Showing papers by "University of New Mexico published in 2012"

Guidelines for the use and interpretation of assays for monitoring autophagy

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Computing Inter-Rater Reliability for Observational Data: An Overview and Tutorial

Abstract: Many research designs require the assessment of inter-rater reliability (IRR) to demonstrate consistency among observational ratings provided by multiple coders. However, many studies use incorrect statistical procedures, fail to fully report the information necessary to interpret their results, or do not address how IRR affects the power of their subsequent analyses for hypothesis testing. This paper provides an overview of methodological issues related to the assessment of IRR with a focus on study design, selection of appropriate statistics, and the computation, interpretation, and reporting of some commonly-used IRR statistics. Computational examples include SPSS and R syntax for computing Cohen’s kappa and intra-class correlations to assess IRR.

American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer

Abstract: An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from 6 working groups, and a recent symposium cosponsored by the ACS, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology, which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (eg, the management of screen positives and screening intervals for screen negatives) of women after screening, the age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections.

Approaching a state shift in Earth’s biosphere

Abstract: There is evidence that human influence may be forcing the global ecosystem towards a rapid, irreversible, planetary-scale shift into a state unknown in human experience. Most forecasts of how the biosphere will change in response to human activity are rooted in projecting trajectories. Such models tend not anticipate critical transitions or tipping points, although recent work indicates a high probability of those taking place. And, at a local scale, ecosystems are known to shift abruptly between states when critical thresholds are passed. These authors review the evidence from across ecology and palaeontology that such a transition is being approached on the scale of the entire biosphere. They go on to suggest how biological forecasting might be improved to allow us to detect early warning signs of critical transitions on a global, as well as local, scale. Localized ecological systems are known to shift abruptly and irreversibly from one state to another when they are forced across critical thresholds. Here we review evidence that the global ecosystem as a whole can react in the same way and is approaching a planetary-scale critical transition as a result of human influence. The plausibility of a planetary-scale ‘tipping point’ highlights the need to improve biological forecasting by detecting early warning signs of critical transitions on global as well as local scales, and by detecting feedbacks that promote such transitions. It is also necessary to address root causes of how humans are forcing biological changes.

The genetic basis of early T-cell precursor acute lymphoblastic leukaemia

Abstract: Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

Advantages of Monte Carlo Confidence Intervals for Indirect Effects

Abstract: Monte Carlo simulation is a useful but underutilized method of constructing confidence intervals for indirect effects in mediation analysis. The Monte Carlo confidence interval method has several distinct advantages over rival methods. Its performance is comparable to other widely accepted methods of interval construction, it can be used when only summary data are available, it can be used in situations where rival methods (e.g., bootstrapping and distribution of the product methods) are difficult or impossible, and it is not as computer-intensive as some other methods. In this study we discuss Monte Carlo confidence intervals for indirect effects, report the results of a simulation study comparing their performance to that of competing methods, demonstrate the method in applied examples, and discuss several software options for implementation in applied settings.

Public Participation in Scientific Research: a Framework for Deliberate Design

Abstract: Members of the public participate in scientific research in many different contexts, stemming from traditions as varied as participatory action research and citizen science. Particularly in conservation and natural resource management contexts, where research often addresses complex social-ecological questions, the emphasis on and nature of this participation can significantly affect both the way that projects are designed and the outcomes that projects achieve. We review and integrate recent work in these and other fields, which has converged such that we propose the term public participation in scientific research (PPSR) to discuss initiatives from diverse fields and traditions. We describe three predominant models of PPSR and call upon case studies suggesting that—regardless of the research context—project outcomes are influenced by (1) the degree of public participation in the research process and (2) the quality of public participation as negotiated during project design. To illustrate relationships between the quality of participation and outcomes, we offer a framework that considers how scientific and public interests are negotiated for project design toward multiple, integrated goals. We suggest that this framework and models, used in tandem, can support deliberate design of PPSR efforts that will enhance their outcomes for scientific research, individual participants, and social-ecological systems.

