Modernization’s Doppelgänger

This is the author accepted manuscript. The final version is available from Cambridge University Press via http://dx.doi.org/10.1017/S147924431500041

Long-Lasting Immune Responses 4 Years after GAD-Alum Treatment in Children with Type 1 Diabetes

A phase II clinical trial with glutamic acid decarboxylase (GAD) 65 formulated with aluminium hydroxide (GAD-alum) has shown efficacy in preserving residual insulin secretion in children and adolescents with recent-onset type 1 diabetes (T1D). We have performed a 4-year follow-up study of 59 of the original 70 patients to investigate long-term cellular and humoral immune responses after GAD-alum-treatment. Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with GAD65. Frequencies of naïve, central and effector memory CD4+ and CD8+ T cells were measured, together with cytokine secretion, proliferation, gene expression and serum GAD65 autoantibody (GADA) levels. We here show that GAD-alum-treated patients display increased memory T-cell frequencies and prompt T-cell activation upon in vitro stimulation with GAD65, but not with control antigens, compared with placebo subjects. GAD65-induced T-cell activation was accompanied by secretion of T helper (Th) 1, Th2 and T regulatory cytokines and by induction of T-cell inhibitory pathways. Moreover, post-treatment serum GADA titres remained persistently increased in the GAD-alum arm, but did not inhibit GAD65 enzymatic activity. In conclusion, memory T- and B-cell responses persist 4 years after GAD-alum-treatment. In parallel to a GAD65-induced T-cell activation, our results show induction of T-cell inhibitory pathways important for regulating the GAD65 immunity

Ten new insights in climate science 2020 – a horizon scan

Non-technical summary We summarize some of the past year's most important findings within climate change-related research. New research has improved our understanding of Earth's sensitivity to carbon dioxide, finds that permafrost thaw could release more carbon emissions than expected and that the uptake of carbon in tropical ecosystems is weakening. Adverse impacts on human society include increasing water shortages and impacts on mental health. Options for solutions emerge from rethinking economic models, rights-based litigation, strengthened governance systems and a new social contract. The disruption caused by COVID-19 could be seized as an opportunity for positive change, directing economic stimulus towards sustainable investments. Technical summary A synthesis is made of ten fields within climate science where there have been significant advances since mid-2019, through an expert elicitation process with broad disciplinary scope. Findings include: (1) a better understanding of equilibrium climate sensitivity; (2) abrupt thaw as an accelerator of carbon release from permafrost; (3) changes to global and regional land carbon sinks; (4) impacts of climate change on water crises, including equity perspectives; (5) adverse effects on mental health from climate change; (6) immediate effects on climate of the COVID-19 pandemic and requirements for recovery packages to deliver on the Paris Agreement; (7) suggested long-term changes to governance and a social contract to address climate change, learning from the current pandemic, (8) updated positive cost–benefit ratio and new perspectives on the potential for green growth in the short- and long-term perspective; (9) urban electrification as a strategy to move towards low-carbon energy systems and (10) rights-based litigation as an increasingly important method to address climate change, with recent clarifications on the legal standing and representation of future generations. Social media summary Stronger permafrost thaw, COVID-19 effects and growing mental health impacts among highlights of latest climate science

