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Traditional methods for evaluating a potential treatment have focused on the average treatment effect. However, there exist situations where individuals can experience significantly heterogeneous responses to a treatment. In these situations, one needs to account for the differences among individuals when estimating the treatment effect. Li et al. (2022) proposed a method based on random forest of interaction trees (RFIT) for a binary or categorical treatment variable, while incorporating the propensity score in the construction of random forest. Motivated by the need to evaluate the effect of tutoring sessions at a Math and Stat Learning Center (MSLC), we extend their approach to an ordinal treatment variable. Our approach improves upon RFIT for multiple treatments by incorporating the ordered structure of the treatment variable into the tree growing process. To illustrate the effectiveness of our proposed method, we conduct simulation studies where the results show that our proposed method has a lower mean squared error and higher optimal treatment classification, and is able to identify the most important variables that impact the treatment effect. We then apply the proposed method to estimate how the number of visits to the MSLC impacts an individual student’s probability of passing an introductory statistics course. Our results show that every student is recommended to go to the MSLC at least once and some can drastically improve their chance of passing the course by going the optimal number of times suggested by our analysis.

We expand methods for estimating an optimal treatment regime (OTR) from the personalized medicine literature to educational data mining applications. As part of this development, we detail and modify the current state-of-the-art, assess the efficacy of the approaches for student success studies, and provide practitioners the machinery to apply the methods in their specific problems. Our particular interest is to estimate an optimal treatment regime for students enrolled in an introductory statistics course at San Diego State University (SDSU). The available treatments are combinations of three programs SDSU implemented to foster student success in this large enrollment, bottleneck STEM course. We leverage tree-based reinforcement learning approaches based on either an inverse probability-weighted purity measure or an augmented probability-weighted purity measure. The thereby deduced OTR promises to significantly increase the average grade in the introductory course and also reveals the need for program recommendations to students as only very few, on their own, selected their optimal treatment.

Despite the importance of monsoon rainfall to over half of the world's population, many climate models of the current generation struggle to capture some of the major features of the various monsoon systems. Studies of the development of errors in several tropical regions have shown that they start to develop very quickly, within the first few days of a model simulation, and can then persist to climate timescales. Understanding the sources of such errors requires the combination of various modelling techniques and sensitivity experiments of varying complexity. Here, we demonstrate how such analysis can shed light on the way in which monsoon errors develop, their local and remote drivers and feedbacks. We make use of the seamless modelling approach adopted by the Met Office, whereby different applications of the Met Office Unified Model (MetUM) use essentially the same model configuration (dynamical core and physical parameterisations) across a range of spatial and temporal scales. Using the Asian summer monsoon (ASM) as an example, we show that error patterns in circulation and rainfall over the ASM region in the MetUM are similar between multidecadal climate simulations and seasonal hindcasts initialised in spring. Analysis of the development of these errors on both short-range and seasonal timescales following model initialisation suggests that both the Maritime Continent and the oceans around the Philippines play a role in the development of East Asian summer monsoon errors, with the Indian summer monsoon region providing an additional contribution, while the errors over the Indian summer monsoon region itself appear to arise locally. Regional modelling with various lateral boundary locations helps to separate local and remote contributions to the errors, while regional relaxation experiments shed light on the influence of errors developing within particular areas on the region as a whole.

Serotonin plays an important role in the development of brainstem circuits that control breathing. Here, we test the hypothesis that developmental nicotine exposure (DNE) alters the breathing-related motor response to serotonin (5HT). Pregnant rats were exposed to nicotine or saline, and brainstem-spinal cord preparations from 1- to 5-day-old pups were studied in a split-bath configuration, allowing drugs to be applied selectively to the medulla or spinal cord. The activity of the fourth cervical ventral nerve roots (C4VR), which contain axons of phrenic motoneurons, was recorded. We applied 5HT alone or together with antagonists of 5HT1A, 5HT2A, or 5HT7 receptor subtypes. In control preparations, 5HT applied to the medulla consistently reduced C4VR frequency and this reduction could not be blocked by any of the three antagonists. In DNE preparations, medullary 5HT caused a large and sustained frequency increase (10 min), followed by a sustained decrease. Notably, the transient increase in frequency could be blocked by the independent addition of any of the antagonists. Experiments with subtype-specific agonists suggest that the 5HT7 subtype may contribute to the increased frequency response in the DNE preparations. Changes in C4VR burst amplitude in response to brainstem 5HT were uninfluenced by DNE. Addition of 5HT to the caudal chamber modestly increased phasic and greatly increased tonic C4VR activity, but there were no effects of DNE. The data show that DNE alters serotonergic signaling within brainstem circuits that control respiratory frequency but does not functionally alter serotonin signaling in the phrenic motoneuron pool.

In this paper, we propose a new random forest method based on completely randomized splitting rules with an acceptance–rejection criterion for quality control. We show how the proposed acceptance–rejection (AR) algorithm can outperform the standard random forest algorithm (RF) and some of its variants including extremely randomized (ER) trees and smooth sigmoid surrogate (SSS) trees. Twenty datasets were analyzed to compare prediction performance and a simulated dataset was used to assess variable selection bias. In terms of prediction accuracy for classification problems, the proposed AR algorithm performed the best, with ER being the second best. For regression problems, RF and SSS performed the best, followed by AR, and then ER at the last. However, each algorithm was most accurate for at least one study. We investigate scenarios where the AR algorithm can yield better predictive performance. In terms of variable importance, both RF and SSS demonstrated selection bias in favor of variables with many possible splits, while both ER and AR largely removed this bias.