GenProg: A Generic Method for Automatic Software Repair

Abstract: This paper describes GenProg, an automated method for repairing defects in off-the-shelf, legacy programs without formal specifications, program annotations, or special coding practices. GenProg uses an extended form of genetic programming to evolve a program variant that retains required functionality but is not susceptible to a given defect, using existing test suites to encode both the defect and required functionality. Structural differencing algorithms and delta debugging reduce the difference between this variant and the original program to a minimal repair. We describe the algorithm and report experimental results of its success on 16 programs totaling 1.25 M lines of C code and 120K lines of module code, spanning eight classes of defects, in 357 seconds, on average. We analyze the generated repairs qualitatively and quantitatively to demonstrate that the process efficiently produces evolved programs that repair the defect, are not fragile input memorizations, and do not lead to serious degradation in functionality.

The NKI-Rockland Sample: A Model for Accelerating the Pace of Discovery Science in Psychiatry.

Abstract: The National Institute of Mental Health strategic plan for advancing psychiatric neuroscience calls for an acceleration of discovery and the delineation of developmental trajectories for risk and resilience across the lifespan. To attain these objectives, sufficiently powered datasets with broad and deep phenotypic characterization, state-of-the-art neuroimaging, and genetic samples must be generated and made openly available to the scientific community. The enhanced Nathan Kline Institute Rockland Sample (NKI-RS) is a response to this need. NKI-RS is an ongoing, institutionally-centered endeavor aimed at creating a large-scale (N>1000), deeply phenotyped, community-ascertained, lifespan sample (ages 6-85 years old) with advanced neuroimaging and genetics. These data will be publically shared, openly and prospectively (i.e., on a weekly basis). Herein, we describe the conceptual basis of the NKI-RS, including study design, sampling considerations, and steps to synchronize phenotypic and neuroimaging assessment. Additionally, we describe our process for sharing the data with the scientific community while protecting participant confidentiality, maintaining an adequate database, and certifying data integrity. The pilot phase of the NKI-RS, including challenges in recruiting, characterizing, imaging, and sharing data, is discussed while also explaining how this experience informed the final design of the enhanced NKI-RS. It is our hope that familiarity with the conceptual underpinnings of the enhanced NKI-RS will facilitate harmonization with future data collection efforts aimed at advancing psychiatric neuroscience and nosology.

American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer

Abstract: An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from 6 working groups, and a recent symposium cosponsored by the ACS, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology, which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (eg, the management of screen positives and screening intervals for screen negatives) of women after screening, the age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections. CA Cancer J Clin 2012;62:147-172. V C

Exercise interventions on health related quality of life for people with cancer during active treatment

