One-year sustained glycaemic control and less hypoglycaemia with new insulin glargine 300 U/ml compared with 100 U/ml in people with type 2 diabetes using basal plus meal-time insulin : the EDITION 1 12-month randomized trial, including 6-month extension

AimsTo evaluate the maintenance of efficacy and safety of insulin glargine 300 U/ml (Gla-300) versus glargine 100 U/ml (Gla-100) in people with type 2 diabetes mellitus (T2DM) using basal plus meal-time insulin for 12 months in the EDITION 1 trial. MethodsEDITION 1 was a multicentre, randomized, open-label, two-arm, phase IIIa study. Participants completing the initial 6-month treatment period continued to receive Gla-300 or Gla-100, as previously randomized, once daily for a further 6-month open-label extension phase. Changes in glycated haemoglobin (HbA1c) and fasting plasma glucose concentrations, insulin dose, hypoglycaemic events and body weight were assessed. ResultsOf 807 participants enrolled in the initial phase, 89% (359/404) assigned to Gla-300 and 88% (355/403) assigned to Gla-100 completed 12 months. Glycaemic control was sustained in both groups (mean HbA1c: Gla-300, 7.24%; Gla-100, 7.42%), with more sustained HbA1c reduction for Gla-300 at 12 months: least squares mean difference Gla-300 vs Gla-100: HbA1c -0.17 [95% confidence interval (CI) -0.30 to -0.05]%. The mean daily basal insulin dose at 12 months was 1.03 U/kg for Gla-300 and 0.90 U/kg for Gla-100. Lower percentages of participants had 1 confirmed [3.9 mmol/l (70 mg/dl)] or severe hypoglycaemic event with Gla-300 than Gla-100 at any time of day [24 h; 86 vs 92%; relative risk 0.94 (95% CI 0.89-0.99)] and during the night [54 vs 65%; relative risk 0.84 (95% CI 0.75-0.94)], while the annualized rates of such hypoglycaemic events were similar. No between-treatment differences in adverse events were apparent. ConclusionDuring 12 months of treatment of T2DM requiring basal and meal-time insulin, glycaemic control was better sustained and fewer individuals reported hypoglycaemia with Gla-300 than with Gla-100. The mean basal insulin dose was higher with Gla-300 compared with Gla-100, but total numbers of hypoglycaemic events and overall tolerability did not differ between treatments.Peer reviewe

The origin and evolution of syntax errors in simple sequence flow models in BPMN

How do syntax errors emerge? What is the earliest moment that potential syntax errors can be detected? Which evolution do syntax errors go through during modeling? A provisional answer to these questions is formulated in this paper based on an investigation of a dataset containing the operational details of 126 modeling sessions. First, a list is composed of the different potential syntax errors. Second, a classification framework is built to categorize the errors according to their certainty and severity during modeling (i.e., in partial or complete models). Third, the origin and evolution of all syntax errors in the dataset are identified. This data is then used to collect a number of observations, which form a basis for future research

Risk Factors for Tungiasis in Nigeria: Identification of Targets for Effective Intervention

Tungiasis is a parasitic skin disease caused by the sand flea Tunga penetrans. After penetration into the skin, the flea grows and reaches the size of a pea. The disease is a neglected public health problem in endemic areas in Latin America, the Caribbean and Africa, and causes considerable morbidity in the affected communities. We performed a study in a rural community in Nigeria to detect factors associated with tungiasis. People were examined for the presence of sand flea lesions, and a questionnaire was applied. Of the 643 individuals examined, 252 (42.5%) had tungiasis. The most important factors independently associated with the disease were: presence of pigs on the compound (adjusted odds ratio [OR] = 17.98), sand or clay floor inside house (OR = 9.33), and having the common resting place outside the house (OR = 7.14). The regular use of closed footwear (OR = 0.34) and the use of insecticides indoors (OR = 0.2) were protective factors. Our data show that tungiasis in this community is determined to an important extent by some variables that may be a target for interventions

Controlling Tungiasis in an Impoverished Community: An Intervention Study

Tungiasis is a disease caused by the sand flea Tunga penetrans, a parasite prevalent in many impoverished communities in developing countries. The female sand flea penetrates into the skin of animals and humans where it grows rapidly in size, feeds on the host's blood, produces eggs which are expelled into the environment, and eventually dies in situ. The lesions become frequently superinfected and the infestation is associated with considerable morbidity. Clearly, tungiasis is a neglected disease of neglected populations. We investigated the impact of a package of intervention measures targeted against on-host and off-host stages of T. penetrans in a fishing community in Northeast Brazil. These measures decreased disease occurrence only temporarily, but had a sustained effect on the intensity of the infestation. Since infestation intensity and morbidity are correlated, presumably the intervention also lowered tungiasis-associated morbidity. Control measures similar to the ones used in this study may help to effectively control tungiasis in impoverished communities

