Shrinking the Malaria Map: A Prospectus on Malaria Elimination

\ud Thirty-nine countries across the world are making progress toward malaria elimination. Some are committed to nationwide elimination, while others are pursuing spatially progressive elimination within their borders. Influential donor and multilateral organizations are supporting their goals of achieving malaria-free status. With elimination back on the global agenda, countries face a myriad of questions. Should they change their programs to eliminate rather than control malaria? What tools are available? What policies need to be put into place? How will they benefit from elimination? Unfortunately, answers to these questions, and resources for agencies and country program managers considering or pursuing elimination, are scarce. The 39 eliminating countries are all positioned along the endemic margins of the disease, yet they naturally experience a variety of country characteristics and epidemiologies that make their malaria situations different from one another. The Malaria Elimination Group (MEG) and this Prospectus recognize\ud that there is no single solution, strategy, or time line that will be appropriate for every country, and each is encouraged to initiate a comprehensive evaluation of its readiness and strategy for elimination. The Prospectus is designed to guide countries in conducting these assessments. The Prospectus provides detailed and informed discussion on the practical means of achieving and sustaining zero transmission. It is designed as a road map, providing direction and options from which to choose an appropriate path. As on all maps, the destination is clearly marked, but the possible routes to reach it are numerous. The Prospectus is divided into two sections: Section 1 Eliminating Malaria comprises four chapters covering the strategic components important to the periods before, during, and after an elimination program. Section 2 Tools for the Job, comprises six chapters that outline basic information about how interventions in an elimination program will be different from those in a control setting. Chapter 1, Making the Decision, evaluates the issues that a country should consider when deciding whether or not to eliminate malaria. The chapter begins with a discussion about the quantitative and qualitative benefits that a country could expect from eliminating malaria and then recommends a thorough feasibility assessment. The feasibility assessment is based on three major components: operational, technical, and financial feasibility. Cross-border and regional collaboration is a key subject in this chapter. Chapter 2, Getting to Zero, describes changes that programs must consider when moving from sustained control to an elimination goal. The key strategic issues that must be addressed are considered, including supply chains, surveillance systems, intersectoral collaboration, political will, and legislative framework. Cross-border collaboration is again a key component in Getting to Zero. Chapter 3, Holding the Line, provides recommendations on how to conduct an assessment of two key factors that will affect preventing the reemergence of malaria once transmission is interrupted: outbreak risk and importation risk. The chapter emphasizes the need for a strong surveillance system in order to prevent and, if necessary, respond to imported cases. Chapter 4, Financing Elimination, reviews the cost-effectiveness of elimination as compared with sustained control and then presents the costs of selected elimination programs as examples. It evaluates four innovative financing mechanisms that must support elimination, emphasizing the need for predictable and stable financing. Case studies from Swaziland and two provinces in China are provided. Chapter 5, Understanding Malaria, considers malaria from the point of view of elimination and provides a concise overview of the current burden of the disease, malaria transmission, and the available interventions that can be used in an elimination program. Chapter 6, Learning from History, extracts important lessons from the Global Malaria Eradication Program and analyzes some elimination efforts that were successful and some that were unsuccessful. The chapter also reviews how the malaria map has been shrinking since 1900. xiv A Prosp ectus on Mala ria Elimi natio n\ud Chapter 7, Measuring Malaria for Elimination, provides a precise language for discussing malaria and gives the elimination discussion a quantitative structure. The chapter also describes the role of epidemiological theory and mathematical modeling in defining and updating an elimination agenda for malaria. Chapter 8, Killing the Parasite, outlines the importance of case detection and management in an elimination setting. Options for diagnosis, the hidden challenge of Plasmodium vivax in an elimination setting, and the impact of immunity are all discussed. Chapter 9, Suppressing the Vector, explores vector control, a necessary element of any malaria program. It considers optimal methods available to interrupt transmission and discusses potential changes, such as insecticide resistance, that may affect elimination efforts. Chapter 10, Identifying the Gaps — What We Need to Know, reviews the gaps in our understanding of what is required for elimination. The chapter outlines a short-term research agenda with a focus on the operational needs that countries are facing today. The Prospectus reviews the operational, technical, and financial feasibility for those working on the front lines and considers whether, when, and how to eliminate malaria. A companion document, A Guide on Malaria Elimination for Policy Makers, is provided for those countries or agencies whose responsibility is primarily to make the policy decisions on whether to pursue or support a malaria elimination strategy. The Guide is available at www.malaria eliminationgroup.org

The T cell antigen receptor complex expressed on normal peripheral blood CD4-, CD8- T lymphocytes. A CD3-associated disulfide-linked gamma chain heterodimer.

