Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, encoding components of the replication-dependent histone pre-mRNA processing complex. Mutations were associated with the misprocessing of canonical histone transcripts, and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic GMP-AMP synthase (cGAS), and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient fibroblasts. Finally, we established that chromatin without linker histone more efficiently stimulates cGAS production in vitro. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.

BackgroundIdentification of children at risk of developmental delay and/or impairment requires valid measurement of early child development (ECD). We systematically assess ECD measurement tools for accuracy and feasibility for use in routine services in low-income and middle-income countries (LMIC).MethodsBuilding on World Bank and peer-reviewed literature reviews, we identified available ECD measurement tools for children aged 0–3 years used in ≥1 LMIC and matrixed these according to when (child age) and what (ECD domains) they measure at population or individual level. Tools measuring <2 years and covering ≥3 developmental domains, including cognition, were rated for accuracy and feasibility criteria using a rating approach derived from Grading of Recommendations, Assessment, Development and Evaluations.Results61 tools were initially identified, 8% (n=5) population-level and 92% (n=56) individual-level screening or ability tests. Of these, 27 tools covering ≥3 domains beginning <2 years of age were selected for rating accuracy and feasibility. Recently developed population-level tools (n=2) rated highly overall, particularly in reliability, cultural adaptability, administration time and geographical uptake. Individual-level tool (n=25) ratings were variable, generally highest for reliability and lowest for accessibility, training, clinical relevance and geographical uptake.Conclusions and implicationsAlthough multiple measurement tools exist, few are designed for multidomain ECD measurement in young children, especially in LMIC. No available tools rated strongly across all accuracy and feasibility criteria with accessibility, training requirements, clinical relevance and geographical uptake being poor for most tools. Further research is recommended to explore this gap in fit-for-purpose tools to monitor ECD in routine LMIC health services.

The Sustainable Development Goals, Global Strategy for Women’s, Children’s and Adolescents’ Health (2016–2030) and Nurturing Care Framework all include targets to ensure children thrive. However, many projects to support early childhood development (ECD) do not ‘scale well’ and leave large numbers of children unreached. This paper is the fifth in a series examining effective scaling of ECD programmes. This qualitative study explored experiences of scaling-up among purposively recruited implementers of ECD projects in low- and middle-income countries. Participants were sampled, by means of snowball sampling, from existing networks notably through Saving Brains®, Grand Challenges Canada®. Findings of a recent literature review on scaling-up frameworks, by the WHO, informed the development of a semistructured interview schedule. All interviews were conducted in English, via Skype, audio recorded and transcribed verbatim. Interviews were analysed using framework analysis. Framework analysis identified six major themes based on a standard programme cycle: planning and strategic choices, project design, human resources, financing and resource mobilisation, monitoring and evaluation, and leadership and partnerships. Key informants also identified an overarching theme regarding what scaling-up means. Stakeholders have not found existing literature and available frameworks helpful in guiding them to successful scale-up. Our research suggests that rather than proposing yet more theoretical guidelines or frameworks, it would be better to support stakeholders in developing organisational leadership capacity and partnership strategies to enable them to effectively apply a practical programme cycle or systematic process in their own contexts.

Background There is still limited knowledge regarding the translation of early child development (ECD) knowledge into effective policies and large-scale programmes. A variety of frameworks that outline the key steps in scaling up exist, but we argue that taking a complex adaptive systems (CAS) approach assists in understanding the complex, dynamic processes that result in programmes being taken to scale. Objectives The objective of this study is to examine the process of scaling up four major countrylevel ECD programmes through the application of a CAS framework. Methods Nine key informants with a deep knowledge of how each ECD programme was established and brought to scale were interviewed via Skype or phone by using open-ended interviews. The interviews were tape recorded and then transcribed verbatim for subsequent coding by using CAS domains. The coding and integration of the results to identify unique and common CAS scaling up features across the case studies involved an iterative process of reaching consensus. Results The scaling up of all four programmes behaved as a CAS including as follows: (i) positive feedback loops (five themes) and negative feedback loops (two themes); (ii) scale-free networks (two themes); (iii) phase transitions (four themes); (iv) path dependence (two themes); and (v) emergent behaviour (six themes). Five additional themes were identified for sustainability, which was repeatedly mentioned as an important consideration when deciding how to scale up programmes. Conclusions CAS analysis is likely to improve our understanding of how effective ECD programmes become scaled up. Prospective CAS implementation research is needed to continue advancing the knowledge in the field.

Psychogenic movement disorders are heterogeneous and diagnostically challenging. Despite the growing literature on adult forms, clinical features in children have received relatively little attention. We retrospectively reviewed medical records and video of patients <18 years diagnosed with a psychogenic movement disorder at our institute between 2007 and 2010. We identified 14 patients (6 males and 8 females) with a mean onset age of 11.5 years. Levels of diagnostic confidence were documented (2 patients), clinically established (8 patients), and probable (4 patients). A single movement disorder was present in 10 patients (71%); 4 patients (29%) presented an association of two or more movement disorders. Eleven patients presented other medically unexplained symptoms associated with their movement disorders. Five patients, among 6 with chronic occurrence, performed a polymyographic study showing significant modifications of frequency, amplitude, and distribution of electromyographic activity, related to distracting maneuvers. The present series represents 5% of all movement disorders observed in the considered period and 32% of nonorganic neurological manifestations. The most frequent movement disorders were tremor (36%) and dystonia (29%). We describe two phenotypes not previously reported among psychogenic movement disorders: myoclonus and association of myoclonus with dystonia. We remark on the presence of psychogenic symptoms associated with movement disorders (79%) as being one of the most useful clinical clues as well as on the value of polymyographic study in chronic psychogenic movement disorders, which provide evidence of the inconsistency of movement disorders.