a viable therapeutic avenue for preventing Aβ-related impairments in Alzheimer’s disease. Copyright © 2020 the authors.Maladaptive plasticity of neurons in lamina I of the spinal cord is a lynchpin for the development of chronic pain, and is critically dependent upon intracellular calcium signaling. However, the relationship between neuronal activity and intracellular calcium in these neurons is unknown. Here we combined two-photon calcium imaging with whole-cell electrophysiology to determine how action potential firing drives calcium responses within subcellular compartments of male rat spinal cord lamina I neurons. We found that single action potentials generated at the soma increase calcium concentration in the somatic cytosol and nucleus, and these calcium responses invade dendrites and dendritic spines by active backpropagation. Calcium responses in each compartment were dependent upon voltage-gated calcium channels, and somatic and nuclear calcium responses were amplified by release of calcium from ryanodine-sensitive intracellular stores. Grouping single action potential-evoked calcium responses by neuron type demonstund that action potential firing induces calcium responses within the somatic cytosol, nucleus, dendrites, and dendritic spines of lamina I neurons. Our findings demonstrate the presence of actively backpropagating action potentials, shifting our understanding of how these neurons process information, such that calcium provides a mechanism for lamina I neurons to track their own activity. Copyright © 2020 the authors.An impediment to the development of effective therapies for neurodegenerative disease is that available animal models do not reproduce important clinical features such as adult-onset and stereotypical patterns of progression. Using in vivo magnetic resonance imaging and behavioural testing to study male and female decrepit mice, we found a stereotypical neuroanatomical pattern of progression of the lesion along the limbic system network and an associated memory impairment. Using structural variant analysis, we identified an intronic mutation in a mitochondrial-associated gene (Mrpl3) that is responsible for the decrepit phenotype. While the function of this gene is unknown, embryonic lethality in Mrpl3 knockout mice suggests it is critical for early development. The observation that a mutation linked to energy metabolism precipitates a pattern of neurodegeneration via cell death across disparate but linked brain regions may explain how stereotyped patterns of neurodegeneration arise in humans or define a not yet identified human disease.Significance Statement The development of novel therapies for adult-onset neurodegenerative disease has been impeded by the limitations of available animal models in reproducing many of the clinical features. Here, we present a novel spontaneous mutation in a mitochondrial-associated gene in a mouse (termed decrepit) that results in adult-onset neurodegeneration with a stereotypical neuroanatomical pattern of progression and an associated memory impairment. The decrepit mouse model may represent a heretofore undiagnosed human disease and could serve as a new animal model to study neurodegenerative disease. Copyright © 2020 the authors.The epilepsy-linked gene SV2A, has a number of potential roles in the synaptic vesicle life cycle. However, how loss of SV2A function translates into presynaptic dysfunction and ultimately seizure activity is still undetermined. In this study, we examined whether the first SV2A mutation identified in human disease (R383Q) could provide information regarding which SV2A-dependent events are critical in the translation to epilepsy. We utilised a molecular replacement strategy in which exogenous SV2A was expressed in mouse neuronal cultures of either sex, which had been depleted of endogenous SV2A to mimic the homozygous human condition. We found that the R383Q mutation resulted in a mislocalisation of SV2A from synaptic vesicles to the plasma membrane, but had no effect on its activity-dependent trafficking. This SV2A mutant displayed reduced mobility when stranded on the plasma membrane and reduced binding to its interaction partner synaptotagmin-1 (Syt1). Furthermore, the R383Q mutant failed to rescue reduced unction to seizure activity. Copyright © 2020 the authors.Loss of sensory hair cells causes permanent hearing and balance deficits in humans and other mammals, but for nonmammals such deficits are temporary. Nonmammals recover hearing and balance sensitivity after supporting cells proliferate and differentiate into replacement hair cells. Evidence of mechanical differences between those sensory epithelia and their supporting cells prompted us to investigate whether the capacity to activate YAP, an effector in the mechanosensitive Hippo pathway, correlates with regenerative capacity in acceleration-sensing utricles of chickens and mice of both sexes. After hair cell ablation, YAP accumulated in supporting cell nuclei in chicken utricles and promoted regenerative proliferation, but YAP remained cytoplasmic and little proliferation occurred in mouse utricles. YAP localization in supporting cells was also more sensitive to shape change and inhibition of MST1/2 in chicken utricles than in mouse utricles. Genetic manipulations showed that in vivo expression of the YAP-S12nce deficits for millions. In nonmammals, damage evokes shape changes in supporting cells, which can divide and regenerate hair cells. Such shape changes are limited in mammalian ears, where supporting cells develop E-cadherin-rich