Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

Investigating Agrobacterium-Mediated Transformation of Verticillium albo-atrum on Plant Surfaces

Background: Agrobacterium tumefaciens has long been known to transform plant tissue in nature as part of its infection process. This natural mechanism has been utilised over the last few decades in laboratories world wide to genetically manipulate many species of plants. More recently this technology has been successfully applied to non-plant organisms in the laboratory, including fungi, where the plant wound hormone acetosyringone, an inducer of transformation, is supplied exogenously. In the natural environment it is possible that Agrobacterium and fungi may encounter each other at plant wound sites, where acetosyringone would be present, raising the possibility of natural gene transfer from bacterium to fungus. Methodology/Principal Findings: We investigate this hypothesis through the development of experiments designed to replicate such a situation at a plant wound site. A. tumefaciens harbouring the plasmid pCAMDsRed was co-cultivated with the common plant pathogenic fungus Verticillium albo-atrum on a range of wounded plant tissues. Fungal transformants were obtained from co-cultivation on a range of plant tissue types, demonstrating that plant tissue provides sufficient vir gene inducers to allow A. tumefaciens to transform fungi in planta. Conclusions/Significance: This work raises interesting questions about whether A. tumefaciens may be able to transform organisms other than plants in nature, or indeed should be considered during GM risk assessments, with furthe

Adaptation and applicability of the "mistreatment" component in Integrated Management of Childhood Illness in Brazil

OBJETIVOS: descrever o processo de adaptação ao contexto brasileiro e da aplicabilidade do conteúdo do módulo de maus-tratos no âmbito da estratégia Atenção Integrada às Doenças Prevalentes na Infância (AIDPI), a partir do original proposto pela Organização Pan-Americana da Saúde. MÉTODOS: O protocolo original foi traduzido para o português, retro-traduzido e revisado de forma independente. Foram incorporados aspectos relativos à legislação, contexto de saúde e organização dos serviços brasileiros. O material foi discutido por especialistas de diferentes áreas até obter consenso a respeito de compreensão e correspondência sobre os conceitos e os instrumentos propostos. A versão preliminar foi testada com grupo de monitores da estratégia AIDPI. Sugestões foram incorporadas ao texto. O módulo final foi aplicado com sucesso em treinamento para monitores em AIDPI na Região Nordeste. RESULTADOS: o material mostrou-se útil, claro e coerente. A classificação de gravidade para maus tratos psicológicos e negligência, além de textos com orientações aos profissionais e pais sobre o desenvolvimento psicomotor e emocional normais da criança foram incluídos. CONCLUSÕES: A incorporação desse módulo de maus-tratos em treinamentos formais na estratégia AIDPI pode preencher uma lacuna na educação do profissional de saúde na atenção primária, onde problemas relacionados à violência contra a criança são frequentes. _________________________________________________________________________________________ ABSTRACT: OBJECTIVES: to describe the process of adaptation to the Brazilian context and the applicability of the "mistreatment" module in the Integrated Mana-gement of Childhood Illness (IMCI) strategy, based on the Pan American Health Organization (PAHO) proposal. METHODS: the original protocol was translated into Portuguese, back-translated and reviewed by an independent observer. Features relating to legislation, the health context and the way Brazilian services are organized were incorporated. The materials were discussed by specialists from various areas until consensus was achieved with regard to the comprehensibility of the text and the correspondence between the wording and the intentions. The preliminary version was tested with a group of IMCI strategy monitors and suggestions arising from this were incorporated into the text. The final module was successfully applied during training of IMCI monitors in the Northeast region of the country. RESULTS: the material was found to be useful, clear and coherent. The ranking of degrees of severity of psychological mistreatment and negligence and texts providing guidelines for health workers and parents on the normal psychomotor and emotional deve-lopment of children were included. CONCLUSIONS: the incorporation of this module on mistreatment in the IMCI strategy's formal training sessions may fill a gap in the education of primary care health workers, who encounter problems relating to violence against children on a regular basis

Avaliação dos serviços de urgência e emergência da rede hospitalar de referência no Nordeste Brasileiro

Este artigo avalia o grau de implantação de dez serviços de urgência/emergência hospitalar, que compõem a rede de referência macro e microrregional em Pernambuco, Nordeste brasileiro. Aborda critérios relativos à estrutura (física-organizacional, recursos materiais e humanos) e ao processo (atividades de rotina e de referência/contra-referência); classificando os hospitais como satisfatório, aceitável e deficiente. Aponta que a maioria dos hospitais se classifica como deficiente, estando entre estes todas as unidades de referência microrregionais e uma macrorregional. Estas últimas apresentam melhor desempenho quanto ao processo de trabalho; e a dimensão estrutura apresenta-se mais bem implantada nos hospitais microrregionais. Os resultados evidenciam como prioridade a qualificação dos hospitais avaliados, mediante o fortalecimento de políticas descentralizadas de recursos humanos e tecnológicos, direcionados à melhoria das práticas de trabalho consensuais aos contextos regionais do estado.This article evaluates the degree of implementation of ten urgent and emergency hospital services comprising the macro and micro-regional referral system in Pernambuco State, Northeast Brazil. The study analyzes criteria related to structure (physical and organizational, and material and human resources) and process (routine and referral/counter-referral activities), classifying the hospitals as satisfactory, acceptable, and deficient. The majority of the hospitals were classified as deficient, including all the micro-regional units and one macro-regional referral unit. Macro-regional units show better performance in the work process, while implementation of the structural dimension is better in the micro-regional hospitals. The results highlight the priority of upgrading these hospitals by strengthening decentralized human resources and technology policies, oriented towards the improvement of work processes in keeping with the State's regional contexts