Association between footwear use and neglected tropical diseases: a systematic review and meta-analysis

BACKGROUND The control of neglected tropical diseases (NTDs) has primarily focused on preventive chemotherapy and case management. Less attention has been placed on the role of ensuring access to adequate water, sanitation, and hygiene and personal preventive measures in reducing exposure to infection. Our aim was to assess whether footwear use was associated with a lower risk of selected NTDs. METHODOLOGY We conducted a systematic review and meta-analysis to assess the association between footwear use and infection or disease for those NTDs for which the route of transmission or occurrence may be through the feet. We included Buruli ulcer, cutaneous larva migrans (CLM), leptospirosis, mycetoma, myiasis, podoconiosis, snakebite, tungiasis, and soil-transmitted helminth (STH) infections, particularly hookworm infection and strongyloidiasis. We searched Medline, Embase, Cochrane, Web of Science, CINAHL Plus, and Popline databases, contacted experts, and hand-searched reference lists for eligible studies. The search was conducted in English without language, publication status, or date restrictions up to January 2014. Studies were eligible for inclusion if they reported a measure of the association between footwear use and the risk of each NTD. Publication bias was assessed using funnel plots. Descriptive study characteristics and methodological quality of the included studies were summarized. For each study outcome, both outcome and exposure data were abstracted and crude and adjusted effect estimates presented. Individual and summary odds ratio (OR) estimates and corresponding 95% confidence intervals (CIs) were calculated as a measure of intervention effect, using random effects meta-analyses. PRINCIPAL FINDINGS Among the 427 studies screened, 53 met our inclusion criteria. Footwear use was significantly associated with a lower odds of infection of Buruli ulcer (OR=0.15; 95% CI: 0.08-0.29), CLM (OR=0.24; 95% CI: 0.06-0.96), tungiasis (OR=0.42; 95% CI: 0.26-0.70), hookworm infection (OR=0.48; 95% CI: 0.37-0.61), any STH infection (OR=0.57; 95% CI: 0.39-0.84), strongyloidiasis (OR=0.56; 95% CI: 0.38-0.83), and leptospirosis (OR=0.59; 95% CI: 0.37-0.94). No significant association between footwear use and podoconiosis (OR=0.63; 95% CI: 0.38-1.05) was found and no data were available for mycetoma, myiasis, and snakebite. The main limitations were evidence of heterogeneity and poor study quality inherent to the observational studies included. CONCLUSIONS/SIGNIFICANCE Our results show that footwear use was associated with a lower odds of several different NTDs. Access to footwear should be prioritized alongside existing NTD interventions to ensure a lasting reduction of multiple NTDs and to accelerate their control and elimination. PROTOCOL REGISTRATION PROSPERO International prospective register of systematic reviews CRD42012003338

Plasmodium chabaudi chabaudi malaria parasites can develop stable resistance to atovaquone with a mutation in the cytochrome b gene

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium falciparum</it>, has developed resistance to many of the drugs in use. The recommended treatment policy is now to use drug combinations. The atovaquone-proguanil (AP) drug combination, is one of the treatment and prophylaxis options. Atovaquone (ATQ) exerts its action by inhibiting plasmodial mitochondria electron transport at the level of the cytochrome bc1 complex. <it>Plasmodium falciparum in vitro </it>resistance to ATQ has been associated with specific point mutations in the region spanning codons 271-284 of the <it>cytochrome b </it>gene. ATQ -resistant <it>Plasmodium yoelii </it>and <it>Plasmodium berghei </it>lines have been obtained and resistant lines have amino acid mutations in their CYT <it>b </it>protein sequences. <it>Plasmodium chabaudi </it>model for studying drug-responses and drug-resistance selection is a very useful rodent malaria model but no ATQ resistant parasites have been reported so far. The aim of this study was to determine the ATQ sensitivity of the <it>P. chabaudi </it>clones, to select a resistant parasite line and to perform genotypic characterization of the <it>cytb </it>gene of these clones.</p> <p>Methods</p> <p>To select for ATQ resistance, <it>Plasmodium. chabaudi chabaudi </it>clones were exposed to gradually increasing concentrations of ATQ during several consecutive passages in mice. <it>Plasmodium chabaudi cytb </it>gene was amplified and sequenced.</p> <p>Results</p> <p>ATQ resistance was selected from the clone AS-3CQ. In order to confirm whether an heritable genetic mutation underlies the response of AS-ATQ to ATQ, the stability of the drug resistance phenotype in this clone was evaluated by measuring drug responses after (i) multiple blood passages in the absence of the drug, (ii) freeze/thawing of parasites in liquid nitrogen and (iii) transmission through a mosquito host, <it>Anopheles stephensi</it>. ATQ resistance phenotype of the drug-selected parasite clone kept unaltered. Therefore, ATQ resistance in clone AS-ATQ is genetically encoded. The Minimum Curative Dose of AS-ATQ showed a six-fold increase in MCD to ATQ relative to AS-3CQ.</p> <p>Conclusions</p> <p>A mutation was found on the <it>P. chabaudi cytb </it>gene from the AS-ATQ sample a substitution at the residue Tyr268 for an Asn, this mutation is homologous to the one found in <it>P. falciparum </it>isolates resistant to ATQ.</p

