DESIGNING NEW BIOMATERIALS: Modifying a Spider Silk Gene For Efficient Bacterial Expression for Industrial Production

Spider silks have remarkable physical properties due to a combination of strength and elasticity. In addition, spider silks are biocompatible and biodegradable. Our laboratory has shown that the strength of products, such as fibers, produced with other silk proteins correlates with the size of the silk protein. The aciniform silk protein (AcSp1), has been shown to produce the thinnest and strongest fibers of all the natural spider silks. Aciniform silk is composed of a nonrepetitive amino-terminal region, 14 repeats of approximately 200 amino acids each, and a nonrepetitive carboxy-terminal region. We have been able to produce different variants of this gene. All AcSp1 protein variants were able to express in E. coli. The bacteria expression of the AcSp1 protein is low and the protein is expressed not only as a full length polypeptide but also as fragments of the protein. We identified a sequence in the amino-terminal region of the first repeat of the AcSp1 gene that acts as an early termination sequence. Our objective is to modify this region on the gene to study changes in the expression efficiency of AcSp1

Book Reviews

Wesleyan Perspectives on the New Creation M. Douglas Meeks, ed. Nashville: Kingswood, 2004, 200 pp., paper, 2004, $30.00 Reviewed by William J Abraham Christ Plays in Ten Thousand Places Eugene H. Peterson Grand Rapids, Michigan: William B. Eerdmans Publishing Company 2005, xii, 368pp. cloth,$25.00 Reviewed by Elaine A. Heath The Evangelical Moment: The Promise of an American Religion By Kenneth J. Collins Grand Rapids: Baker Academic Press 2005, 288 pp., paper, 22.99 Reviewed by Nathan Crawford Theology as History and Hermeneutics: A Post-Critical Evangelical Conversation with Contemporary Theology Laurence W. Wood Lexington: Emeth Publisher 2004, 261 pp. Reviewed by Nathan Crawford Resistance and Theological Ethics Ronald H. Stone and Robert L. Stivers, eds. Lanham, Maryland: Roman & Littlefield Publishers 2004, ri, 334 pp. paper, 28.95 Reviewed by Joerg Rieger The Ripple Church: Multiply Your Ministry by Parenting New Churches Phil Stevenson Indianapolis, IN: Wesleyan Publishing House 2004. pp. 186, $12.99. Reviewed by J.D. Payne The Struggle to Understand Isaiah as Christian Scripture Brevard S. Childs Grand Rapids, Michigan: Wm. B. Eerdmans Publishing Co. 2004, xii, 332 pp. caseboulld,$35.00 Reviewed by John N. Oswalt God is Not Religious, Nice, One of Us, an American, a Capitalist D. Brent Laytham, ed. Grand Rapids, Michigan: Press. 2004, 152 pp., paper, $15.99 Reviewed by Michael Rynkiwitch A Short Introduction to Hermeneutics David Jasper Louisville, KY: Westmilnster John Knox Press 2004, xii, 148 pp. paper,$19.95 Reviewed by Charles M. Woo

Moving beyond silos: How do we provide distributed personalized medicine to pregnant women everywhere at scale? Insights from PRE-EMPT.

While we believe that pre-eclampsia matters-because it remains a leading cause of maternal and perinatal morbidity and mortality worldwide-we are convinced that the time has come to look beyond single clinical entities (e.g. pre-eclampsia, postpartum hemorrhage, obstetric sepsis) and to look for an integrated approach that will provide evidence-based personalized care to women wherever they encounter the health system. Accurate outcome prediction models are a powerful way to identify individuals at incrementally increased (and decreased) risks associated with a given condition. Integrating models with decision algorithms into mobile health (mHealth) applications could support community and first level facility healthcare providers to identify those women, fetuses, and newborns most at need of facility-based care, and to initiate lifesaving interventions in their communities prior to transportation. In our opinion, this offers the greatest opportunity to provide distributed individualized care at scale, and soon

