In resource-limited settings, where resistance testing is unavailable, confirmatory testing for patients with high viral loads (VL) delays antiretroviral therapy (ART) switches for persons with ...resistance. We developed a risk score algorithm to predict need for ART change by identifying resistance among persons with persistently elevated VL.
We analyzed data from a Phase IV open-label trial. Using logistic regression, we identified demographic and clinical characteristics predictive of need for ART change among participants with VLs ≥1000 copies/ml, and assigned model-derived scores to predictors. We designed three models, including only variables accessible in resource-limited settings.
Among 290 participants with at least one VL ≥1000 copies/ml, 51 % (148/290) resuppressed and did not have resistance testing; among those who did not resuppress and had resistance testing, 47 % (67/142) did not have resistance and 53 % (75/142) had resistance (ART change needed for 25.9 % (75/290)). Need for ART change was directly associated with higher baseline VL and higher VL at time of elevated measure, and inversely associated with treatment duration. Other predictors included body mass index and adherence. Area under receiver operating characteristic curves ranged from 0.794 to 0.817. At a risk score ≥9, sensitivity was 14.7-28.0 % and specificity was 96.7-98.6 %.
Our model performed reasonably well and may be a tool to quickly transition persons in need of ART change to more effective regimens when resistance testing is unavailable. Use of this algorithm may result in public health benefits and health system savings through reduced transmissions of resistant virus and costs on laboratory investigations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of ...neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
High-throughput sequencing technology enables population-level surveys of human genomic variation. Here, we examine the joint allele frequency distributions across continental human populations and ...present an approach for combining complementary aspects of whole-genome, low-coverage data and targeted high-coverage data. We apply this approach to data generated by the pilot phase of the Thousand Genomes Project, including whole-genome 2-4x coverage data for 179 samples from HapMap European, Asian, and African panels as well as high-coverage target sequencing of the exons of 800 genes from 697 individuals in seven populations. We use the site frequency spectra obtained from these data to infer demographic parameters for an Out-of-Africa model for populations of African, European, and Asian descent and to predict, by a jackknife-based approach, the amount of genetic diversity that will be discovered as sample sizes are increased. We predict that the number of discovered nonsynonymous coding variants will reach 100,000 in each population after
A comparison of the genomic sequence of a tumor sample from a patient with acute myeloid leukemia (AML) and that of a normal skin sample from the same patient revealed an estimated 750 somatic ...mutations, of which 12 were in the coding sequences of genes and 52 were in conserved regions or regions with regulatory potential. Four mutations were found to be recurrent in AML, including mutations in
NRAS, NPM1, IDH1,
and a conserved region on chromosome 10.
A comparison of the genomic sequence of a tumor sample from a patient with acute myeloid leukemia (AML) and that of a normal skin sample from the same patient revealed an estimated 750 somatic mutations. Four mutations were found to be recurrent in AML.
Acute myeloid leukemia (AML) is a clonal hematopoietic disease caused by both inherited and acquired genetic alterations.
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Current AML classification and prognostic systems incorporate genetic information but are limited to known abnormalities that have previously been identified with the use of cytogenetics, array comparative genomic hybridization (CGH), gene-expression profiling, and the resequencing of candidate genes (see the Glossary).
The karyotyping of AML cells remains the most powerful predictor of the outcome in patients with AML and is routinely used by clinicians.
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As an adjunct to cytogenetic studies, small subcytogenetic amplifications and deletions can be identified with the use . . .
Gene expression measurement techniques such as quantitative reverse transcriptase (qRT)-PCR require a normalization strategy to allow meaningful comparisons across biological samples. Typically, this ...is accomplished through the use of an endogenous housekeeping gene that is presumed to show stable expression levels in the samples under study. There is concern regarding how precisely specific genes can be measured in limited amounts of mRNA such as those from microdissected (MD) tissues. To address this issue, we evaluated three different approaches for qRT-PCR normalization of dissected samples; cell count during microdissection, total RNA measurement, and endogenous control genes. The data indicate that both cell count and total RNA are useful in calibrating input amounts at the outset of a study, but do not provide enough precision to serve as normalization standards. However, endogenous control genes can accurately determine the relative abundance of a target gene relative to the entire cellular transcriptome. Taken together, these results suggest that precise gene expression measurements can be made from MD samples if the appropriate normalization strategy is employed.
A major use of the 1000 Genomes Project (1000 GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing ...data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000 GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants.
Tenofovir-lamivudine-dolutegravir (TLD) is the preferred first-line antiretroviral therapy (ART) regimen. An additional 50 mg dose of dolutegravir (TLD + 50) is required with rifampin-containing ...tuberculosis (TB) co-treatment. There are limited data on the effectiveness of TLD + 50 in individuals with TB/HIV.
Prospective, observational cohort study at 12 sites in Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe. Participants starting TLD and rifampin-containing TB treatment were eligible. Primary outcome was HIV-1 RNA ≤1000 copies/mL at end of TB treatment.
