Health economic analyses of latent tuberculosis infection screening and preventive treatment among people living with HIV in lower tuberculosis incidence settings: a systematic review [version 1; peer review: awaiting peer review]

INTRODUCTION: In lower tuberculosis (TB) incidence countries (<100 cases/100,000/year), screening and preventive treatment (PT) for latent TB infection (LTBI) among people living with HIV (PLWH) is often recommended, yet guidelines advising which groups to prioritise for screening can be contradictory and implementation patchy. Evidence of LTBI screening cost-effectiveness may improve uptake and health outcomes at reasonable cost. METHODS: Our systematic review assessed cost-effectiveness estimates of LTBI screening/PT strategies among PLWH in lower TB incidence countries to identify model-driving inputs and methodological differences. Databases were searched 1980-2020. Studies including health economic evaluation of LTBI screening of PLWH in lower TB incidence countries (<100 cases/100,000/year) were included. Study quality was assessed using the CHEERS checklist. RESULTS: Of 2,644 articles screened, nine studies were included. Cost-effectiveness estimates of LTBI screening/PT for PLWH varied widely, with universal screening/PT found highly cost-effective by some studies, while only targeting to high-risk groups (such as those from mid/high TB incidence countries) deemed cost-effective by others. Cost-effectiveness of strategies screening all PLWH from studies published in the past five years varied from US$2828 to US$144,929/quality-adjusted life-year gained (2018 prices). Study quality varied, with inconsistent reporting of methods and results limiting comparability of studies. Cost-effectiveness varied markedly by screening guideline, with British HIV Association guidelines more cost-effective than NICE guidelines in the UK. DISCUSSION: Cost-effectiveness studies of LTBI screening/PT for PLWH in lower TB incidence settings are scarce, with large variations in methods and assumptions used, target populations and screening/PT strategies evaluated. The limited evidence suggests LTBI screening/PT may be cost-effective for some PLWH groups but further research is required, particularly on strategies targeting screening/PT to PLWH at higher risk. Standardisation of model descriptions and results reporting could facilitate reliable comparisons between studies, particularly to identify those factors driving the wide disparity between cost-effectiveness estimates. REGISTRATION: PROSPERO CRD42020166338 (18/03/2020)

Latent tuberculosis infection screening and treatment in HIV: insights from evaluation of UK practice

Latent TB infection (LTBI) screening and treatment in HIV-positive individuals in the UK is advocated by the British HIV Association (BHIVA) and National Institute for Health and Care Excellence (NICE), although each recommends differing strategies. We undertook an evaluation of UK practice, relating the responses to the local HIV/TB disease burden. 162 of 188 (86%) UK geographical areas responded; only 93/162 (57.4%) offer LTBI testing with considerable heterogeneity in practice, and no difference in HIV/TB burden between areas offering testing and those who do not. Only 33/93 (35.5%) and 6/93 (6.5%) reported full compliance with BHIVA and NICE guidance respectively. A uniform national guideline is required

A High Deuterium Abundance at z=0.7

Of the light elements, the primordial abundance of deuterium, (D/H)_p, provides the most sensitive diagnostic for the cosmological mass density parameter Omega_B. Recent high redshift (D/H) measurements are highly discrepant, although this may reflect observational uncertainties. The larger (D/H) values, which imply a low Omega_B and require the Universe to be dominated by non-baryonic matter (dynamical studies indicate a higher total density parameter), cause problems for galactic chemical evolution models since they have difficulty in reproducing the large decline down to the lower present-day (D/H). Conversely, low (D/H) values imply an Omega_B greater than derived from ^7Li and ^4He abundance measurements, and may require a deuterium abundance evolution that is too low to easily explain. Here we report the first measurement at intermediate redshift, where the observational difficulties are smaller, of a gas cloud with ideal characteristics for this experiment. Our analysis of the z = 0.7010 absorber toward 1718+4807 indicates (D/H) = 2.0 +/- 0.5 x 10^{-4} which is in the high range. This and other independent observations suggests there may be a cosmological inhomogeneity in (D/H)_p of at least a factor of ten.Comment: 6 pages, 1 figur

