The effect of a one-year vigorous physical activity intervention on fitness, cognitive performance and mental health in young adolescents: the Fit to Study cluster randomised controlled trial.

BACKGROUND: Physical activity (PA) may positively stimulate the brain, cognition and mental health during adolescence, a period of dynamic neurobiological development. High-intensity interval training (HIIT) or vigorous PA interventions are time-efficient, scalable and can be easily implemented in existing school curricula, yet their effects on cognitive, academic and mental health outcomes are unclear. The primary aim of the Fit to Study trial was to investigate whether a pragmatic and scalable HIIT-style VPA intervention delivered during school physical education (PE) could improve attainment in maths. The primary outcome has previously been reported and was null. Here, we report the effect of the intervention on prespecified secondary outcomes, including cardiorespiratory fitness, cognitive performance, and mental health in young adolescents. METHODS: The Fit to Study cluster randomised controlled trial included Year 8 pupils (n = 18,261, aged 12-13) from 104 secondary state schools in South/Mid-England. Schools were randomised into an intervention condition (n = 52), in which PE teachers delivered an additional 10 min of VPA per PE lesson for one academic year (2017-2018), or into a "PE as usual" control condition. Secondary outcomes included assessments of cardiorespiratory fitness (20-m shuttle run), cognitive performance (executive functions, relational memory and processing speed) and mental health (Strength and Difficulties Questionnaire and self-esteem measures). The primary intention-to-treat (ITT) analysis used linear models and structural equation models with cluster-robust standard errors to test for intervention effects. A complier-average causal effect (CACE) was estimated using a two-stage least squares procedure. RESULTS: The HIIT-style VPA intervention did not significantly improve cardiorespiratory fitness, cognitive performance (executive functions, relational memory or processed speed), or mental health (all p > 0.05). Subgroup analyses showed no significant moderation of intervention effects by sex, socioeconomic status or baseline fitness levels. Changes in cardiorespiratory fitness were not significantly related to changes in cognitive or mental health outcomes. The trial was marked by high drop-out and low intervention compliance. Findings from the CACE analysis were in line with those from the ITT analysis. CONCLUSION: The one-academic year HIIT-style VPA intervention delivered during regular school PE did not significantly improve fitness, cognitive performance or mental health, but these findings should be interpreted with caution given low implementation fidelity and high drop-out. Well-controlled, large-scale, school-based trials that examine the effectiveness of HIIT-style interventions to enhance cognitive and mental health outcomes are warranted. TRIAL REGISTRATION: ISRCTN registry, 15,730,512 . Trial protocol and analysis plan for primary outcome prospectively registered on 30th March 2017. ClinicalTrials.gov , NCT03286725 . Secondary measures (focus of current manuscript) retrospectively registered on 18 September 2017.

Effects of a programme of vigorous physical activity during secondary school physical education on academic performance, fitness, cognition, mental health and the brain of adolescents (Fit to Study): study protocol for a cluster-randomised trial.

BACKGROUND: Early adolescence is a period of dynamic neurobiological change. Converging lines of research suggest that regular physical activity (PA) and improved aerobic fitness have the potential to stimulate positive brain changes, improve cognitive function and boost academic attainment in this age group, but high-quality studies are needed to substantiate these findings. The primary aim of the Fit to Study trial is to investigate whether short infusions of vigorous PA (VPA) delivered during secondary school physical education (PE) can improve attainment in maths, as described in a protocol published by NatCen Social Research. The present protocol concerns the trial's secondary outcome measures, which are variables thought to moderate or mediate the relationship between PA and attainment, including the effect of the intervention on cardiorespiratory fitness, cognitive performance, mental health and brain structure and function. METHOD: The Fit to Study project is a cluster-randomised controlled trial that includes Year 8 pupils (aged 12-13) from secondary state schools in South/Mid-England. Schools were randomised into an intervention condition in which PE teachers delivered an additional 10 min of VPA per PE lesson for one academic year, or a 'PE as usual' control condition. Intervention and control groups were stratified according to whether schools were single-sex or co-educational. Assessments take place at baseline (end of Year 7, aged 11-12) and after 12 months (Year 8). Secondary outcomes are cardiorespiratory fitness, objective PA during PE, cognitive performance and mental health. The study also includes exploratory measures of daytime sleepiness, attitudes towards daily PA and PE enjoyment. A sub-set of pupils from a sub-set of schools will also take part in a brain imaging sub-study, which is embedded in the trial. DISCUSSION: The Fit to Study trial could advance our understanding of the complex relationships between PA and aerobic fitness, the brain, cognitive performance, mental health and academic attainment during adolescence. Further, it will add to our understanding of whether school PE is an effective setting to increase VPA and fitness, which could inform future PA interventions and education policy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03286725 . Retrospectively registered on 18 September 2017. ClinicalTrials.gov, NCT03593863 . Retrospectively registered on 19 July 2018.

