A randomised trial of an eight-week, once weekly primaquine regimen to prevent relapse of plasmodium vivax in Northwest Frontier Province, Pakistan.

BACKGROUND: Vivax malaria remains a major cause of morbidity in the subtropics. To undermine the stability of the disease, drugs are required that prevent relapse and provide reservoir reduction. A 14-day course of primaquine (PQ) is effective but cannot safely be used in routine practice because of its interaction with glucose-6-phosphate dehydrogenase (G6PD) deficiency for which testing is seldom available. Safe and effective use of PQ without the need for G6PD testing would be ideal. The efficacy and safety of an 8-week, once weekly PQ regimen was compared with current standard treatment (chloroquine alone) and a 14-day PQ regimen. METHODS AND PRINCIPAL FINDINGS: 200 microscopically confirmed Plasmodium vivax patients were randomly assigned to either once weekly 8-week PQ (0.75 mg/kg/week), once weekly 8-week placebo, or 14-day PQ (0.5mg/kg/day) in North West Frontier Province, Pakistan. All patients were treated with a standard chloroquine dose and tested for G6PD deficiency. Deficient patients were assigned to the 8-week PQ group. Failure was defined as any subsequent episode of vivax malaria over 11 months of observation. There were 22/71 (31.0%) failures in the placebo group and 1/55 (1.8%) and 4/75 (5.1%) failures in the 14-day and 8-week PQ groups, respectively. Adjusted odds ratios were: for 8-week PQ vs. placebo-0.05 (95%CI: 0.01-0.2, p<0.001) and for 14-day PQ vs. placebo-0.01 (95%CI: 0.002-0.1, p<0.001). Restricted analysis allowing for a post-treatment prophylactic effect confirmed that the 8-week regimen was superior to current treatment. Only one G6PD deficient patient presented. There were no serious adverse events. CONCLUSIONS: A practical radical treatment for vivax malaria is essential for control and elimination of the disease. The 8-week PQ course is more effective at preventing relapse than current treatment with chloroquine alone. Widespread use of the 8-week regimen could make an important contribution to reservoir reduction or regional elimination where G6PD testing is not available. TRIAL REGISTRATION: ClinicalTrials.gov NCT00158587

Social transformation in the Delta from the terminal predynastic to the early dynastic period: a comparative study

In this thesis I examine evidence for change in social and political organisation at four cemetery sites within the northeast Delta of Egypt. The time period with which I am concerned, the Terminal Predynastic to Early Dynastic, coincides with the final stages of a process of cultural and political development and integration from the early fourth to the early third millennium BC. The Delta has remained, until recent years, poorly researched, in comparison to the Nile Valley. This thesis makes an important contribution towards understanding the prehistory of this region through a comparative study of the mortuary evidence from the sites of Kafr Hassan Dawood, Kufur Nigm, Minshat Abu Omar and Tell Ibrahim Awad. This thesis research has two over-arching aims: 1) to elucidate change in social and political organisation as reflected through the mortuary evidence at the key sites in the northeast Delta, and how this relates to the funerary record throughout Predynastic and Early Dynastic Egypt; and 2) to assess how the evidence from the northeast Delta sites affects our consideration of previous hypotheses regarding the development of social complexity in early Egypt. In order to achieve this, the thesis gradually narrows its focus onto the Delta, following a discussion of previous hypotheses on the origins of state society in Egypt, and a review of temporal and geographic diversity in Predynastic and Early Dynastic burial trends. I have critically incorporated elements of socio-evolutionary theory within my theoretical approach, and evaluated aspects of previous research into mortuary contexts worldwide, to assess which elements I consider appropriate to include within my methodology. My methodology presents a new four-stage sequence of statistical analysis that seeks to maximise the analytical potential of mortuary data through investigation of a wide range of variables relating to the wealth and effort expended on the grave, and the changing relationship between these elements and the age and sex of the deceased. Geographical Information Systems technology is used for spatial analysis at the site of Kafr Hassan Dawood, to explore the data from a visual perspective. The results prove both revealing and are, in some instances, quite unexpected. The analysis of the key sites reveals societies expressing organisational characteristics ranging from ranked to stratified, and striking differences in terms of internal site development. The widest temporal scopes for development are observed at Kafr Hassan Dawood and Minshat Abu Omar, where we witness the change from the early importance of kin groups with clear variability within ideology, to increasing cohesion in the latter stages of the sites' histories, with the declining importance of kin groups seemingly in tandem with heightening external contact. The height of prosperity visible in the latter history of the sites, however, is short-lived, with three of the four cemeteries falling into disuse. This decline would appear due to the economic repercussions of the rise of the centralised state on their livelihood

Syntactic representations are both abstract and semantically constrained : evidence from children’s and adults’ comprehension and production/priming of the English passive