Background: When performing a medial patellofemoral ligament (MPFL) reconstruction, surgeons may place the MPFL graft under higher than anatomic tension to minimize the chance of recurrent instability. Purpose: To investigate whether a lateral retinacular release (LRR) significantly decreases patellofemoral contact pressures after an overtensioned (OT) MPFL reconstruction. Study Design: Controlled laboratory study. Methods: Mean and peak pressure across the patellofemoral joint at 30°, 45°, and 60° of flexion was assessed in 14 cadaveric knee specimens with intact MPFL, transected MPFL, reconstructed MPFL with graft OT, and OT MPFL with LRR. The Wilcoxon signed rank test was used to determine differences across states, with W and C values calculated when possible. Results: Mean pressure decreased significantly after MPFL transection compared with intact at 30° (456.9 ± 116.8 vs 410.9 ± 109.4 N, P = .006, W < 7) and 45° (404.9 ± 91.7 vs 369.4 ± 85.3 N, P = .005, W < 5) and increased significantly from intact to OT graft at 30° (456.9 ± 116.8 vs 563.0 ± 11.2 N, P = .003, W < 7), 45° (404.9 ± 91.7 vs 481.4 ± 14.8 N, P = .005, W < 5), and 60° (272.9 ± 139.0 vs 367.0 ± 53.7 N, P = .007, W < 3). Peak pressure increased significantly between intact and OT graft at 30° (1364.0 ± 478.2 vs 2094.4 ± 619.8 N, P = .002, W < 9), 45° (1224.7 ± 491.5 vs 1676.7 ± 779.1 N, P = .005, W < 5), and 60° (1117.7 ± 566.8 vs 1604.2 ± 772.9 N, W < 3). In knees with significantly increased mean pressure after overtensioning, mean pressure increased by 23.3% (11/14 knees) at 30°, 18.3% (10/14 knees) at 45°, and 35.0% (10/14 knees) at 60°. Peak pressure increased significantly by 35.3% (30°), 25.2% (45°), and 29.3% (60°). A significant decrease in mean pressure, toward but not to baseline, was observed between the OT and LRR states at 30° (563.0 ± 11.2 vs 501.5 ± 9.3 N, W < 7) and 60° (367.0 ± 53.7 vs 302.0 ± 13.8 N, W < 5) and a decrease in peak pressure at 30° (2094.4 ± 619.8 vs 1886.5 ± 655.3 N; W < 9). Conclusion: LRR led to a statistically significant decrease in pressure across the patellofemoral joint in knees that demonstrated increased contact pressures after an OT MPFL graft. Clinical Relevance: LRR after an MPFL reconstruction in which the MPFL graft has been OT may help reduce patellofemoral contact pressures at the time of surgery.

We tested the hypothesis that nicotine exposure in utero and after birth [developmental nicotine exposure (DNE)] disrupts development of glycinergic synaptic transmission to hypoglossal motoneurons (XIIMNs). Glycinergic spontaneous and miniature inhibitory postsynaptic currents (sIPSC/mIPSC) were recorded from XIIMNs in brain stem slices from 1- to 5-day-old rat pups of either sex, under baseline conditions and following stimulation of nicotinic acetylcholine (ACh) receptors with nicotine (i.e., an acute nicotine challenge). Under baseline conditions, there were no significant effects of DNE on the amplitude or frequency of either sIPSCs or mIPSCs. In addition, DNE did not alter the magnitude of the whole cell current evoked by bath application of glycine, consistent with an absence of change in postsynaptic glycine-mediated conductance. An acute nicotine challenge (bath application of 0.5 μM nicotine) increased sIPSC frequency in the DNE cells, but not control cells. In contrast, nicotine challenge did not change mIPSC frequency in either control or DNE cells. In addition, there were no significant changes in the amplitude of either sIPSCs or mIPSCs in response to nicotine challenge. The increased frequency of sIPSCs in response to an acute nicotine challenge in DNE cells reflects an enhancement of action potential-mediated input from glycinergic interneurons to hypoglossal motoneurons. This could lead to more intense inhibition of hypoglossal motoneurons in response to exogenous nicotine or endogenous ACh. The former would occur with smoking or e-cigarette use while the latter occurs with changes in sleep state and with hypercapnia.NEW & NOTEWORTHY Here we show that perinatal nicotine exposure does not impact baseline glycinergic neurotransmission to hypoglossal motoneurons but enhances glycinergic inputs to hypoglossal motoneurons in response to activation of nicotinic acetylcholine (ACh) receptors with acute nicotine. Given that ACh is the endogenous ligand for nicotinic ACh receptors, the latter reveals a potential mechanism whereby perinatal nicotine exposure alters motor function under conditions where ACh release increases, such as the transition from non-rapid-eye movement to rapid-eye movement sleep, and during hypercapnia.

Assessing heterogeneous treatment effects has become a growing interest in advancing precision medicine. Individualized treatment effects (ITE) play a critical role in such an endeavor. Concerning experimental data collected from randomized trials, we put forward a method, termed random forests of interaction trees (RFIT), for estimating ITE on the basis of interaction trees (Su et al., 2009). To this end, we first propose a smooth sigmoid surrogate (SSS) method, as an alternative to greedy search, to speed up tree construction. RFIT outperforms the traditional `separate regression' approach in estimating ITE. Furthermore, standard errors for the estimated ITE via RFIT can be obtained with the infinitesimal jackknife method. We assess and illustrate the use of RFIT via both simulation and the analysis of data from an acupuncture headache trial., 32 pages, 6 figures

Statistical predictive models play an important role in learning analytics. In this work, we seek to harness the power of predictive modeling methodology for the development of an analytics framewo...

KEY POINTS Critical homeostatic behaviours such as suckling, swallowing and breathing depend on the precise control of tongue muscle activity. Perinatal nicotine exposure has multiple effects on baseline inhibitory GABAergic neurotransmission to hypoglossal motoneurons (XIIMNs), consistent with homeostatic compensations directed at maintaining normal motoneuron output. Developmental nicotine exposure (DNE) alters how GABAergic neurotransmission is modulated by acute activation of nicotinic acetylcholine receptors, which may provide insight into mechanisms by which nicotine exposure alters motor function under conditions that result in increased release of GABA, such as hypoxia, or endogenous acetylcholine, as occurs in the transition from NREM to REM sleep, or in response to exogenous nicotine. ABSTRACT Nicotinic acetylcholine receptor (nAChR) signalling regulates neuronal differentiation and synaptogenesis. Here we test the hypothesis that developmental nicotine exposure (DNE) disrupts the development of GABAergic synaptic transmission to hypoglossal motoneurons (XIIMNs). GABAergic spontaneous and miniature inhibitory postsynaptic currents (sIPSCs/mIPSCs) were recorded from XIIMNs in brainstem slices from control and DNE rat pups of either sex, 1-5 days old, at baseline and following acute stimulation of nAChRs with nicotine. At baseline, sIPSCs were less frequent and smaller in DNE cells (consistent with decreased action potential-mediated GABA release), and mIPSCs were more frequent (consistent with increased vesicular GABA release from presynaptic terminals). Acute nicotine challenge increased sIPSC frequency in both groups, though the increase was greater in DNE cells. Acute nicotine challenge did not change the frequency of mIPSCs in either group, though mIPSC amplitude increased significantly in DNE cells, but not control cells. Stimulation of postsynaptic GABAA receptors with muscimol caused a significantly greater chloride current in DNE cells than in control cells. The increased quantal release of GABA, coupled with the rise in the strength of postsynaptic inhibition may be homeostatic adjustments to the decreased action-potential-mediated input from GABAergic interneurons. However, this will exaggerate synaptic inhibition under conditions where the release of GABA (e.g. hypoxia) or ACh (sleep-wake transitions) is increased. These findings reveal a mechanism that may explain why DNE is associated with deficits in the ability to respond appropriately to chemosensory stimuli or to changes in neuromodulation secondary to changes in central nervous system state.