Unacceptably High Mortality Related to Measles Epidemics in Niger, Nigeria, and Chad

BACKGROUND: Despite the comprehensive World Health Organization (WHO)/United Nations Children's Fund (UNICEF) measles mortality–reduction strategy and the Measles Initiative, a partnership of international organizations supporting measles mortality reduction in Africa, certain high-burden countries continue to face recurrent epidemics. To our knowledge, few recent studies have documented measles mortality in sub-Saharan Africa. The objective of our study was to investigate measles mortality in three recent epidemics in Niamey (Niger), N'Djamena (Chad), and Adamawa State (Nigeria). METHODS AND FINDINGS: We conducted three exhaustive household retrospective mortality surveys in one neighbourhood of each of the three affected areas: Boukoki, Niamey, Niger (April 2004, n = 26,795); Moursal, N'Djamena, Chad (June 2005, n = 21,812); and Dong District, Adamawa State, Nigeria (April 2005, n = 16,249), where n is the total surveyed population in each of the respective areas. Study populations included all persons resident for at least 2 wk prior to the study, a duration encompassing the measles incubation period. Heads of households provided information on measles cases, clinical outcomes up to 30 d after rash onset, and health-seeking behaviour during the epidemic. Measles cases and deaths were ascertained using standard WHO surveillance-case definitions. Our main outcome measures were measles attack rates (ARs) and case fatality ratios (CFRs) by age group, and descriptions of measles complications and health-seeking behaviour. Measles ARs were the highest in children under 5 y old (under 5 y): 17.1% in Boukoki, 17.2% in Moursal, and 24.3% in Dong District. CFRs in under 5-y-olds were 4.6%, 4.0%, and 10.8% in Boukoki, Moursal, and Dong District, respectively. In all sites, more than half of measles cases in children aged under 5 y experienced acute respiratory infection and/or diarrhoea in the 30 d following rash onset. Of measles cases, it was reported that 85.7% (979/1,142) of patients visited a health-care facility within 30 d after rash onset in Boukoki, 73.5% (519/706) in Moursal, and 52.8% (603/1,142) in Dong District. CONCLUSIONS: Children in these countries still face unacceptably high mortality from a completely preventable disease. While the successes of measles mortality–reduction strategies and progress observed in measles control in other countries of the region are laudable and evident, they should not overshadow the need for intensive efforts in countries that have just begun implementation of the WHO/UNICEF comprehensive strategy

Comparison of the treatment of men with prostate cancer between the US and England: an international population-based study.

INTRODUCTION: The treatment of prostate cancer varies between the United States (US) and England, however this has not been well characterised using recent data. We therefore investigated the extent of the differences between US and English patients with respect to initial treatment. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify men diagnosed with prostate cancer in the US and the treatments they received. We also used the National Prostate Cancer Audit (NPCA) database for the same purposes among men diagnosed with prostate cancer in England. Next, we used multivariable regression to estimate the adjusted risk ratio (aRR) of receiving radical local treatment for men with non-metastatic prostate cancer according to the country of diagnosis (US vs. England). The five-tiered Cambridge Prognostic Group (CPG) classification was included as an interaction term. RESULTS: We identified 109,697 patients from the SEER database, and 74,393 patients from the NPCA database, who were newly diagnosed with non-metastatic prostate cancer between April 1st 2014 and December 31st 2016 with sufficient information for risk stratification according to the CPG classification. Men in the US were more likely to receive radical local treatment across all prognostic groups compared to men in England (% radical treatment US vs. England, CPG1: 38.1% vs. 14.3% - aRR 2.57, 95% CI 2.47-2.68; CPG2: 68.6% vs. 52.6% - aRR 1.27, 95% CI 1.25-1.29; CPG3: 76.7% vs. 67.1% - aRR 1.12, 95% CI 1.10-1.13; CPG4: 82.6% vs. 72.4% - aRR 1.09, 95% CI 1.08-1.10; CPG5: 78.2% vs. 71.7% - aRR 1.06, 95% CI 1.04-1.07) CONCLUSIONS: Treatment rates were higher in the US compared to England raising potential over-treatment concerns for low-risk disease (CPG1) in the US and under-treatment of clinically significant disease (CPG3-5) in England

Safety and Immunogenicity of ChAd63/MVA Pfs25-IMX313 in a Phase I First-in-Human Trial.

