Measuring ventilation and modelling M. tuberculosis transmission in indoor congregate settings, rural KwaZulu-Natal.

SETTING: Molecular epidemiology suggests that most Mycobacterium tuberculosis transmission in high-burden settings occurs outside the home. OBJECTIVE: To estimate the risk of M. tuberculosis transmission inside public buildings in a high TB burden community in KwaZulu-Natal, South Africa. DESIGN: Carbon dioxide (CO2) sensors were placed inside eight public buildings. Measurements were used with observations of occupancy to estimate infection risk using an adaptation of the Wells-Riley equation. Ventilation modelling using CONTAM was used to examine the impact of low-cost retrofits on transmission in a health clinic. RESULTS: Measurements indicate that infection risk in the church, classroom and clinic waiting room would be high with typical ventilation, occupancy levels and visit durations. For example, we estimated that health care workers in a clinic waiting room had a 16.9-24.5% annual risk of M. tuberculosis infection. Modelling results indicate that the simple addition of two new windows allowing for cross-ventilation, at a cost of US$330, would reduce the annual risk to health care workers by 57%. CONCLUSIONS: Results indicate that public buildings in this community have a range of ventilation and occupancy characteristics that may influence transmission risks. Simple retrofits may result in dramatic reductions in M. tuberculosis transmission, and intervention studies should therefore be considered.

GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study.

GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-associated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was associated with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.

Liver injury is associated with mortality in sickle cell disease.

BACKGROUND: Increased life expectancy in sickle cell disease (SCD) has resulted in greater recognition of the consequences of repeated intravascular vaso-occlusion and chronic haemolysis to multiple organ systems. AIM: To report the long-term consequences of liver dysfunction in SCD. METHODS: A cohort of SCD patients was prospectively evaluated at the National Institutes of Health (NIH) Clinical Center. The association of mortality with liver enzymes, parameters of liver synthetic function and iron overload was evaluated using Cox regression. RESULTS: Exactly, 247 SCD patients were followed up for 30 months of whom 22 (9%) died. After controlling for predictors, increased direct bilirubin (DB), ferritin, alkaline phosphatase and decreased albumin were independently associated with mortality. In a multivariable model, only high DB and ferritin remained significant. Ferritin correlated with hepatic iron content and total blood transfusions but not haemolysis markers. Forty patients underwent liver biopsies and 11 (28%) had fibrosis. Twelve of 26 patients (48%) had portal hypertension by hepatic venous pressure gradient (HVPG) measurements. All patients with advanced liver fibrosis had iron overload; however, most patients (69%) with iron overload were without significant hepatic fibrosis. Ferritin did not correlate with left ventricular dysfunction by echocardiography. DB correlated with bile acid levels suggesting liver pathology. Platelet count and soluble CD14 correlated with HVPG indicating portal hypertension. CONCLUSIONS: Ferritin and direct bilirubin are independently associated with mortality in sickle cell disease. Ferritin likely relates to transfusional iron overload, while direct bilirubin suggests impairment of hepatic function, possibly impairing patients' ability to tolerate systemic insults.

Does the corollary discharge of attention exist?

We discuss experimental support for the existence of a corollary discharge signal of attention movement control and its formulation in terms of the corollary discharge of attention model of attention movement (CODAM). The data is from fMRI, MEG and EEG activity observed about 200 ms after stimulus onset in various attention paradigms and in which the activity is mainly sited in parietal and extra-striate visual areas. Moreover the data arises from neural activity observed before report of a subject's experience occurs. The overall experimental support for the existence of a copy of the attention movement control signal generates, it is suggested, a viable route to explore the relation between this signal and human consciousness, as concluded in the paper.

CODAM: a neural network model of consciousness.

We present a review of the CODAM neural network control model of consciousness and develop it to arrive at a functional account of consciousness. The main feature is as a speed-up and error-correcting mechanism known, in engineering control theory, to be efficient in improving the speed of response and accuracy of any control system. We use the CODAM model to generate a set of predictions as to how such speed-up is achieved, as well as relate to previous explanations by CODAM of various attention-based phenomena.

Resolving some confusions over attention and consciousness.

There is presently an ongoing debate about the relation between attention and consciousness. Thus debate is being fuelled by results from experimental paradigms which probe various forms of the interaction between attention and consciousness, such as the attentional blink, object-substitution masking and change blindness. We present here simulations of these three paradigms which can all be produced from a single overarching control model of attention. This model helps to suggest an explanation of consciousness as created through attention, and helps to explore the complex nature of attention. It indicates how it is possible to accommodate the relevant experimental results without needing to regard consciousness and attention as independent processes.

On the neurodynamics of the creation of consciousness.