IL-2-dependent cell lines were established from normal peripheral blood T lymphocytes that express neither CD4 nor CD8 differentiation antigens. CD3+,4-,8- cell lines from 15 different donors failed to react with WT31, an mAb directed against the T cell antigen receptor alpha/beta heterodimer. Anti-Leu-4 mAb was used to isolate the CD3/T cell antigen receptor complex from 125I-labeled CD3+,4-,8- (WT31-) T cells. Using detergent conditions that preserved the CD3/T cell antigen receptor complex, an approximately 90 kD disulfide-linked heterodimer, composed of approximately 45- and approximately 40- (or approximately 37-) kD subunits, was coimmunoprecipitated with the invariant 20-29-kD CD3 complex. Analysis of these components by nonequilibrium pH gradient electrophoresis indicated that the approximately 40-kD and approximately 37-kD subunits were similar, and quite distinct from the more basic approximately 45-kD subunit. None of these three subunits reacted with an antibody directed against a beta chain framework epitope. Heteroantiserum against a T cell receptor gamma chain peptide specifically reacted with both the approximately 37- and approximately 40-kD CD3-associated proteins, but not with the approximately 45-kD subunit. CD3+,4-,8- cells failed to transcribe substantial amounts of functional 1.3-kb beta or 1.6-kb alpha mRNA, but produced abundant 1.6-kb gamma mRNA. Southern blot analysis revealed that these CD3+,4-,8- cell lines rearranged both gamma and beta genes, and indicated that the populations were polyclonal. The expression of a CD3-associated disulfide-linked heterodimer on CD3+,4-,8- T cell lines established from normal, adult peripheral blood contrasts with prior reports describing a CD3-associated non-disulfide-linked heterodimer on CD3+/WT31- cell lines established from thymus and peripheral blood obtained from patients with immunodeficiency diseases. We propose that this discrepancy may be explained by preferential usage of the two C gamma genes in T lymphocytes

Preclinical anti-cancer activity and multiple mechanisms of action of a cationic silver complex bearing N-heterocyclic carbene ligands

Organometallic complexes offer the prospect of targeting multiple pathways that are important in cancer biology. Here, the preclinical activity and mechanism(s) of action of a silver-bis(N-heterocyclic carbine) complex (Ag8) were evaluated. Ag8 induced DNA damage via several mechanisms including topoisomerase I/II and thioredoxin reductase inhibition and induction of reactive oxygen species. DNA damage induction was consistent with cytotoxicity observed against proliferating cells and Ag8 induced cell death by apoptosis. Ag8 also inhibited DNA repair enzyme PARP1, showed preferential activity against cisplatin resistant A2780 cells and potentiated the activity of temozolomide. Ag8 was substantially less active against non-proliferating non-cancer cells and selectively inhibited glycolysis in cancer cells. Ag8 also induced significant anti-tumour effects against cells implanted intraperitoneally in hollow fibres but lacked activity against hollow fibres implanted subcutaneously. Thus, Ag8 targets multiple pathways of importance in cancer biology, is less active against non-cancer cells and shows activity in vivo in a loco-regional settin

Advance care plans and hospitalized frail older adults: a systematic review.

INTRODUCTION: Frail older people are known to have low rates of advance care planning (ACP). Many frail patients prefer less aggressive treatment, but these preferences are often not known or respected. Frail patients often have multiple hospital admissions, potentially providing opportunities for ACP. OBJECTIVE: To systematically review the literature concerning ACP with frail older people in the acute hospital, with particular reference to: (1) Does ACP improve outcomes? (2) What are the views of patients, relatives and healthcare professionals regarding ACP? (3) Does ACP currently occur? (4) What are the facilitators and barriers to ACP? DESIGN: Systematic literature review and narrative synthesis. Electronic search of MEDLINE, CINAHL, ASSIA, PsycINFO and Embase databases from January 1990 to May 2019 inclusive. Studies in the acute setting of populations with a mean age >75 years, not focused on a disease-specific terminal condition were included. RESULTS: 16 133 articles were retrieved, 14 met inclusion criteria. No studies used an objective measure of frailty. One randomised controlled trial (RCT) found that ACP improves outcomes for older patients. Although 74%-84% of capacitous older inpatients are receptive to ACP, rates of ACP are 0%-5%; the reasons for this discrepancy have been little studied. The nature of ACP in clinical practice is unknown thus the extent to which it reflects the RCT intervention cannot be assessed. The outcomes that are important to patients are poorly understood and family and physician experiences have not been explored. CONCLUSIONS: A better understanding of this area could help to improve end-of-life care for frail older people. PROSPERO REGISTRATION NUMBER: CRD42017080246

