Prognostic and surrogate markers for outcome in the treatment of pulmonary tuberculosis

Phase III trials for new tuberculosis treatment regimens require large numbers of participants and can take over five years to complete. A surrogate marker for poor outcome (failure at end of treatment or recurrence following successful treatment), the established endpoint in such trials, could shorten trial duration and reduce trial size. Culture results after two months of treatment have shown the most promise but, prior to this research, no formal evaluation had been performed. In this thesis, culture results during treatment are evaluated as prognostic and surrogate markers for poor outcome using data on 6974 patients from twelve tuberculosis treatment randomised controlled multi-arm trials conducted in East Africa and East Asia. A strong association was found between culture results during treatment and poor outcome. Nevertheless, culture results were not good patient-specific predictors of poor outcome with low sensitivities and specificities. Existing meta-analytic methods for evaluating surrogate markers are not wholly suited to this setting of multi-arm trials with binary true and surrogate endpoints. Extending these methods, the two month culture was found to be a good surrogate marker using data from Hong Kong trials and the three month culture was found to be a good surrogate marker using data from East African trials. These results are an indication that cultures during treatment do capture some of the treatment effect. Further work is needed in understanding the differences between the Hong Kong and East African trials. The meta-analytic methods for evaluating surrogate markers in this thesis included a graphical representation that permitted a clear visual evaluation of the surrogate. Methods developed in this thesis for modelling the relationship between the treatment effects on the true and surrogate endpoints were not satisfactory. The deficiencies were not overcome with the two extensions proposed. Further work is needed in developing a more appropriate model

Tests of the Accelerating Universe with Near-Infrared Observations of a High-Redshift Type Ia Supernova

We have measured the rest-frame B,V, and I-band light curves of a high-redshift type Ia supernova (SN Ia), SN 1999Q (z=0.46), using HST and ground-based near-infrared detectors. A goal of this study is the measurement of the color excess, E_{B-I}, which is a sensitive indicator of interstellar or intergalactic dust which could affect recent cosmological measurements from high-redshift SNe Ia. Our observations disfavor a 30% opacity of SN Ia visual light by dust as an alternative to an accelerating Universe. This statement applies to both Galactic-type dust (rejected at the 3.4 sigma confidence level) and greyer dust (grain size > 0.1 microns; rejected at the 2.3 to 2.6 sigma confidence level) as proposed by Aguirre (1999). The rest-frame $I$-band light cur ve shows the secondary maximum a month after B maximum typical of nearby SNe Ia of normal luminosi ty, providing no indication of evolution as a function of redshift out to z~0.5. A n expanded set of similar observations could improve the constraints on any contribution of extragalactic dust to the dimming of high-redshift SNe Ia.Comment: Accepted to the Astrophysical Journal, 12 pages, 2 figure

Hubble Space Telescope and Ground-Based Observations of Type Ia Supernovae at Redshift 0.5: Cosmological Implications

We present observations of the Type Ia supernovae (SNe) 1999M, 1999N, 1999Q, 1999S, and 1999U, at redshift z~0.5. They were discovered in early 1999 with the 4.0~m Blanco telescope at Cerro Tololo Inter-American Observatory by the High-z Supernova Search Team (HZT) and subsequently followed with many ground-based telescopes. SNe 1999Q and 1999U were also observed with the Hubble Space Telescope. We computed luminosity distances to the new SNe using two methods, and added them to the high-z Hubble diagram that the HZT has been constructing since 1995. The new distance moduli confirm the results of previous work. At z~0.5, luminosity distances are larger than those expected for an empty universe, implying that a ``Cosmological Constant,'' or another form of ``dark energy,'' has been increasing the expansion rate of the Universe during the last few billion years.Comment: 68 pages, 22 figures. Scheduled for the 01 February 2006 issue of Ap.J. (v637

Phase Correlations in Cosmic Microwave Background Temperature Maps

We study the statistical properties of spherical harmonic modes of temperature maps of the cosmic microwave background. Unlike other studies, which focus mainly on properties of the amplitudes of these modes, we look instead at their phases. In particular, we present a simple measure of phase correlation that can be diagnostic of departures from the standard assumption that primordial density fluctuations constitute a statistically homogeneous and isotropic Gaussian random field, which should possess phases that are uniformly random on the unit circle. The method we discuss checks for the uniformity of the distribution of phase angles using a non-parametric descriptor based on the use order statistics, which is known as Kuiper's statistic. The particular advantage of the method we present is that, when coupled to the judicious use of Monte Carlo simulations, it can deliver very interesting results from small data samples. In particular, it is useful for studying the properties of spherical harmonics at low l for which there are only small number of independent values of m and which therefore furnish only a small number of phases for analysis. We apply the method to the COBE-DMR and WMAP sky maps, and find departures from uniformity in both. In the case of WMAP, our results probably reflect Galactic contamination or the known variation of signal-to-noise across the sky rather than primordial non-Gaussianity.Comment: 18 pages, 4 figures, accepted for publication in MNRA

Optical Spectra of Type Ia Supernovae at z=0.46 and z=1.2

We present optical spectra, obtained with the Keck 10-m telescope, of two high-redshift type Ia supernovae (SNe Ia) discovered by the High-z Supernova Search Team: SN 1999ff at z=0.455 and SN 1999fv at z~1.2, the highest-redshift published SN Ia spectrum. Both SNe were at maximum light when the spectra were taken. We compare our high-z spectra with low-z normal and peculiar SNe Ia as well as with SNe Ic, Ib, and II. There are no significant differences between SN 1999ff and normal SNe Ia at low redshift. SN 1999fv appears to be a SN Ia and does not resemble the most peculiar nearby SNe Ia.Comment: 6 pages including 2 figures; to appear in The Astrophysical Journal Letter

Cost-effectiveness of donepezil and memantine in moderate to severe Alzheimer's disease (the DOMINO-AD trial).

OBJECTIVE: Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild-to-moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost-effective for community-dwelling, moderate-to-severe Alzheimer's disease patients. METHODS: Cost-effectiveness analysis was based on a 52-week, multicentre, double-blind, placebo-controlled, factorial clinical trial. A total of 295 community-dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine. RESULTS: Continuing donepezil for 52 weeks was more cost-effective than discontinuation, considering cognition, activities of daily living and health-related quality of life. Starting memantine was more cost-effective than donepezil discontinuation. Donepezil-memantine combined is not more cost-effective than donepezil alone. CONCLUSIONS: Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd

Towards a comprehensive research and development plan to support the control, elimination and eradication of neglected tropical diseases.

To maximise the likelihood of success, global health programmes need repeated, honest appraisal of their own weaknesses, with research undertaken to address any identified gaps. There is still much to be learned to optimise work against neglected tropical diseases. To facilitate that learning, a comprehensive research and development plan is required. Here, we discuss how such a plan might be developed

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts