•Meta-analysis reinterprets influential evaluations of social accountability through a new lens.•The “what works” question needs to distinguish between tactical and strategic approaches.•Tactical ...approaches assume problems are local and information is power.•Strategic approaches scale up collective action & bolster state capacity to respond.•Conclusion: voice needs teeth to have bite – but teeth may not bite without voice.
Empirical evidence of tangible impacts of social accountability initiatives is mixed. This meta-analysis reinterprets evaluations through a new lens: the distinction between tactical and strategic approaches to the promotion of citizen voice to contribute to improved public sector performance. Field experiments study bounded, tactical interventions based on optimistic assumptions about the power of information alone, both to motivate collective action and to influence the state. Enabling environments for collective action combined with bolstered state capacity to respond to citizen voice are more promising. Sandwich strategies can help ‘voice’ and ‘teeth’ to become mutually empowering, through state–society synergy.
This book delves into the extent of government involvement in religion between 1990 and 2002 using both quantitative and qualitative methodology. The study is based on the Religion and State dataset, ...which includes 175 governments across the globe, all of which are addressed individually in this book. The forms of involvement examined in this study include whether the government has an official religion, whether some religions are given preferential treatment, religious discrimination against minority religion, government regulation of the majority religion, and religious legislation. The study shows that government involvement in religion is ubiquitous, that it increased significantly during this period, and that only a minority of states, including a minority of democracies, have separation of religion and state. These findings contradict the predictions of religion's reduced public significance found in modernization and secularization theory. The findings also demonstrate that state religious monopolies are linked to reduced religious participation.
The concepts of transparency and accountability are closely linked: transparency is supposed to generate accountability. This article questions this widely held assumption. Transparency mobilises the ...power of shame, yet the shameless may not be vulnerable to public exposure. Truth often fails to lead to justice. After exploring different definitions and dimensions of the two ideas, the more relevant question turns out to be: what kinds of transparency lead to what kinds of accountability, and under what conditions? The article concludes by proposing that the concept can be unpacked in terms of two distinct variants. Transparency can be either 'clear' or 'opaque', while accountability can be either 'soft' or 'hard'.
Religious discrimination is the norm in many countries around the world, and the rate is rising. Nearly every country which discriminates does so unequally, singling out some religious minorities for ...more discrimination than others. Religious tradition does not explain this complex issue. For example, Muslim majority states include both the most discriminatory and tolerant states in the world, as is also the case with Christian majority states. Religious ideologies, nationalism, regime, culture, security issues, and political issues are also all part of the answer. In The Unfree Exercise of Religion Jonathan Fox examines how we understand concepts like religious discrimination and religious freedom, and why countries discriminate. He makes a study of religious discrimination against 597 religious minorities in 177 countries between 1990 and 2008. While 29 types of discrimination are discussed in this book, the most common include restrictions in places of worship, proselytizing, and religious education.
This study examines whether religion clauses in countries’ constitutions predict levels of government-based discrimination (GRD) against religious minorities. Using the Religion and State (RAS) and ...Religion and State-Constitutions (RAS-Constitutions) datasets, I find that clauses declaring official religion, separation of religion and state (SRAS), and religious freedom have no significant influence on GRD. In fact, 152 of 154 types of religion clauses found in constitutions measured by the RAS-Constitutions dataset do not significantly predict GRD. However, constitutional clauses banning religious hate speech and protecting the right to not be religious are associated with higher levels of GRD. I theorize that these causes likely represent an anti-religious form of secularism, which can be hostile to religious minorities.
Huntington's disease (HD) is a neurodegenerative disorder caused by a dominant CAG-repeat expansion in the huntingtin gene. Microglial activation is a key feature of HD pathology, and is present ...before clinical disease onset. The kynurenine pathway (KP) of tryptophan degradation is activated in HD, and is thought to contribute to disease progression. Indoleamine-2,3-dioxygenase (IDO) catalyzes the first step in this pathway; this and other pathway enzymes reside with microglia. While HD brain microglia accumulate iron, the role of iron in promoting microglial activation and KP activity is unclear. Here we utilized the neonatal iron supplementation model to investigate the relationship between iron, microglial activation and neurodegeneration in adult HD mice. We show in the N171-82Q mouse model of HD microglial morphologic changes consistent with immune activation. Neonatal iron supplementation in these mice promoted neurodegeneration and resulted in additional microglial activation in adults as determined by increased soma volume and decreased process length. We further demonstrate that iron activates IDO, both in brain lysates and purified recombinant protein (EC50 = 1.24 nM). Brain IDO activity is increased by HD. Neonatal iron supplementation further promoted IDO activity in cerebral cortex, altered KP metabolite profiles, and promoted HD neurodegeneration as measured by brain weights and striatal volumes. Our results demonstrate that dietary iron is an important activator of microglia and the KP pathway in this HD model, and that this occurs in part through a direct effect on IDO. The findings are relevant to understanding how iron promotes neurodegeneration in HD.
