Tuberculosis preventive therapy : An underutilised strategy to reduce individual risk of TB and contribute to TB control

PKTuberculosis (TB) remains a global health problem, and South Africa (SA) has one of the world’s worst TB epidemics. The World Health Organization (WHO) estimated in 1999 that one-third of the world’s population was latently infected with TB. In SA up to 88% of HIV-uninfected young adults (31 - 35 years) are latently infected with TB. In the most recent meta-analysis, 6 - 12 months of isoniazid preventive therapy (IPT) was associated with a lower incidence of active TB than placebo (relative risk (RR) 0.68; 95% confidence interval (CI) 0.54 - 0.85), with the greatest benefit among individuals with a positive tuberculin skin test (TST) (RR 0.38; 95% CI 0.25 - 0.57). A clinical trial of IPT given with antiretroviral therapy (ART) for 12 months reduced TB incidence by 37% compared with ART alone (hazard ratio (HR) 0.63; 95% CI 0.41 - 0.94). The effect of IPT is limited in high-burden countries. IPT for 36 months v. 6 months reduced TB incidence among HIV-positive, TST-positive participants by 74% (HR 0.26; 95% CI 0.09 - 0.80). A study of more than 24 000 goldminers confirmed that IPT is safe, with only 0.5% experiencing adverse events. A meta-analysis of studies of IPT since 1951 did not show an increased risk of developing resistance. Alternative TB preventive therapy regimens, including high-dose isoniazid and rifapentine given weekly for 3 months, have been shown to have similar efficacy to IPT. Mathematical modelling suggests that scaling up continuous IPT targeted to HIV-positive persons, when used in combination with other treatment and prevention strategies, may substantially improve TB control

A Model of Habitability Within the Milky Way Galaxy

We present a model of the Galactic Habitable Zone (GHZ), described in terms of the spatial and temporal dimensions of the Galaxy that may favour the development of complex life. The Milky Way galaxy is modelled using a computational approach by populating stars and their planetary systems on an individual basis using Monte-Carlo methods. We begin with well-established properties of the disk of the Milky Way, such as the stellar number density distribution, the initial mass function, the star formation history, and the metallicity gradient as a function of radial position and time. We vary some of these properties, creating four models to test the sensitivity of our assumptions. To assess habitability on the Galactic scale, we model supernova rates, planet formation, and the time required for complex life to evolve. Our study improves on other literature on the GHZ by populating stars on an individual basis and by modelling SNII and SNIa sterilizations by selecting their progenitors from within this preexisting stellar population. Furthermore, we consider habitability on tidally locked and non-tidally locked planets separately, and study habitability as a function of height above and below the Galactic midplane. In the model that most accurately reproduces the properties of the Galaxy, the results indicate that an individual SNIa is ~5.6 \times more lethal than an individual SNII on average. In addition, we predict that ~1.2% of all stars host a planet that may have been capable of supporting complex life at some point in the history of the Galaxy. Of those stars with a habitable planet, ~75% of planets are predicted to be in a tidally locked configuration with their host star. The majority of these planets that may support complex life are found towards the inner Galaxy, distributed within, and significantly above and below, the Galactic midplane.Comment: Accepted for publication in Astrobiology. 40 pages, 12 figures, 3 table

Computational and Biological Analogies for Understanding Fine-Tuned Parameters in Physics

In this philosophical paper, we explore computational and biological analogies to address the fine-tuning problem in cosmology. We first clarify what it means for physical constants or initial conditions to be fine-tuned. We review important distinctions such as the dimensionless and dimensional physical constants, and the classification of constants proposed by Levy-Leblond. Then we explore how two great analogies, computational and biological, can give new insights into our problem. This paper includes a preliminary study to examine the two analogies. Importantly, analogies are both useful and fundamental cognitive tools, but can also be misused or misinterpreted. The idea that our universe might be modelled as a computational entity is analysed, and we discuss the distinction between physical laws and initial conditions using algorithmic information theory. Smolin introduced the theory of "Cosmological Natural Selection" with a biological analogy in mind. We examine an extension of this analogy involving intelligent life. We discuss if and how this extension could be legitimated. Keywords: origin of the universe, fine-tuning, physical constants, initial conditions, computational universe, biological universe, role of intelligent life, cosmological natural selection, cosmological artificial selection, artificial cosmogenesis.Comment: 25 pages, Foundations of Science, in pres