Estimating the efficacy of different instructional modalities, techniques, and interventions is challenging because teaching style covaries with instructor, and the typical student only takes a course once. We introduce the individualized treatment effect (ITE) from analyses of personalized medicine as a means to quantify individual student performance under different instructional modalities or intervention strategies, despite the fact that each student may experience only one “treatment.” The ITE is presented within an ensemble machine learning approach to evaluate student performance, identify factors indicative of student success, and estimate persistence. A key element is the use of a priori student information from institutional records. The methods are motivated and illustrated by a comparison of online and standard face-to-face offerings of an upper division applied statistics course that is a curriculum bottleneck at San Diego State University. The ITE allows us to characterize students that benefit from either the online or the traditional offerings. We find that students in the online class performed at least as well as the traditional lecture class on a common final exam. We discuss the general implications of this analytics framework for assessing pedagogical innovations and intervention strategies, identifying and characterizing at-risk students, and optimizing the individualized student learning environment.

Developmental nicotine exposure (DNE) is associated with increased risk of cardiorespiratory, intellectual, and behavioral abnormalities in neonates, and is a risk factor for apnea of prematurity, altered arousal responses and Sudden Infant Death Syndrome. Alterations in nicotinic acetylcholine receptor signaling (nAChRs) after DNE lead to changes in excitatory neurotransmission in neural networks that control breathing, including a heightened excitatory response to AMPA microinjection into the hypoglossal motor nucleus. Here, we report on experiments designed to probe possible postsynaptic and presynaptic mechanisms that may underlie this plasticity. Pregnant dams were exposed to nicotine or saline via an osmotic mini-pump implanted on the 5th day of gestation. We used whole-cell patch clamp electrophysiology to record from hypoglossal motoneurons (XIIMNs) in thick medullary slices from neonatal rat pups (N= 26 control and 24 DNE cells). To enable the translation of our findings to breathing-related consequences of DNE, we only studied XIIMNs that were receiving rhythmic excitatory drive from the respiratory central pattern generator. Tetrodotoxin was used to isolate XIIMNs from presynaptic input, and their postsynaptic responses to bath application of L-glutamic acid (glutamate) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) were studied under voltage clamp. DNE had no influence on inward current magnitude evoked by either glutamate or AMPA. However, in cells from DNE animals, bath application of AMPA was associated with a right shift in the amplitude distribution (P = 0.0004), but no change in the inter-event interval distribution of miniature excitatory postsynaptic currents (mEPSCs). DNE had no influence on mEPSC amplitude or frequency evoked by glutamate application, or under (unstimulated) baseline conditions. Thus, in the presence of AMPA, DNE is associated with a small but significant increase in quantal size, but no change in the probability of glutamate release.

The mammalian tongue contains eight muscles that collaborate to ensure that suckling, swallowing, and other critical functions are robust and reliable. Seven of the eight tongue muscles are innervated by hypoglossal motoneurons (XIIMNs). A somatotopic organization of the XII motor nucleus, defined in part by the mechanical action of a neuron’s target muscle, has been described, but whether or not XIIMNs within a compartment are functionally specialized is unsettled. We hypothesize that developing XIIMNs are assigned unique functional properties that reflect the challenges that their target muscle faces upon the transition from in utero to terrestrial life. To address this, we studied XIIMNs that innervate intrinsic and extrinsic tongue muscles, because intrinsic muscles play a more prominent role in suckling than the extrinsic muscles. We injected dextran-rhodamine into the intrinsic longitudinal muscles (IL) and the extrinsic genioglossus, and physiologically characterized the labeled XIIMNs. Consistent with earlier work, IL XIIMNs ( n = 150) were located more dorsally within the nucleus, and GG XIIMNs ( n = 55) more ventrally. Whole cell recordings showed that resting membrane potential was, on average, 9 mV more depolarized in IL than in GG XIIMNs ( P = 0.0019), and the firing threshold in response to current injection was lower in IL (−31 ± 23 pA) than in GG XIIMNs (225 ± 39 pA; P < 0.0001). We also found that the appearance of net outward currents in GG XIIMNs occurred at more hyperpolarized membrane potentials than IL XIIMNs, consistent with lower excitability in GG XIIMNs. These observations document muscle-specific functional specializations among XIIMNs. NEW & NOTEWORTHY The hypoglossal motor nucleus contains motoneurons responsible for innervating one of seven different muscles with notably different biomechanics and patterns of use. Whether or not motoneurons innervating the different muscles also have unique functional properties (e.g., spiking behavior, synaptic physiology) is poorly understood. In this work we show that neonatal hypoglossal motoneurons innervating muscles that shape the tongue (intrinsic longitudinal muscles) have different electrical properties than those innervating the genioglossus, which controls tongue position.

Interrater reliability studies are used in a diverse set of fields. Often, these investigations involve three or more raters, and thus, require the use of indices such as Fleiss’s kappa, Conger’s kappa, or Krippendorff’s alpha. Through two motivating examples—one theoretical and one from practice—this article exposes limitations of these indices when the units to be rated are not well-distributed across the rating categories. Then, using a Monte Carlo simulation and information visualizations, we argue for the use of two alternative indices, the Brennan–Prediger coefficient and Gwet’s AC2, because the agreement levels reported by these indices are more robust to variation in the distribution of units that raters encounter. The article concludes by exploring the complex, interwoven relationship between the number of levels in a rating instrument, the agreement level present among raters, and the distribution of units that are to be scored. Supplementary materials for this article are available online.

Prenatal nicotine exposure with continued exposure through breast milk over the first week of life (developmental nicotine exposure, DNE) alters the development of brainstem circuits that control breathing. Here, we test the hypothesis that DNE alters the respiratory motor response to endogenous and exogenous acetylcholine (ACh) in neonatal rats. We used the brainstem-spinal cord preparation in the split-bath configuration, and applied drugs to the brainstem compartment while measuring the burst frequency and amplitude of the fourth cervical ventral nerve roots (C4VR), which contain the axons of phrenic motoneurons. We applied ACh alone; the nicotinic acetylcholine receptor (nAChR) antagonist curare, either alone or in the presence of ACh; and the muscarinic acetylcholine receptor (mAChR) antagonist atropine, either alone or in the presence of ACh. The main findings include: (1) atropine reduced frequency similarly in controls and DNE animals, while curare caused modest slowing in controls but no consistent change in DNE animals; (2) DNE greatly attenuated the increase in C4VR frequency mediated by exogenous ACh; (3) stimulation of nAChRs with ACh in the presence of atropine increased frequency markedly in controls, but not DNE animals; (4) stimulation of mAChRs with ACh in the presence of curare caused a modest increase in frequency, with no treatment group differences. DNE blunts the response of the respiratory central pattern generator to exogenous ACh, consistent with reduced availability of functionally competent nAChRs; DNE did not alter the muscarinic control of respiratory motor output. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1138-1149, 2016.