Abstract: Background People with cancer undergoing active treatment experience numerous disease- and treatment-related adverse outcomes and poorer health-related quality of life (HRQoL). Exercise interventions are hypothesized to alleviate these adverse outcomes. HRQoL and its domains are important measures of cancer survivorship, both during and after the end of active treatment for cancer. Objectives To evaluate the effectiveness of exercise on overall HRQoL outcomes and specific HRQoL domains among adults with cancer during active treatment. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed MEDLINE, EMBASE, CINAHL, PsycINFO, PEDRO, LILACS, SIGLE, SportDiscus, OTSeeker, Sociological Abstracts from inception to November 2011 with no language or date restrictions. We also searched citations through Web of Science and Scopus, PubMed's related article feature, and several websites. We reviewed reference lists of included trials and other reviews in the field. Selection criteria We included all randomized controlled trials (RCTs) and quasi-randomized controlled clinical trials (CCTs) comparing exercise interventions with usual care or other type of non-exercise comparison intervention to maintain or enhance, or both, overall HRQoL or at least one distinct domain of HRQoL. Included trials tested exercise interventions that were initiated when adults with cancer were undergoing active cancer treatment or were scheduled to initiate treatment. Data collection and analysis Five paired review authors independently extracted information on characteristics of included trials, data on effects of the intervention, and assessed risk of bias based on predefined criteria. Where possible, we performed meta-analyses for HRQoL and HRQoL domains for the reported difference between baseline values and follow-up values using standardized mean differences (SMDs) and a random-effects model by length of follow-up. We also reported the SMD at follow-up between the exercise and control groups. Because investigators used many different HRQoL and HRQoL domain instruments and often more than one for the same domain, we selected the more commonly used instrument to include in the SMD meta-analyses. We also report the mean difference for each type of instrument separately. Main results We included 56 trials with 4826 participants randomized to an exercise (n = 2286) or comparison (n = 1985) group. Cancer diagnoses in trial participants included breast, prostate, gynecologic, hematologic, and other. Thirty-six trials were conducted among participants who were currently undergoing active treatment for their cancer, 10 trials were conducted among participants both during and post active cancer treatment, and the remaining 10 trials were conducted among participants scheduled for active cancer treatment. Mode of exercise intervention differed across trials and included walking by itself or in combination with cycling, resistance training, or strength training; resistance training; strength training; cycling; yoga; or Qigong. HRQoL and its domains were assessed using a wide range of measures. The results suggest that exercise interventions compared with control interventions have a positive impact on overall HRQoL and certain HRQoL domains. Exercise interventions resulted in improvements in: HRQoL from baseline to 12 weeks' follow-up (SMD 0.33; 95% CI 0.12 to 0.55) or when comparing difference in follow-up scores at 12 weeks (SMD 0.47; 95% CI 0.16 to 0.79); physical functioning from baseline to 12 weeks' follow-up (SMD 0.69; 95% CI 0.16 to 1.22) or 6 months (SMD 0.28; 95% CI 0.00 to 0.55); or when comparing differences in follow-up scores at 12 weeks (SMD 0.28; 95% CI 0.11 to 0.45) or 6 months (SMD 0.29; 95% CI 0.07 to 0.50); role function from baseline to 12 weeks' follow-up (SMD 0.48; 95% CI 0.07 to 0.90) or when comparing differences in follow-up scores at 12 weeks (SMD 0.17; 95% CI 0.00 to 0.34) or 6 months (SMD 0.32; 95% CI 0.03 to 0.61); and, in social functioning at 12 weeks' follow-up (SMD 0.54; 95% CI 0.03 to 1.05) or when comparing differences in follow-up scores at both 12 weeks (SMD 0.16; 95% CI 0.04 to 0.27) and 6 months (SMD 0.24; 95% CI 0.03 to 0.44). Further, exercise interventions resulted in a decrease in fatigue from baseline to 12 weeks' follow-up (SMD -0.38; 95% CI -0.57 to -0.18) or when comparing difference in follow-up scores at follow-up of 12 weeks (SMD -0.73; 95% CI -1.14 to -0.31). Since there is consistency of findings on both types of measures (change scores and difference in follow-up scores) there is greater confidence in the robustness of these findings. When examining exercise effects by subgroups, exercise interventions had significantly greater reduction in anxiety for survivors with breast cancer than those with other types of cancer. Further, there was greater reduction in depression, fatigue, and sleep disturbances, and improvement in HRQoL, emotional wellbeing (EWB), physical functioning, and role function for cancer survivors diagnosed with cancers other than breast cancer but not for breast cancer. There were also greater improvements in HRQoL and physical functioning, and reduction in anxiety, fatigue, and sleep disturbances when prescribed a moderate or vigorous versus a mild exercise program. Results of the review need to be interpreted cautiously owing to the risk of bias. All the trials reviewed were at high risk for performance bias. In addition, the majority of trials were at high risk for detection, attrition, and selection bias. Authors' conclusions This systematic review indicates that exercise may have beneficial effects at varying follow-up periods on HRQoL and certain HRQoL domains including physical functioning, role function, social functioning, and fatigue. Positive effects of exercise interventions are more pronounced with moderate- or vigorous-intensity versus mild-intensity exercise programs. The positive results must be interpreted cautiously because of the heterogeneity of exercise programs tested and measures used to assess HRQoL and HRQoL domains, and the risk of bias in many trials. Further research is required to investigate how to sustain positive effects of exercise over time and to determine essential attributes of exercise (mode, intensity, frequency, duration, timing) by cancer type and cancer treatment for optimal effects on HRQoL and its domains.