All accounts of language acquisition agree that, by around age 4, children’s knowledge of grammatical constructions is abstract, rather than tied solely to individual lexical items. The aim of the present research was to investigate, focusing on the passive, whether children’s and adults’ performance is additionally semantically constrained, varying according to the distance between the semantics of the verb and those of the construction. In a forced‐choice pointing study (Experiment 1), both 4‐ to 6‐year olds (N = 60) and adults (N = 60) showed support for the prediction of this semantic construction prototype account of an interaction such that the observed disadvantage for passives as compared to actives (i.e., fewer correct points/longer reaction time) was greater for experiencer‐theme verbs than for agent‐patient and theme‐experiencer verbs (e.g., Bob was seen/hit/frightened by Wendy). Similarly, in a production/priming study (Experiment 2), both 4‐ to 6‐year olds (N = 60) and adults (N = 60) produced fewer passives for experiencer‐theme verbs than for agent‐patient/theme‐experiencer verbs. We conclude that these findings are difficult to explain under accounts based on the notion of A(rgument) movement or of a monostratal, semantics‐free, level of syntax, and instead necessitate some form of semantic construction prototype account

Aircraft measurements of the latitudinal, vertical, and seasonal variations of NMHCs, methyl nitrate, methyl halides, and DMS during the First Aerosol Characterization Experiment (ACE 1)

Canister sampling for the determination of atmospheric mixing ratios of nonmethane hydrocarbons (NMHCs), selected halocarbons, and methyl nitrate was conducted aboard the National Center for Atmospheric Research (NCAR) C-130 aircraft over the Pacific and Southern Oceans as part of the First Aerosol Characterization Experiment (ACE 1) during November and December 1995. A latitudinal profile, flown from 76°N to 60°S, revealed latitudinal gradients for most trace gases. NMHC and halocarbon gases with predominantly anthropogenic sources, including ethane, ethyne, and tetrachloroethene, exhibited significantly higher mixing ratios in the northern hemisphere at all altitudes. Methyl chloride exhibited its lowest mixing ratios at the highest northern hemisphere latitudes, and the distributions of methyl nitrate and methyl iodide were consistent with tropical and subtropical oceanic sources. Layers containing continental air characteristic of aged biomass burning emissions were observed above about 3 km over the remote southern Pacific and near New Zealand between approximately 19°S and 43°S. These plumes originated from the west, possibly from fires in southern Africa. The month-long intensive investigation of the clean marine southern midlatitude troposphere south of Australia revealed decreases in the mixing ratios of ethane, ethyne, propane, and tetrachloroethene, consistent with their seasonal mixing ratio cycle. By contrast, increases in the average marine boundary layer concentrations of methyl iodide, methyl nitrate, and dimethyl sulfide (DMS) were observed as the season progressed to summer conditions. These increases were most appreciable in the region south of 44°S over Southern Ocean waters characterized as subantarctic and polar, indicating a seasonal increase in oceanic productivity for these gases. Copyright 1999 by the American Geophysical Union

Does speed of processing or vocabulary size predict later language growth in toddlers?

It is becoming increasingly clear that the way that children acquire cognitive representations depends critically on how their processing system is developing. In particular, recent studies suggest that individual differences in language processing speed play an important role in explaining the speed with which children acquire language. Inconsistencies across studies, however, mean that it is not clear whether this relationship is causal or correlational, whether it is present right across development, or whether it extends beyond word learning to affect other aspects of language learning, like syntax acquisition. To address these issues, the current study used the looking-while-listening paradigm devised by Fernald, Swingley, and Pinto (2001) to test the speed with which a large longitudinal cohort of children (the Language 0–5 Project) pro-cessed language at 19, 25, and 31 months of age, and took multiple measures of vocabulary (UK-CDI, Lincoln CDI, CDI-III) and syntax (Lincoln CDI) between 8 and 37 months of age. Processing speed correlated with vocabulary size - though this relationship changed over time, and was observed only when there was variation in how well the items used in the looking-while-listening task were known. Fast processing speed was a positive predictor of subsequent vocabulary growth, but only for children with smaller vocabularies. Faster processing speed did, however, predict faster syntactic growth across the whole sample, even when controlling for concurrent vocabulary. The results indicate a relatively direct relationship between processing speed and syntactic development, but point to a more complex interaction between processing speed, vocabulary size and subsequent vocabulary growth

Black-Box α-divergence minimization

Black-box alpha (BB-α) is a new approximate inference method based on the minimization of α-divergences. BB-α scales to large datasets because it can be implemented using stochastic gradient descent. BB-α can be applied to complex probabilistic models with little effort since it only requires as input the likelihood function and its gradients. These gradients can be easily obtained using automatic differentiation. By changing the divergence parameter α, the method is able to interpolate between variational Bayes (VB) (α → 0) and an algorithm similar to expectation propagation (EP) (α = 1). Experiments on probit regression and neural network regression and classification problems show that BB-a with non-standard settings of α, such as α = 0.5, usually produces better predictions than with α → 0 (VB) or α = 1 (EP).JMHL acknowledges support from the Rafael del Pino Foundation. YL thanks the Schlumberger Foundation Faculty for the Future fellowship on supporting her PhD study. MR acknowledges support from UK Engineering and Physical Sciences Research Council (EPSRC) grant EP/L016516/1 for the University of Cambridge Centre for Doctoral Training, the Cambridge Centre for Analysis. TDB thanks Google for funding his European Doctoral Fellowship. DHL acknowledge support from Plan National I+D+i, Grant TIN2013-42351-P and TIN2015- 70308-REDT, and from Comunidad de Madrid, Grant S2013/ICE-2845 CASI-CAM-CM. RET thanks EPSRC grant #EP/L000776/1 and #EP/M026957/1