BACKGROUND: Transmission blocking vaccines targeting the sexual-stages of the malaria parasite could play a major role to achieve elimination and eradication of malaria. The Plasmodium falciparum Pfs25 protein (Pfs25) is the most clinically advanced candidate sexual-stage antigen. IMX313, a complement inhibitor C4b-binding protein that forms heptamers with the antigen fused to it, improve antibody responses. This is the first time that viral vectors have been used to induce antibodies in humans against an antigen that is expressed only in the mosquito vector. METHODS: Clinical trial looking at safety and immunogenicity of two recombinant viral vectored vaccines encoding Pfs25-IMX313 in healthy malaria-naive adults. Replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA), encoding Pfs25-IMX313, were delivered by the intramuscular route in a heterologous prime-boost regimen using an 8-week interval. Safety data and samples for immunogenicity assays were taken at various time-points. RESULTS: The reactogenicity of the vaccines was similar to that seen in previous trials using the same viral vectors encoding other antigens. The vaccines were immunogenic and induced both antibody and T cell responses against Pfs25, but significant transmission reducing activity (TRA) was not observed in most volunteers by standard membrane feeding assay. CONCLUSION: Both vaccines were well tolerated and demonstrated a favorable safety profile in malaria-naive adults. However, the transmission reducing activity of the antibodies generated were weak, suggesting the need for an alternative vaccine formulation. TRIAL REGISTRATION: Clinicaltrials.gov NCT02532049

Prognostic algorithms for post-discharge readmission and mortality among mother-infant dyads: an observational study protocol

IntroductionIn low-income country settings, the first six weeks after birth remain a critical period of vulnerability for both mother and newborn. Despite recommendations for routine follow-up after delivery and facility discharge, few mothers and newborns receive guideline recommended care during this period. Prediction modelling of post-delivery outcomes has the potential to improve outcomes for both mother and newborn by identifying high-risk dyads, improving risk communication, and informing a patient-centered approach to postnatal care interventions. This study aims to derive post-discharge risk prediction algorithms that identify mother-newborn dyads who are at risk of re-admission or death in the first six weeks after delivery at a health facility.MethodsThis prospective observational study will enroll 7,000 mother-newborn dyads from two regional referral hospitals in southwestern and eastern Uganda. Women and adolescent girls aged 12 and above delivering singletons and twins at the study hospitals will be eligible to participate. Candidate predictor variables will be collected prospectively by research nurses. Outcomes will be captured six weeks following delivery through a follow-up phone call, or an in-person visit if not reachable by phone. Two separate sets of prediction models will be built, one set of models for newborn outcomes and one set for maternal outcomes. Derivation of models will be based on optimization of the area under the receiver operator curve (AUROC) and specificity using an elastic net regression modelling approach. Internal validation will be conducted using 10-fold cross-validation. Our focus will be on the development of parsimonious models (5–10 predictor variables) with high sensitivity (>80%). AUROC, sensitivity, and specificity will be reported for each model, along with positive and negative predictive values.DiscussionThe current recommendations for routine postnatal care are largely absent of benefit to most mothers and newborns due to poor adherence. Data-driven improvements to postnatal care can facilitate a more patient-centered approach to such care. Increasing digitization of facility care across low-income settings can further facilitate the integration of prediction algorithms as decision support tools for routine care, leading to improved quality and efficiency. Such strategies are urgently required to improve newborn and maternal postnatal outcomes. Clinical trial registrationhttps://clinicaltrials.gov/, identifier (NCT05730387)

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes