Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2.

Funder: Isaac Newton Trust; FundRef: http://dx.doi.org/10.13039/501100004815Funder: Alborada Trust; FundRef: http://dx.doi.org/10.13039/100008288Funder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100004440Funder: University of Cambridge; FundRef: http://dx.doi.org/10.13039/501100000735Funder: Global Health Innovative Technology Fund; FundRef: http://dx.doi.org/10.13039/501100013996Funder: Rosetrees Trust; FundRef: http://dx.doi.org/10.13039/501100000833Funder: Royal Society; FundRef: http://dx.doi.org/10.13039/501100000288HAP2 is a transmembrane gamete fusogen found in multiple eukaryotic kingdoms and is structurally homologous to viral class II fusogens. Studies in Plasmodium have suggested that HAP2 is an attractive target for vaccines that block transmission of malaria. HAP2 has three extracellular domains, arranged in the order D2, D1, and D3. Here, we report monoclonal antibodies against the D3 fragment of Plasmodium berghei HAP2 and crystal structures of D3 in complex with Fab fragments of two of these antibodies, one of which blocks fertilization of Plasmodium berghei in vitro and transmission of malaria in mosquitoes. We also show how this Fab binds the complete HAP2 ectodomain with electron microscopy. The two antibodies cross-react with HAP2 among multiple plasmodial species. Our characterization of the Plasmodium D3 structure, HAP2 ectodomain architecture, and mechanism of inhibition provide insights for the development of a vaccine to block malaria transmission

Development and validation of a multivariable prediction model in open abdomen patients for entero-atmospheric fistula

Background: Laparostomy or Open Abdomen (OA) has matured into an effective strategy in the management of abdominal catastrophe. Single prognostic factors have been identified in a previous systematic review regarding entero-atmospheric fistula (EAF). Unfortunately, no prognostic multivariable model for EAF exist. The aim was to develop and validate a multivariable prediction model from a retrospective cohort study involving three hospital’s databases. Methods: Fifty-seven variables were evaluated to develop a multivariable model. Univariate and multivariable logistic regression analyses were performed for on a developmental data set from two hospitals. Receiver operator characteristics analysis with area under the curve (AUC) and 95% confidence intervals (CI) were performed on the developmental data set (internal validation) as well as on an additional validation data set from another hospital (external validation). Results: Five-hundred and forty-eight patients managed with an OA. Two variables remained in the multivariable prediction model for EAF. The AUC for EAF on internal validation were 0.74 (95% CI: 0.58–0.86) and 0.79 (95% CI: 0.67–0.92) on external validation. Conclusions: A multivariable prediction model for EAF was externally validated and an easy-to-use probability nomogram was constructed using the two predictor variables

Treatments and other prognostic factors in the management of the open abdomen: a systematic review

Background: The open abdomen (OA) is an important approach for managing intraabdominal catastrophes and continues to be the standard of care. Despite this, challenges remain with it associated with a high incidence of complications and poor outcomes. The objective of this article is to perform a systematic review in accordance with PRISMA guidelines to identify prognostic factors in OA patients in regards to definitive fascial closure (DFC), mortality and intra-abdominal complications.\ud \ud Methods: An electronic database search was conducted involving Medline, Excerpta Medica, Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature and Clinicaltrials.gov. All studies that described prognostic factors in regards to the above outcomes in OA patients were eligible for inclusion. Data collected were synthesised by each outcome of interest and assessed for methodological quality.\ud \ud Results: Thirty-one studies were included in the final synthesis. Enteral nutrition, organ dysfunction, local and systemic infection, number of re-explorations, worsening ISS and the development of a fistula appeared to significantly delay DFC. Age and APACHE II score were predictors for in-hospital mortality. Failed DFC, large bowel resection and > 5-10 litres of intravenous fluids in < 48 hours were predictors of entero-atmospheric fistula. The source of infection (small bowel as opposed to colon) was a predictor for ventral hernia. Large bowel resection, > 5-10 and > 10 litres of intravenous fluids in < 48 hours were predictors of intra-abdominal abscess. Fascial closure on (or after) day 5 and having a bowel anastomosis were predictors for anastomotic leak. Overall methodological quality was of a moderate level.\ud \ud Limitations: Overall methodological quality, high number of retrospective studies, low reporting of prognostic factors and the multitude of factors potentially affecting patient outcome that were not analysed.\ud \ud Conclusions: Careful selection and management of OA patients will avoid prolonged treatment and facilitate early DFC. Future research should focus on the development of a prognostic model