TREATMENT HETEROGENEITY AND POTENTIAL OUTCOMES IN LINEAR MIXED EFFECTS MODELS

Studies commonly focus on estimating a mean treatment effect in a population. However, in some applications the variability of treatment effects across individual units may help to characterize the overall effect of a treatment across the population. Consider a set of treatments, {T,C}, where T denotes some treatment that might be applied to an experimental unit and C denotes a control. For each of N experimental units, the duplet {rTᵢ,rCᵢ}, i = 1,2, … , N, represents the potential response of the i th experimental unit if treatment were applied and the response of the experimental unit if control were applied, respectively. The causal effect of T compared to C is the difference between the two potential responses, rTᵢ - rCᵢ. Much work has been done to elucidate the statistical properties of a causal effect, given a set of particular assumptions. Gadbury and others have reported on this for some simple designs and primarily focused on finite population randomization based inference. When designs become more complicated, the randomization based approach becomes increasingly difficult. Since linear mixed effects models are particularly useful for modeling data from complex designs, their role in modeling treatment heterogeneity is investigated. It is shown that an individual treatment effect can be conceptualized as a linear combination of fixed treatment effects and random effects. The random effects are assumed to have variance components specified in a mixed effects “potential outcomes” model when both potential outcomes, rT, rC, are variables in the model. The variance of the individual causal effect is used to quantify treatment heterogeneity. Post treatment assignment, however, only one of the two potential outcomes is observable for a unit. It is then shown that the variance component for treatment heterogeneity becomes non-estimable in an analysis of observed data. Furthermore, estimable variance components in the observed data model are demonstrated to arise from linear combinations of the non-estimable variance components in the potential outcomes model. Mixed effects models are considered in context of a particular design in an effort to illuminate the loss of information incurred when moving from a potential outcomes framework to an observed data analysis

H\u3csub\u3e2\u3c/sub\u3e Temperatures in the Crab Nebula

We used K-band spectra to measure the H2 excitation temperatures in six molecular knots associated with the filaments in the Crab Nebula. The temperatures are quite high – in the range T∼ 2000–3000 K, just below the H2 dissociation temperature. This is the temperature range over which the H2 1–0 S(1) line at λ2.121 μm has its maximum emissivity per unit mass, so there may be many additional H2 cores with lower temperatures that are too faint to detect. We also measured the electron density in adjacent ionized gas, which on the assumption of gas pressure balance indicates densities in the molecular region nmol∼ 20 000 H baryons cm−3, although this really is just a lower limit since the H2 gas may be confined by other means. The excited region may be just a thin skin on a much more extensive blob of molecular gas that does not have the correct temperature and density to be as easily detectable. At the opposite extreme, the observed knots could consist of a fine mist of molecular gas in which we are detecting essentially all of the H2. Future CO observations could distinguish between these two cases. The Crab filaments serve as the nearby laboratories for understanding the very much larger filamentary structures that have formed in the intracluster medium of cool-core galaxy clusters

The Nature of the H\u3csub\u3e2\u3c/sub\u3e-Emitting Gas in the Crab Nebula

Understanding how molecules and dust might have formed within a rapidly expanding young supernova remnant is important because of the obvious application to vigorous supernova activity at very high redshift. In previous papers, we have mapped the Crab nebula (the Crab) in a rotovibrational H2emission line, and then measured the molecular excitation temperature for a few of the brighter H2-emitting knots that we have found to be scattered throughout the Crab\u27s filaments. We found that H2 emission is often quite strong, correlates with optical low-ionization emission lines and has a surprisingly high excitation temperature. Here, we study Knot 51, a representative, bright example. It is a spatially isolated structure for which we have available long-slit optical and near-infrared (NIR) spectra covering emission lines from ionized, neutral and molecular gas, as well asHubble Space Telescope visible and Southern Astrophysical Research telescope NIR narrow-band images. We present a series of CLOUDYsimulations to probe the excitation mechanisms, formation processes and dust content in environments that can produce the observed H2 emission. There is still considerable ambiguity about the geometry of Knot 51, so we do not try for an exact match between model and observations. Rather, we aim to explain how the bright H2 emission lines can be formed from within a cloud of the size of Knot 51 that also produces the observed optical emission from ionized and neutral gas. Our models that are powered only by the Crab\u27s synchrotron radiation are ruled out because they are not able to reproduce the observed strong H2 emission coming from thermally populated levels. The simulations that come closest to fitting the observations (although they still have conspicuous discrepancies) have the core of Knot 51 almost entirely atomic with the H2 emission coming from just a trace molecular component, and in which there is extra heating. In this unusual environment, H2 forms primarily through H− by radiative detachment rather than by grain catalysis. In this picture, the 55 H2-emitting cores that we have previously catalogued in the Crab have a total mass of about 0.1 M⊙, which is about 5 per cent of the total mass of the system of filaments. We also explore the effect of varying the dust abundance. We discuss possible future observations that could further elucidate the nature of these H2 knots

The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.

Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma

Estimating Incidence Curves of Several Infections Using Symptom Surveillance Data

We introduce a method for estimating incidence curves of several co-circulating infectious pathogens, where each infection has its own probabilities of particular symptom profiles. Our deconvolution method utilizes weekly surveillance data on symptoms from a defined population as well as additional data on symptoms from a sample of virologically confirmed infectious episodes. We illustrate this method by numerical simulations and by using data from a survey conducted on the University of Michigan campus. Last, we describe the data needs to make such estimates accurate

Heavy Coronal Ions in the Heliosphere: I. Global Distribution of Charge-states of C, N, O, Mg, Si and S

Aims: Investigate/Study de-charging of solar wind C, N, O, Mg, Si and S ions and assess fluxes of resulting ENA in the heliosphere. Methods: The model treats the heavy ions as test particles convected by (and in a particular case also diffusing through) a hydrodynamically calculated background plasma flow, from 1 AU to the termination shock (TS), to heliosheath (HS) and finally to heliospheric tail (HT). The ions undergo radiative and dielectronic recombinations, charge exchanges, photo- and electron impact ionizations with plasma particles, interstellar neutral atoms (calculated on a Monte-Carlo model) and solar photons. Results: Highly-charged heavy coronal ions flowing with the solar wind undergo successive de-ionizations, mainly in the heliosheath, leading to charge-states much lower than in the supersonic solar wind. If Coulomb scattering is the main ion energy loss mechanism, the end product of these deionizations are fluxes of ENA of ~1 keV/nucleon originating in the upwind heliosheath that for C, Mg, Si and S may constitute sources of pickup ions (PUI) significantly exceeding the interstellar supply. Conclusions: Discussed processes result in (i) distinct difference of ion charge q in the supersonic solar wind (approximately q >= +Z/2, Z = atomic number) compared to that in the HS (approximately 0 <= q <= +Z/2)), (ii) probable concentration of singly ionized atoms (q = +1) in the heliosheath towards the heliopause (HP) and in the HT, (iii) possible significant production of ENA in the HS offering natural explanation for production of PUI, and -- after acceleration at the TS -- anomalous cosmic rays (ACR) of species (like C, Mg, Si, S) unable to enter the heliospheric cavity from outside because of their total ionization in the local interstellar medium.Comment: Reduced-resolution version, submitted to A&A; full resolution: http://articles.cbk.waw.pl/0printed/g/grzedzielski_etal08a.pdf. One figure correcte

Supported self-management for adults with type 2 diabetes and a learning disability (OK-Diabetes): study protocol for a randomised controlled feasibility trial

Background: Individuals with a learning disability (LD) are at higher risk of developing type 2 diabetes, but LD is not straightforward to define or identify, especially at the milder end of the spectrum, which makes case finding difficult. While supported self-management of health problems is now established, current material is largely educational and didactic with little that facilitates behavioural change. The interaction between the person with diabetes and others supporting their care is also largely unknown. For these reasons, there is considerable work needed to prepare for a definitive trial. The aim of this paper is to publish the abridged protocol of this preparatory work. Methods/Design: Phase I is a prospective case-finding study (target n = 120 to 350) to identify and characterise potential participants, while developing a standardised supported self-management intervention. Phase II is a randomised feasibility trial (target n = 80) with blinded outcome assessment. Patients identified in Phase I will be interviewed and consented prior to being randomised to (1) standard treatment, or (2) supported self-management. Both arms will also be provided with an ‘easy read’ accessible information resource on managing type 2 diabetes. The intervention will be standardised but delivered flexibly depending on patient need, including components for the participant, a supporter, and shared activities. Outcomes will be (i) robust estimates of eligibility, consent and recruitment rates with refined recruitment procedures; (ii) characterisation of the eligible population; (iii) a standardised intervention with associated written materials, (iv) adherence and negative outcomes measures; (v) preliminary estimates of adherence, acceptability, follow-up and missing data rates, along with refined procedures; and (vi) description of standard treatment. Discussion: Our study will provide important information on the nature of type 2 diabetes in adults with LD living in the community, on the challenges of identifying those with milder LD, and on the possibilities of evaluating a standardised intervention to improve self-management in this population. Trial registration: Current Controlled Trials ISRCTN41897033 (registered 21 January 2013)

Avelumab Alone or in Combination With Chemotherapy Versus Chemotherapy Alone in Platinum-Resistant or Platinum-Refractory Ovarian Cancer (JAVELIN Ovarian 200): An Open-Label, Three-Arm, Randomised, Phase 3 Study

The majority of patients with ovarian cancer will experience relapse and develop platinum-resistant disease after being treated with frontline platinum-based chemotherapy. Treatment options for platinum-resistance or platinum-refractory disease are very limited, usually involving nonplatinum chemotherapy, and they are associated with poor objective response rates and life expectancy

Common Variants within MECP2 Confer Risk of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a predominantly female autoimmune disease that affects multiple organ systems. Herein, we report on an X-chromosome gene association with SLE. Methyl-CpG-binding protein 2 (MECP2) is located on chromosome Xq28 and encodes for a protein that plays a critical role in epigenetic transcriptional regulation of methylation-sensitive genes. Utilizing a candidate gene association approach, we genotyped 21 SNPs within and around MECP2 in SLE patients and controls. We identify and replicate association between SLE and the genomic element containing MECP2 in two independent SLE cohorts from two ethnically divergent populations. These findings are potentially related to the overexpression of methylation-sensitive genes in SLE