We enrolled 91 participants with TB/HIV: 75 (82%) ART-naïve participants starting TLD after a median 15 days on TB treatment, 10 (11%) ART-naïve participants starting TLD and TB treatment, 5 (5%) starting TB treatment after a median 3.3 years on TLD, and 1 (1%) starting TB treatment and TLD after changing from efavirenz/lamivudine/tenofovir. Median age was 37 years, 35% female, median CD4 count 120 cells/mm3 (IQR 50-295), 87% had HIV-1 RNA >1000 copies/mL. Two participants died during TB treatment. Among 89 surviving participants, 80 were followed to TB treatment completion, including 7 who had no HIV-1 RNA result due to missed visits. Primary virologic outcome was assessed in 73 participants, of whom 69 (95%, 95% CI 89-100%) had HIV-1 RNA ≤1000 copies/mL. No dolutegravir resistance mutations were detected among four participants with HIV-1 RNA >1000 copies/mL.
In routine programmatic settings, concurrent rifampin-containing TB treatment and TLD + 50 was feasible, well-tolerated, and achieved high rates of viral suppression in a cohort of predominantly ART-naïve people with TB/HIV.
A bolide that impacted NW Australia during the Late Quaternary left a circular depression more than 100 m deep and nearly a kilometer in diameter, with a crater rim ∼30 m above the regional terrain. ...The resultant crater is a window into the regional water table. The surface of the contemporary central pan is 25 m below the adjacent terrain, coincident with the late Holocene regional water table modified by local evaporative processes. Shielded from aeolian deflation by the crater rim, the central depression has slowly filled with dust, sand, and chemical precipitates, estimated to be 20–100 m thick based on geophysical surveys, one of the few continuous depocenters in the Australian Arid Zone. The nature of the crater's sediment fill is controlled by interactions between the water table, primarily in response to changes in summer monsoon rain, changes in the delivery of sand and dust to the crater by the prevailing easterly winds, and the level of the sedimentary fill surface. Optically Stimulated Luminescence (OSL) and 14C dates constrain an age model indicating the upper 10 m of sediment fill recovered from the central pan span the past ∼60 ka. The lowest 3 m consist of clayey sand deposited in perennial water during Marine Isotope Stage (MIS) 3. The water table subsequently dropped rapidly ∼35 ka and remained more than 7 m below the late Holocene level through most of MIS 2, during which 2 m of sandy clay was deposited on a dry crater floor, confirming a dry and dusty Last Glacial Maximum (LGM) climate. By 14 ka a rising water table intersected the crater surface, modifying the upper 50 cm of LGM sediment, and syndepositionally modifying another 60 cm of subsequent sandy clay deposition. Aeolian sediment delivery effectively ceased ∼13 ka, and the upper 4.8 m is a gypsum-dominated precipitate, which initially accumulated rapidly, before equilibrating with the late Holocene water table shortly after 6 ka. Lacustrine carbonate encrustations on rocks at the base of the crater wall and ∼4 m above the central pan with 14C ages >40 ka document a time when regional groundwater maintained a water body in the crater 3.5–4.5 m above the modern groundwater level. The crater wall deflected the prevailing easterly winds, creating a horseshoe-dune extending westerly on both sides of the crater, with an extension rate of 35 m ka−1. An augered hole through the northern dune revealed 10 m of sediment overlying ferricrete. The lowest meter is a mixture of broken ferricrete and sand that we interpret to be debris from the bolide impact. Three OSL dates through the dune project an age for the debris-dune contact of 120 ± 10 ka. Changes in physical properties and bulk sediment δ13C through the 9 m of aeolian sediment indicate the lowest 1.8 m was deposited during MIS 5 (120–85 ka), under a uniformly wetter climate than present. The overlying 4.3 m of sediment was deposited between 85 and 14 ka (MIS 4, 3, 2) and exhibits transitional characteristics between the lower unit and the upper 3.8 of sand, which was deposited primarily during the Holocene. Large changes in the regional water table occurred over the past 60 ka, including an LGM water table persistently ≥7 m lower than late Holocene levels, and 3.5–4.5 m higher prior to 40 ka, plausibly in MIS 5, indicative of a stronger Australian Summer Monsoon than at any time subsequently. Age models and sediment properties from the two sedimentary records indicate the crater was formed >60 ka and most likely ∼120 ka, more recently than previous estimates.
•Wolfe Creek Crater provides a continuous Late Quaternary sedimentary record for monsoonal Australia.•A 10 m augered hole from the crater fill provides a ∼60 ka record of monsoon rainfall via changes in the crater's water table.•A sedimentary δ13C record through the dune created by the impact wall provides a 120 ka vegetation record of local moisture .•OSL dating of the horseshoe dune yields a 120 ka date for meteorite impact, much younger than previous estimates.•Our findings reinforce the “Holocene Enigma”: why no strong Holocene monsoon despite favorable primary forcings?
The rhesus macaque (Macaca mulatta) is an abundant primate species that diverged from the ancestors of Homo sapiens about 25 million years ago. Because they are genetically and physiologically ...similar to humans, rhesus monkeys are the most widely used nonhuman primate in basic and applied biomedical research. We determined the genome sequence of an Indian-origin Macaca mulatta female and compared the data with chimpanzees and humans to reveal the structure of ancestral primate genomes and to identify evidence for positive selection and lineage-specific expansions and contractions of gene families. A comparison of sequences from individual animals was used to investigate their underlying genetic diversity. The complete description of the macaque genome blueprint enhances the utility of this animal model for biomedical research and improves our understanding of the basic biology of the species.
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