Dynamic Prediction of Survival in Cystic Fibrosis: A Landmarking Analysis Using UK Patient Registry Data.

BACKGROUND: Cystic fibrosis (CF) is an inherited, chronic, progressive condition affecting around 10,000 individuals in the United Kingdom and over 70,000 worldwide. Survival in CF has improved considerably over recent decades, and it is important to provide up-to-date information on patient prognosis. METHODS: The UK Cystic Fibrosis Registry is a secure centralized database, which collects annual data on almost all CF patients in the United Kingdom. Data from 43,592 annual records from 2005 to 2015 on 6181 individuals were used to develop a dynamic survival prediction model that provides personalized estimates of survival probabilities given a patient's current health status using 16 predictors. We developed the model using the landmarking approach, giving predicted survival curves up to 10 years from 18 to 50 years of age. We compared several models using cross-validation. RESULTS: The final model has good discrimination (C-indexes: 0.873, 0.843, and 0.804 for 2-, 5-, and 10-year survival prediction) and low prediction error (Brier scores: 0.036, 0.076, and 0.133). It identifies individuals at low and high risk of short- and long-term mortality based on their current status. For patients 20 years of age during 2013-2015, for example, over 80% had a greater than 95% probability of 2-year survival and 40% were predicted to survive 10 years or more. CONCLUSIONS: Dynamic personalized prediction models can guide treatment decisions and provide personalized information for patients. Our application illustrates the utility of the landmarking approach for making the best use of longitudinal and survival data and shows how models can be defined and compared in terms of predictive performance.US NIH Grant K25 HL12595

Individual Differences in Dopamine Are Associated with Reward Discounting in Clinical Groups But Not in Healthy Adults.

Some people are more willing to make immediate, risky, or costly reward-focused choices than others, which has been hypothesized to be associated with individual differences in dopamine (DA) function. In two studies using PET imaging, one empirical (Study 1: N = 144 males and females across 3 samples) and one meta-analytic (Study 2: N = 307 across 12 samples), we sought to characterize associations between individual differences in DA and time, probability, and physical effort discounting in human adults. Study 1 demonstrated that individual differences in DA D2-like receptors were not associated with time or probability discounting of monetary rewards in healthy humans, and associations with physical effort discounting were inconsistent across adults of different ages. Meta-analytic results for temporal discounting corroborated our empirical finding for minimal effect of DA measures on discounting in healthy individuals but suggested that associations between individual differences in DA and reward discounting depend on clinical features. Addictions were characterized by negative correlations between DA and discounting, but other clinical conditions, such as Parkinson's disease, obesity, and attention-deficit/hyperactivity disorder, were characterized by positive correlations between DA and discounting. Together, the results suggest that trait differences in discounting in healthy adults do not appear to be strongly associated with individual differences in D2-like receptors. The difference in meta-analytic correlation effects between healthy controls and individuals with psychopathology suggests that individual difference findings related to DA and reward discounting in clinical samples may not be reliably generalized to healthy controls, and vice versa.SIGNIFICANCE STATEMENT Decisions to forgo large rewards for smaller ones due to increasing time delays, uncertainty, or physical effort have been linked to differences in dopamine (DA) function, which is disrupted in some forms of psychopathology. It remains unclear whether alterations in DA function associated with psychopathology also extend to explaining associations between DA function and decision making in healthy individuals. We show that individual differences in DA D2 receptor availability are not consistently related to monetary discounting of time, probability, or physical effort in healthy individuals across a broad age range. By contrast, we suggest that psychopathology accounts for observed inconsistencies in the relationship between measures of DA function and reward discounting behavior

Improvement and evaluation of the mesoscale meteorological model MM5 for air-quality applications in Southern California and the San Joaquin Valley: Final Report