Maternal smoking or use of other products containing nicotine during pregnancy can have significant adverse consequences for respiratory function in neonates. We have shown, in previous studies, that developmental nicotine exposure (DNE) in a model system compromises the normal function of respiratory circuits within the brainstem. The effects of DNE include alterations in the excitability and synaptic interactions of the hypoglossal motoneurons, which innervate muscles of the tongue. This study was undertaken to test the hypothesis that these functional consequences of DNE are accompanied by changes in the dendritic morphology of hypoglossal motoneurons. Hypoglossal motoneurons in brain stem slices were filled with neurobiotin during whole-cell patch clamp recordings and subjected to histological processing to reveal dendrites. Morphometric analysis, including the Sholl method, revealed significant effects of DNE on dendritic branching patterns. In particular, whereas within the first five postnatal days there was significant growth of the higher-order dendritic branches of motoneurons from control animals, the growth was compromised in motoneurons from neonates that were subjected to DNE. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1125-1137, 2016.

Nocturnal hypoglycemia is a common phenomenon among patients with diabetes and can lead to a broad range of adverse events and complications. Identifying factors associated with hypoglycemia can improve glucose control and patient care. We propose a repeated measures random forest (RMRF) algorithm that can handle nonlinear relationships and interactions and the correlated responses from patients evaluated over several nights. Simulation results show that our proposed algorithm captures the informative variable more often than naively assuming independence. RMRF also outperforms standard random forest and extremely randomized trees algorithms. We demonstrate scenarios where RMRF attains greater prediction accuracy than generalized linear models. We apply the RMRF algorithm to analyze a diabetes study with 2524 nights from 127 patients with type 1 diabetes. We find that nocturnal hypoglycemia is associated with HbA1c, bedtime blood glucose (BG), insulin on board, time system activated, exercise intensity, and daytime hypoglycemia. The RMRF can accurately classify nights at high risk of nocturnal hypoglycemia.

Smoothly graded muscle contractions depend in part on the precision and reliability of motoneuron action potential generation. Whether or not a motoneuron generates spikes precisely and reliably depends on both its intrinsic membrane properties and the nature of the synaptic input that it receives. Factors that perturb neuronal intrinsic properties and/or synaptic drive may compromise the temporal precision and the reliability of action potential generation. We have previously shown that developmental nicotine exposure (DNE) alters intrinsic properties and synaptic transmission in hypoglossal motoneurons (XIIMNs). Here we show that the effects of DNE also include alterations in spike-timing precision and reliability, and spike-frequency adaptation, in response to sinusoidal current injection. Current-clamp experiments in brainstem slices from neonatal rats show that DNE lowers the threshold for spike generation but increases the variability of spike-timing mechanisms. DNE is also associated with an increase in spike-frequency adaptation and reductions in both peak and steady-state firing rate in response to brief, square wave current injections. Taken together, our data indicate that DNE causes significant alterations in the input-output efficiency of XIIMNs. These alterations may play a role in the increased frequency of obstructive apneas and altered suckling strength and coordination observed in nicotine-exposed neonatal humans.

While genome-wide association studies (GWAS) have discovered thousands of risk loci for heritable disorders, so far even very large meta-analyses have recovered only a fraction of the heritability of most complex traits. Recent work utilizing variance components models has demonstrated that a larger fraction of the heritability of complex phenotypes is captured by the additive effects of SNPs than is evident only in loci surpassing genome-wide significance thresholds, typically set at a Bonferroni-inspired $p\le5\times10^{-8}$. Procedures that control false discovery rate can be more powerful, yet these are still under-powered to detect the majority of nonnull effects from GWAS. The current work proposes a novel Bayesian semiparametric two-group mixture model and develops a Markov Chain Monte Carlo (MCMC) algorithm for a covariate-modulated local false discovery rate (cmfdr). The probability of being nonnull depends on a set of covariates via a logistic function, and the nonnull distribution is approximated as a linear combination of B-spline densities, where the weight of each B-spline density depends on a multinomial function of the covariates. The proposed methods were motivated by work on a large meta-analysis of schizophrenia GWAS performed by the Psychiatric Genetics Consortium (PGC). We show that the new cmfdr model fits the PGC schizophrenia GWAS test statistics well, performing better than our previously proposed parametric gamma model for estimating the nonnull density and substantially improving power over usual fdr. Using loci declared significant at cmfdr $\le0.20$, we perform follow-up pathway analyses using the Kyoto Encyclopedia of Genes and Genomes (KEGG) Homo sapiens pathways database. We demonstrate that the increased yield from the cmfdr model results in an improved ability to test for pathways associated with schizophrenia compared to using those SNPs selected according to usual fdr.

While genome-wide association studies (GWAS) have discovered thousands of risk loci for heritable disorders, so far even very large meta-analyses have recovered only a fraction of the heritability of most complex traits. Recent work utilizing variance components models has demonstrated that a larger fraction of the heritability of complex phenotypes is captured by the additive effects of SNPs than is evident only in loci surpassing genome-wide significance thresholds, typically set at a Bonferroni-inspired p ≤ 5 x 10-8. Procedures that control false discovery rate can be more powerful, yet these are still under-powered to detect the majority of non-null effects from GWAS. The current work proposes a novel Bayesian semi-parametric two-group mixture model and develops a Markov Chain Monte Carlo (MCMC) algorithm for a covariate-modulated local false discovery rate (cmfdr). The probability of being non-null depends on a set of covariates via a logistic function, and the non-null distribution is approximated as a linear combination of B-spline densities, where the weight of each B-spline density depends on a multinomial function of the covariates. The proposed methods were motivated by work on a large meta-analysis of schizophrenia GWAS performed by the Psychiatric Genetics Consortium (PGC). We show that the new cmfdr model fits the PGC schizophrenia GWAS test statistics well, performing better than our previously proposed parametric gamma model for estimating the non-null density and substantially improving power over usual fdr. Using loci declared significant at cmfdr ≤ 0.20, we perform follow-up pathway analyses using the Kyoto Encyclopedia of Genes and Genomes (KEGG) homo sapiens pathways database. We demonstrate that the increased yield from the cmfdr model results in an improved ability to test for pathways associated with schizophrenia compared to using those SNPs selected according to usual fdr.