Compact Remnant Mass Function: Dependence on the Explosion Mechanism and Metallicity

Abstract: The mass distribution of neutron stars and stellar-mass black holes provides vital clues into the nature of stellar core collapse and the physical engine responsible for supernova explosions. A number of supernova engines have been proposed: neutrino- or oscillation-driven explosions enhanced by early (developing in 10-50 ms) and late-time (developing in 200 ms) convection as well as magnetic field engines (in black hole accretion disks or neutron stars). Using our current understanding of supernova engines, we derive mass distributions of stellar compact remnants. We provide analytic prescriptions for both single-star models (as a function of initial star mass) and for binary-star models-prescriptions for compact object masses for major population synthesis codes. These prescriptions have implications for a range of observations: X-ray binary populations, supernova explosion energies, and gravitational wave sources. We show that advanced gravitational radiation detectors (like LIGO/VIRGO or the Einstein Telescope) will be able to further test the supernova explosion engine models once double black hole inspirals are detected.

Consensus paper: roles of the cerebellum in motor control--the diversity of ideas on cerebellar involvement in movement.

Abstract: Considerable progress has been made in developing models of cerebellar function in sensorimotor control, as well as in identifying key problems that are the focus of current investigation. In this consensus paper, we discuss the literature on the role of the cerebellar circuitry in motor control, bringing together a range of different viewpoints. The following topics are covered: oculomotor control, classical conditioning (evidence in animals and in humans), cerebellar control of motor speech, control of grip forces, control of voluntary limb movements, timing, sensorimotor synchronization, control of corticomotor excitability, control of movement-related sensory data acquisition, cerebro-cerebellar interaction in visuokinesthetic perception of hand movement, functional neuroimaging studies, and magnetoencephalographic mapping of cortico-cerebellar dynamics. While the field has yet to reach a consensus on the precise role played by the cerebellum in movement control, the literature has witnessed the emergence of broad proposals that address cerebellar function at multiple levels of analysis. This paper highlights the diversity of current opinion, providing a framework for debate and discussion on the role of this quintessential vertebrate structure.

Exercise interventions on health related quality of life for cancer survivors

Abstract: There is a steady increase in the number of cancer survivors, that is people diagnosed with cancer (Aziz 2003), worldwide. This is due, in a large part, to the dramatic advances in cancer treatment and management (Aziz 2002; Aziz 2003), growing attention to multidisciplinary post-treatment care (Demark-Wahnefried 2000; Stull 2007), and healthier lifestyles (Demark-Wahnefried 2005; Stull 2007). These factors and trends especially when considered in light of an aging population (Aziz 2008; Stewart 2003), suggest that we can continue to expect increasing numbers of cancer survivors with greater expected length of survival. Ensuring the quality of that survival thus becomes a key priority. The objectives are as follows: To evaluate the effectiveness of exercise on overall HRQoL outcomes and specific HRQoL domains (e.g. physical, psychological, economic, social, and spiritual well-being, and key disease and/or treatment symptoms such as sexual functioning, neuropathy or cognitive changes, and chronic fatigue) among adult post-treatment cancer survivors (i.e. people with a history of cancer who are beyond active treatment, excluding those who are terminally ill and receiving hospice). We will focus on post-treatment cancer survivors so that we can evaluate the effectiveness of exercise on HRQoL without having to adjust for the adverse effects of cancer and/or its treatment on HRQoL. 1. A secondary objective is to examine the effectiveness of exercise on HRQoL outcomes among adult post-treatment cancer survivors stratified by the following: 2. Age at diagnosis (i.e. less than 65 years or greater than or equal to 65 years); 3. Age at trial enrolment (i.e. less than 65 years or greater than or equal to 65 years); 4. Sex; 5. Type of prescribed exercise (i.e. aerobic, anaerobic, combination); 6. Physical condition prior to cancer treatment (i.e. obesity, heart disease, smoking status, asthma); 7. Intensity of exercise (i.e. mild, moderate, vigorous); and Format of exercise (i.e. individual or group, professionally led or not, home or group facility).

