Immunogenicity of Self-Associated Aggregates and Chemically Cross-Linked Conjugates of the 42 kDa Plasmodium falciparum Merozoite Surface Protein-1

Self-associated protein aggregates or cross-linked protein conjugates are, in general, more immunogenic than oligomeric or monomeric forms. In particular, the immunogenicity in mice of a recombinant malaria transmission blocking vaccine candidate, the ookinete specific Plasmodium falciparum 25 kDa protein (Pfs25), was increased more than 1000-fold when evaluated as a chemical cross-linked protein-protein conjugate as compared to a formulated monomer. Whether alternative approaches using protein complexes improve the immunogenicity of other recombinant malaria vaccine candidates is worth assessing. In this work, the immunogenicity of the recombinant 42 kDa processed form of the P. falciparum merozoite surface protein 1 (MSP142) was evaluated as a self-associated, non-covalent aggregate and as a chemical cross-linked protein-protein conjugate to ExoProtein A, which is a recombinant detoxified form of Pseudomonas aeruginosa exotoxin A. MSP142 conjugates were prepared and characterized biochemically and biophysically to determine their molar mass in solution and stoichiometry, when relevant. The immunogenicity of the MSP142 self-associated aggregates, cross-linked chemical conjugates and monomers were compared in BALB/c mice after adsorption to aluminum hydroxide adjuvant, and in one instance in association with the TLR9 agonist CPG7909 with an aluminum hydroxide formulation. Antibody titers were assessed by ELISA. Unlike observations made for Pfs25, no significant enhancement in MSP142 specific antibody titers was observed for any conjugate as compared to the formulated monomer or dimer, except for the addition of the TLR9 agonist CPG7909. Clearly, enhancing the immunogenicity of a recombinant protein vaccine candidate by the formation of protein complexes must be established on an empirical basis

Upper Limb Entheseal Change With the Transition to Agriculture in the Southeastern United States: A View from Moundville and the Central Tombigbee River Valley

We analyzed entheseal change in 159 skeletons from Moundville and surrounding settlements using primary fibrocartilaginous attachments of the upper limbs. Risk of entheseal change did not differ bilaterally, suggesting a wide variety of activities were used to exploit a diverse ecosystem. Consistent with predictions, Mississippian (1000-1500 CE) agriculturalists experienced greater risk of entheseal change than did Late Woodland (500-900 CE) hunter-gatherers. Attachments used in arm flexion were most affected, while rotator cuff entheses remained consistent over time. A temporal increase in muscular changes in males in concert with faunal evidence for resurgence of larger game (e.g., deer) is consistent with continued reliance on hunting alongside domestication of maize. Among Mississippians, younger males appear to have been carrying out the most strenuous tasks, contrary to earlier studies that suggested a decline in male activities with domestication. Mound centers consistently experienced the greatest upper body changes, in spite of faunal and botanical data supporting provisioning of elites by outlying sites. Center males, respectively, experienced more than 26 and 12 times greater changes at elbow extensors and brachialis than those from outlying settlements, with a significant decline from young to middle age among adults. Center females experienced increased risk at biceps insertions and common extensors of the humeri - trends that disappeared with age. Overall findings suggest increased upper body demands and shifting sex and age-dependent divisions of labor with maize intensification, but trends across settlements point to significant status-related body size selection in center males, with fewer differences among females. (C) 2012 Elsevier GmbH. All rights reserved