Transthyretin (TTR) amyloidosis is an underdiagnosed disease caused by destabilization of TTR due to pathogenic mutations or aging. Both pathogenic and protective mutations illuminate mechanisms of ...disease and potential interventions. AG10 is a selective, oral TTR stabilizer under development for transthyretin amyloidosis cardiomyopathy (ATTR-CM) that mimics a protective TTR mutation.
This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AG10 in ATTR-CM patients with symptomatic, chronic heart failure.
ATTR-CM, New York Heart Association functional class II to III subjects (n = 49, mutant or wild-type) were randomized 1:1:1 to AG10 400 mg, AG10 800 mg, or placebo twice daily for 28 days. Safety and tolerability were assessed by clinical and laboratory criteria. AG10 plasma levels were measured. TTR stability was assessed by changes in serum TTR, and 2 established ex vivo assays (fluorescent probe exclusion and Western blot).
AG10 treatment was well-tolerated, achieved target plasma concentrations and demonstrated near-complete stabilization of TTR. TTR stabilization was more complete and less variable at the higher dose with stabilization by fluorescent probe exclusion of 92 ± 10% (mean ± SD) at trough and 96 ± 9% at peak (both p < 10−12 vs. placebo). Average serum TTR increased by 36 ± 21% and 51 ± 38% at 400 and 800 mg, respectively (both p < 0.0001 vs. placebo). Baseline serum TTR in treated subjects was below normal in 80% of mutant and 33% of wild-type subjects. AG10 treatment restored serum TTR to the normal range in all subjects.
AG10 has the potential to be a safe and effective treatment for patients with ATTR-CM. A phase 3 trial is ongoing. (Study of AG10 in Amyloid Cardiomyopathy; NCT03458130)
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Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-encoding CAG expansion in the huntingtin gene. Iron accumulates in the brains of HD patients and mouse ...disease models. However, the cellular and subcellular sites of iron accumulation, as well as significance to disease progression are not well understood. We used independent approaches to investigate the location of brain iron accumulation. In R6/2 HD mouse brain, synchotron x-ray fluorescence analysis revealed iron accumulation as discrete puncta in the perinuclear cytoplasm of striatal neurons. Further, perfusion Turnbull's staining for ferrous iron (II) combined with transmission electron microscope ultra-structural analysis revealed increased staining in membrane bound peri-nuclear vesicles in R6/2 HD striatal neurons. Analysis of iron homeostatic proteins in R6/2 HD mice revealed decreased levels of the iron response proteins (IRPs 1 and 2) and accordingly decreased expression of iron uptake transferrin receptor (TfR) and increased levels of neuronal iron export protein ferroportin (FPN). Finally, we show that intra-ventricular delivery of the iron chelator deferoxamine results in an improvement of the motor phenotype in R6/2 HD mice. Our data supports accumulation of redox-active ferrous iron in the endocytic / lysosomal compartment in mouse HD neurons. Expression changes of IRPs, TfR and FPN are consistent with a compensatory response to an increased intra-neuronal labile iron pool leading to increased susceptibility to iron-associated oxidative stress. These findings, together with protection by deferoxamine, support a potentiating role of neuronal iron accumulation in HD.
A better understanding of the factors that contribute to heterogeneous outcomes and lifetime disease burden in hypertrophic cardiomyopathy (HCM) is critically needed to improve patient management and ...outcomes. The Sarcomeric Human Cardiomyopathy Registry (SHaRe) was established to provide the scale of data required to address these issues, aggregating longitudinal datasets curated by eight international HCM specialty centers.
Data on 4591 HCM patients (2763 genotyped), followed for a mean of 5.4±6.9 years (24,791 patient-years; median interquartile range 2.9 0.3-7.9 years) were analyzed regarding cardiac arrest, cardiac transplantation, appropriate implantable cardioverter-defibrillator (ICD) therapy, all-cause death, atrial fibrillation, stroke, New York Heart Association Functional Class III/IV symptoms (all comprising the overall composite endpoint), and left ventricular ejection fraction (LVEF)<35%. Outcomes were analyzed individually and as composite endpoints.
Median age of diagnosis was 45.8 30.9-58.1 years and 37% of patients were female. Age of diagnosis and sarcomere mutation status were predictive of outcomes. Patients <40 years old at diagnosis had a 77% 95% confidence interval: 72%, 80% cumulative incidence of the overall composite outcome by age 60, compared to 32% 29%, 36% by age 70 for patients diagnosed >60 years. Young HCM patients (20-29 years) had 4-fold higher mortality than the general United States population at a similar age. Patients with pathogenic/likely pathogenic sarcomere mutations had two-fold greater risk for adverse outcomes compared to patients without mutations; sarcomere variants of uncertain significance were associated with intermediate risk. Heart failure and atrial fibrillation were the most prevalent adverse events, although typically not emerging for several years after diagnosis. Ventricular arrhythmias occurred in 32% 23%, 40% of patients <40 years at diagnosis, but in 1% 1%, 2% >60 years.
The cumulative burden of HCM is substantial and dominated by heart failure and atrial fibrillation occurring many years following diagnosis. Young age of diagnosis and the presence of a sarcomere mutation are powerful predictors of adverse outcomes. These findings highlight the need for close surveillance throughout life, and the need to develop disease-modifying therapies.
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