Neurons in the arcuate nucleus that coexpress kisspeptin, neurokinin B (NKB), and dynorphin (KNDy neurons) play an important role in the modulation of reproduction by estrogens. Here, we study the anatomical and electrophysiological properties of arcuate NKB neurons in heterozygous female transgenic mice with enhanced green fluorescent protein (EGFP) under the control of the Tac2 (NKB) promoter (Tac2-EGFP mice). The onset of puberty, estrous cyclicity, and serum LH were comparable between Tac2-EGFP and wild-type mice. The location of EGFP-immunoreactive neurons was consistent with previous descriptions of Tac2 mRNA-expressing neurons in the rodent. In the arcuate nucleus, nearly 80% of EGFP neurons expressed pro-NKB-immunoreactivity. Moreover, EGFP fluorescent intensity in arcuate neurons was increased by ovariectomy and reduced by 17β-estradiol (E2) treatment. Electrophysiology of single cells in tissue slices was used to examine the effects of chronic E2 treatment on Tac2-EGFP neurons in the arcuate nucleus of ovariectomized mice. Whole-cell recordings revealed arcuate NKB neurons to be either spontaneously active or silent in both groups. E2 had no significant effect on the basic electrophysiological properties or spontaneous firing frequencies. Arcuate NKB neurons exhibited either tonic or phasic firing patterns in response to a series of square-pulse current injections. Notably, E2 reduced the number of action potentials evoked by depolarizing current injections. This study demonstrates the utility of the Tac2-EGFP mouse for electrophysiological and morphological studies of KNDy neurons in tissue slices. In parallel to E2 negative feedback on LH secretion, E2 decreased the intensity of the EGFP signal and reduced the excitability of NKB neurons in the arcuate nucleus of ovariectomized Tac2-EGFP mice.

This tutorial presents topic models for organizing and comparing documents. The technique and corresponding discussion focuses on analysis of short text documents, particularly micro-blogs. However, the base topic model and R implementation are generally applicable to text analytics of document databases.

Nicotine exposure during the fetal and neonatal periods (Developmental nicotine exposure, DNE) is associated with ineffective upper airway protective reflexes in infants. This could be explained by desensitized chemoreceptors and/or mechanoreceptors, diminished neuromuscular transmission or altered synaptic transmission among central neurons, as each of these systems depend in part on cholinergic signaling through nicotinic acetylcholine receptors (nAChRs). Here we showed that DNE blunts the response of the genioglossus muscle to nasal airway occlusion in lightly anesthetized rat pups. The genioglossus muscle helps keep the upper airway open and is innervated by hypoglossal motoneurons (XIIMNs). Experiments using the phrenic nerve-diaphragm preparation showed that DNE does not alter transmission across the neuromuscular junction. Accordingly, we used whole cell recordings from XIIMNs in brainstem slices to examine the influence of DNE on glutamatergic synaptic transmission under baseline conditions and in response to an acute nicotine challenge. DNE did not alter excitatory transmission under baseline conditions. Analysis of cumulative probability distributions revealed that acute nicotine challenge of P1-P2 preparations resulted in an increase in the frequency of nicotine-induced glutamatergic inputs to XIIMNs in both control and DNE. By contrast, P3-P5 DNE pups showed a decrease, rather than an increase in frequency. We suggest that this, together with previous studies showing that DNE is associated with a compensatory increase in inhibitory synaptic input to XIIMNs, leads to an excitatory-inhibitory imbalance. This imbalance may contribute to the blunting of airway protective reflexes observed in nicotine exposed animals and human infants. Significance statement The number one risk factor for sudden infant death (SIDS) is maternal smoking. While the use of nicotine delivery devices such as e-cigarettes is increasing among women of childbearing age, reflecting the belief that the use of nicotine alone is safer than tobacco, SIDS deaths are not decreasing, suggesting that nicotine is the link between maternal smoking and SIDS. Here we show that perinatal nicotine exposure alters a major motor pathway responsible for upper airway patency during sleep. We also introduce an animal model that is well suited to probing the mechanisms underlying the link between maternal nicotine consumption and SIDS, and a phenotype that nicely models key aspects of the events believed to give rise to SIDS.

Glaucoma is a chronic, progressive and potentially blinding condition. Predicting which patients will experience significant progression is recognized as a crucially needed development in the management of this disease. Application of the CART (Classification And Regression Trees) methodology has demonstrated that certain patterns of visual field findings may convey greater predictive information for glaucoma progression. However, the current standard classification tree method was developed for uncorrelated data. In this article a classification tree method is extended to correlated binary data. The robust Wald test statistic from generalized estimating equations (GEE) is used to measure the between-node difference while adjusting for correlation between the eyes of a patient. The proposed method is assessed through simulations conducted under a variety of model configurations and is used to analyze the perimetry and psychophysics in glaucoma (PPIG) study data. Employing an amalgamation algorithm from the result of a best-sized tree, each eye is classified to one of two prognosis categories (less likely, or more likely, to progress). Receiver operating characteristics (ROC) and area under the curve (AUC) indicate that the proposed method, applied to data from both eyes of the same patient, provides much improved prediction accuracy compared with application of standard CART method to the same PPIG data.

We previously showed that nicotine exposure in utero and after birth via breast milk [developmental nicotine exposure (DNE)] is associated with many changes in the structure and function of hypoglossal motoneurons (XIIMNs), including a reduction in the size of the dendritic arbor and an increase in cell excitability. Interestingly, the elevated excitability was associated with a reduction in the expression of glutamate receptors on the cell body. Together, these observations are consistent with a homeostatic compensation aimed at restoring cell excitability. Compensation for increased cell excitability could also occur by changing potassium conductance, which plays a critical role in regulating resting potential, spike threshold, and repetitive spiking behavior. Here we test the hypothesis that the previously observed increase in the excitability of XIIMNs from DNE animals is associated with an increase in whole cell potassium currents. Potassium currents were measured in XIIMNs in brain stem slices derived from DNE and control rat pups ranging in age from 0 to 4 days by whole cell patch-clamp electrophysiology. All currents were measured after blockade of action potential-dependent synaptic transmission with tetrodotoxin. Compared with control cells, XIIMNs from DNE animals showed significantly larger transient and sustained potassium currents, but this was observed only under conditions of increased cell and network excitability, which we evoked by raising extracellular potassium from 3 to 9 mM. These observations suggest that the larger potassium currents in nicotine-exposed neurons are an important homeostatic compensation that prevents “runaway” excitability under stressful conditions, when neurons are receiving elevated excitatory synaptic input. NEW & NOTEWORTHY Developmental nicotine exposure is associated with increased cell excitability, which is often accompanied by compensatory changes aimed at normalizing excitability. Here we show that whole cell potassium currents are also increased in hypoglossal motoneurons from nicotine-exposed neonatal rats under conditions of increased cell and network excitability. This is consistent with a compensatory response aimed at preventing instability under conditions in which excitatory synaptic input is high and is compatible with the concept of homeostatic plasticity.