Managing the patient journey through enteral nutritional care.

Nutritional support provision does not happen by accident. Clinical dimensions include screening and assessment, estimation of requirements, identification of a feeding route and the subsequent need for monitoring. Patients may need different forms of nutritional intervention during the course of their illness. Furthermore, these may need to be provided in different locations as their clinical status changes. If this is not properly managed there is potential for inappropriate treatment to be given. Clinical processes can only be effectively implemented if there is a robust infrastructure. The clinical team need to understand the different elements involved in effective service provision and this depends on bringing together disciplines which do not feature overtly on the clinical agenda including catering, finance and senior management. Excellent communication skills at all levels, financial awareness and insight into how other departments function are fundamental to success. Practice needs to be reviewed constantly and creativity about all aspects of service delivery is essential. Finally, it is important that key stakeholders are identified and involved so that they can support any successes and developments. This will raise awareness of the benefits of nutritional intervention and help to ensure that the right resources are available when they are needed.

Retinopathy of prematurity: recent advances in our understanding.

Retinopathy of prematurity (ROP) has been recognised as an important cause of childhood visual impairment and blindness since the 1940s when improved facilities and treatment increased the survival rate of premature infants. Although its incidence and severity have been decreasing in developed countries over the past two decades, both are increasing in developing nations. ROP is consequently targeted as an important but avoidable disease. This review provides an updated summary and discussion of much of the work that has been produced through population, animal, cell culture, and genetic research. The authors examine the prevalence, risk factors, and possible causes of the disease with a particular focus on genetic studies. They conclude that while significant reductions in the disease have occurred in developed countries, further research is required to fully understand and prevent the disease. In the meantime, development and implementation of appropriate screening and treatment strategies will be critical in reducing blindness in developing countries.

Retinopathy of prematurity: recent advances in our understanding.

Retinopathy of prematurity (ROP) has been recognised as an important cause of childhood visual impairment and blindness since the 1940s when improved facilities and treatment increased the survival rate of premature infants. Although its incidence and severity have been decreasing in developed countries over the past two decades, both are increasing in developing nations. ROP is consequently targeted as an important but avoidable disease. This review provides an updated summary and discussion of much of the work that has been produced through population, animal, cell culture, and genetic research. The authors examine the prevalence, risk factors, and possible causes of the disease with a particular focus on genetic studies. They conclude that while significant reductions in the disease have occurred in developed countries, further research is required to fully understand and prevent the disease. In the meantime, development and implementation of appropriate screening and treatment strategies will be critical in reducing blindness in developing countries.

Clathrin-dependent and -independent internalization of plasma membrane sphingolipids initiates two Golgi targeting pathways.

Sphingolipids (SLs) are plasma membrane constituents in eukaryotic cells which play important roles in a wide variety of cellular functions. However, little is known about the mechanisms of their internalization from the plasma membrane or subsequent intracellular targeting. We have begun to study these issues in human skin fibroblasts using fluorescent SL analogues. Using selective endocytic inhibitors and dominant negative constructs of dynamin and epidermal growth factor receptor pathway substrate clone 15, we found that analogues of lactosylceramide and globoside were internalized almost exclusively by a clathrin-independent ("caveolar-like") mechanism, whereas an analogue of sphingomyelin was taken up approximately equally by clathrin-dependent and -independent pathways. We also showed that the Golgi targeting of SL analogues internalized via the caveolar-like pathway was selectively perturbed by elevated intracellular cholesterol, demonstrating the existence of two discrete Golgi targeting pathways. Studies using SL-binding toxins internalized via clathrin-dependent or -independent mechanisms confirmed that endogenous SLs follow the same two pathways. These findings (a) provide a direct demonstration of differential SLs sorting into early endosomes in living cells, (b) provide a "vital marker" for endosomes derived from caveolar-like endocytosis, and (c) identify two independent pathways for lipid transport from the plasma membrane to the Golgi apparatus in human skin fibroblasts.

Isolating the M(y)-cell response in dyslexia using the spatial frequency doubling illusion.

The contribution of M(y)-cell activity within a framework of a magnocellular-deficit theory of dyslexia is currently unknown. Twenty-one dyslexic readers and 19 control readers were compared on their threshold detection for the frequency doubling illusion - an index of M(y)-cell activity, coherent motion, and a visual acuity task. The dyslexic group performed more poorly on detection of the frequency doubling illusion and coherent motion compared to the control group, but both groups performed comparably on the visual acuity task. The results from this study indicate that if a magno deficit exists in dyslexia, it may originate at a retinal level at least partly mediated by M(y)-cell abnormalities.

Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1.

Niemann-Pick disease type C (NPC) is a fatal, autosomal recessive lipidosis characterized by lysosomal accumulation of unesterified cholesterol and multiple neurological symptoms, such as vertical supranuclear ophthalmoplegia, progressive ataxia, and dementia. More than 90% of cases of NPC are due to a defect in Niemann-Pick C1 (NPC1), a late endosomal, integral membrane protein that plays a role in cholesterol transport or homeostasis. Biochemical diagnosis of NPC has relied on the use of patient skin fibroblasts in an assay to demonstrate delayed low-density lipoprotein (LDL)-derived cholesterol esterification and a cytological technique-filipin staining-to demonstrate the intracellular accumulation of cholesterol. A small percentage of patients, referred to as "NPC variants," present with clinical symptoms of NPC but show near-normal results of these biochemical tests, making laboratory confirmation of NPC disease problematic. Here, we demonstrate that NPC-variant fibroblast samples can be detected as sphingolipid storage disease cells, using a fluorescent sphingolipid analog, BODIPY-lactosylceramide. This lipid accumulated in endosomes/lysosomes in variant cells preincubated with LDL cholesterol but targeted to the Golgi complex in normal cells under these conditions. The reproducibility of this technique was validated in a blinded study. In addition, we performed mutation analysis of the NPC1 gene in NPC variant and "classical" NPC cell samples and found a high incidence of specific mutations within the cysteine-rich region of NPC1 in variants. We also found that 5 of the 12 variant cell samples had no apparent defect in NPC1 but were otherwise indistinguishable from other variant cells. This is a surprising result, since, in general, approximately 90% of patients with NPC possess defects in NPC1. Our findings should be useful for the detection of NPC variants and also may provide significant new insight regarding NPC1 genotype/phenotype correlations.

Home enteral tube feeding following cerebrovascular accident.

BACKGROUND AND AIMS: In the UK, cerebrovascular accident (CVA) is the third commonest cause of death and the commonest diagnosis in patients receiving home enteral feeding (HETF). This study aimed to use data from the British Artificial Nutrition Survey (BANS) collected between 1996 and 1999 to assess the outcome of patients on HETF, including mortality, return to oral feeding, level of physical activity, and level of dependency, which has resource implications. RESULTS: it is estimated that about 1.7% of all patients suffering a CVA in the UK between 1996 and 1999 received HETF. At one year, 29.6% died while receiving HETF and another 13% returned to oral feeding. Mortality increased with age and was twice as high in those managed in nursing homes compared to those in their own homes. The patients receiving tube feeding spent only 0.6% of their time in hospital. A total of 43.9% of patients were bed-bound at home (1.9% unconscious) and an additional 30.3% were house-bound. Only 21.2% were independent, and the majority were totally dependent on their carers. In CVA patients on HETF the level of dependency was greater than for those with all types of diagnoses (n=12,997). CONCLUSION: This study has described the outcome of a large number of patients receiving HETF in the UK. Since patients spent less than 1% of their time in hospital, HETF relieves pressure on the expensive hospital environment, but places more demands on the carers, who have to deal with severely disabled patients. Recovery of swallowing function should be assessed intermittently to prevent unnecessary HETF.

Developing skills in leg ulcer nursing: the lessons learned.

The high treatment costs of inappropriate leg ulcer management are well referenced. Wide variations in practice have also been reported. A training programme for community nurses has been in place in Leicestershire and Rutland NHS Trust for five years. Its objective is to promote evidence-based leg ulcer management. The aim of this prospective audit was to assess and compare the effectiveness of the compression bandage systems used in the trust: the original Charing Cross system (August 1996 to September 1997) and Robinson's Ultra Four kit (October 1997 to December 1998). All patients with leg ulceration were assessed using the Leicestershire leg ulcer assessment form. This was submitted along with an audit tool to the tissue viability service in exchange for a 12-week supply of compression bandages. The audit form was resubmitted after each subsequent 12-week period until the patient either had healed or was withdrawn from the audit. Differences between the two groups in mobility, previous deep vein thrombosis, fixed ankle deformity, the male to female ratio, duration of ulcer and ulcer surface area were noted. Patients using the Ultra Four kit had faster healing times than those given the Charing Cross system, but this was not statistically significant. Cost comparisons between the previous dressing regimen and compression bandaging showed a significance difference (p < 0.001). There was also a significant reduction in nurse time (p < 0.001). The audit results showed that compression bandaging therapy was an effective method of achieving healing in patients with venous leg ulcers and that significant cost savings were made in terms of dressing cost and nurse time. Furthermore, there were potential benefits in continuing compression therapy for the group of non-healers.