Purine-Rich Foods Intake and Recurrent Gout Attacks

OBJECTIVE: To examine and quantify the relation between purine intake and the risk of recurrent gout attacks among gout patients. METHODS: The authors conducted a case-crossover study to examine associations of a set of putative risk factors with recurrent gout attacks. Individuals with gout were prospectively recruited and followed online for 1 year. Participants were asked about the following information when experiencing a gout attack: the onset date of the gout attack, clinical symptoms and signs, medications (including antigout medications), and presence of potential risk factors (including daily intake of various purine-containing food items) during the 2-day period prior to the gout attack. The same exposure information was also assessed over 2-day control periods. RESULTS: This study included 633 participants with gout. Compared with the lowest quintile of total purine intake over a 2-day period, OR of recurrent gout attacks were 1.17, 1.38, 2.21 and 4.76, respectively, with each increasing quintile (p for trend <0.001). The corresponding OR were 1.42, 1.34, 1.77 and 2.41 for increasing quintiles of purine intake from animal sources (p for trend <0.001), and 1.12, 0.99, 1.32 and 1.39 from plant sources (p=0.04), respectively. The effect of purine intake persisted across subgroups by sex, use of alcohol, diuretics, allopurinol, NSAIDs and colchicine. CONCLUSIONS: The study findings suggest that acute purine intake increases the risk of recurrent gout attacks by almost fivefold among gout patients. Avoiding or reducing amount of purine-rich foods intake, especially of animal origin, may help reduce the risk of gout attacks

Reconstructing complex regions of genomes using long-read sequencing technology

Cataloged from PDF version of article.Obtaining high-quality sequence continuity of complex regions of recent segmental duplication remains one of the major challenges of finishing genome assemblies. In the human and mouse genomes, this was achieved by targeting large-insert clones using costly and laborious capillary-based sequencing approaches. Sanger shotgun sequencing of clone inserts, however, has now been largely abandoned, leaving most of these regions unresolved in newer genome assemblies generated primarily by next-generation sequencing hybrid approaches. Here we show that it is possible to resolve regions that are complex in a genome-wide context but simple in isolation for a fraction of the time and cost of traditional methods using long-read single molecule, real-time (SMRT) sequencing and assembly technology from Pacific Biosciences (PacBio). We sequenced and assembled BAC clones corresponding to a 1.3-Mbp complex region of chromosome 17q21.31, demonstrating 99.994% identity to Sanger assemblies of the same clones. We targeted 44 differences using Illumina sequencing and find that PacBio and Sanger assemblies share a comparable number of validated variants, albeit with different sequence context biases. Finally, we targeted a poorly assembled 766-kbp duplicated region of the chimpanzee genome and resolved the structure and organization for a fraction of the cost and time of traditional finishing approaches. Our data suggest a straightforward path for upgrading genomes to a higher quality finished state

Mortality associated with delays between clinic entry and ART initiation in resource-limited settings: results of a transition-state model.

OBJECTIVE: To estimate the mortality impact of delay in antiretroviral therapy (ART) initiation from the time of entry into care. DESIGN: A state-transition Markov process model. This technique allows for assessing mortality before and after ART initiation associated with delays in ART initiation among a general population of ART-eligible patients without conducting a randomized trial. METHODS: We used patient-level data from 3 South African cohorts to determine transition probabilities for pre-ART CD4 count changes and pre-ART and on-ART mortality. For each parameter, we generated probabilities and distributions for Monte Carlo simulations with 1-week cycles to estimate mortality 52 weeks from clinic entry. RESULTS: We estimated an increase in mortality from 11.0% to 14.7% (relative increase of 34%) with a 10-week delay in ART for patients entering care with our pre-ART cohort CD4 distribution. When we examined low CD4 ranges, the relative increase in mortality delays remained similar; however, the absolute increase in mortality rose. For example, among patients entering with CD4 count 50-99 cells per cubic millimeter, 12-month mortality increased from 13.3% with no delay compared with 17.0% with a 10-week delay and 22.9% with a 6-month delay. CONCLUSIONS: Delays in ART initiation, common in routine HIV programs, can lead to important increases in mortality. Prompt ART initiation for patients entering clinical care and eligible for ART, especially those with lower CD4 counts, could be a relatively low-cost approach with a potential marked impact on mortality

