Challenges to sustainable immunization systems in Gavi transitioning countries.

The Global Vaccine Action Plan 2011-2020 (GVAP) aims to extend the full benefit of vaccination against vaccine-preventable diseases to all individuals. More than halfway through the Decade of Vaccines, countries classified as Middle-Income by the World Bank struggle to achieve several GVAP targets. Countries transitioning from Gavi, the Vaccine Alliance, represent a key sub-group of Middle Income Countries. Through a review of available literature on the subject, this study documents the lack of comparative analyses on immunization system performance in countries transitioning from Gavi support. Despite increased emphasis on the importance of programmatic sustainability beyond financing through the Gavi 2016-2020 Strategy and availability of data, existing literature has predominantly documented challenges related to domestic financing of immunization. This study complements a review of current literature with an analysis of country assessments conducted by immunization partners since 2011, in an effort to document programmatic challenges related to decision-making for immunization policy, delivery of services, and access to affordable and timely supply in Gavi transitioning countries. In light of the findings, we suggest continued systematic compilation of country performance data beyond financing to inform policy-making, in particular for: (i) development of a more nuanced theory of change towards sustainable immunization programmes and (ii) measurement of progress and key areas for attention and investment

Phenotypic models of perfect adaptation by CD8+ T cells

T cells receive continuous antigenic stimulation in peripheral tolerance, cancer, and chronic infection. Persistent antigen exposure induces an initial cellular response. However, over time, T cells become unresponsive to the stimulus and cease activity, a behaviour known as adaptation. Although it is generally known that T cells adapt to persistent stimuli, the properties of this adaptation remain understudied. This thesis aims to characterize phenotypes of T cell adaptation and to suggest the possibility of relating these phenotypes to basic network models that produce adaptation. To better understand T cell adaptive behaviour, a plate-based T cell receptor system was used to expose cells to step changes in antigen dose. In response to persistent antigen exposure, T cells can display perfect adaptation in cytokine production with incomplete TCR downregulation. Increasing the antigen dose leads to further tuning of the surface TCR level, independent of previous antigen exposure, with limited additional cytokine production. Thus, partial TCR downregulation tunes to antigen dose and perfect adaptation is observed even with partial downregulation. If T cells are exposed to gradual, incremental increases in antigen dose rather than a single dose, the cells are similarly silenced. The experimental data was subsequently examined in the context of seven basic, preliminary models of adaptation. A model based on partial TCR downregulation with a second downstream mechanism aligns with experimental observations, suggesting the potential relevance of TCR downregulation. Clinically, T cell-modulating therapies often cause potent early cytokine production. As a proof-of-concept, I demonstrate that otelixizumab induces T cell adaptation as a non-pMHC stimulus. Further study of T cell adaptation is thus invaluable both to understanding T cell behaviour as well as therapeutic design

ADVANCES IN PEDIATRIC REFERENCE INTERVALS FOR BIOCHEMICAL MARKERS: ESTABLISHMENT OF THE CALIPER DATABASE IN HEALTHY CHILDREN AND ADOLESCENTS NAPREDAK U OBLASTI PEDIJATRIJSKIH REFERENTNIH INTERVALA ZA BIOHEMIJSKE MARKERE: IZRADA BAZE PODATAKA CALIPER KOD Z

Summary Clinical laboratory reference intervals provide valuable information to medical practitioners in their interpretation of quantitative laboratory test results, and therefore are critical in the assessment of patient health and in clinical decisionmaking. The reference interval serves as a health-associated benchmark with which to compare an individual test result. Unfortunately, critical gaps currently exist in accurate and upto-date pediatric reference intervals for accurate interpretation of laboratory tests performed in children and adolescents. These critical gaps in the available laboratory reference intervals have the clear potential of contributing to erroneous diagnosis or misdiagnosis of many diseases. To address these important gaps, several initiatives have begun internationally by a number of bodies including the KiGGS initiative in Germany, the Aussie Normals in Australia, the AACC-National Children Study in USA, the NORICHILD Initiative in Scandinavia, and the CALIPER study in Canada. In the present article, we will review the gaps in pediatric reference intervals, challenges in establishing pediatric norms in healthy children and adolescents, and the major contributions of the CALIPER program to closing the gaps in this crucial area of pediatric laboratory medicine. We will also dis- Kratak sadr`aj Klini~ki laboratorijski referentni intervali pru`aju lekarima podatke koji su va`ni za tuma~enje rezultata kvantitativnih laboratorijskih testova i stoga su od klju~ne vrednosti za procenu zdravstvenog stanja pacijenta i dono{enje klini~kih odluka. Referentni interval slu`i kao reper u smislu zdravlja s kojim }e se porediti rezultat pojedina~nog testa. Na`alost, trenutno postoje velike razlike u ta~nim i savremenim pedijatrijskim referentnim intervalima za ta~no tuma~enje laboratorijskih testova koji se obavljaju kod dece i adolescenata. Ove velike razlike u dostupnim laboratorijskim referentnim intervalima o~ito lako mogu dovesti do dijagnosti~ke gre{ke ili po gre{nog dijagnostikovanja mnogih bolesti. Nekoliko inicijativa pokrenuto je od strane vi{e tela na me|unarodnom nivou sa ciljem da se re{i problem ovih razlika, me|u njima inicijativa KiGGS u Nema~koj, Aussie Normals u Australiji, AACC -Nacionalna de~ija studija u SAD, Inicijativa NORICHILD u Skandinaviji i studija CALIPER u Kanadi. U ovom ~lanku da}emo pregled razlika u pedijatrijskim referentnim interva lima, izazova vezanih za utvr|ivanje pedijatrijskih normi kod zdrave dece i adolescenata i glavnih doprinosa programa CALIPER u pogledu otklanjanja razlika u ovoj najva`nijoj oblasti pedijatrijske laboratorijske medicine

Nanoparticles for Immune Cytokine TRAIL-Based Cancer Therapy

The immune cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received significant attention as a cancer therapeutic due to its ability to selectively trigger cancer cell apoptosis without causing toxicity in vivo. While TRAIL has demonstrated significant promise in preclinical studies in mice as a cancer therapeutic, challenges including poor circulation half-life, inefficient delivery to target sites, and TRAIL resistance have hindered clinical translation. Recent advances in drug delivery, materials science, and nanotechnology are now being exploited to develop next-generation nanoparticle platforms to overcome barriers to TRAIL therapeutic delivery. Here, we review the design and implementation of nanoparticles to enhance TRAIL-based cancer therapy. The platforms we discuss are diverse in their approaches to the delivery problem and provide valuable insight into guiding the design of future nanoparticle-based TRAIL cancer therapeutics to potentially enable future translation into the clinic. ©2018 American Chemical Society.Cancer Center Support (core) Grant (P30-CA14051)Ruth L. Kirschstein National Research Service Award from the NIH (F32CA200351)Burroughs Wellcome Fund (No. 1015145