Consciousness is expected to have a specific temporal dynamics. The COrollary Discharge of Attention Movement (CODAM) model of consciousness is deduced from an engineering approach to attention and motor attention. This model is briefly described, as is support arising from brain dynamics, especially that for the attentional blink. The understanding of known temporal dynamics in the brain associated with the emergence of consciousness is then developed from CODAM, and specifically related to the N2 ERP brain signal. How the pre-reflective self, as content-free, interacts with the content of experience is discussed in terms of the possibility that such experience arises from some proto-self generated by body signals; experiments are described which indicate that no pre-reflective self based on body signals is observable. Only a content-free pre-reflective self is consistent with this data, as CODAM suggests. How such a pre-reflective self can be further fused to give temporal continuity of a sense of self is considered in terms of various mechanisms which could be present for preserving the sense of self. The observation of the N2 signal in hippocampal encoding is proposed as providing a justification for the encoding of the N2-P3 sequence of brain signals. This would correspond to episodic encoding of the sequence of experiences of the pre-reflective self; this will thereby provide the necessary control signals in time so that 'I' is experienced as part of the retrieval of such memories.

Emotion recognition in human-computer interaction.

In this paper, we outline the approach we have developed to construct an emotion-recognising system. It is based on guidance from psychological studies of emotion, as well as from the nature of emotion in its interaction with attention. A neural network architecture is constructed to be able to handle the fusion of different modalities (facial features, prosody and lexical content in speech). Results from the network are given and their implications discussed, as are implications for future direction for the research.

Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection.

Human mannose-binding protein (MBL) is a component of innate immunity. To capture the common genetic variants of MBL2, we resequenced a 10.0 kb region that includes MBL2 in 102 individuals representing four major US ethnic groups. In all, 87 polymorphic sites were observed, indicating a high level of heterozygosity (total pi=18.3 x 10(-4)). Estimates of linkage disequilibrium across MBL2 indicate that it is divided into two blocks, with a probable recombination hot spot in the 3' end. Three non-synonymous SNPs in exon 1 of the encoding MBL2 gene and three upstream SNPs form common 'secretor haplotypes' that can predict circulating levels. Common variants have been associated with increased susceptibility to infection and autoimmune diseases. The high frequencies of B, C and D alleles in certain populations suggest a possible selective advantage for heterozygosity. There is limited diversity of haplotype structure; the 'secretor haplotypes' lie on a restricted number of extended haplotypes, which could include additional linked SNPs, which might also have possible functional implications. There is evidence for gene conversion in the region between the two blocks, in the last exon. Our data should form the basis for conducting MBL2 candidate gene association studies using a locus-wide approach.

Neural activity in human primary motor cortex areas 4a and 4p is modulated differentially by attention to action.

The mechanisms underlying attention to action are poorly understood. Although distracted by something else, we often maintain the accuracy of a movement, which suggests that differential neural mechanisms for the control of attended and nonattended action exist. Using functional magnetic resonance imaging (fMRI) in normal volunteers and probabilistic cytoarchitectonic maps, we observed that neural activity in subarea 4p (posterior) within the primary motor cortex was modulated by attention to action, while neural activity in subarea 4a (anterior) was not. The data provide the direct evidence for differential neural mechanisms during attended and unattended action in human primary motor cortex.

A control model of the movement of attention.

A control model of the movement of the focus of attention is developed and applied to explain its observed effects on single cell activity and to various quantitative features of the Posner benefit paradigm. This supports the presence of an inverse controller and a rules component in the control model. The ability of the control model to explain a range of deficits is then analyzed, as is its relation to other modeling approaches.

Using genetic variation to study human disease.

The generation of a draft sequence of the human genome has spawned a unique opportunity to investigate the role of genetic variation in human diseases. The difference between any two human genomes has been estimated to be less than 0.1% overall, but still, this means that there are at least several million nucleotide differences per individual. The study of single nucleotide polymorphisms (SNPs), the most common type of variant, is likely to contribute substantially to deciphering genetic determinants of common and rare diseases. The effort to identify SNPs has been accelerated by three developments: the availability of sequence data from the genome project, improved informatic tools for searching the former and high-throughput genotype platforms. With these new tools in hand, dissecting the genetics of disease will rapidly move forward, although a number of formidable challenges will have to be met to see its promise realized in clinical medicine.

The central role of the parietal lobes in consciousness.

There are now various approaches to understand where and how in the brain consciousness arises from neural activity, none of which is universally accepted. Difficulties among these approaches are reviewed, and a missing ingredient is proposed here to help adjudicate between them, that of "perspectivalness." In addition to a suitable temporal duration and information content of the relevant bound brain activity, this extra component is posited as being a further important ingredient for the creation of consciousness from neural activity. It guides the development of what is termed the "Central Representation," which is supposed to be present in all mammals and extended in humans to support self-consciousness as well as phenomenal consciousness. Experimental evidence and a theoretical framework for the existence of the central representation are presented, which relates the extra component to specific buffer working memory sites in the inferior parietal lobes, acting as attentional coordinators on the spatial maps making up the central representation. The article closes with a discussion of various open questions.