Tuberculosis and Hepatic Steatosis Are Prevalent Liver Pathology Findings among HIV-Infected Patients in South Africa

Liver disease epidemiology in sub-Saharan Africa has shifted as a result of HIV and the increased use of antiretroviral therapy leading to a need for updated data on common causes of liver disease. We retrospectively reviewed records from all hospitalized patients who had liver biopsy at a single hospital in South Africa from 2001 to 2009 and compared diagnosis by HIV status. During the period of study 262 patients had liver biopsy, 108 (41%) were HIV-infected, 25 (10%) were HIV-sero-negative, and 129 (49%) had unknown or unrecorded HIV status. Overall 81% of biopsies provided additional diagnostic data. Malignancy was the most common finding reported on 56 (21%) biopsies followed by granuloma or TB, hepatic steatosis, and fibrosis or cirrhosis. HIV-infected patients were more likely to have granulomas and steatosis. Half of patients with granulomas were already on TB treatment, suggesting paradoxical reactions or drug induced liver injury may have been important causes of liver inflammation among these patients. We note that TB, paradoxical reactions during TB treatment, possible drug induced liver injury, and hepatic steatosis are important causes of liver pathology among HIV-infected hospitalized patients with unclear etiology of liver disease after initial assessment. Among HIV sero-negative patients, malignancy was the major cause of liver disease. Our findings re-enforce the importance of TB as a diagnosis among HIV-infected individuals.\ud \u

Error threshold in optimal coding, numerical criteria and classes of universalities for complexity

The free energy of the Random Energy Model at the transition point between ferromagnetic and spin glass phases is calculated. At this point, equivalent to the decoding error threshold in optimal codes, free energy has finite size corrections proportional to the square root of the number of degrees. The response of the magnetization to the ferromagnetic couplings is maximal at the values of magnetization equal to half. We give several criteria of complexity and define different universality classes. According to our classification, at the lowest class of complexity are random graph, Markov Models and Hidden Markov Models. At the next level is Sherrington-Kirkpatrick spin glass, connected with neuron-network models. On a higher level are critical theories, spin glass phase of Random Energy Model, percolation, self organized criticality (SOC). The top level class involves HOT design, error threshold in optimal coding, language, and, maybe, financial market. Alive systems are also related with the last class. A concept of anti-resonance is suggested for the complex systems.Comment: 17 page

Resolving the complexity of the human genome using single-molecule sequencing

The human genome is arguably the most complete mammalian reference assembly, yet more than 160 euchromatic gaps remain and aspects of its structural variation remain poorly understood ten years after its completion. To identify missing sequence and genetic variation, here we sequence and analyse a haploid human genome (CHM1) using single-molecule, real-time DNA sequencing. We close or extend 55% of the remaining interstitial gaps in the human GRCh37 reference genome - 78% of which carried long runs of degenerate short tandem repeats, often several kilobases in length, embedded within (G+C)-rich genomic regions. We resolve the complete sequence of 26,079 euchromatic structural variants at the base-pair level, including inversions, complex insertions and long tracts of tandem repeats. Most have not been previously reported, with the greatest increases in sensitivity occurring for events less than 5 kilobases in size. Compared to the human reference, we find a significant insertional bias (3:1) in regions corresponding to complex insertions and long short tandem repeats. Our results suggest a greater complexity of the human genome in the form of variation of longer and more complex repetitive DNA that can now be largely resolved with the application of this longer-read sequencing technology