Reign in Blood : Immune Regulation in Type 1 Diabetes

Type 1 Diabetes (T1D) is an autoimmune disease resulting in insulin deficiency as a result ofautoimmune destruction of pancreatic β-cells. Preserving β-cell function in patients with T1D would be of great benefit since patients with sustained endogenous insulin secretion are known to suffer less from secondary complications due to hyperglycemia. Glutamic acid decarboxylase 65 (GAD65) is a major autoantigen targeted by self-reactive lymphocytes in T1D, and has been used in several attempts at treating T1D by inducing tolerance to β-cell antigens. We showed positive clinical effects of GAD65 formulated with aluminium hydroxide (GAD-alum) on preservation of C-peptide secretion in a phase II clinical trial. Unfortunately, a phase III clinical trial in a larger population failed to confirm this finding. Regulatory T cells (Treg) are instrumental in maintaining peripheral tolerance to self-antigens. Deficiencies in Treg function are thought to influence the pathogenesis of autoimmune diseases, including T1D. One proposed mechanism of achieving tolerance to β-cell antigens in T1D is the induction of antigen-specific Treg through immunomodulation. The general aim of this thesis was to study immune regulation in T1D, the role of Treg and immunomodulatory effects of GAD-alum treatment in particular. Our hypothesis was that Treg biology is altered in T1D and pre-diabetes, and that an induction of GAD65-specific Treg contributes to the clinical efficacy of GAD-alum treatment. We demonstrated that T cells expressing Treg-associated markers were increased in number in patients with recent-onset T1D, as well as in children with high risk of developing T1D. We found that antigen recall 4 years after GAD-alum treatment induced cells with both regulatory and effector phenotypes in GAD-alum treated patients. Furthermore there was no effect on Treg-mediated suppression in GAD-alum treated patients, while patients with T1D, regardless of treatment, exhibited deficient Treg-mediated suppression of Teff that was intrinsic to the Treg population. We followed patients participating in a phase III trial of GAD-alum, and using an extended antibody panel we demonstrated that antigen recall induced mainly Teff cells in treated patients, along  with increased frequencies of memory T cells, non-suppressive CD45RA-FOXP3lo cells and increased GAD65-induced proliferation of mainly Teff and memory T cells. Finally we examined whether SNPs in genes encoding inflammasome components contributed to T1D risk, but found no effects of variant alleles on the risk of developing T1D, or on the efficacy of GAD-alum treatment. We show small effects on C-peptide secretion and autoantibody positivity in patients with T1D. In conclusion, we find that while Treg are deficient in patients with T1D, induction of Treg is an unlikely mechanism of action of GAD-alum treatment

Systemledarskapets inverkan på resultaten i internationella kunskapsmätningar : En jämförande fallstudie av Finlands och Sveriges utbildningssystem

Uppstatsens huvudsyfte är att försöka finna tänkbara förklaringar till varför grundskoleelever i Finland presterar bättre i internationella kunskapsmätningar än svenska elever. Genom en jämförande fallstudie, av typen mest lika design, där alternativa förklaringar utesluts genom att de förekommer i båda utbildningssystemen isoleras effekten av den avsedda förklaringsvariabeln. Förutsättningarna för ledarskapet på olika nivåer inom utbildningssystemen utgör variabeln som avser förklara resultatskillnaden mellan Sverige och Finland i internationella kunskapsmätningar. Ledarskapet delas upp i kategorierna förvaltningsmodell, utvärdering, decentralisering och professionen. Varje kategori operationaliseras och undersöks separat inom båda utbildningssystemen. Empirin i undersökningen utgörs av lagtexter, läroplaner, myndighetsinformation och data från andra vetenskapliga undersökningar som analyseras för att beskriva ledarskapets förutsättningar inom respektive utbildningssystem. I resultatet framkommer det att den största variationen påträffas i förvaltningsmodell och profession men även viss skillnad i kategorin decentralisering. Därefter utvecklas resonemanget att professionsstatusen och förvaltningsmodellen i Finland skapar bättre förutsättningar för ledarskap och samarbete mellan skolor vilket leder till högre resultat i internationella mätningar. Slutligen hävdas det att samtliga resonemang som kan föras utifrån resultatet utgår från läraryrkets professionalitet vilket innebär att den aspekten av ledarskapet betraktas som en viktig förutsättning i ett framgångsrikt utbildningssystem