The objective of the Penn State University (PSU) part of the study was to investigate the MM5's ability to simulate wintertime fog in the San Joaquin Valley (SJV) and summertime sea breeze flows in the South Coast Air Basin (SoCAB). For the SJV work the MM5 was configured with four nested grid and an advanced turbulence sub-model. Applied to the event of 7-12 December 1995, observed during the IMS-95 program, the model's innermost domain used 40 vertical layers and a 4-km mesh. Several experiments were performed to improve the turbulence sub-model for saturated conditions and to provide more accurate initial conditions for soil temperature and moisture. Results showed the MM5 correctly predicted the type of visibility obscuration (fog, haze, status or clear) in 14 out of the 18 events. For depth was estimated by the MM5 with a mean absolute error of only 92 m and a mean error of -41 m. Mean errors for both the surface temperature and dew point were within +1C, while the mean absolute errors were ~1.5-2.0 C. As a consequence, the mean error for dew-point depression is very small. Thus, the MM5 was shown to simulate fog and haze in the SJV with considerable accuracy. Extensions of the turbulence sub-model to include saturation effects and the specification of accurate soil temperature and moisture were important for simulating fog characteristics in the case. Additionally, MM5 was able to simulate the light and variable winds in the Sacramento and San Joaquin Valleys that prevailed during this event. Moreover, the winds responded quite well to the slowly changing synoptic-scale weather, as well, as confirmed by the observations. the objective for the San Jose State University (SJSU) work included use of SCOS97 data and MM5 simulations to understand meteorological factors in the formation of high ozone concentrations during 4-7 August 1997. Meteorological data for the case study included observations at 110 SCOS97 surface sites and upper air measurements from 12 rawinsonde and 26 RWP/RASS profilers. the MM5 version contained the PSU Marine Boundary Layer Initialization (MBLI) scheme, quadruple nested grids (horizontal resolutions of 135, 45, 15, and 5 km), 30 vertical layers, minimum sigma level of 46 m, USGS global land-use, GDAS global gridded model analyses and SSTs, analysis nudging, observational nudging, force-restore surface temperature, 1.5 order TKE, one-way continuous nesting, and a MAPS statistical evaluation. Analysis showed the ozone episode resulting from a unique combination of large-scale upper level synoptic forcings that included a weak local coastal 700 mb anticyclone. Its movement around SoCAB rotated the upper level synoptic background flow from its normal westerly onshore direction to a less common offshore easterly flow during the nighttime period preceding the episode. The resulting easterly upper level synoptic background winds influenced surface flow direction at inland sites, so that a surface frontal convergence zone resulted where the easterly flow met the westerly onshore sea breeze flow. The maximum inland penetration of the convergence zone was about to the San Gabriel Mountain peaks, the location of daytime maximum ozone-episode concentrations. The current MM5 simulations reproduced the main qualitative features of the evolution of the diurnal sea breeze cycle in the SoCAB with reasonable accuracy. The position of the sea breeze front during its daytime inland penetration and nighttime retreat could be determined from the simulated wind fields. the accuracy of predicted MM5 surface winds and temperatures over SoCAB were improved by the modifications of its deep-soil temperatures, interpolation of predicted temperatures and winds to SCOS97 observational levels, use of updated urban land-use patterns, and use of corrected input values for ocean and urban surface roughness parameter values.Prepared for the California Air Resources Board and California Environmental Protection AgencySJSU Foundation Subcontract no. 22-1505-7384Approved for public release; distribution is unlimited

Earliest Archaeological Evidence of Persistent Hominin Carnivory

The emergence of lithic technology by ∼2.6 million years ago (Ma) is often interpreted as a correlate of increasingly recurrent hominin acquisition and consumption of animal remains. Associated faunal evidence, however, is poorly preserved prior to ∼1.8 Ma, limiting our understanding of early archaeological (Oldowan) hominin carnivory. Here, we detail three large well-preserved zooarchaeological assemblages from Kanjera South, Kenya. The assemblages date to ∼2.0 Ma, pre-dating all previously published archaeofaunas of appreciable size. At Kanjera, there is clear evidence that Oldowan hominins acquired and processed numerous, relatively complete, small ungulate carcasses. Moreover, they had at least occasional access to the fleshed remains of larger, wildebeest-sized animals. The overall record of hominin activities is consistent through the stratified sequence – spanning hundreds to thousands of years – and provides the earliest archaeological evidence of sustained hominin involvement with fleshed animal remains (i.e., persistent carnivory), a foraging adaptation central to many models of hominin evolution

Perceptions of knowledge sharing among small family firm leaders: a structural equation model

Small family firms have many unique relational qualities with implications for how knowledge is passed between individuals. Extant literature posits leadership approach as important in explaining differences in knowledge-sharing climate from one firm to another. This study investigates how leadership approaches interact with family influence to inform perceptions of knowledge sharing. We utilize survey data (n = 110) from owner-managers of knowledge-intensive small family firms in Scotland. Our findings present a choice in leadership intention, contrasting organization-focused participation against family-influenced guidance. Insight is offered on the implications of this leadership choice at both organizational and familial level

Earliest archaeological evidence of persistent hominin carnivory

The emergence of lithic technology by ~2.6 million years ago (Ma) is often interpreted as a correlate of increasingly recurrent hominin acquisition and consumption of animal remains. Associated faunal evidence, however, is poorly preserved prior to ~1.8 Ma, limiting our understanding of early archaeological (Oldowan) hominin carnivory. Here, we detail three large well-preserved zooarchaeological assemblages from Kanjera South, Kenya. The assemblages date to ~2.0 Ma, pre-dating all previously published archaeofaunas of appreciable size. At Kanjera, there is clear evidence that Oldowan hominins acquired and processed numerous, relatively complete, small ungulate carcasses. Moreover, they had at least occasional access to the fleshed remains of larger, wildebeest-sized animals. The overall record of hominin activities is consistent through the stratified sequence ??? spanning hundreds to thousands of years ??? and provides the earliest archaeological evidence of sustained hominin involvement with fleshed animal remains (i.e., persistent carnivory), a foraging adaptation central to many models of hominin evolution.This research was supported by funding from the National Science Foundation, Leakey Foundation, Wenner-Gren Foundation, National Geographic Society, The Leverhulme Trust, University of California, Baylor University, and the City University of New York. Additional logistical support was provided by the Smithsonian Institution???s Human Origins Program and the Peter Buck Fund for Human Origins Research, the British Institute in Eastern Africa, and the National Museums of Kenya. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001