Control of Tungiasis through Intermittent Application of a Plant-Based Repellent: An Intervention Study in a Resource-Poor Community in Brazil

Tungiasis is a parasitic skin disease caused by the female sand flea Tunga penetrans. The disease is frequent in resource-poor communities in South America and sub-Saharan Africa and affects the poorest of the poor. Sand flea disease is associated with a considerable morbidity and may lead to tetanus in non-vaccinated individuals. The degree of morbidity depends on the intensity of infestation, i.e., the number of embedded sand fleas a person has. Since tungiasis is a zoonosis involving a host of animal reservoirs, and because an effective treatment is not at hand, in resource-poor settings elimination is not feasible. Preventing morbidity to develop is therefore the only means to protect exposed individuals from sand flea disease. Similar to other arthropods, sand fleas can be repelled before they penetrate into the skin. In this study we show that the intermittent application of a plant-based repellent, of which the major component is coconut oil, reduces the intensity of infestation dramatically during the whole transmission season and prevents tungiasis-associated morbidity from developing. The prevention can be performed at the household level by the affected individuals themselves with minimal input from the health sector

A Grammatical Model for the Specification of Administrative Workflow Using Scenario as Modelling Unit

International audienceProcess modelling is a crucial phase of Business Process Management (BPM). Despite the many efforts made in producing process modelling tools, existing tools (languages) are not commonly accepted. They are mainly criticised for their inability to specify both the tasks making up the processes and their scheduling (their lifecycle models), the data they manipulate (their information models) and their organizational models. Process modelling in these languages often results in a single task graph; such a graph can quickly become difficult to read and maintain. Moreover, these languages are often too general (they have a very high expressiveness); this makes their application to specific types of processes complex: especially for administrative processes. In this paper, we present a new language for administrative processes modelling that allows designers to specify the lifecycle, information and organizational models of such processes using a mathematical tool based on a variant of attributed grammars. The approach imposed by the new language requires the designer to subdivide his process into scenarios, then to model each scenario individually using a simple task graph (an annotated tree) from which a grammatical model is further derived. At each moment then, the designer manipulates only a scenario of the studied process: this approach is more intuitive and modular; it allows to produce task graphs that are more refined and therefore, more readable and easier to maintain

The Enteropathogenic E. coli (EPEC) Tir Effector Inhibits NF-κB Activity by Targeting TNFα Receptor-Associated Factors

Enteropathogenic Escherichia coli (EPEC) disease depends on the transfer of effector proteins into epithelia lining the human small intestine. EPEC E2348/69 has at least 20 effector genes of which six are located with the effector-delivery system genes on the Locus of Enterocyte Effacement (LEE) Pathogenicity Island. Our previous work implied that non-LEE-encoded (Nle) effectors possess functions that inhibit epithelial anti-microbial and inflammation-inducing responses by blocking NF-κB transcription factor activity. Indeed, screens by us and others have identified novel inhibitory mechanisms for NleC and NleH, with key co-operative functions for NleB1 and NleE1. Here, we demonstrate that the LEE-encoded Translocated-intimin receptor (Tir) effector has a potent and specific ability to inhibit NF-κB activation. Indeed, biochemical, imaging and immunoprecipitation studies reveal a novel inhibitory mechanism whereby Tir interaction with cytoplasm-located TNFα receptor-associated factor (TRAF) adaptor proteins induces their proteasomal-independent degradation. Infection studies support this Tir-TRAF relationship but reveal that Tir, like NleC and NleH, has a non-essential contribution in EPEC's NF-κB inhibitory capacity linked to Tir's activity being suppressed by undefined EPEC factors. Infections in a disease-relevant intestinal model confirm key NF-κB inhibitory roles for the NleB1/NleE1 effectors, with other studies providing insights on host targets. The work not only reveals a second Intimin-independent property for Tir and a novel EPEC effector-mediated NF-κB inhibitory mechanism but also lends itself to speculations on the evolution of EPEC's capacity to inhibit NF-κB function