Investeringsprocessen - organisation, bedömning och beslut

Syftet med uppsatsen är att beskriva och analysera studieobjektens investeringsprocesser med fokus på deras investeringsbeslutsprocesser, klassificering av investeringar samt deras val av kalkylmetoder och kalkylkrav. Vi har valt att genomföra en fallstudie och vår undersökning består utav kvalitativa semistrukturerade intervjuer med våra två fallföretag; Smurfit Kappa Sverige AB (SK Sverige) och Perstorp. Vi studerar även tilldelade dokument angående företagens investeringsprocesser. Vår teoretiska referensram består utav teorier som berör ämnena investeringsbedömning, investeringsprocess, klassificering och kalkylmetoder. Vår empiri består utav det material som samlats in genom dokumentstudier och vid intervjuer hos fallföretagen SK Sverige och Perstorp. Efter en omfattande analys har vi kommit fram till olika slutsatser för våra två fallföretag. Vi har kunnat konstatera att SK Sveriges investeringsbeslut fattas på begränsade kalkylmetodmässiga grunder. Det finns även risker att investeringsbesluten blir lidande då det är upp till ledningen att bedöma hur omfattande beslutsunderlag som är nödvändigt. En lösning kan vara att utforma en ny investeringsmanual som är anpassad för SK Sveriges investeringar och därmed ställer rimliga krav. Perstopkoncernens storlek begränsar möjligheterna för hur deras beslutsprocess rimligtvis kan se ut. I en sådan organisation bör man inkludera ett flertal beslutsnivåer för att på så sätt inkludera nivåernas olika perspektiv, vilket alltså görs i Perstorpkoncernen. I övrigt ser vi positivt på den organisatoriska lösningen med specialorganen group technology och investeringskommittén. Vidare använder sig Perstorpkoncernen av rimliga beslutsunderlag vid investeringsbeslut. Deras tre kalkylmetoder kompletterar varandra väl. En viss kritik kan möjligtvis riktas mot deras begränsade indelning av investeringar. En indelning i olika klasser hade kunnat bidra med en ökad tydlighet i beslutssituationen

Increased expression of regulatory T cell-associated markers in recent-onset diabetic children

CD4+CD25hi T cells are thought to be crucial for the maintenance of immunological tolerance to self antigens. In this study, we investigated the frequencies of these cells in the early stage of type 1 diabetes, as well as in a setting of possible pre-diabetic autoimmunity. Hence, the expression of FOXP3, CTLA-4, and CD27 in CD4+ CD25hi T cells was analyzed using flow cytometry in 14 patients with recent onset type 1 diabetes, in 9 at-risk individuals, and 9 healthy individuals with no known risk for type 1 diabetes. Our results show there were no differences in the frequency of CD4+CD25hi cells between groups. However, compared to controls, recent-onset type 1 diabetic patients had higher expression of FOXP3, CTLA-4, and CD27 in CD4+ CD25hi cells from peripheral blood. The median fluorescence intensity of FOXP3 was significantly higher in CD4+CD25hi cells from patients with type 1 diabetes than from controls. Furthermore, a positive correlation between the frequency of FOXP3+ cells and the median fluorescence intensity of FOXP3 was observed among patients with type 1 diabetes. These data suggest that the frequency of CD4+CD25hi FOXP3+ T cells in the periphery is not decreased but rather increased at onset of type 1 diabetes. Thus, functional deficiencies rather than reduced numbers of CD4+CD25hi cells could contribute to the development of type 1 diabetes.

Open Journal of Immunology

Increased expression of regulatory T cell-associated markers in recent-onset diabetic childre

Cellular and Humoral Immune responses in Type 1 Diabetic patients participating in a Phase III GAD-alum Intervention Trial

OBJECTIVEGAD formulated in aluminum hydroxide (GAD-alum) has previously been shown to induce preservation of residual insulin secretion in recent-onset type 1 diabetes, but recent phase II and III GAD-alum trials failed to reach primary outcomes. The European phase III study was therefore closed after 15 months, and only a minority of patients completed the 30 months of follow-up.RESEARCH DESIGN AND METHODSThis study aimed to characterize cellular and humoral responses in the Swedish patients (n = 148) participating in the phase III trial, receiving four (4D) or two (2D) GAD-alum doses or placebo. Serum GAD(65) antibody (GADA) levels, GADA IgG1-4 subclass distribution, cytokine secretion, and proliferative responses in peripheral blood mononuclear cells (PBMCs) were analyzed.RESULTSThe GAD(65)-induced cytokine profile tended to switch toward a predominant Th2-associated profile over time both in the 2D and 4D group. The groups also displayed increased GADA levels and PBMC proliferation compared with placebo, whereas GADA IgG subclass distribution changed in 4D patients.CONCLUSIONSBoth 2D and 4D patients displayed GAD(65)-specifc cellular and humoral effects after GAD-alum treatment, but at different time points and magnitudes. No specific immune markers could be associated with treatment efficacy