apical junctions reinforced by robust F-actin bands, and the cells fail to divide. Here, we find that damage readily activates YAP in supporting cells within balance epithelia of chickens, but not mice. Deleting LATS kinases or expressing YAP variants that evade LATS-mediated inhibitory phosphorylation induces proliferation in supporting cells of adult mice. YAP signaling eventually may be harnessed to overcome proliferative quiescence that limits regeneration in mammalian ears. Copyright © 2020 the authors.Hypoglycaemic due to congenital hyperinsulinism in Beckwith-Wiedemann syndrome is commonly seen. It is usually transient and is managed by enteral feeds, high glucose-containing intravenous fluids and medications like diazoxide. We describe a case of an infant with genetically proven Beckwith-Wiedemann syndrome with prolonged hyperinsulinemic hypoglycaemia. Despite treatment with high glucose-containing intravenous fluids, diazoxide and octreotide, her hypoglycaemia persisted. In addition to this, she also developed features of intestinal obstruction, which further complicated the management of hypoglycaemia. She underwent a rectal biopsy for this, which was highly suggestive of Hirschprung’s disease. Following surgery, her abdominal distension and feed intolerance were settled and sugar control was improved. We present a rare association of Hirschsprung’s disease with Beckwith-Wiedemann syndrome. To the best of our knowledge, this association has not been previously reported and this added to the difficulty in managing hyperinsulinemic hypoglycaemia in our patient. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.A 36-year-old woman presented to the radiology department with a history of gradual increase in the size of her left breast and greenish discolouration of the skin over it since 1.5 months. Physical examination revealed a soft non-tender mass involving the whole of the left breast. Radiological investigations further established the presence of multiple well-defined lobulated multiseptated and cystic fluid-containing lesions involving the entire left breast and extending to the axillary tail. Successful surgical excision was performed. The patient made a good recovery without any signs of recurrence. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.An 8-year-old girl with subacute submandibular lymphadenitis and no other complaints is described. After failure of parenteral antistaphylococcal therapy, she underwent incision and drainage of the involved lymph node. The responsible pathogen was identified as Mycobacterium malmoense by GenoType CM assay and sequencing of the 16S ribosomalRNA (rRNA) gene. The patient remains healthy, 11 months after surgery, even though it took approximately 4 months for the surgical incision to heal completely. While M. malmoense is a relatively common cause of non-tuberculous mycobacteria (NTM) lymphadenitis in Northern Europe, this is the first reported case from Greece. We conclude that in a young child with lymphadenitis without systemic symptoms, the microbiology laboratory should be notified in advance in order to extend the duration of mycobacterial cultures. Application of molecular methods will increase the number of reported cases of rare NTM in the future. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.An 87-year-old man with dementia with Lewy bodies, living in residential aged care, exhibited rapid functional decline and weight loss associated with injurious falls over 9 months. Independent clinicians (geriatrician and exercise physiologist) assessed him during an extended wait-list period prior to his commencement of a pilot exercise trial. The highly significant role of treatable factors including polypharmacy, sarcopenia and malnutrition as contributors to frailty and rapid functional decline in this patient are described. The results of a targeted intervention of deprescribing, robust exercise and increased caloric intake on his physical and neuropsychological health status are presented. This case highlights the need to aggressively identify and robustly treat reversible contributors to frailty, irrespective of advanced age, progressive 'untreatable’ neurodegenerative disease and rapidly deteriorating health in such individuals. Frailty is not a contraindication to robust exercise; it is, in fact, one of the most important reasons to prescribe it. © BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.BACKGROUND Conflict has played a role in the large-scale deterioration of health systems in low-income and middle-income countries (LMICs) and increased risk of infections and outbreaks. This systematic review aimed to synthesise the literature on mechanisms of delivery for a range of infectious disease-related interventions provided to conflict-affected women, children and adolescents. METHODS We searched Medline, Embase, CINAHL and PsychINFO databases for literature published in English from January 1990 to March 2018. Eligible publications reported on conflict-affected neonates, children, adolescents or women in LMICs who received an infectious disease intervention. We extracted and synthesised information on delivery characteristics, including delivery site and personnel involved, as well as barriers and facilitators, and we tabulated reported intervention coverage and effectiveness data. RESULTS A majority of the 194 eligible publications reported on intervention delivery in sub-Saharan Africa. Vaccines for measles and polio were the most commonly reported interventions, followed by malaria treatment.