Future perspectives: What lies ahead for Neuronal Ceroid Lipofuscinosis research?

Progress is being made in all aspects of Neuronal Ceroid Lipofuscinosis (NCL) research, resulting in many recent advances. These advances encompass several areas that were previously thought intractable, ranging from basic science, through to a better understanding of the clinical presentation of different forms of NCL, therapeutic development, and new clinical trials that are underway. Increasing numbers of original NCL research papers continue to be published, and this new sense of momentum is greatly encouraging for the field. Here, we make some predictions as to what we can anticipate in the next few years

A circuit mechanism for irrationalities in decision-making and NMDA receptor hypofunction: behaviour, computational modelling, and pharmacology

Decision-making biases can be systematic features of normal behaviour, or deficits underlying neuropsychiatric symptoms. We used behavioural psychophysics, spiking-circuit modelling and pharmacological manipulations to explore decision-making biases in health and disease. Monkeys performed an evidence integration task in which they showed a pro-variance bias (PVB): a preference to choose options with more variable evidence. The PVB was also present in a spiking circuit model, revealing a neural mechanism for this behaviour. Because NMDA receptor (NMDA-R) hypofunction is a leading hypothesis for neuropathology in schizophrenia, we simulated behavioural effects of NMDA-R hypofunction onto either excitatory or inhibitory neurons in the model. These were tested experimentally using the NMDA-R antagonist ketamine, yielding changes in decision-making consistent with lowered cortical excitation/inhibition balance from NMDA-R hypofunction onto excitatory neurons. These results provide a circuit-level mechanism that bridges across explanatory scales, from the synaptic to the behavioural, in neuropsychiatric disorders where decision-making biases are prominent. Significance People can make apparently irrational decisions because of underlying features in their decision circuitry. Deficits in the same neural circuits may also underlie debilitating cognitive symptoms of neuropsychiatric patients. Here, we reveal a neural circuit mechanism explaining an irrationality frequently observed in healthy humans making binary choices – the pro-variance bias. Our circuit model could be perturbed by introducing deficits in either excitatory or inhibitory neuron function. These two perturbations made specific, dissociable predictions for the types of irrational decisionmaking behaviour produced. We used the NMDA-R antagonist ketamine, an experimental model for schizophrenia, to test if these predictions were relevant to neuropsychiatric pathophysiology. The results were consistent with impaired excitatory neuron function, providing important new insights into the pathophysiology of schizophrenia

A circuit mechanism for decision-making biases and NMDA receptor hypofunction

Decision-making biases can be features of normal behaviour, or deficits underlying neuropsychiatric symptoms. We used behavioural psychophysics, spiking-circuit modelling and pharmacological manipulations to explore decision-making biases during evidence integration. Monkeys showed a pro-variance bias (PVB): a preference to choose options with more variable evidence. The PVB was also present in a spiking circuit model, revealing a potential neural mechanism for this behaviour. To model possible effects of NMDA receptor (NMDA-R) antagonism on this behaviour, we simulated the effects of NMDA-R hypofunction onto either excitatory or inhibitory neurons in the model. These were then tested experimentally using the NMDA-R antagonist ketamine, a pharmacological model of schizophrenia. Ketamine yielded an increase in subjects' PVB, consistent with lowered cortical excitation/inhibition balance from NMDA-R hypofunction predominantly onto excitatory neurons. These results provide a circuit-level mechanism that bridges across explanatory scales, from the synaptic to the behavioural, in neuropsychiatric disorders where decision-making biases are prominent

A prospective cohort study comparing the reactogenicity of trivalent influenza vaccine in pregnant and non-pregnant women

Background: Influenza vaccination during pregnancy can prevent serious illness in expectant mothers and provide protection to newborns; however, historically uptake has been limited due to a number of factors, including safety concerns. Symptomatic complaints are common during pregnancy and may be mistakenly associated with reactions to trivalent influenza vaccine (TIV). To investigate this, we compared post-vaccination events self-reported by pregnant women to events reported by non-pregnant women receiving TIV. Methods: A prospective cohort of 1,086 pregnant women and 314 non-pregnant female healthcare workers (HCWs) who received TIV between March-May 2014 were followed-up seven days post-vaccination to assess local and systemic adverse events following immunisation (AEFIs). Women were surveyed by text message regarding perceived reactions to TIV. Those reporting an AEFI completed an interview by telephone or mobile phone to ascertain details. Logistic regression models adjusting for age and residence were used to compare reactions reported by pregnant women and non-pregnant HCWs. Results: Similar proportions of pregnant women and non-pregnant, female HCWs reported ≥1 reaction following vaccination with TIV (13.0% and 17.3%, respectively; OR = 1.2 [95% CI: 0.8-1.8]). Non-pregnant, female HCWs were more likely to report fever or headache compared to pregnant women (OR: 4.6 [95% CI 2.1-10.3] and OR: 2.2 [95% CI 1.0-4.6], respectively). No other significant differences in reported symptoms were observed. No serious vaccine-associated adverse events were reported, and less than 2% of each group sought medical advice for a reaction. Conclusions: We found no evidence suggesting pregnant women are more likely to report adverse events following influenza vaccination when compared to non-pregnant female HCWs of similar age, and in some cases, pregnant women reported significantly fewer adverse events. These results further support the safety of TIV administered in pregnant women