We propose a new sparse estimation method, termed MIC (Minimum approximated Information Criterion), for generalized linear models (GLM) in fixed dimensions. What is essentially involved in MIC is the approximation of the $\ell_0$-norm with a continuous unit dent function. Besides, a reparameterization step is devised to enforce sparsity in parameter estimates while maintaining the smoothness of the objective function. MIC yields superior performance in sparse estimation by optimizing the approximated information criterion without reducing the search space and is computationally advantageous since no selection of tuning parameters is required. Moreover, the reparameterization tactic leads to valid significance testing results that are free of post-selection inference. We explore the asymptotic properties of MIC and illustrate its usage with both simulated experiments and empirical examples., 23 pages, 3 figures

A community diagnostics and performance metrics tool for the evaluation of Earth system models (ESMs) has been developed that allows for routine comparison of single or multiple models, either against predecessor versions or against observations. The priority of the effort so far has been to target specific scientific themes focusing on selected essential climate variables (ECVs), a range of known systematic biases common to ESMs, such as coupled tropical climate variability, monsoons, Southern Ocean processes, continental dry biases, and soil hydrology–climate interactions, as well as atmospheric CO2 budgets, tropospheric and stratospheric ozone, and tropospheric aerosols. The tool is being developed in such a way that additional analyses can easily be added. A set of standard namelists for each scientific topic reproduces specific sets of diagnostics or performance metrics that have demonstrated their importance in ESM evaluation in the peer-reviewed literature. The Earth System Model Evaluation Tool (ESMValTool) is a community effort open to both users and developers encouraging open exchange of diagnostic source code and evaluation results from the Coupled Model Intercomparison Project (CMIP) ensemble. This will facilitate and improve ESM evaluation beyond the state-of-the-art and aims at supporting such activities within CMIP and at individual modelling centres. Ultimately, we envisage running the ESMValTool alongside the Earth System Grid Federation (ESGF) as part of a more routine evaluation of CMIP model simulations while utilizing observations available in standard formats (obs4MIPs) or provided by the user., Geoscientific Model Development, 9 (5), ISSN:1991-9603, ISSN:1991-959X

The Florida Initiative for Quality Cancer Care (FIQCC) was established to evaluate the quality of cancer care at the regional level across the state of Florida. This study assessed adherence to validated quality indicators in colorectal cancer (CRC) and the variability in adherence by practice site, volume, and patient age.The FIQCC is a consortium of 11 medical oncology practices in Florida. Medical record reviews were conducted for 507 patients diagnosed with CRC and seen as new medical oncology patients in 2006. Thirty-five indicators were evaluated individually and categorized across clinical domains and components of care.The mean adherence for 19 of 35 individual indicators was85%. Pathology reports were compliant on reporting depth of tumor invasion (96%; range, 86% to 100%), grade (93%; range, 72% to 100%), and status of proximal and distal surgical resection margins (97%; range. 86% to 100%); however, documentation of lymphovascular and perineural invasion did not meet adherence standards (76%; range, 53% to 100% and 39%; range, 5% to 83%, respectively). Among patients with nonmetastatic rectal cancer, documentation of the status of surgical radial margins was consistently low across sites (42%; range, 0% to 100%; P = .19). Documentation of planned treatment regimens for adjuvant chemotherapy was noted in only 58% of eligible patients.In this large regional initiative, we found high levels of adherence to more than half of the established quality indicators. Although the quality of care delivered within FIQCC practices seems to be high, several components of care were identified that warrant further scrutiny on both a systemic level and at individual centers.

Diversity in the expression of K+channels among neurons allows a wide range of excitability, growth, and functional regulation. Ether-à-go-go (EAG), a voltage-gated K+channel, was first characterized in Drosophila mutants by spontaneous firing in nerve terminals and enhanced neurotransmitter release. Although diverse functions have been ascribed to this protein, its role within neurons remains poorly understood. The aim of this study was to characterize the function of EAG in situ in Drosophila larval motoneurons. Whole cell patch-clamp recordings performed from the somata revealed a decrease in IAvand IKvK+currents in eag mutants and with targeted eag RNAi expression. Spontaneous spike-like events were observed in eag mutants but absent in wild-type motoneurons. Thus our results provide evidence that EAG represents a unique K+channel contributing to multiple K+currents in motoneurons helping to regulate excitability, consistent with previous observations in the Drosophila larval muscle.

Potassium currents play key roles in regulating motoneuron activity, including functional specializations that are important for locomotion. The thoracic and abdominal segments in the Drosophila larval ganglion have repeated arrays of motoneurons that innervate body-wall muscles used for peristaltic movements during crawling. Although abdominal motoneurons and their muscle targets have been studied in detail, owing, in part, to their involvement in locomotion, little is known about the cellular properties of motoneurons in thoracic segments. The goal of this study was to compare firing properties among thoracic motoneurons and the potassium currents that influence them. Whole-cell, patch-clamp recordings performed from motoneurons in two thoracic and one abdominal segment revealed both transient and sustained voltage-activated K+currents, each with Ca++-sensitive and Ca++-insensitive [A-type, voltage-dependent transient K+current (IAv)] components. Segmental differences in the expression of voltage-activated K+currents were observed. In addition, we demonstrate that Shal contributes to IAvcurrents in the motoneurons of the first thoracic segment.

Key points • Neurons in the brain express a diversity of ion channels to impart specialized functional properties. • At least three distinct voltage gated calcium channel gene families are known, each of which is thought to produce calcium channels with unique properties, which in turn, differently affect neuronal function. • Here we use a genetic model system to determine which genes are responsible for the calcium currents in an identified motoneuron. • Surprisingly, the same ion channel gene encodes two distinct currents with fundamentally different properties, and the data also suggest that the normal function of this calcium channel gene is affected by the expression of another one. • The results provide insights into the relationship between gene expression and ionic currents, and thus, into the regulation of normal neuronal function. Abstract Different blends of membrane currents underlie distinct functions of neurons in the brain. A major step towards understanding neuronal function, therefore, is to identify the genes that encode different ionic currents. This study combined in situ patch clamp recordings of somatodendritic calcium currents in an identified adult Drosophila motoneuron with targeted genetic manipulation. Voltage clamp recordings revealed transient low voltage-activated (LVA) currents with activation between –60 mV and –70 mV as well as high voltage-activated (HVA) current with an activation voltage around –30 mV. LVA could be fully inactivated by prepulses to –50 mV and was partially amiloride sensitive. Recordings from newly generated mutant flies demonstrated that DmαG (Cav3 homolog) encoded the amiloride-sensitive portion of the transient LVA calcium current. We further demonstrated that the Cav2 homolog, Dmca1A, mediated the amiloride-insensitive component of LVA current. This novel role of Cav2 channels was substantiated by patch clamp recordings from conditional mutants, RNAi knock-downs, and following Dmca1A overexpression. In addition, we show that Dmca1A underlies the HVA somatodendritic calcium currents in vivo. Therefore, the Drosophila Cav2 homolog, Dmca1A, underlies HVA and LVA somatodendritic calcium currents in the same neuron. Interestingly, DmαG is required for regulating LVA and HVA derived from Dmca1A in vivo. In summary, each vertebrate gene family for voltage-gated calcium channels is represented by a single gene in Drosophila, namely Dmca1D (Cav1), Dmca1A (Cav2) and DmαG (Cav3), but the commonly held view that LVA calcium currents are usually mediated by Cav3 rather than Cav2 channels may require reconsideration.

Neuronal nicotinic acetylcholine receptors (nAChRs) are expressed on hypoglossal motor neurons (XII MNs) that innervate muscles of the tongue. Activation of XII MN nAChRs evokes depolarizing currents, which are important for regulating the size and stiffness of the upper airway. Although data show that chronic developmental nicotine exposure (DNE) blunts cholinergic neurotransmission in the XII motor nucleus, it is unclear how nAChRs are involved. Therefore, XII MN nAChR desensitization and recovery were examined in tissues from DNE or control pups using a medullary slice preparation and tight-seal whole cell patch-clamp recordings. nAChR-mediated inward currents were evoked by brief pressure pulses of nicotine or the α4β2 nAChR agonist RJR-2403. We found that, regardless of treatment, activatable nAChRs underwent desensitization, but, following DNE, nAChRs exhibited increased desensitization and delayed recovery. Similar results were produced using RJR-2403, showing that DNE influences primarily the α4β2 nAChR subtype. These results show that while some nAChRs preserve their responsiveness to acute nicotine following DNE, they more readily desensitize and recover more slowly from the desensitized state. These data provide new evidence that chronic DNE modulates XII MN nAChR function, and suggests an explanation for the association between DNE and the incidence of central and obstructive apneas.

Objective: To test the hypothesis that high circulating concen-trations of maternal anti-angiogenic factors are associated with increased risk of respiratory distress syndrome (RDS). Study Design: This is a nested case-control study of nulliparous women who delivered less than 37 weeks of gestation within the Calcium for Preeclampsia Prevention (CPEP) trial. The study included 116 women with preeclampsia or gestational hyperten-sion and 323 normotensive controls. Soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endo-glin (sEng) in maternal serum were measured at 21–32 weeks of gestation. Results: Preterm infants born to hypertensive mothers were more likely to develop RDS (22.5% vs. 20.9%, p =0.03). After adjustment for gestational age at delivery, the odds ratio for the relationship between hypertension in pregnancy and RDS was 2.18 (95% CI 1.08–4.39). In hypertensive pregnancies women whose infants developed RDS had significantly higher circulating mean sFlt1 levels during midpregnancy (21–32 weeks of gestation) even after adjustment for gestational age at delivery (21,516 pg/mL vs. 7,000 pg/mL, p =0.01). Conclusions: Preterm preeclampsia and gestational hypertension, charac-terized by high circulating levels of sFlt1, are associated with a twofold increased risk of RDS in infants delivered before 37 weeks. Among women with these hypertensive pregnancies circulating sFlt1 concentrations during midpregnancy were substantially higher in women whose infants developed RDS.

The development of an accurate prognosis is an integral component of treatment planning in the practice of periodontics. Prior work has evaluated the validity of using various clinical measured parameters for assigning periodontal prognosis as well as for predicting tooth survival and change in clinical conditions over time. We critically review the application of multivariate Classification And Regression Trees (CART) for survival in developing evidence-based periodontal prognostic indicators. We focus attention on two distinct methods of multivariate CART for survival: the marginal goodness-of-fit approach, and the multivariate exponential approach. A number of common clinical measures have been found to be significantly associated with tooth loss from periodontal disease, including furcation involvement, probing depth, mobility, crown-to-root ratio, and oral hygiene. However, the inter-relationships among these measures, as well as the relevance of other clinical measures to tooth loss from periodontal disease (such as bruxism, family history of periodontal disease, and overall bone loss), remain less clear. While inferences drawn from any single current study are necessarily limited, the application of new approaches in epidemiologic analyses to periodontal prognosis, such as CART for survival, should yield important insights into our understanding, and treatment, of periodontal diseases.

Although methylenetetrahydrofolate reductase, a folate enzyme gene, has been associated with idiopathic male infertility, few studies have examined other folate-related metabolites and genes. We investigated whether idiopathic male infertility is associated with variants in folate, vitamin B(12) (B12) and total homocysteine (tHcy)-related genes and measured these metabolites in blood. We conducted a case-control study that included 153 men with idiopathic infertility and 184 fertile male controls recruited at the Fertility Center and Antenatal Care Center, University Hospital, Malmö and Lund, Sweden. Serum folate, red cell folate (RCF), serum B12, plasma tHcy and semen quality were measured. Subjects were genotyped for 20 common variants in 12 genes related to folate/B12/homocysteine metabolism. Metabolite concentrations and genotype distributions were compared between cases and controls using linear and logistic regression with adjustment for covariates. The phosphatidylethanolamine N-methyltransferase (PEMT) M175V and TCblR rs173665 polymorphisms were significantly associated with infertility (P=0.01 and P=0.009, respectively), but not with semen quality. Among non-users of supplements, infertile men had lower serum folate concentrations than fertile men (12.89 vs. 14.73 nmol l(-1); P=0.02), but there were no significant differences in RCF, B12 or tHcy. Folate, B12 and tHcy concentrations were not correlated with any semen parameters. This study provides little support for low folate or B12 status in the pathogenesis of idiopathic male infertility. Although additional data are needed to confirm these initial findings, our results suggest that PEMT and TCblR, genes involved in choline and B12 metabolism, merit further investigation in idiopathic male infertility.

Hypoglossal motoneurons (XII MNs) control muscles of the mammalian tongue and are rhythmically active during breathing. Acetylcholine (ACh) modulates XII MN activity by promoting the release of glutamate from neurons that express nicotinic ACh receptors (nAChRs). Chronic nicotine exposure alters nAChRs on neurons throughout the brain, including brain stem respiratory neurons. Here we test the hypothesis that developmental nicotine exposure (DNE) reduces excitatory synaptic input to XII MNs. Voltage-clamp experiments in rhythmically active medullary slices showed that the frequency of excitatory postsynaptic currents (EPSCs) onto XII MNs from DNE animals is reduced by 61% (DNE = 1.7 ± 0.4 events/s; control = 4.4 ± 0.6 events/s; P < 0.002). We also examine the intrinsic excitability of XII MNs to test whether cells from DNE animals have altered membrane properties. Current-clamp experiments showed XII MNs from DNE animals had higher intrinsic excitability, as evaluated by measuring their response to injected current. DNE cells had high-input resistances (DNE = 131.9 ± 13.7 MΩ, control = 78.6 ± 9.7 MΩ, P < 0.008), began firing at lower current levels (DNE = 144 ± 22 pA, control = 351 ± 45 pA, P < 0.003), and exhibited higher frequency–current gain values (DNE = 0.087 ± 0.012 Hz/pA, control = 0.050 ± 0.004 Hz/pA, P < 0.02). Taken together, our data show previously unreported effects of DNE on XII MN function and may also help to explain the association between DNE and the incidence of central and obstructive apneas.

