APPLICATION OF SEMIPARAMETRIC METHODS FOR REGRESSION MODELS WITH MISSING COVARIATE INFORMATION

This dissertation addresses regression models with missing covariate data. These methods are shown to be significant to public health research since they enable researchers to use a wider spectrum of data. Unbiased estimating equations are the focus of this dissertation, predominantly semiparametric methods utilized to solve for regression parameters in the presence of missing covariate data. The first aim of this dissertation is to evaluate the properties of an efficient score, an inverse probability weighted estimating equation approach, for logistic regression in a two-phase design. Simulation studies showed that the efficient score is more efficient than two other pseudo-likelihood methods when the correlation between the missing covariate and its surrogate is high. The second aim of this dissertation is to develop a methodology for left truncated covariate data with a binary outcome. To address this problem, we proposed two methods, a likelihood-based approach and an estimating equation approach, to estimate the coefficients and their standard errors for a regression model with a left truncated covariate. The estimating equation technique is close to completion, and once solved should be the most efficient method. The likelihood-based method is compared to standard methods of filling in the truncated values with the lower threshold value or using only the nontruncated values. Simulation studies demonstrated that the likelihood-based method has the best variance correction and moderate bias correction. The application of this method is illustrated in a sepsis study conducted at the University of Pittsburgh

Investigation of irradiated monolithic transistors for space applications

In this paper experimental results on radiation effects on a BICMOS high speed commercial technology, manufactured by STMicroelectronics, are reported. Bipolar transistors were irradiated by neutrons, ions, or by both of them. Fast neutrons, as well as other types of particles, produce defects, mainly by displacing silicon atoms from their lattice positions to interstitial locations, i.e. generating vacancy-interstitial pairs, the so-called Frenkel pairs (FP). Defects introduce trapping energy states which degrade the common emitter current gain β. The gain degradation has been investigated for collector current Ic between 1 μA and 1 mA. It was found a linear dependence of Δ(1/β)=1/βi−1/β (where βi and β are the gain after and before the irradiation) as a function of the concentration of FP. The bipolar transistors made on this technology have shown to be particularly radiation resistant. Both base and collector currents have been also systematically investigated

Study of radiation effects on bipolar transistors

Abstract In this paper it was shown that the irradiation with neutrons and carbon ions leads to gain degradation in bipolar transistors due to generation of defects. The density of these generated defects is independent of the type of irradiation (neutrons or carbon ions). Thus, it is possible to evaluate Δ(1/β), once the expected Frenkel pair density is known. The dependence of the damage constant on collector current is a power law function, with the exception of the lateral pnp transistors, that shows a higher sensitivity to radiation and a different behaviour. Neutrons give a smaller density of Frenkel pairs (CF) than the two sorts of carbon ions of high energy (CHE) and medium energy (CME). It was found that CME causes a higher concentration of CF. The calculated ratio R=CF/Φ, where CF is the Frenkel pair density and Φ fluence does not depend on Φ, for a given type of radiation. However, it depends on the incoming particle type. Its smallest calculated value was obtained for neutrons (R=6.1×10), which increases to 1.25×103 for CHE and to 1.1×104 for CME

Inactivation mechanisms of influenza A virus under pH conditions encountered in aerosol particles as revealed by whole-virus HDX-MS

Multiple respiratory viruses, including influenza A virus (IAV), can be transmitted via expiratory aerosol particles, and aerosol pH was recently identified as a major factor influencing airborne virus infectivity. Indoors, small exhaled aerosols undergo rapid acidification to pH ~4. IAV is known to be sensitive to mildly acidic conditions encountered within host endosomes; however, it is unknown whether the same mechanisms could mediate viral inactivation within the more acidic aerosol micro-environment. Here, we identified that transient exposure to pH 4 caused IAV inactivation by a two-stage process, with an initial sharp decline in infectious titers mainly attributed to premature attainment of the post-fusion conformation of viral protein haemagglutinin (HA). Protein changes were observed by hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS) as early as 10 s post-exposure to acidic conditions. Our HDX-MS data are in agreement with other more labor-intensive structural analysis techniques, such as X-ray crystallography, highlighting the ease and usefulness of whole-virus HDX-MS for multiplexed protein analyses, even within enveloped viruses such as IAV. Additionally, virion integrity was partially but irreversibly affected by acidic conditions, with a progressive unfolding of the internal matrix protein 1 (M1) that aligned with a more gradual decline in viral infectivity with time. In contrast, no acid-mediated changes to the genome or lipid envelope were detected. Improved understanding of respiratory virus fate within exhaled aerosols constitutes a global public health priority, and information gained here could aid the development of novel strategies to control the airborne persistence of seasonal and/or pandemic influenza in the future. IMPORTANCE: It is well established that COVID-19, influenza, and many other respiratory diseases can be transmitted by the inhalation of aerosolized viruses. Many studies have shown that the survival time of these airborne viruses is limited, but it remains an open question as to what drives their infectivity loss. Here, we address this question for influenza A virus by investigating structural protein changes incurred by the virus under conditions relevant to respiratory aerosol particles. From prior work, we know that expelled aerosols can become highly acidic due to equilibration with indoor room air, and our results indicate that two viral proteins are affected by these acidic conditions at multiple sites, leading to virus inactivation. Our findings suggest that the development of air treatments to quicken the speed of aerosol acidification would be a major strategy to control infectious bioburdens in the air