HIV-1 is able to elicit broadly potent neutralizing antibodies in a very small subset of individuals only after several years of infection, and therefore, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that moderate protection is possible and that this protection may correlate with antibody-dependent cellular cytotoxicity (ADCC) activity. Our previous studies demonstrated that in an HIV vaccine phase I trial, the DP6-001 trial, a polyvalent Env DNA prime-protein boost formulation could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities. Here we report on the production and analysis of HIV-1 Env-specific human monoclonal antibodies (hMAbs) isolated from vaccinees in the DP6-001 trial. For this initial report, 13 hMAbs from four vaccinees in the DP6-001 trial showed broad binding to gp120 proteins of diverse subtypes both autologous and heterologous to vaccine immunogens. Equally cross-reactive Fc receptor-mediated functional activities, including ADCC and antibody-dependent cellular phagocytosis (ADCP) activities, were present with both immune sera and isolated MAbs, confirming the induction of nonneutralizing functional hMAbs by the DNA prime-protein boost vaccination. Elicitation of broadly reactive hMAbs by vaccination in healthy human volunteers confirms the value of the polyvalent formulation in this HIV vaccine design. IMPORTANCE: The roles of Fc receptor-mediated protective antibody responses are gaining more attention due to their potential contribution to the low-level protection against HIV-1 infection that they provided in the RV144 trial. At the same time, information about hMabs from other human HIV vaccine studies is very limited. In the current study, both immune sera and monoclonal antibodies from vaccinated humans showed not only high-level ADCC and ADCP activities but also cross-subtype ADCC and ADCP activities when a polyvalent DNA prime-protein boost vaccine formulation was used

Ethical and methodological issues in engaging young people living in poverty with participatory research methods

This paper discusses the methodological and ethical issues arising from a project that focused on conducting a qualitative study using participatory techniques with children and young people living in disadvantage. The main aim of the study was to explore the impact of poverty on children and young people's access to public and private services. The paper is based on the author's perspective of the first stage of the fieldwork from the project. It discusses the ethical implications of involving children and young people in the research process, in particular issues relating to access and recruitment, the role of young people's advisory groups, use of visual data and collection of data in young people's homes. The paper also identifies some strategies for addressing the difficulties encountered in relation to each of these aspects and it considers the benefits of adopting participatory methods when conducting research with children and young people

Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques.

Broadly neutralizing monoclonal antibodies protect against infection with HIV-1 in animal models, suggesting that a vaccine that elicits these antibodies would be protective in humans. However, it has not yet been possible to induce adequate serological responses by vaccination. Here, to activate B cells that express precursors of broadly neutralizing antibodies within polyclonal repertoires, we developed an immunogen, RC1, that facilitates the recognition of the variable loop 3 (V3)-glycan patch on the envelope protein of HIV-1. RC1 conceals non-conserved immunodominant regions by the addition of glycans and/or multimerization on virus-like particles. Immunization of mice, rabbits and rhesus macaques with RC1 elicited serological responses that targeted the V3-glycan patch. Antibody cloning and cryo-electron microscopy structures of antibody-envelope complexes confirmed that immunization with RC1 expands clones of B cells that carry the anti-V3-glycan patch antibodies, which resemble precursors of human broadly neutralizing antibodies. Thus, RC1 may be a suitable priming immunogen for sequential vaccination strategies in the context of polyclonal repertoires

Numerical Prediction of Submesoscale Flow in the Nocturnal Stable Boundary Layer over Complex Terrain

Numerical weather prediction models often perform poorly for weakly forced, highly variable winds in nocturnal stable boundary layers (SBLs). When used as input to air-quality and dispersion models, these wind errors can lead to large errors in subsequent plume forecasts. Finer grid resolution and improved model numerics and physics can help reduce these errors. The Advanced Research Weather Research and Forecasting model (ARW-WRF) has higher-order numerics that may improve predictions of finescale winds (scales <~20 km) in nocturnal SBLs. However, better understanding of the physics controlling SBL flow is needed to take optimal advantage of advanced modeling capabilities. To facilitate ARW-WRF evaluations, a small network of instrumented towers was deployed in the ridge-and-valley topography of central Pennsylvania (PA). Time series of local observations and model forecasts on 1.333- and 0.444-km grids were filtered to isolate deterministic lower-frequency wind components. The time-filtered SBL winds have substantially reduced root-mean-square errors and biases, compared to raw data. Subkilometer horizontal and very fine vertical resolutions are found to be important for reducing model speed and direction errors. Nonturbulent fluctuations in unfiltered, very finescale winds, parts of which may be resolvable by ARW-WRF, are shown to generate horizontal meandering in stable weakly forced conditions. These submesoscale motions include gravity waves, primarily horizontal 2D motions, and other complex signatures. Vertical structure and low-level biases of SBL variables are shown to be sensitive to parameter settings defining minimum “background” mixing in very stable conditions in two representative turbulence schemes.Keywords: Numerical weather prediction/forecasting, Boundary laye