HIV-1 viral load outcomes and the evolution of drug-resistance in low-income settings without virological monitoring

WHO guidelines recommend viral load monitoring for all HIV-1 positive patients on antiretroviral therapy (ART). However, few low-income countries have virological monitoring widely available, and patients may remain on virologically failing regimens. This could compromise future ART through the accumulation of drug resistance mutations and result in worse long-term clinical outcomes. The DART trial was conducted in Uganda and Zimbabwe and compared clinically driven monitoring with or without routine CD4 measurement in ART-naïve adult patients. Annual plasma viral load was retrospectively measured for 1,762 patients. This thesis investigates how no laboratory monitoring impacts virological failure and the development of drug resistance. Time to persistent virological failure was analysed, and analytical weights were calculated to correct for non-random sampling. The long-term durability of first-line ART was remarkable; 21% of patients on an NRTI-NNRTI regimen and 40% on a triple-NRTI regimen experienced persistent virological failure by 240 weeks. Routine CD4 monitoring did not reduce virological failure. Deaths after 48 weeks of ART are widely assumed to be due to virological failure or non-adherence. Analyses revealed that a surprisingly high number of these deaths (40%) occurred without virological criteria for treatment switch being met. Routine CD4 monitoring reduced the rate of death with virological failure but did not impact deaths with virological suppression. Cross-sectional analyses quantified HIV-1 drug resistance at the end of first-line ART. On NRTI-NNRTI regimens, 88% had NRTI resistance, and 66% had NNRTI resistance. Routine CD4 monitoring did not reduce the prevalence or extent of drug resistance. The order and rate of HIV-1 drug resistance mutations were explored using repeated genotypes within patients. On NRTI-NNRTI regimens, NRTI and NNRTI mutations developed at a rate of 0.96 and 0.21 per year respectively. Mutagenic tree models demonstrated that ART regimen influenced the order and rate in which mutations occurred

Experimental evidence of cut-wire-induced enhanced transmission of transverse-electric fields through sub-wavelength slits in a thin metallic screen

Recent numerical studies have demonstrated the possibility of achieving substantial enhancements in the transmission of transverse-electric-polarized electromagnetic fields through subwavelength slits in a thin metallic screen by placing single or paired metallic cut-wire arrays at a close distance from the screen. In this Letter, we report on the first experimental evidence of such extraordinary transmission phenomena, via microwave (X/Ku-band) measurements on printed-circuit-board prototypes. Experimental results agree very well with full-wave numerical predictions, and indicate an intrinsic robustness of the enhanced transmission phenomena with respect to fabrication tolerances and experimental imperfections.Comment: 6 pages, 4 figures (slight revision

The virological durability of first-line ART among HIV-positive adult patients in resource limited settings without virological monitoring: a retrospective analysis of DART trial data

BACKGROUND: Few low-income countries have virological monitoring widely available. We estimated the virological durability of first-line antiretroviral therapy (ART) after five years of follow-up among adult Ugandan and Zimbabwean patients in the DART study, in which virological assays were conducted retrospectively. METHODS: DART compared clinically driven monitoring with/without routine CD4 measurement. Annual plasma viral load was measured on 1,762 patients. Analytical weights were calculated based on the inverse probability of sampling. Time to virological failure, defined as the first viral load measurement ≥200 copies/mL after 48 weeks of ART, was analysed using Kaplan-Meier plots and Cox regression models. RESULTS: Overall, 65% of DART trial patients were female. Patients initiated first-line ART at a median (interquartile range; IQR) age of 37 (32-42) and with a median CD4 cell count of 86 (32-140). After 240 weeks of ART, patients initiating dual-class nucleoside reverse-transcriptase inhibitor (NRTI) -non-nucleoside reverse-transcriptase (NNRTI) regimens containing nevirapine + zidovudine + lamivudine had a lower incidence of virological failure than patients on triple-NRTI regimens containing tenofovir + zidovudine + lamivudine (21% vs 40%; hazard ratio (HR) =0.48, 95% CI:0.38-0.62; p < 0.0001). In multivariate analyses, female patients (HR = 0.79, 95% CI: 0.65-0.95; p = 0.02), older patients (HR = 0.73 per 10 years, 95% CI: 0.64-0.84; p < 0.0001) and patients with a higher pre-ART CD4 cell count (HR = 0.64 per 100 cells/mm(3), 95% CI: 0.54-0.75; p < 0.0001) had a lower incidence of virological failure after adjusting for adherence to ART. No difference in failure rate between the two randomised monitoring strategies was observed (p= 0.25). CONCLUSIONS: The long-term durability of virological suppression on dual-class NRTI-NNRTI first-line ART without virological monitoring is remarkable and is enabled by high-quality clinical management and a consistent drug supply. To achieve higher rates of virological suppression viral-load-informed differentiated care may be required. TRIAL REGISTRATION: Prospectively registered on 18/10/2000 as ISRCTN13968779

