assay was monitored with two controls representing high and low binding properties and an acceptable inter-assay consistency was achieved. This platform has been successfully used for the determination of serum protein binding in multiple species for more than 4000 compounds.

Background: Elevated levels of arsenic in drinking water in Cambodia were first identified in 1999. The first cases of suspected arsenicosis were identified by the WHO in 2002, and the first laboratory confirmed cases were found in 2006. Objective: Present three patients with ulcerating tumors of the legs who came from two different districts in Cambodia. Results: Cutaneous lesions characteristic of chronic arsenicosis were exhibited, and squamous cell carcinomas requiring amputation had developed. The clinical features of chronic arsenicosis and its surgical management were examined, in addition to its impact in Cambodia and current preventive strategies Conclusion: There will be an increased incidence of these problems in the future. Medical practitioners in the Mekong River Basin should be aware of them, so as to recognize them early, and treat them appropriately. Keywords: Amputation, arsenicosis, Cambodia, drinking water, squamous cell carcinoma

Background.—Puberty is assumed to influence the occurrence of headache, increasing the risk for recurrent episodes, especially in girls. The increase of headache, in particular recurrent headache, in girls from around the age of 12 on, is often ascribed to the occurrence of menarche as the most stringent indicator of completed puberty. Objectives.—We examined the hypothesis that the occurrence of menarche in girls is predictive of recurrent headache in reference to no or rare headache in the past 6 months. Furthermore, the assumption was tested that headache episodes increase after onset of menarche but remain unchanged in girls not having experienced their first menstruation. We also expected a higher probability of migraine type of headache after menarche. In a further analysis girls with and without menarche were compared with boys, and a difference between gender only for girls with menarche was predicted. Methods.—In an epidemiological study recruiting 8800 families with children 7-14 years in Southern Lower Saxony (Germany), we conducted 3 yearly panels based on postal questionnaires. Headache data are based on self-report of children from 9 years on. Parents were asked for information regarding the onset of menarche. Approximately 1100 girls and about the same number of boys constitute the sample for our analyses. Results.—The results of a logistic regression analysis demonstrate that in 11- to 16-year-old girls having experienced menarche in either the year of the assessment of headache or 2 years before that, the risk for recurrent headache is increased when compared with girls without menarche. Intraindividual longitudinal analyses, however, do not support our hypotheses that after the onset of menarche headaches become more frequent. The expected differences in headache between girls with menarche and boys were found. The risk for migraine-like headaches is not significantly higher after onset of menarche than before. Conclusions.—Thus, results do not consistently support the hypothesis that puberty is a moderator of headache frequency. Even in cases where the outcome of regression analyses is supportive of our expectations, explained variance is diminutive (maximum 2.2%). Thus, the influence of menarche on headache seems to be only marginal.

Background The objective of the present study was to assess the concordance between parent and child report regarding different domains of pediatric health, headache in particular. In addition, the influence of potential moderator variables on the agreement between parents and children was examined. Methodology In an epidemiologic study on a randomly drawn sample of households with at least 1 child in the family between 7 and 14 years of age (community registries), various pediatric health disturbances (headache, other pains, somatic symptoms, and depression/anxiety) were assessed via both child (from the age of 9 y on) and parent report (n=3461). Results A relatively high parent-child agreement (sigmaM=0.61) was found regarding the variable headache frequency, whereas consensus regarding other pains was, for the most part, markedly lower. The lowest agreement (sigmaM=0.27) was found for depression/anxiety symptoms. A moderator analysis (with age, sex, and parental headache) between child and parent failed to reveal significant differences regarding the degree of agreement between the 2 data sources. Children reported more frequent and more severe symptoms in all health domains. Conclusion The examined potential moderator variables did not elucidate processes underlying the differences in child and parent agreement. There is no convincing evidence that the children's appraisal is less valid than their parents'. In summary, parents' reports cannot be viewed as a substitute for children's reports in pediatric pain and health assessment. Instead, each perspective represents a unique subjective reality and as such, both are of importance for research on pediatric pain and other health variables.