Reconfigurable Antennas for Wireless and Space Applications

Abstract: Reconfigurable antennas, with the ability to radiate more than one pattern at different frequencies and polarizations, are necessary in modern telecommunication systems. The requirements for increased functionality (e.g., direction finding, beam steering, radar, control, and command) within a confined volume place a greater burden on today's transmitting and receiving systems. Reconfigurable antennas are a solution to this problem. This paper discusses the different reconfigurable components that can be used in an antenna to modify its structure and function. These reconfiguration techniques are either based on the integration of radio-frequency microelectromechanical systems (RF-MEMS), PIN diodes, varactors, photoconductive elements, or on the physical alteration of the antenna radiating structure, or on the use of smart materials such as ferrites and liquid crystals. Various activation mechanisms that can be used in each different reconfigurable implementation to achieve optimum performance are presented and discussed. Several examples of reconfigurable antennas for both terrestrial and space applications are highlighted, such as cognitive radio, multiple-input-multiple-output (MIMO) systems, and satellite communication.

Clinical Recommendations for Cardiopulmonary Exercise Testing Data Assessment in Specific Patient Populations

Abstract: From an evidence-based perspective, cardiopulmonary exercise testing (CPX) is a well-supported assessment technique in both the United States (US) and Europe. The combination of standard exercise testing (ET) (ie, progressive exercise provocation in association with serial electrocardiograms [ECG], hemodynamics, oxygen saturation, and subjective symptoms) and measurement of ventilatory gas exchange amounts to a superior method to: 1) accurately quantify cardiorespiratory fitness (CRF), 2) delineate the physiologic system(s) underlying exercise responses, which can be applied as a means to identify the exercise-limiting pathophysiologic mechanism(s) and/or performance differences, and 3) formulate function-based prognostic stratification. Cardiopulmonary ET certainly carries an additional cost as well as competency requirements and is not an essential component of evaluation in all patient populations. However, there are several conditions of confirmed, suspected, or unknown etiology where the data gained from this form of ET is highly valuable in terms of clinical decision making.1 Several CPX statements have been published by well-respected organizations in both the US and Europe.1–5 Despite these prominent reports and the plethora of pertinent medical literature which they feature, underutilization of CPX persists. This discrepancy is at least partly attributable to the fact that the currently available CPX consensus statements are inherently complex and fail to convey succinct, clinically centered strategies to utilize CPX indices effectively. Likewise, current CPX software packages generate an overwhelming abundance of data, which to most clinicians are incomprehensible and abstract. Ironically, in contrast to the protracted scientific statements and dense CPX data outputs, the list of CPX variables that have proven clinical application is concise and uncomplicated. Therefore, the goal of this writing group is to present an approach of CPX in a way that assists in making meaningful decisions regarding a patient’s care. Experts from the European Association for Cardiovascular Prevention and Rehabilitation and American Heart Association have joined in this effort to distill easy-to-follow guidance on CPX interpretation based upon current scientific evidence. This document also provides a series of forms that are designed to highlight the utility of CPX in clinical decision-making. Not only will this improve patient management, it will also catalyze uniform and unambiguous data interpretation across laboratories on an international level. The primary target audience of this position paper is clinicians who have limited orientation with CPX but whose caregiving would be enhanced by familiarity and application of this assessment. The ultimate goal is to increase awareness of the value of CPX and to increase the number of healthcare professionals who are able to perform clinically meaningful CPX interpretation. Moreover, this document will hopefully lead to an increase in appropriate patient referrals to CPX with enhanced efficiencies in patient management. For more detailed information on CPX, including procedures for patient preparation, equipment calibration, and conducting the test, readers are encouraged to review other publications that address these and other topics in great detail.1–5

Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial

Abstract: Summary Background Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of PATRICIA (PApilloma TRIal against Cancer In young Adults). Methods Healthy women aged 15–25 years with no more than six lifetime sexual partners were included in PATRICIA, irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with ClinicalTrials.gov, number NCT00122681. Findings Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5–100) in the TVC-naive and 45·7% (22·9–62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9–98·7) in the TVC-naive and 45·6% (28·8–58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15–17 year age group and progressively decreased in the 18–20 year and 21–25 year age groups. Vaccine efficacy against all AIS was 100% (31·0–100) and 76·9% (16·0–95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination. Interpretation PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer. Funding GlaxoSmithKline Biologicals.

