Knockout studies reveal an important role of <i>plasmodium</i> lipoic acid protein ligase a1 for asexual blood stage parasite survival

Lipoic acid (LA) is a dithiol-containing cofactor that is essential for the function of a-keto acid dehydrogenase complexes. LA acts as a reversible acyl group acceptor and 'swinging arm' during acyl-coenzyme A formation. The cofactor is post-translationally attached to the acyl-transferase subunits of the multienzyme complexes through the action of octanoyl (lipoyl): &lt;i&gt;N&lt;/i&gt;-octanoyl (lipoyl) transferase (LipB) or lipoic acid protein ligases (LplA). Remarkably, apicomplexan parasites possess LA biosynthesis as well as scavenging pathways and the two pathways are distributed between mitochondrion and a vestigial organelle, the apicoplast. The apicoplast-specific LipB is dispensable for parasite growth due to functional redundancy of the parasite's lipoic acid/octanoic acid ligases/transferases. In this study, we show that &lt;i&gt;LplA1&lt;/i&gt; plays a pivotal role during the development of the erythrocytic stages of the malaria parasite. Gene disruptions in the human malaria parasite &lt;i&gt;P.falciparum&lt;/i&gt; consistently were unsuccessful while in the rodent malaria model parasite &lt;i&gt;P. berghei&lt;/i&gt; the &lt;i&gt;LplA1&lt;/i&gt; gene locus was targeted by knock-in and knockout constructs. However, the &lt;i&gt;LplA1&lt;/i&gt; &lt;sup&gt;(-)&lt;/sup&gt; mutant could not be cloned suggesting a critical role of LplA1 for asexual parasite growth &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;. These experimental genetics data suggest that lipoylation during expansion in red blood cells largely occurs through salvage from the host erythrocytes and subsequent ligation of LA to the target proteins of the malaria parasite

Access to primary care for socio-economically disadvantaged older people in rural areas: exploring realist theory using structural equation modelling in a linked dataset

Background: Realist approaches seek to answer questions such as ‘how?’, ‘why?’, ‘for whom?’, ‘in what circumstances?’ and ‘to what extent?’ interventions ‘work’ using context-mechanism-outcome (CMO) configurations. Quantitative methods are not well-established in realist approaches, but structural equation modelling (SEM) may be useful to explore CMO configurations. Our aim was to assess the feasibility and appropriateness of SEM to explore CMO configurations and, if appropriate, make recommendations based on our access to primary care research. Our specific objectives were to map variables from two large population datasets to CMO configurations from our realist review looking at access to primary care, generate latent variables where needed, and use SEM to quantitatively test the CMO configurations. Methods: A linked dataset was created by merging individual patient data from the English Longitudinal Study of Ageing and practice data from the GP Patient Survey. Patients registered in rural practices and who were in the highest deprivation tertile were included. Three latent variables were defined using confirmatory factor analysis. SEM was used to explore the nine full CMOs. All models were estimated using robust maximum likelihoods and accounted for clustering at practice level. Ordinal variables were treated as continuous to ensure convergence. Results: We successfully explored our CMO configurations, but analysis was limited because of data availability. Two hundred seventy-six participants were included. We found a statistically significant direct (context to outcome) or indirect effect (context to outcome via mechanism) for two of nine CMOs. The strongest association was between ‘ease of getting through to the surgery’ and ‘being able to get an appointment’ with an indirect mediated effect through convenience (proportion of the indirect effect of the total was 21%). Healthcare experience was not directly associated with getting an appointment, but there was a statistically significant indirect effect through convenience (53% mediated effect). Model fit indices showed adequate fit. Conclusions: SEM allowed quantification of CMO configurations and could complement other qualitative and quantitative techniques in realist evaluations to support inferences about strengths of relationships. Future research exploring CMO configurations with SEM should aim to collect, preferably continuous, primary data

Les politiques agricoles et commerciales des pays du champ et leurs relations avec celles des pays hors champ. Apport de la 22e Conférence internationale des économistes agricoles