A dynamical model for the analysis and acceleration of learning in feedforward networks.

A dynamical system model is derived for feedforward neural networks with one layer of hidden nodes. The model is valid in the vicinity of flat minima of the cost function that rise due to the formation of clusters of redundant hidden nodes with nearly identical outputs. The derivation is carried out for networks with an arbitrary number of hidden and output nodes and is, therefore, a generalization of previous work valid for networks with only two hidden nodes and one output node. The Jacobian matrix of the system is obtained, whose eigenvalues characterize the evolution of learning. Flat minima correspond to critical points of the phase plane trajectories and the bifurcation of the eigenvalues signifies their abandonment. Following the derivation of the dynamical model, we show that identification of the hidden nodes clusters using unsupervised learning techniques enables the application of a constrained application (Dynamically Constrained Back Propagation-DCBP) whose purpose is to facilitate prompt bifurcation of the eigenvalues of the Jacobian matrix and, thus, accelerate learning. DCBP is applied to standard benchmark tasks either autonomously or as an aid to other standard learning algorithms in the vicinity of flat minima. Its application leads to significant reduction in the number of required epochs for convergence.

Practice-based research: lessons from community pharmacist participants.

We designed this project to determine community pharmacists' opinions regarding the challenges and motivations of their recent participation in a pharmacy practice-based research study At the conclusion of a randomized, multicenter study, 87 community pharmacist-investigators were sent a questionnaire that explored four areas: motivating factors to participate, barriers to participation, communication tools used by study coordinators, and design issues for future studies. Fifty-eight (67%) completed questionnaires were returned. Key factors motivating participation in the study were desire to improve the profession and opportunity to learn. Time was the greatest barrier to participation. Pharmacy practice-based research has two distinct advantages. First, it translates clinical knowledge into direct application in the community. Second, it provides needed data to demonstrate the value of enhanced pharmacy practice. Thorough understanding of pharmacists' opinions is necessary to optimize the design of future studies.

The motion aftereffect: more than area V5/MT? Evidence from 15O-butanol PET studies.

The motion aftereffect is a perceptual phenomenon which has been extensively investigated both psychologically and physiologically. Neuroimaging techniques have recently demonstrated that area V5/MT is activated during the perception of this illusion. The aim of this study was to test the hypothesis if a more broadly distributed network of brain regions subserves the motion aftereffect. To identify the neuronal structures involved in the perception of the motion aftereffect, regional cerebral blood flow (rCBF) measurements with positron emission tomography were performed in six normal volunteers. Data were analysed using SPM96. The motion-sensitive visual areas including area V5/MT were activated in both hemispheres. Additionally, the lateral parietal cortex bilaterally, the right dorsolateral prefrontal cortex, the anterior cingulate cortex and the left cerebellum showed significant increases in rCBF values during the experience of the waterfall illusion. In a further reference condition with identical attentional demand but no perception of a motion aftereffect elevated rCBF were found in these regions as well. In conclusion, our findings support the notion that the perceptual illusion of motion arises exclusively in the motion-sensitive visual area V5/MT. In addition, a more widespread network of brain regions including the prefrontal and parietal cortex is activated during the waterfall illusion which represents a non-motion aftereffect-specific subset of brain areas but is involved in more basic attentional processing and cognition.

Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S.

The malaria hypothesis proposes a survival advantage for individuals with hemoglobin variants in areas of endemic Plasmodium falciparum malaria. Hemoglobin C (HbC) is a possible example in West Africa, where this hemoglobin has a centric distribution with high frequencies among certain populations including the Dogon ethnic group. To test whether HbC is associated with protection from malaria, we performed a case-control study in the Dogon of Bandiagara, Mali. HbC was present in 68 of 391 (17.4%) of uncomplicated malaria control cases, whereas it was detected in only 3 of 67 cases (4.5%) of severe malaria (odds ratio [OR], 0.22; P =. 01). Further, HbC was present in only 1 of 34 cases (2.9%) with cerebral manifestations, the most common presentation of severe malaria in this population (OR, 0.14; P =.03). Episodes of uncomplicated malaria and parasitemias (4800-205 050/microL) were identified in cases of homozygous HbC (HbCC), which indicates that P falciparum parasites are able to efficiently replicate within HbCC erythrocytes in vivo. These findings suggest that HbC does not protect against infection or uncomplicated malaria but can protect against severe malaria in the Dogon population of Bandiagara, Mali. The data also suggest that the protective effect associated with HbC may be greater than that of HbS in this population.