Objective: An American Psychosocial Oncology Society workgroup has developed indicators of the quality of psychosocial care that can be measured through review of medical records. The present report describes the first large-scale use of these indicators to evaluate psychosocial care in outpatient medical oncology settings. Methods: Medical records of 1660 colorectal, breast and non-small cell cancer patients first seen by a medical oncologist in 2006 at 11 practice sites in Florida were reviewed for performance on indicators of the quality of psychosocial care. Results: Assessment of emotional well-being was significantly less likely to be documented than assessment of pain (52 vs 87%, po0.001). A problem with emotional well-being was documented in 13% of records and evidence of action taken was documented in 58% of these records. Ten of eleven practice sites performed below an 85% threshold on each indicator of psychosocial care. Variability in assessment of emotional-well being was associated (po0.02) with practice site and patient gender and age while variability in assessment of pain was associated (po0.001) with practice site and cancer type. Conclusions: Findings illustrate how use of the psychosocial care indicators permits identification of specific practice sites and processes of care that should be targeted for quality improvement efforts. Additionally, findings demonstrate the extent to which routine assessment of emotional well-being lags behind routine assessment of pain in cancer patients. Copyright r 2010 John Wiley & Sons, Ltd.

Please cite this paper as: Lynch A, Murphy J, Gibbs R, Levine R, Giclas P, Salmon J, Holers V. The interrelationship of complement-activation fragments and angiogenesis-related factors in early pregnancy and their association with pre-eclampsia. BJOG 2010; 117:456–462. Objective To determine the interrelationships during early pregnancy of complement-activation fragments Bb, C3a and sC5b-9, and angiogenesis-related factors placental growth factor (PiGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), and their associations with pre-eclampsia. Design Prospective cohort study. Setting Denver complement study (June 2005–June 2008). Population A total of 668 pregnant women with singleton gestations, recruited between 10 and 15 weeks of gestation. Methods Using univariable and multivariable logistic regression analysis, concentrations of complement-activation fragments and angiogenesis-related factors were compared between 10 and 15 weeks of gestation in women who subsequently did or did not develop pre-eclampsia. Interrelationships between these variables were tested using the non-parametric Spearman rank correlation coefficient. Main outcome measure Pre-eclampsia. The association of complement-activation fragments and angiogenesis-related factors with obesity was also examined. Results The mean (±SD) levels of complement Bb in early pregnancy among women who did and did not develop pre-eclampsia were 0.84 (±0.26) μg/ml and 0.69 (±0.2) μg/ml, respectively (P = 0.001). Concentrations of PiGF were significantly (P = 0.01) lower (31 ± 12 pg/ml) in early pregnancy in the pre-eclamptic group of women, as compared with the normotensive group (39 ± 32 pg/ml). The adjusted odds ratio (AOR) of Bb and PiGF were 2.1 (CI = 1.4–3.1, P

Background: The American Psychosocial Oncology Society has developed the first indicators of the quality of psychosocial care for cancer patients. This report describes the initial evaluation of these indicators. Methods: Medical records of 388 colorectal cancer patients first seen by a medical oncologist in 2006 at seven practice sites were reviewed by trained abstractors whose accuracy was documented by periodic checks. Results: Rates of assessment of emotional well-being within 1 month of a patient’s first visit with a medical oncologist ranged from 6% to 84% (mean = 60%; P < .001). Among the 45 patients identified as having a problem with emotional well-being, rates of evidence of action taken (or explanation for no action) ranged from 0% to 100% (mean = 51%; P = .85). A direct comparison showed that pain was assessed more often than emotional well-being in these patients (87% vs 60%, P < .001). Conclusions: Findings show these indicators can be measured easily and reliably, demonstrate variability across practices that suggests potential for improvement, and yield information that can be used to take actions to improve quality. Additional findings suggest that, to date, efforts to promote routine symptom assessment have been more successful for pain than for emotional well-being.

The sintering process is ubiquitous in manufacturing, but the design-oriented modeling of sintering has presented considerable challenges. This type of modeling is necessary to be able to predict deformation and thus design appropriate powder compacts so that after they are sintered, the desired dimensions will be achieved. Currently this is done through a costly and time-consuming trial and error process. In our research, an application of the Skorohod–Olevsky viscous sintering constitutive equation in a finite-element (FE) model is developed and used to model solar cell manufacturing. Experimental measurements are used to determine the properties of the solar cell materials, and these are used to calculate the parameters for the FE model. Simulation results are compared with experimental data and analysis has been made to evaluate the adequacy and usefulness of this approach.

Preeclampsia (PE) is diagnosed using clinical criteria and in atypical cases the diagnosis may be inaccurate as there are no specific tests to confirm or exclude PE. This study sought to evaluate the utility of angiogenic biomarkers, sFlt1, sEng and PlGF to distinguish patients with gestational thrombocytopenia and immune thrombocytopenic purpura (ITP) from patients with thrombocytopenia resulting from the HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, a complication of severe PE.Serum was collected and the angiogenic biomarkers of patients with ITP and gestational thrombocytopenia (N = 9) were compared to patients with HELLP (N = 11) and PE (N = 11). Circulating levels of these angiogenic biomarkers were also compared by gestational age to 1564 randomly selected normotensive women from the Calcium for Preeclampsia Prevention study.Patients with non-HELLP thrombocytopenia had lower sFlt1 (7.3 +/- 3.8 ng/ml vs. 15.5 +/- 5 ng/ml, P0.001), lower sEng (8.7 +/- 3.6 vs. 34 +/- 17, P0.001) and higher PlGF (484 +/- 412 vs. 66.3 +/- 44, P = 0.003) than patients with HELLP syndrome. Angiogenic factor abnormalities in patients with PE were similar to patients with HELLP syndrome, suggesting a common pathogenesis. Patients with non-HELLP thrombocytopenia had angiogenic profiles similar to normotensive controls, whereas patients with HELLP syndrome had levels higher than the 90th percentile for sFlt1 and sEng and lower than the 10th percentile for PlGF.Angiogenic biomarkers may be useful in excluding conditions that mimic PE.