Propagation of activity through the cortical hierarchy and perception are determined by neural variability

Brains are composed of anatomically and functionally distinct regions performing specialized tasks, but regions do not operate in isolation. Orchestration of complex behaviors requires communication between brain regions, but how neural dynamics are organized to facilitate reliable transmission is not well understood. Here we studied this process directly by generating neural activity that propagates between brain regions and drives behavior, assessing how neural populations in sensory cortex cooperate to transmit information. We achieved this by imaging two densely interconnected regions—the primary and secondary somatosensory cortex (S1 and S2)—in mice while performing two-photon photostimulation of S1 neurons and assigning behavioral salience to the photostimulation. We found that the probability of perception is determined not only by the strength of the photostimulation but also by the variability of S1 neural activity. Therefore, maximizing the signal-to-noise ratio of the stimulus representation in cortex relative to the noise or variability is critical to facilitate activity propagation and perception

Cost-effectiveness of malaria diagnosis using rapid diagnostic tests compared to microscopy or clinical symptoms alone in Afghanistan.

BACKGROUND: Improving access to parasitological diagnosis of malaria is a central strategy for control and elimination of the disease. Malaria rapid diagnostic tests (RDTs) are relatively easy to perform and could be used in primary level clinics to increase coverage of diagnostics and improve treatment of malaria. METHODS: A cost-effectiveness analysis was undertaken of RDT-based diagnosis in public health sector facilities in Afghanistan comparing the societal and health sector costs of RDTs versus microscopy and RDTs versus clinical diagnosis in low and moderate transmission areas. The effect measure was 'appropriate treatment for malaria' defined using a reference diagnosis. Effects were obtained from a recent trial of RDTs in 22 public health centres with cost data collected directly from health centres and from patients enrolled in the trial. Decision models were used to compare the cost of RDT diagnosis versus the current diagnostic method in use at the clinic per appropriately treated case (incremental cost-effectiveness ratio, ICER). RESULTS: RDT diagnosis of Plasmodium vivax and Plasmodium falciparum malaria in patients with uncomplicated febrile illness had higher effectiveness and lower cost compared to microscopy and was cost-effective across the moderate and low transmission settings. RDTs remained cost-effective when microscopy was used for other clinical purposes. In the low transmission setting, RDTs were much more effective than clinical diagnosis (65.2% (212/325) vs 12.5% (40/321)) but at an additional cost (ICER) of US$4.5 per appropriately treated patient including a health sector cost (ICER) of US$2.5 and household cost of US$2.0. Sensitivity analysis, which varied drug costs, indicated that RDTs would remain cost-effective if artemisinin combination therapy was used for treating both P. vivax and P. falciparum. Cost-effectiveness of microscopy relative to RDT is further reduced if the former is used exclusively for malaria diagnosis. In the health service setting of Afghanistan, RDTs are a cost-effective intervention compared to microscopy. CONCLUSIONS: RDTs remain cost-effective across a range of drug costs and if microscopy is used for a range of diagnostic services. RDTs have significant advantages over clinical diagnosis with minor increases in the cost of service provision. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov under identifier NCT00935688

Relations Among Anhedonia, Reinforcement Learning, and Global Functioning in Help-seeking Youth

Dysfunction in the neural circuits underlying salience signaling is implicated in symptoms of psychosis and may predict conversion to a psychotic disorder in youth at clinical high risk (CHR) for psychosis. Additionally, negative symptom severity, including consummatory and anticipatory aspects of anhedonia, may predict functional outcome in individuals with schizophrenia-spectrum disorders. However, it is unclear whether anhedonia is related to the ability to attribute incentive salience to stimuli (through reinforcement learning [RL]) and whether measures of anhedonia and RL predict functional outcome in a younger, help-seeking population. We administered the Salience Attribution Test (SAT) to 33 participants who met criteria for either CHR or a recent-onset psychotic disorder and 29 help-seeking youth with nonpsychotic disorders. In the SAT, participants must identify relevant and irrelevant stimulus dimensions and be sensitive to different reinforcement probabilities for the 2 levels of the relevant dimension ("adaptive salience"). Adaptive salience attribution was positively related to both consummatory pleasure and functioning in the full sample. Analyses also revealed an indirect effect of adaptive salience on the relation between consummatory pleasure and both role (αβ = .22, 95% CI = 0.02, 0.48) and social functioning (αβ = .14, 95% CI = 0.02, 0.30). These findings suggest a distinct pathway to poor global functioning in help-seeking youth, via impaired reward sensitivity and RL