A systematic study of automated program repair: fixing 55 out of 105 bugs for $8 each

Abstract: There are more bugs in real-world programs than human programmers can realistically address. This paper evaluates two research questions: ``What fraction of bugs can be repaired automatically?'' and ``How much does it cost to repair a bug automatically?'' In previous work, we presented GenProg, which uses genetic programming to repair defects in off-the-shelf C programs. To answer these questions, we: (1) propose novel algorithmic improvements to GenProg that allow it to scale to large programs and find repairs 68% more often, (2) exploit GenProg's inherent parallelism using cloud computing resources to provide grounded, human-competitive cost measurements, and (3) generate a large, indicative benchmark set to use for systematic evaluations. We evaluate GenProg on 105 defects from 8 open-source programs totaling 5.1 million lines of code and involving 10,193 test cases. GenProg automatically repairs 55 of those 105 defects. To our knowledge, this evaluation is the largest available of its kind, and is often two orders of magnitude larger than previous work in terms of code or test suite size or defect count. Public cloud computing prices allow our 105 runs to be reproduced for $403; a successful repair completes in 96 minutes and costs $7.32, on average.

The Smartphone Psychology Manifesto

Abstract: By 2025, when most of today's psychology undergraduates will be in their mid-30s, more than 5 billion people on our planet will be using ultra-broadband, sensor-rich smartphones far beyond the abilities of today's iPhones, Androids, and Blackberries. Although smartphones were not designed for psychological research, they can collect vast amounts of ecologically valid data, easily and quickly, from large global samples. If participants download the right "psych apps," smartphones can record where they are, what they are doing, and what they can see and hear and can run interactive surveys, tests, and experiments through touch screens and wireless connections to nearby screens, headsets, biosensors, and other peripherals. This article reviews previous behavioral research using mobile electronic devices, outlines what smartphones can do now and will be able to do in the near future, explains how a smartphone study could work practically given current technology (e.g., in studying ovulatory cycle effects on women's sexuality), discusses some limitations and challenges of smartphone research, and compares smartphones to other research methods. Smartphone research will require new skills in app development and data analysis and will raise tough new ethical issues, but smartphones could transform psychology even more profoundly than PCs and brain imaging did.

Ecoenzymatic Stoichiometry and Ecological Theory

Abstract: The net primary production of the biosphere is consumed largely by microorganisms, whose metabolism creates the trophic base for detrital foodwebs, drives element cycles, and mediates atmospheric composition. Biogeochemical constraints on microbial catabolism, relative to primary production, create reserves of detrital organic carbon in soils and sediments that exceed the carbon content of the atmosphere and biomass. The production of organic matter is an intracellular process that generates thousands of compounds from a small number of precursors drawn from intermediary metabolism. Osmotrophs generate growth substrates from the products of biosynthesis and diagenesis by enzyme-catalyzed reactions that occur largely outside cells. These enzymes, which we define as ecoenzymes, enter the environment by secretion and lysis. Enzyme expression is regulated by environmental signals, but once released from the cell, ecoenzymatic activity is determined by environmental interactions, represented as a kinetic casca...

Childhood outcomes after hypothermia for neonatal encephalopathy.

Abstract: Background We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic–ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available. Methods In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70. Results Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) ...

Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants

Abstract: Background Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. Methods We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. Results Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variant...

The future of citizen science: emerging technologies and shifting paradigms

Abstract: Citizen science creates a nexus between science and education that, when coupled with emerging technologies, expands the frontiers of ecological research and public engagement. Using representative technologies and other examples, we examine the future of citizen science in terms of its research processes, program and participant cultures, and scientific communities. Future citizen-science projects will likely be influenced by sociocultural issues related to new technologies and will continue to face practical programmatic challenges. We foresee networked, open science and the use of online computer/video gaming as important tools to engage non-traditional audiences, and offer recommendations to help prepare project managers for impending challenges. A more formalized citizen-science enterprise, complete with networked organizations, associations, journals, and cyberinfrastructure, will advance scientific research, including ecology, and further public education.