Prediction of social structure and genetic relatedness in colonies of the facultative polygynous stingless bee Melipona bicolor (Hymenoptera, Apidae)

Stingless bee colonies typically consist of one single-mated mother queen and her worker offspring. The stingless bee Melipona bicolor (Hymenoptera: Apidae) shows facultative polygyny, which makes this species particularly suitable for testing theoretical expectations concerning social behavior. In this study, we investigated the social structure and genetic relatedness among workers from eight natural and six manipulated colonies of M. bicolor over a period of one year. The populations of M. bicolor contained monogynous and polygynous colonies. The estimated genetic relatedness among workers from monogynous and polygynous colonies was 0.75 ± 0.12 and 0.53 ± 0.16 (mean ± SEM), respectively. Although the parental genotypes had significant effects on genetic relatedness in monogynous and polygynous colonies, polygyny markedly decreased the relatedness among nestmate workers. Our findings also demonstrate that polygyny in M. bicolor may arise from the adoption of related or unrelated queens

Genes optimized by evolution for accurate and fast translation encode in Archaea and Bacteria a broad and characteristic spectrum of protein functions

BACKGROUND: In many microbial genomes, a strong preference for a small number of codons can be observed in genes whose products are needed by the cell in large quantities. This codon usage bias (CUB) improves translational accuracy and speed and is one of several factors optimizing cell growth. Whereas CUB and the overrepresentation of individual proteins have been studied in detail, it is still unclear which high-level metabolic categories are subject to translational optimization in different habitats. RESULTS: In a systematic study of 388 microbial species, we have identified for each genome a specific subset of genes characterized by a marked CUB, which we named the effectome. As expected, gene products related to protein synthesis are abundant in both archaeal and bacterial effectomes. In addition, enzymes contributing to energy production and gene products involved in protein folding and stabilization are overrepresented. The comparison of genomes from eleven habitats shows that the environment has only a minor effect on the composition of the effectomes. As a paradigmatic example, we detailed the effectome content of 37 bacterial genomes that are most likely exposed to strongest selective pressure towards translational optimization. These effectomes accommodate a broad range of protein functions like enzymes related to glycolysis/gluconeogenesis and the TCA cycle, ATP synthases, aminoacyl-tRNA synthetases, chaperones, proteases that degrade misfolded proteins, protectants against oxidative damage, as well as cold shock and outer membrane proteins. CONCLUSIONS: We made clear that effectomes consist of specific subsets of the proteome being involved in several cellular functions. As expected, some functions are related to cell growth and affect speed and quality of protein synthesis. Additionally, the effectomes contain enzymes of central metabolic pathways and cellular functions sustaining microbial life under stress situations. These findings indicate that cell growth is an important but not the only factor modulating translational accuracy and speed by means of CUB

Early and Late Pathogenic Events of Newborn Mice Encephalitis Experimentally Induced by Itacaiunas and Curionópolis Bracorhabdoviruses Infection

In previous reports we proposed a new genus for Rhabdoviridae and described neurotropic preference and gross neuropathology in newborn albino Swiss mice after Curionopolis and Itacaiunas infections. In the present report a time-course study of experimental encephalitis induced by Itacaiunas and Curionopolis virus was conducted both in vivo and in vitro to investigate cellular targets and the sequence of neuroinvasion. We also investigate, after intranasal inoculation, clinical signs, histopathology and apoptosis in correlation with viral immunolabeling at different time points. Curionopolis and Itacaiunas viral antigens were first detected in the parenchyma of olfactory pathways at 2 and 3 days post-inoculation (dpi) and the first clinical signs were observed at 4 and 8 dpi, respectively. After Curionopolis infection, the mortality rate was 100% between 5 and 6 dpi, and 35% between 8 and 15 dpi after Itacaiunas infection. We identified CNS mice cell types both in vivo and in vitro and the temporal sequence of neuroanatomical olfactory areas infected by Itacaiunas and Curionopolis virus. Distinct virulences were reflected in the neuropathological changes including TUNEL immunolabeling and cytopathic effects, more intense and precocious after intracerebral or in vitro inoculations of Curionopolis than after Itacaiunas virus. In vitro studies revealed neuronal but not astrocyte or microglial cytopathic effects at 2 dpi, with monolayer destruction occurring at 5 and 7 dpi with Curionopolis and Itacaiunas virus, respectively. Ultrastructural changes included virus budding associated with interstitial and perivascular edema, endothelial hypertrophy, a reduced and/or collapsed small vessel luminal area, thickening of the capillary basement membrane, and presence of phagocytosed apoptotic bodies. Glial cells with viral budding similar to oligodendrocytes were infected with Itacaiunas virus but not with Curionopolis virus. Thus, Curionopolis and Itacaiunas viruses share many pathological and clinical features present in other rhabdoviruses but distinct virulence and glial targets in newborn albino Swiss mice brain