Trans-Atlantic slavery : isotopic evidence for forced migration to Barbados

The question of the ultimate origin of African slaves is one of the most perplexing in the history of trans-Atlantic slavery. Here we present the results of a small, preliminary isotopic study that was conducted in order to determine the geographical origin of 25 enslaved Africans who were buried at the Newton plantation, Barbados, sometime between the late 17th and early 19th century. In order to gain a more nuanced understanding of the slaves' origin, we used a combination of carbon, nitrogen, oxygen, and strontium isotope analyses. Carbon and nitrogen isotope ratios were determined in bone and dentinal collagen; oxygen and strontium isotopes were measured in tooth enamel. Results suggest that the majority of individuals were born on the island, if not the estate itself. Seven individuals, however, yielded enamel oxygen and strontium ratios that are inconsistent with a Barbadian origin, which strongly suggests that we are dealing with first-generation captives who were brought to the island with the slave trade. This idea is also supported by the fact that their carbon and nitrogen stable isotope values differ markedly between their teeth and bones. These intra-skeletal shifts reflect major dietary changes that probably coincided with their enslavement and forced migration to Barbados. While it is impossible to determine their exact origins, the results clearly demonstrate that the slaves did not all grow up in the same part of Africa. Instead, the data seem to suggest that they originated from at least three different areas, possibly including the Gold Coast and the Senegambia. Am J Phys Anthropol, 2009

Systematic review of perfusion imaging with computed tomography and magnetic resonance in acute ischemic stroke: heterogeneity of acquisition and postprocessing parameters: a translational medicine research collaboration multicentre acute stroke imaging study

<b>Background and Purpose</b>-Heterogeneity of acquisition and postprocessing parameters for magnetic resonance– and computed tomography–based perfusion imaging in acute stroke may limit comparisons between studies, but the current degree of heterogeneity in the literature has not been precisely defined.<p></p> <b>Methods</b>-We examined articles published before August 30, 2009 that reported perfusion thresholds, average lesion perfusion values, or correlations of perfusion deficit volumes from acute stroke patients <24 hours postictus. We compared acquisition parameters from published studies with guidance from the Acute Stroke Imaging Research Roadmap1. In addition, we assessed the consistency of postprocessing parameters.<p></p> <b>Results</b>-Twenty computed tomography perfusion and 49 perfusion-weighted imaging studies were included from 7152 articles. Although certain parameters were reported frequently, consistently, and in line with the Roadmap proposals, we found substantial heterogeneity in other parameters, and there was considerable variation and underreporting of postprocessing methodology.<p></p> <b>Conclusions</b>-There is substantial scope to increase homogeneity in future studies, eg, through reporting standards

A Machine Learning Algorithm to Identify Patients at Risk of Unplanned Subsequent Surgery After Intramedullary Nailing for Tibial Shaft Fractures

Objectives: In the SPRINT trial, 18% of patients with a tibial shaft fracture (TSF) treated with intramedullary nailing (IMN) had one or more unplanned subsequent surgical procedures. It is clinically relevant for surgeon and patient to anticipate unplanned secondary procedures, other than operations that can be readily expected such as reconstructive procedures for soft tissue defects. Therefore, the objective of this study was to develop a machine learning (ML) prediction model using the SPRINT data that can give individual patients and their care team an estimate of their particular probability of an unplanned second surgery. Methods: Patients from the SPRINT trial with unilateral TSFs were randomly divided into a training set (80%) and test set (20%). Five ML algorithms were trained in recognizing patterns associated with subsequent surgery in the training set based on a subset of variables identified by random forest algorithms. Performance of each ML algorithm was evaluated and compared based on (1) area under the ROC curve, (2) calibration slope and intercept, and (3) the Brier score. Results: Total data set comprised 1198 patients, of whom 214 patients (18%) underwent subsequent surgery. Seven variables were used to train ML algorithms: (1) Gustilo-Anderson classification, (2) Tscherne classification, (3) fracture location, (4) fracture gap, (5) polytrauma, (6) injury mechanism, and (7) OTA/AO classification. The best-performing ML algorithm had an area under the ROC curve, calibration slope, calibration intercept, and the Brier score of 0.766, 0.954, -0.002, and 0.120 in the training set and 0.773, 0.922, 0, and 0.119 in the test set, respectively. Conclusions: An ML algorithm was developed to predict the probability of subsequent surgery after IMN for TSFs. This ML algorithm may assist surgeons to inform patients about the probability of subsequent surgery and might help to identify patients who need a different perioperative plan or a more intensive approach.Orthopaedics, Trauma Surgery and Rehabilitatio