Ancient genomes in South Patagonia reveal population movements associated with technological shifts and geography

Archaeological research documents major technological shifts among people who have lived in the southern tip of South America (South Patagonia) during the last thirteen millennia, including the development of marine-based economies and changes in tools and raw materials. It has been proposed that movements of people spreading culture and technology propelled some of these shifts, but these hypotheses have not been tested with ancient DNA. Here we report genome-wide data from 20 ancient individuals, and co-analyze it with previously reported data. We reveal that immigration does not explain the appearance of marine adaptations in South Patagonia. We describe partial genetic continuity since ~6600 BP and two later gene flows correlated with technological changes: one between 4700–2000 BP that affected primarily marine-based groups, and a later one impacting all <2000 BP groups. From ~2200–1200 BP, mixture among neighbors resulted in a cline correlated to geographic ordering along the coast.Fil: Nakatsuka, Nathan. Harvard Medical School; Estados UnidosFil: Luisi, Pierre. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades; ArgentinaFil: Motti, Josefina María Brenda. Universidad Nacional del Centro de la Provincia de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Salemme, Monica Cira. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; Argentina. Universidad Nacional de Tierra del Fuego; ArgentinaFil: Santiago, Fernando Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: D'angelo del Campo, Manuel Domingo. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Sociales. Grupo de Estudios Interdisciplinarios sobre Poblaciones Humanas de Patagonia Austral; Argentina. Universidad Autónoma de Madrid; EspañaFil: Vecchi, Rodrigo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Sur; ArgentinaFil: Espinosa Parrilla, Yolanda. Consejo Superior de Investigaciones Científicas; EspañaFil: Prieto, Alfredo. Universidad de Magallanes; ChileFil: Adamski, Nicole. Harvard Medical School; Estados UnidosFil: Lawson, Ann Marie. Harvard Medical School; Estados UnidosFil: Harper, Thomas K.. University of Pennsylvania; Estados UnidosFil: Culleton, Brendan J.. University of Pennsylvania; Estados UnidosFil: Kennett, Douglas J.. University of California; Estados UnidosFil: Lalueza Fox, Carles. Consejo Superior de Investigaciones Científicas; EspañaFil: Mallick, Swapan. Harvard Medical School; Estados UnidosFil: Rohland, Nadin. Harvard Medical School; Estados UnidosFil: Guichón, Ricardo A.. Universidad Nacional del Centro de la Provincia de Buenos Aires; ArgentinaFil: Cabana, Graciela S.. University of Tennessee; Estados UnidosFil: Nores, Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Antropología de Córdoba. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Instituto de Antropología de Córdoba; ArgentinaFil: Reich, David. Harvard Medical School. Department Of Medicine; Estados Unido

Generation of Reference Vehicle Trajectories in real-world Situations using Aerial Imagery from a Helicopter

Highly accurate reference vehicle trajectories are required in the automotive domain e.\,g. for testing mobile GNSS devices. Common methods used to determine reference trajectories are based on the same working principles as the device under test and suffer from the same underlying error problems. In this paper, a new method to generate reference vehicle trajectories in real-world situations using simultaneously acquired aerial imagery from a helicopter is presented. This method requires independent height information which is coming from a LIDAR DTM and the relative height of the GNSS device. The reference trajectory is then derived by forward intersection of the vehicle position in each image with the DTM. In this context, the influence of all relevant error sources were analysed, like the error from the LIDAR DTM, from the sensor latency, from the semi-automatic matching of the vehicle marking, and from the image orientation. Results show that the presented method provides a tool for creating reference trajectories that is independent of the GNSS reception at the vehicle. Moreover, it can be demonstrated that the proposed method reaches an accuracy level of 10 cm, which is defined as necessary for certification and validation of automotive GNSS devices

Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy

In Duchenne muscular dystrophy (DMD), progressive loss of respiratory function leads to restrictive pulmonary disease and places patients at significant risk for severe respiratory complications. Of particular concern are ineffective cough, secretion retention and recurrent respiratory tract infections. In a Phase 3 randomized controlled study (DMD Long-term Idebenone Study, DELOS) in DMD patients 10–18 years of age and not taking concomitant glucocorticoid steroids, idebenone (900 mg/day) reduced significantly the loss of respiratory function over a 1-year study period. In a post-hoc analysis of DELOS we found that more patients in the placebo group compared to the idebenone group experienced bronchopulmonary adverse events (BAEs): placebo: 17 of 33 patients, 28 events; idebenone: 6 of 31 patients, 7 events. The hazard ratios (HR) calculated “by patient” (HR 0.33, p = 0.0187) and for “all BAEs” (HR 0.28, p = 0.0026) indicated a clear idebenone treatment effect. The overall duration of BAEs was 222 days (placebo) vs. 82 days (idebenone). In addition, there was also a difference in the use of systemic antibiotics utilized for the treatment of BAEs. In the placebo group, 13 patients (39.4%) reported 17 episodes of antibiotic use compared to 7 patients (22.6%) reporting 8 episodes of antibiotic use in the idebenone group. Furthermore, patients in the placebo group used systemic antibiotics for longer (105 days) compared to patients in the idebenone group (65 days). This post-hoc analysis of DELOS indicates that the protective effect of idebenone on respiratory function is associated with a reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics

The Golgi and the centrosome: building a functional partnership

The mammalian Golgi apparatus is characterized by a ribbon-like organization adjacent to the centrosome during interphase and extensive fragmentation and dispersal away from the centrosome during mitosis. It is not clear whether this dynamic association between the Golgi and centrosome is of functional significance. We discuss recent findings indicating that the Golgi–centrosome relationship may be important for directional protein transport and centrosome positioning, which are both required for cell polarization. We also summarize our current knowledge of the link between Golgi organization and cell cycle progression

Refinement of 1p36 Alterations Not Involving PRDM16 in Myeloid and Lymphoid Malignancies

Fluorescence in situ hybridization was performed to characterize 81 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations not affecting the PRDM16 locus. In total, three subgroups were identified: balanced translocations (N = 27) and telomeric rearrangements (N = 15), both mainly observed in myeloid disorders; and unbalanced non-telomeric rearrangements (N = 39), mainly observed in lymphoid proliferations and frequently associated with a highly complex karyotype. The 1p36 rearrangement was isolated in 12 cases, mainly myeloid disorders. The breakpoints on 1p36 were more widely distributed than previously reported, but with identifiable rare breakpoint cluster regions, such as the TP73 locus. We also found novel partner loci on 1p36 for the known multi-partner genes HMGA2 and RUNX1. We precised the common terminal 1p36 deletion, which has been suggested to have an adverse prognosis, in B-cell lymphomas [follicular lymphomas and diffuse large B-cell lymphomas with t(14;18)(q32;q21) as well as follicular lymphomas without t(14;18)]. Intrachromosomal telomeric repetitive sequences were detected in at least half the cases of telomeric rearrangements. It is unclear how the latter rearrangements occurred and whether they represent oncogenic events or result from chromosomal instability during oncogenesis

Developing a core outcome set for future infertility research : An international consensus development study

STUDY QUESTION: Can a core outcome set to standardize outcome selection, collection and reporting across future infertility research be developed? SUMMARY ANSWER: A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential treatments for infertility. WHAT IS KNOWN ALREADY: Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret. STUDY DESIGN, SIZE, DURATION: A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries). PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus science methods. MAIN RESULTS AND THE ROLE OF CHANCE: The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition and an arbitrary consensus threshold. WIDER IMPLICATIONS OF THE FINDINGS: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. The funder had no role in the design and conduct of the study, the collection, management, analysis or interpretation of data, or manuscript preparation. B.W.J.M. is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). S.B. was supported by University of Auckland Foundation Seelye Travelling Fellowship. S.B. reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.J.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. A.S. reports consultancy fees from Guerbet. E.H.Y.N. reports research sponsorship from Merck. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form