High-fat, low-carbohydrate diets, known as ketogenic diets, have been used as a non-pharmacological treatment for refractory epilepsy. A key mechanism of this treatment is thought to be the ...generation of ketones, which provide brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose, resulting in beneficial downstream metabolic changes, such as increasing adenosine levels, which might have effects on seizure control. However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis. Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise seizure threshold. The mechanisms underlying the ketogenic diet might also have roles in other disorders, such as preventing neurodegeneration in Alzheimer's disease, the proliferation and spread of cancer, and insulin resistance in type 2 diabetes. Analysing medium-chain fatty acids in future ketogenic diet studies will provide further insights into their importance in modified forms of the diet. Moreover, the results of these studies could facilitate the development of new pharmacological and dietary therapies for epilepsy and other disorders.
The CRADLE (Community blood pressure monitoring in Rural Africa: Detection of underLying pre-Eclampsia) Vital Signs Alert device-designed specifically to improve maternity care in low resource ...settings-had varying impact when trialled in different countries. To better understand the contextual factors that may contribute to this variation, this study retrospectively evaluated the adoption of CRADLE, during scale-up in Sierra Leone.
This was a mixed methods study. A quantitative indicator of adoption (the proportion of facilities trained per district) was calculated from existing training records, then focus groups were held with 'CRADLE Champions' in each district (n = 32), to explore adoption qualitatively. Template Analysis was used to deductively interpret qualitative data, guided by the NASSS (non-adoption, abandonment, scale-up, spread, sustainability) Framework.
Substantial but non-significant variation was found in the proportion of facilities trained in each district (range 59-90%) X
(7, N = 8) = 10.419, p = 0.166. Qualitative data identified complexity in two NASSS domains that may have contributed to this variation: 'the technology' (for example, charging issues, difficulty interpreting device output and concerns about ongoing procurement) and 'the organisation' (for example, logistical barriers to implementing training, infighting and high staff turnover). Key strategies mentioned to mitigate against these issues included: transparent communication at all levels; encouraging localised adaptations during implementation (including the involvement of community leaders); and selecting Champions with strong soft skills (particularly conflict resolution and problem solving).
Complexity related to the technology and the organisational context were found to influence the adoption of CRADLE in Sierra Leone, with substantial inter-district variation. These findings emphasise the importance of gaining an in-depth understanding of the specific system and context in which a new healthcare technology is being implemented. This study has implications for the ongoing scale-up of CRADLE, and for those implementing or evaluating other health technologies in similar contexts.
Intercity (or long-distance) coach transport has long remained a marginal mode in Western and Southern Europe. It connected mainly residual origin-destination relationships, to marginal areas without ...rail transport or, at best, as an ancillary mode to extend the range of rail accessibility.
However, the recent experiences of German and Italian liberalisations can represent a turning point in the redefinition of the role of this industry. In particular, Germany showed that a competitive environment could foster the sector and make it a true alternative for car and rail, especially in the low cost demand segment. In Italy, instead, the liberalisation effects are appearing more slowly, also due to the fragmentation of the sector and to the relative maturity of the historical market, but more and more pervasively.
While it is clear that a favourable legislative context and the limitedness level of entry barriers are necessary conditions for liberalisation, other elements appear to have a profound influence to explain the important differences between the two cases of Italy and Germany. The paper aims at discussing the role of two further aspects: i) the characteristics, and in particular the dimension and concentration, of the before-liberalisation market, and ii) the geography of the countries. When considering these elements, it becomes clearer why the processes ran at very different speeds north and south of the Alps and why the two markets still appear different.
Recent deregulation in German long distance bus services lead to highly dynamic developments in this market. Long-distance coach services in the U.S. have been deregulated since the 1980th. The aim ...of this paper is to compare one established and one young/emerging market with the example of the U.S. and Germany. We first investigate how the framework conditions and market structures have developed in both countries. Based on a unique dataset with more than 2000 US and more than 150 German routes including various variables on long-distance coach services, we analyse in a second step the supply and ticket prices in both markets that results from the different regulative settings. The results show that distance, the number of stops and frequency are highly significant determinants explaining the size of ticket price. Regarding competitive behaviour, we identify operators determining significant lower ticket prices in the markets compared to others. Finally, we consider how the spatial structure in the US influences the supply. We find that spatial distribution of the cities as well as demographic attributes such as the size population and the share of white population are determining the supply of intercity bus services in the US.
IntroductionVitamin B12 deficiency is widely prevalent across many low- and middle-income countries, especially where the diet is low in animal sources. While many observational studies show ...associations between B12 deficiency in pregnancy and infant cognitive function (including memory, language and motor skills), evidence from clinical trials is sparse and inconclusive.Methods and analysisThis double-blind, multicentre, randomised controlled trial will enrol 720 vegetarian pregnant women in their first trimester from antenatal clinics at two hospitals (one in India and one in Nepal). Eligible mothers who give written consent will be randomised to receive either 250 mcg methylcobalamin or 50 mcg (quasi control), from enrolment to 6 months post-partum, given as an oral daily capsule. All mothers and their infants will continue to receive standard clinical care. The primary trial outcome is the offspring’s neurodevelopment status at 9 months of age, assessed using the Development Assessment Scale of Indian Infants. Secondary outcomes include the infant’s biochemical B12 status at age 9 months and maternal biochemical B12 status in the first and third trimesters. Maternal biochemical B12 status will also be assessed in the first trimester. Modification of association by a priori identified factors will also be explored.Ethical considerations and disseminationThe study protocol has been approved by ethical committees at each study site (India and Nepal) and at University College London, UK. The study results will be disseminated to healthcare professionals and academics globally via conferences, presentations and publications. Researchers at each study site will share results with participants during their follow-up visits.Trial registration numberCTRI/2018/07/015048 (Clinical Trial Registry of India); NCT04083560 (ClinicalTrials.gov)
The medium chain triglyceride ketogenic diet is an established treatment for drug-resistant epilepsy that increases plasma levels of decanoic acid and ketones. Recently, decanoic acid has been shown ...to provide seizure control in vivo, yet its mechanism of action remains unclear. Here we show that decanoic acid, but not the ketones β-hydroxybutryate or acetone, shows antiseizure activity in two acute ex vivo rat hippocampal slice models of epileptiform activity. To search for a mechanism of decanoic acid, we show it has a strong inhibitory effect on excitatory, but not inhibitory, neurotransmission in hippocampal slices. Using heterologous expression of excitatory ionotropic glutamate receptor AMPA subunits in Xenopus oocytes, we show that this effect is through direct AMPA receptor inhibition, a target shared by a recently introduced epilepsy treatment perampanel. Decanoic acid acts as a non-competitive antagonist at therapeutically relevant concentrations, in a voltage- and subunit-dependent manner, and this is sufficient to explain its antiseizure effects. This inhibitory effect is likely to be caused by binding to sites on the M3 helix of the AMPA-GluA2 transmembrane domain; independent from the binding site of perampanel. Together our results indicate that the direct inhibition of excitatory neurotransmission by decanoic acid in the brain contributes to the anti-convulsant effect of the medium chain triglyceride ketogenic diet.
Abstract
The role of eHealth in conflict settings is increasingly important to address geographic, epidemiologic and clinical disparities. This study categorizes various forms of eHealth usage in ...conflict and aims to identify gaps in evidence to make recommendations for further research and practice. The analysis was carried out via a narrative hermeneutic review methodology. Articles that fulfilled the following screening criteria were reviewed: (1) describing an eHealth intervention in active conflict or ongoing insurgency, (2) an eHealth intervention targeting a conflict-affected population, (3) an e-learning platform for delivery in conflict settings and (4) non-interventional descriptive reviews relating to eHealth in conflict. Of the 489 papers eligible for screening, 46 merited final inclusion. Conflict settings described include Somalia, Sudan, Afghanistan, Syria, Iraq, Pakistan, Chechnya, Gaza and the Democratic Republic of Congo. Thirty-six studies described specific eHealth initiatives, while the remainder were more generic review papers exploring general principles. Analysis resulted in the elucidation of three final categories of current eHealth activity in conflict-affected settings: (1) eHealth for clinical management, (2) e-learning for healthcare in conflict and (3) eHealth for information management in conflict. Obvious disparities in the distribution of technological dividends from eHealth in conflict are demonstrated by this review. Conflict-affected populations are predominantly subject to ad hoc and voluntary initiatives delivered by diaspora and civil society organizations. While the deployment of eHealth technologies in conflict settings is increasingly normalized, there is a need for further clarification of global norms relating to practice in this context.
Summary
Perampanel is an adjunctive treatment for epilepsy that works through the direct inhibition of AMPA receptors. The same molecular mechanism has recently been shown for a fatty acid, decanoic ...acid, prescribed in the medium chain triglyceride ketogenic diet for the treatment of patients with drug‐resistant epilepsy. Because each compound has been proposed to act through a distinct AMPA receptor binding site, we predicted that perampanel and decanoic acid would act synergistically against AMPA receptors and, consequently, seizures. Here, we show a synergistic interaction between perampanel and decanoic acid in direct AMPA receptor inhibition, in an ex vivo model of seizure activity, and against seizure‐induced activity in human brain slices. These data support a potential role for combination treatment using perampanel and dietary decanoic acid to provide enhanced seizure control.
This workshop discussed the functioning of deregulated public transport markets, examining competition options for deregulated markets. The regulatory needs of such market initiative ‘deregulated’ ...markets have been considered both from practical and theoretical evidence, covering both local and long-distance markets (bus, coach and rail). Practical evidence has been presented from mature deregulated markets (such as buses in Great Britain outside London) and updates on experiments in countries such as Japan, New Zealand and Sweden. Emerging evidence on the liberalisation and deregulation of long-distance and international markets in Europe and elsewhere was considered, both for coach and rail. The devising of ‘rules of the game’ formed a centrepiece in the discussions, looking at alternative ways to organise the regulatory guidance of such markets.
Vitamin B
deficiency is widely prevalent across many low- and middle-income countries, especially where the diet is low in animal sources. While many observational studies show associations between B
...deficiency in pregnancy and infant cognitive function (including memory, language and motor skills), evidence from clinical trials is sparse and inconclusive.
This double-blind, multicentre, randomised controlled trial will enrol 720 vegetarian pregnant women in their first trimester from antenatal clinics at two hospitals (one in India and one in Nepal). Eligible mothers who give written consent will be randomised to receive either 250 mcg methylcobalamin or 50 mcg (quasi control), from enrolment to 6 months post-partum, given as an oral daily capsule. All mothers and their infants will continue to receive standard clinical care. The primary trial outcome is the offspring's neurodevelopment status at 9 months of age, assessed using the Development Assessment Scale of Indian Infants. Secondary outcomes include the infant's biochemical B
status at age 9 months and maternal biochemical B
status in the first and third trimesters. Maternal biochemical B
status will also be assessed in the first trimester. Modification of association by a priori identified factors will also be explored.
The study protocol has been approved by ethical committees at each study site (India and Nepal) and at University College London, UK. The study results will be disseminated to healthcare professionals and academics globally via conferences, presentations and publications. Researchers at each study site will share results with participants during their follow-up visits.
CTRI/2018/07/015048 (Clinical Trial Registry of India); NCT04083560 (ClinicalTrials.gov).
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