Interleukin-1ß mRNA expression in ischemic rat cortex

Background and Pur pose: Interleukin-1ß is a proinftammatory cytokine produced by blood-borne and resident brain inftammatory cells. The present study was conducted to determine if interleukin-1ß mRNA was produced in the brain of rats subjected to permanent focal ischemia. Methods: Rat interleukin-1ß cDNA, synthesized from stimulated rat peritoneal macrophage RNA by reverse transcription and polymerase chain reaction and c10ned in plasmid Bluescript KS+, was used to evaluate the expression of interleukin-1ß mRNA in cerebral cortex from spontaneously hypertensive rats and normotensive rats subjected to permanent middle cerebral artery occlusion. Interleukin-1ß mRNA was quantified by Northern blot analysis and compared with rat macrophage RNA standard. To correct for gel loading, blots were also analyzed with cyclophilin cDNA, which encodes an abundant, conserved protein that was unchanged by the experimental conditions. Results: Interleukin-1ß mRNA produced in the ischemic zone was significantly increased from 6 hours to 120 hours, with a maximum of211±24% ofinterleukin-1ß reference standard, ie, 0.2 ng stimulated rat macrophage RNA, mRNA compared with the level in nonischemic cortices (4±2%) at 12 hours after ischemia (P<.OI; n=6). Interleukin-1ß mRNA at 12 hours after ischemia was markedly elevated in hypertensive rats over levels found in two normotensive rat strains. Neurological deficits were also apparent only in the hypertensive rats. Conclusions: Brain interleukin-1ß mRNA is elevated acutely after permanent focal ischemia and especially in hypertensive rats. These data suggest that this potent proinflammatory and procoagulant cytokine might have a role in brain damage following ischemia

Tandem quadruplication of HMA4 in the zinc (Zn) and cadmium (Cd) hyperaccumulator noccaea caerulescens

Zinc (Zn) and cadmium (Cd) hyperaccumulation may have evolved twice in the Brassicaceae, in Arabidopsis halleri and in the Noccaea genus. Tandem gene duplication and deregulated expression of the Zn transporter, HMA4, has previously been linked to Zn/Cd hyperaccumulation in A. halleri. Here, we tested the hypothesis that tandem duplication and deregulation of HMA4 expression also occurs in Noccaea. A Noccaea caerulescens genomic library was generated, containing 36,864 fosmid pCC1FOSTM clones with insert sizes ~20–40 kbp, and screened with a PCR-generated HMA4 genomic probe. Gene copy number within the genome was estimated through DNA fingerprinting and pooled fosmid pyrosequencing. Gene copy numbers within individual clones was determined by PCR analyses with novel locus specific primers. Entire fosmids were then sequenced individually and reads equivalent to 20-fold coverage were assembled to generate complete whole contigs. Four tandem HMA4 repeats were identified in a contiguous sequence of 101,480 bp based on sequence overlap identities. These were flanked by regions syntenous with up and downstream regions of AtHMA4 in Arabidopsis thaliana. Promoter-reporter b-glucuronidase (GUS) fusion analysis of a NcHMA4 in A. thaliana revealed deregulated expression in roots and shoots, analogous to AhHMA4 promoters, but distinct from AtHMA4 expression which localised to the root vascular tissue. This remarkable consistency in tandem duplication and deregulated expression of metal transport genes between N. caerulescens and A. halleri, which last shared a common ancestor >40 mya, provides intriguing evidence that parallel evolutionary pathways may underlie Zn/Cd hyperaccumulation in Brassicaceae

Simple, Fast and Accurate Implementation of the Diffusion Approximation Algorithm for Stochastic Ion Channels with Multiple States

The phenomena that emerge from the interaction of the stochastic opening and closing of ion channels (channel noise) with the non-linear neural dynamics are essential to our understanding of the operation of the nervous system. The effects that channel noise can have on neural dynamics are generally studied using numerical simulations of stochastic models. Algorithms based on discrete Markov Chains (MC) seem to be the most reliable and trustworthy, but even optimized algorithms come with a non-negligible computational cost. Diffusion Approximation (DA) methods use Stochastic Differential Equations (SDE) to approximate the behavior of a number of MCs, considerably speeding up simulation times. However, model comparisons have suggested that DA methods did not lead to the same results as in MC modeling in terms of channel noise statistics and effects on excitability. Recently, it was shown that the difference arose because MCs were modeled with coupled activation subunits, while the DA was modeled using uncoupled activation subunits. Implementations of DA with coupled subunits, in the context of a specific kinetic scheme, yielded similar results to MC. However, it remained unclear how to generalize these implementations to different kinetic schemes, or whether they were faster than MC algorithms. Additionally, a steady state approximation was used for the stochastic terms, which, as we show here, can introduce significant inaccuracies. We derived the SDE explicitly for any given ion channel kinetic scheme. The resulting generic equations were surprisingly simple and interpretable - allowing an easy and efficient DA implementation. The algorithm was tested in a voltage clamp simulation and in two different current clamp simulations, yielding the same results as MC modeling. Also, the simulation efficiency of this DA method demonstrated considerable superiority over MC methods.Comment: 32 text pages, 10 figures, 1 supplementary text + figur