Ce rapport d'étude, à l'occasion de la 22e Conférence internationale des économistes agricoles à Harare les 22-29/08/1994, est construit à partir d'enquêtes auprès d'experts économistes internationaux et africains et d'une analyse critique des communications présentées à la conférence. Il s'attache à définir les grands axes selon lesquels s'analyse aujourd'hui l'insertion des pays d'Afrique francophone, dans les champs régionaux et internationaux

Les politiques agricoles et commerciales des pays du champ et leurs relations avec celles des pays hors champ. Apport de la 22e Conférence internationale des économistes agricoles

Ce rapport d'étude, à l'occasion de la 22e Conférence internationale des économistes agricoles à Harare les 22-29/08/1994, est construit à partir d'enquêtes auprès d'experts économistes internationaux et africains et d'une analyse critique des communications présentées à la conférence. Il s'attache à définir les grands axes selon lesquels s'analyse aujourd'hui l'insertion des pays d'Afrique francophone, dans les champs régionaux et internationaux

Early abolition of cough reflex predicts mortality in deeply sedated brain-injured patients

Background: Deep sedation may hamper the detection of neurological deterioration in brain-injured patients. Impaired brainstem reflexes within the first 24 h of deep sedation are associated with increased mortality in non-brain-injured patients. Our objective was to confirm this association in brain-injured patients. Methods: This was an observational prospective multicenter cohort study involving four neuro-intensive care units. We included acute brain-injured patients requiring deep sedation, defined by a Richmond Assessment Sedation Scale (RASS) < -3. Neurological assessment was performed at day 1 and included pupillary diameter, pupillary light, corneal and cough reflexes, and grimace and motor response to noxious stimuli. Pre-sedation Glasgow Coma Scale (GCS) and Simplified Acute Physiology Score (SAPS-II) were collected, as well as the cause of death in the Intensive Care Unit (ICU). Results: A total of 137 brain-injured patients were recruited, including 70 (51%) traumatic brain-injured patients, 40 (29%) vascular (subarachnoid hemorrhage or intracerebral hemorrhage). Thirty patients (22%) died in the ICU. At day 1, the corneal (OR 2.69, p = 0.034) and cough reflexes (OR 5.12, p = 0.0003) were more frequently abolished in patients that died in the ICU. In a multivariate analysis, abolished cough reflex was associated with ICU mortality after adjustment to pre-sedation GCS, SAPS-II, RASS (OR: 5.19, 95% CI [1.92-14.1], p = 0.001) or dose of sedatives (OR: 8.89, 95% CI [2.64-30.0], p = 0.0004). Conclusion: Early (day 1) cough reflex abolition is an independent predictor of mortality in deeply sedated brain-injured patients. Abolished cough reflex likely reflects a brainstem dysfunction that might result from the combination of primary and secondary neuro-inflammatory cerebral insults revealed and/or worsened by sedation

Patient navigation for colorectal cancer screening in deprived areas: the COLONAV cluster randomized controlled trial

International audienceAbstract Background The objective of this study was to assess the effectiveness of a Patient Navigation Intervention targeting deprived patients for Colo-Rectal Cancer (CRC) screening participation. Methods A cluster randomized controlled trial was conducted in 5 districts. Peer Lay Patient Navigators were recruited to operate in deprived areas. Eligible participants had to be between 50 and 74 years old, live in these deprived areas and receive an invitation to the nationally organized Colo-Rectal Cancer (CRC) screening during the study period. The theory-driven navigation intervention was deployed for 18 months. A population Health Intervention Research assessment method was used to assess effectiveness and context interaction. The primary criterion was screening participation at 12 months. Results Twenty-four thousand two hundred eighty-one individuals were included inside 40 clusters. The increase in participation in the intervention group was estimated at 23%, (ORa = 1.23, CI95% [1.07–1.41], p = 0.003). For the subgroup of individuals who participated, the time delay to participating was reduced by 26% (ORa = 0.74, CI95% [0.57–0.96], p = 0.021). Main factors modulating the effect of the intervention were: closeness of navigator profiles to the targeted population, navigators’ abilities to adapt their modus operandi, and facilitating attachment structure. Conclusion The ColoNav Intervention succeeded in demonstrating its effectiveness, for CRC screening. Patient Navigation should be disseminate with broader health promotion goals in order to achieve equity in health care. Trial registration clinicaltrials.gov NCT02369757 24/02/2015