Search for squarks and gluinos with the ATLAS detector in final states with jets and missing transverse momentum using √s=8 TeV proton-proton collision data

A search for squarks and gluinos in final states containing high-p T jets, missing transverse momentum and no electrons or muons is presented. The data were recorded in 2012 by the ATLAS experiment in s√=8 TeV proton-proton collisions at the Large Hadron Collider, with a total integrated luminosity of 20.3 fb−1. Results are interpreted in a variety of simplified and specific supersymmetry-breaking models assuming that R-parity is conserved and that the lightest neutralino is the lightest supersymmetric particle. An exclusion limit at the 95% confidence level on the mass of the gluino is set at 1330 GeV for a simplified model incorporating only a gluino and the lightest neutralino. For a simplified model involving the strong production of first- and second-generation squarks, squark masses below 850 GeV (440 GeV) are excluded for a massless lightest neutralino, assuming mass degenerate (single light-flavour) squarks. In mSUGRA/CMSSM models with tan β = 30, A 0 = −2m 0 and μ > 0, squarks and gluinos of equal mass are excluded for masses below 1700 GeV. Additional limits are set for non-universal Higgs mass models with gaugino mediation and for simplified models involving the pair production of gluinos, each decaying to a top squark and a top quark, with the top squark decaying to a charm quark and a neutralino. These limits extend the region of supersymmetric parameter space excluded by previous searches with the ATLAS detector

Measurement of the production of a W boson in association with a charm quark in pp collisions at √s = 7 TeV with the ATLAS detector

The production of a W boson in association with a single charm quark is studied using 4.6 fb−1 of pp collision data at s√ = 7 TeV collected with the ATLAS detector at the Large Hadron Collider. In events in which a W boson decays to an electron or muon, the charm quark is tagged either by its semileptonic decay to a muon or by the presence of a charmed meson. The integrated and differential cross sections as a function of the pseudorapidity of the lepton from the W-boson decay are measured. Results are compared to the predictions of next-to-leading-order QCD calculations obtained from various parton distribution function parameterisations. The ratio of the strange-to-down sea-quark distributions is determined to be 0.96+0.26−0.30 at Q 2 = 1.9 GeV2, which supports the hypothesis of an SU(3)-symmetric composition of the light-quark sea. Additionally, the cross-section ratio σ(W + +c¯¯)/σ(W − + c) is compared to the predictions obtained using parton distribution function parameterisations with different assumptions about the s−s¯¯¯ quark asymmetry

Measurement of the top pair production cross section in 8 TeV proton-proton collisions using kinematic information in the lepton plus jets final state with ATLAS

A measurement is presented of the $t\bar{t}$ inclusive production cross-section in $pp$ collisions at a center-of-mass energy of $\sqrt{s}=8$ TeV using data collected by the ATLAS detector at the CERN Large Hadron Collider. The measurement was performed in the lepton+jets final state using a data set corresponding to an integrated luminosity of 20.3 fb$^{-1}$. The cross-section was obtained using a likelihood discriminant fit and $b$-jet identification was used to improve the signal-to-background ratio. The inclusive $t\bar{t}$ production cross-section was measured to be $260\pm 1{\textrm{(stat.)}} ^{+22}_{-23} {\textrm{(syst.)}}\pm 8{\textrm{(lumi.)}}\pm 4{\mathrm{(beam)}}$ pb assuming a top-quark mass of 172.5 GeV, in good agreement with the theoretical prediction of $253^{+13}_{-15}$ pb. The $t\bar{t}\to (e,\mu)+{\mathrm{jets}}$ production cross-section in the fiducial region determined by the detector acceptance is also reported.Comment: Published version, 19 pages plus author list (35 pages total), 3 figures, 2 tables, all figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/TOPQ-2013-06