Fundamental Strings, Holography, and Nonlinear Superconformal Algebras

We discuss aspects of holography in the AdS_3 \times S^p near string geometry of a collection of straight fundamental heterotic strings. We use anomalies and symmetries to determine general features of the dual CFT. The symmetries suggest the appearance of nonlinear superconformal algebras, and we show how these arise in the framework of holographic renormalization methods. The nonlinear algebras imply intricate formulas for the central charge, and we show that in the bulk these correspond to an infinite series of quantum gravity corrections. We also makes some comments on the worldsheet sigma-model for strings on AdS_3\times S^2, which is the holographic dual geometry of parallel heterotic strings in five dimensions.Comment: 25 page

The Imprint of Galaxy Formation on X-ray Clusters

It is widely believed that structure in the Universe evolves hierarchically, as primordial density fluctuations, amplified by gravity, collapse and merge to form progressively larger systems. The structure and evolution of X-ray clusters, however, seems at odds with this hierarchical scenario for structure formation. Poor clusters and groups, as well as most distant clusters detected to date, are substantially fainter than expected from the tight relations between luminosity, temperature and redshift predicted by these models. Here we show that these discrepancies arise because, near the centre, the entropy of the hot, diffuse intracluster medium (ICM) is higher tha$achievable through gravitational collapse, indicating substantial non-gravitational heating of the ICM. We estimate this excess entropy for the first time, and argue that it represents a relic of the energetic winds through which forming galaxies polluted the ICM with metals. Energetically, this is onl$ possible if the ICM is heated at modest redshift (z \ltsim 2) but prior to cluster collapse, indicating that the formation of galaxies precedes that of clusters and that most clusters have been assembled very recently.Comment: 5 pages, plus 2 postscript figures (one in colour), accepted for publication in Natur

The what and where of adding channel noise to the Hodgkin-Huxley equations

One of the most celebrated successes in computational biology is the Hodgkin-Huxley framework for modeling electrically active cells. This framework, expressed through a set of differential equations, synthesizes the impact of ionic currents on a cell's voltage -- and the highly nonlinear impact of that voltage back on the currents themselves -- into the rapid push and pull of the action potential. Latter studies confirmed that these cellular dynamics are orchestrated by individual ion channels, whose conformational changes regulate the conductance of each ionic current. Thus, kinetic equations familiar from physical chemistry are the natural setting for describing conductances; for small-to-moderate numbers of channels, these will predict fluctuations in conductances and stochasticity in the resulting action potentials. At first glance, the kinetic equations provide a far more complex (and higher-dimensional) description than the original Hodgkin-Huxley equations. This has prompted more than a decade of efforts to capture channel fluctuations with noise terms added to the Hodgkin-Huxley equations. Many of these approaches, while intuitively appealing, produce quantitative errors when compared to kinetic equations; others, as only very recently demonstrated, are both accurate and relatively simple. We review what works, what doesn't, and why, seeking to build a bridge to well-established results for the deterministic Hodgkin-Huxley equations. As such, we hope that this review will speed emerging studies of how channel noise modulates electrophysiological dynamics and function. We supply user-friendly Matlab simulation code of these stochastic versions of the Hodgkin-Huxley equations on the ModelDB website (accession number 138950) and http://www.amath.washington.edu/~etsb/tutorials.html.Comment: 14 pages, 3 figures, review articl

Work-related psychological health among clergywomen in Australia

Drawing on the classic model of balanced affect, the Francis Burnout Inventory conceptualises good work-related psychological health among clergy in terms of negative affect being balanced by positive affect. This paper sets out to explore the relationship between work-related psychological health and psychological type (as assessed by the Francis Psychological-Type Scales) among a sample of 212 Australian clergywomen who completed the National Church Life Survey Form L in 2006. The data supported the internal consistency reliability of the Francis Burnout Inventory and Francis Psychological-Type Scales and found that work-related psychological health was positively related to extraversion and sensing