Breeding ground correlates of the distribution and decline of the Common Cuckoo Cuculus canorus at two spatial scales

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordMany migratory bird species are undergoing population declines as a result of potentially multiple, interacting mechanisms. Understanding the environmental associations of spatial variation in population change can help tease out the likely mechanisms involved. Common Cuckoo Cuculus canorus populations have declined by 69% in England but increased by 33% in Scotland. The declines have mainly occurred in lowland agricultural landscapes, but their mechanisms are unknown. At both the local scale within the county of Devon (SE England) and at the national (UK) scale, we analysed the breeding season distribution of Cuckoos in relation to habitat variation, the abundance of host species and the abundance of moth species whose caterpillars are a key food of adult Cuckoos. At the local scale, we found that Cuckoos were more likely to be detected in areas with more semi-natural habitat, more Meadow Pipits Anthus pratensis (but fewer Dunnocks Prunella modularis) and where, later in the summer, higher numbers of moths were captured whose larvae are Cuckoo prey. Nationally, Cuckoos have become more associated with upland heath characterized by the presence of Meadow Pipit hosts, and with wetland habitats occupied by Eurasian Reed Warbler Acrocephalus scirpaceus hosts. The core distribution of Cuckoos has shifted from south to north within the UK. By the end of 2009, the abundance of macro-moth species identified as prey had also declined four times faster than that of species not known to be taken by Cuckoos. The abundance of these moths has shown the sharpest declines in grassland, arable and woodland habitats and has increased in semi-natural habitats (heaths and rough grassland). Our study suggests that Cuckoos are likely to remain a very scarce bird in lowland agricultural landscapes without large-scale changes in agricultural practices.Biotechnology and Biological Sciences Research Council (BBSRC)Royal Society for the Protection of Birds and Natural Englan

Treatment compliance and effectiveness of a cognitive behavioural intervention for low back pain : a complier average causal effect approach to the BeST data set

Background: Group cognitive behavioural intervention (CBI) is effective in reducing low-back pain and disability in comparison to advice in primary care. The aim of this analysis was to investigate the impact of compliance on estimates of treatment effect and to identify factors associated with compliance. Methods: In this multicentre trial, 701 adults with troublesome sub-acute or chronic low-back pain were recruited from 56 general practices. Participants were randomised to advice (control n = 233) or advice plus CBI (n = 468). Compliance was specified a priori as attending a minimum of three group sessions and the individual assessment. We estimated the complier average causal effect (CACE) of treatment. Results: Comparison of the CACE estimate of the mean treatment difference to the intention-to-treat (ITT) estimate at 12 months showed a greater benefit of CBI amongst participants compliant with treatment on the Roland Morris Questionnaire (CACE: 1.6 points, 95% CI 0.51 to 2.74; ITT: 1.3 points, 95% CI 0.55 to 2.07), the Modified Von Korff disability score (CACE: 12.1 points, 95% CI 6.07 to 18.17; ITT: 8.6 points, 95% CI 4.58 to 12.64) and the Modified von Korff pain score (CACE: 10.4 points, 95% CI 4.64 to 16.10; ITT: 7.0 points, 95% CI 3.26 to 10.74). People who were non-compliant were younger and had higher pain scores at randomisation. Conclusions: Treatment compliance is important in the effectiveness of group CBI. Younger people and those with more pain are at greater risk of non-compliance

Process evaluation of integrated diabetes management at primary healthcare facilities in Pakistan: a mixed-methods study

Background: Integrated care for diabetes and associated conditions at primary level health facilities can make care available to a much larger population, especially in rural areas. Aim: This process evaluation was to understand how the authors' integrated care was implemented and experienced by the care providers and patients, and to inform modifications prior to province-wide scale-up. Design & setting: The mixed-method study was conducted as part of a cluster randomised trial on integrated diabetes care at 14 public health facilities. Method: The care practices were assessed by analysing the routine clinical records of 495 registered patients with diabetes. Then semi-structured interviews with service providers and patients were used to understand their respective care experiences. A framework approach was applied to analyse and interpret the qualitative data. Results: The intervention and the study were implemented as intended under routine conditions in rural health centres. Key service processes effectively delivered included: skill-based training; screening and diagnostic tests; treatment card records; and the additional case management as per desk guide, including monitoring progress in glucose and weight at follow-up consultations, and mobile phone calls to help adherence. However, social and cultural factors affected clients' ability to change lifestyles, especially for women. The intervention effect was limited by the short study follow-up of only 9 months. Conclusion: Integrated diabetes care was feasible, both for providers and patients, and potentially scalable at primary care facilities under routine conditions in Pakistan. Additional operational interventions are required for sustained drug supplies, supervision, in-service training, and to address the social challenges to healthy activity and eating, especially for women

Underwriting Apophenia and Cryptids: Are Cycles Statistical Figments of our Imagination?

This paper re-examines the evidence in favour of the existence of underwriting cycles in property and casualty insurance and their economical significance. Using a meta-analysis of published papers in the area of insurance economics, we show that the evidence supporting the existence of underwriting cycles is misleading. There is, in fact, little evidence in favour of insurance cycles with a linear autoregressive character. This means that any cyclicality in firm profitability in the property and casualty insurance industry is not predictable in a classical econometric framework. It follows that pricing in the property and casualty insurance industry is not incompatible with that of a competitive market