Broad screening test for sphingolipid-storage diseases.

BACKGROUND: Lipid-storage diseases are collectively important because they cause substantial morbidity and mortality, and because they may present as dementia, major psychiatric illness, developmental delay, or cerebral palsy. At present, no single assay can be used as an initial general screen for lipid-storage diseases. METHODS: We used a fluorescent analogue of lactosylceramide, called N-[5-(5,7-dimethylborondipyrromethenedifluoride)-1-pentanoyl]D- lactosylsphingosine (BODIPY-LacCer), the emission of which changes from green to red wavelengths with increasing concentrations in membranes, to examine the intracellular distribution of the lipid within living cells. FINDINGS: During a brief pulse-chase experiment, the fluorescent lipid accumulated in the lysosomes of fibroblasts from patients with Fabry's disease, GM1 gangliosidosis, GM2 gangliosidosis (Tay-Sachs and Sandhoff forms), metachromatic leucodystrophy, mucolipidosis type IV, Niemann-Pick disease (types A, B, and C), and sphingolipid-activator-protein-precursor (prosaposin) deficiency. In control cells, the lipid was mainly confined to the Golgi complex. In a masked study, replicate samples of 25 of 26 unique cell lines representing ten different lipid-storage diseases, and 18 of 20 unique cell lines representing controls were correctly identified; the sensitivity was 96.2% (95% CI 80.4-99.9) and the specificity 90.0% (68.3-98.8). INTERPRETATION: This method may be useful as an initial general screen for lipid-storage diseases, and, with modification, could be used for large-scale automated screening of drugs to abrogate lysosomal storage in various lipidoses. The unexpected accumulation of BODIPY-LacCer in several biochemically distinct diseases raises important questions about common mechanisms of cellular dysfunction in these disorders.

Use of N-[5-(5,7-dimethyl boron dipyrromethene difluoride-sphingomyelin to study membrane traffic along the endocytic pathway.

We have used N-[5-(5,7-dimethyl boron dipyrromethene difluoride)-1-pentanoyl]-D-erythro-sphingosylphosphorylcholine (C5-DMB-SM or 'BODIPY-SM'), a fluorescent analog of sphingomyelin, to study lipid transport along the endocytic pathway of human skin fibroblasts. The unique spectral properties of the BODIPY fluorophore allow the investigator to distinguish various populations of labeled endosomes and lysosomes within the living cell by fluorescence microscopy, and in conjunction with quantitative fluorescence microscopy, to estimate the concentration of these lipids in different intracellular compartments. This methodology is also applicable for visualizing the accumulation of lipids in the endosomes and lysosomes of storage disease fibroblasts.

Discrete pathways for arachidonic acid release from tannin versus beta-glucan-stimulated rabbit alveolar macrophages.

Previously, we observed both tannin and beta-glucan to be agonists for arachidonic acid (AA) release from rabbit alveolar macrophages. Although tannin inhibited reincorporation of exogenous AA, beta-glucan had no apparent effect, suggesting separate signal transduction pathways leading to elevated AA levels. In this study alveolar macrophages were pretreated with the tyrosine phosphatase inhibitor sodium orthovanadate then stimulated with either condensed tannin or beta-glucan. Vanadate exerted opposing effects on AA release. Furthermore, vanadate reversed the ability of tannin to inhibit reacylation. Additional studies using the phospholipase A probe bis-BODIPY-C11-PC indicated that although the known phospholipase A2 activators, calcium ionophore A23187, insoluble immune complexes, and beta-glucan, generated an increase in fluorescence consistent with phospholipase A activation, tannin had no effect. These findings suggest the increase in free AA resulting from stimulation of macrophages by either tannin or beta-glucan is produced via two different mechanisms.

Home nutrition survey in the UK: the patient's perspective.

A detailed survey questionnaire compiled by the executive committee of Patients on Intravenous and Nasogastric Nutrition Therapy (PINNT) was circulated in November 1991 to the postal addresses of all full (patient) members of PINNT in the UK. The objective of the survey was to identify current practices and problems of home nutrition support as seen from the patients perspective. 128 questionnaires were distributed. 87 (68%) analysable questionnaires were completed and returned. 77 were for parenteral nutrition (HPN) patients and 10 for patients on enteral nutrition (HEN). Areas of concern for patients include the practicalities of administration of lipid and additives, and problems associated with the appearance of air in infusion bags. Although most patients appeared happy with the home nutrition support services 18% commented on particular negative aspects. This survey highlights such areas which may not be identified during routine patient/clinician contact.