Procedures for listing loci and alleles of ruminants: 1991 proposals

The following procedures for listing loci in ruminants were proposed at the 1991 1st Workshop on Genetic Nomenclature of Farm Ruminants organised by COGNOSAG (Committee on Genetic Nomenclature of Sheep and Goats): identification of locus, genomic location, gene effect classification (24 entries), summary of alleles and, for each allele, after identification, phenotypic effect, inheritance and breeds implied. This set of procedures is intended for the first edition of the MIS, MIG and MIC catalogues (mendelian inheritance in sheep, goats and cattle, respectively) and is a basis for future data banking.Au cours du premier Atelier de Nomenclature Génétique des Ruminants de Ferme organisé par le COGOVICA (Comité de Nomenclature Génétique des Ovins et Caprins) en 1991, les procédures suivantes de listage des loci chez les Ruminants ont été proposées: identification du locus, localisation sur le génome, effet du gène (24 entrées), tableau des allèles et, pour chaque allèle, outre l’identification, l’effet phénotypique, l’hérédité et les races concernées. Conçue pour être utilisée dans la première édition des catalogues MIS, MIG et MIC (Mendelian Inheritance in Sheep, Goats and Cattle resp), cette grille peut servir de base pour une future banque de données

Single- and multi-peak solitons in two-component models of metamaterials and photonic crystals

We report results of the study of solitons in a system of two nonlinear-Schrodinger (NLS) equations coupled by the XPM interaction, which models the co-propagation of two waves in metamaterials(MMs). The same model applies to photonic crystals (PCs), as well as to ordinary optical fibers, close to the zero-dispersion point. A peculiarity of the system is a small positive or negative value of the relative group-velocity dispersion (GVD) coefficient in one equation, assuming that the dispersion is anomalous in the other. In contrast to earlier studied systems of nonlinearly coupled NLS equations with equal GVD coefficients, which generate only simple single-peak solitons, the present model gives rise to families of solitons with complex shapes, which feature extended oscillatory tails and/or a double-peak structure at the center. Regions of existence are identified for single- and double-peak bimodal solitons, demonstrating a broad bistability in the system. Behind the existence border, they degenerate into single-component solutions. Direct simulations demonstrate stability of the solitons in the entire existence regions. Effects of the group-velocity mismatch (GVM) and optical loss are considered too. It is demonstrated that the solitons can be stabilized against the GVM by means of the respective "management" scheme. Under the action of the loss, complex shapes of the solitons degenerate into simple ones, but periodic compensation of the loss supports the complexity.Comment: Optics Communications, in press (Special Issue on Nonlinear Metamaterials

Acceptability of an open-label wait-listed trial design: Experiences from the PROUD PrEP study

Background PROUD participants were randomly assigned to receive pre-exposure prophylaxis (PrEP) immediately or after a deferred period of one-year. We report on the acceptability of this open-label wait-listed trial design. Methods Participants completed an acceptability questionnaire, which included categorical study acceptability data and free-text data on most and least liked aspects of the study. We also conducted in-depth interviews (IDI) with a purposely selected sub-sample of participants. Results Acceptability questionnaires were completed by 76% (415/544) of participants. After controlling for age, immediate-group participants were almost twice as likely as deferred-group participants to complete the questionnaire (AOR:1.86;95%CI:1.24,2.81). In quantitative data, the majority of participants in both groups found the wait-listed design acceptable when measured by satisfaction of joining the study, intention to remain in the study, and interest in joining a subsequent study. However, three-quarters thought that the chance of being in the deferred-group might put other volunteers off joining the study. In free-text responses, data collection tools were the most frequently reported least liked aspect of the study. A fifth of deferred participants reported ‘being deferred’ as the thing they least liked about the study. However, more deferred participants disliked the data collection tools than the fact that they had to wait a year to access PrEP. Participants in the IDIs had a good understanding of the rationale for the open-label wait-listed study design. Most accepted the design but acknowledged they were, or would have been, disappointed to be randomised to the deferred group. Five of the 25 participants interviewed reported some objection to the wait-listed design. Conclusion The quantitative and qualitative findings suggest that in an environment where PrEP was not available, the rationale for the wait-listed trial design was well understood and generally acceptable to most participants in this study

Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.

To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID-associated genes using targeted next-generation sequencing. Likely pathogenic rare variants were found in ∼11% of the cases (113 variants in 107/986 individuals: ∼8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas ∼3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%-15% yield from array CGH alone.Action Medical Research (SP4640); the Birth Defect Foundation (RG45448); the Cambridge National Institute for Health Research Biomedical Research Centre (RG64219); the NIHR Rare Diseases BioResource (RBAG163); Wellcome Trust award WT091310; The Cell lines and DNA bank of Rett Syndrome, X-linked mental retardation and other genetic diseases (member of the Telethon Network of Genetic Biobanks (project no. GTB12001); the Genetic Origins of Congenital Heart Disease Study (GO-CHD)- funded by British Heart Foundation (BHF)This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/humu.2290