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Introduction: People in low socioeconomic circumstances are more susceptible to dyslipidemia and cardiovascular disease than those living in more affluent populations. Limited healthcare access and low preventive care uptake widen health inequalities. Understanding how primary care can better serve socioeconomically disadvantaged communities is urgently needed. Aim: To explore lipid management delivery in socioeconomically disadvantaged areas and identify barriers and enablers for lipid optimization for socioeconomically disadvantaged populations. Method: Individual semi-structured remote interviews with clinicians, purposively recruited from primary care practices serving extremely socioeconomically disadvantaged communities in Northern England, UK, who were involved in the delivery and organization of lipid management. Interviews were recorded, transcribed, and analyzed thematically following framework analysis. Results: Fifteen interviews were undertaken. Five themes emerged: complex and multimorbid patients with competing priorities, limited access and follow-up to supporting services, being flexible and working beyond guidelines, high workload with inadequate staff support, and the need for care integrity and sustainable support. Conclusion: The findings of this study have been fed back to the delivery of the national program to improve cardiovascular health. Socioeconomically disadvantaged communities have complex health needs posing risks of multimorbidity but living with low health literacy, competing demands upon time, and financial constraints. Clinicians are willing to adapt services but a lack of guidance for care and funded services remains a significant barrier to targeted service delivery. Research is needed to inform the effectiveness and acceptability of interventions for lipid management tailored for those experiencing low socioeconomic disadvantage.

Abstract Orthostatic hypotension (OH) is common in older people. We examined the influence of self-reported occupational-related physical activity (PA) and leisure-time physical exercise (PE) on orthostatic response in a sample of older people over a 2 year period. Supine and orthostatic systolic blood pressure (sBP), diastolic blood pressure (dBP), and mean blood pressure (mBP) were assessed in response to Active Stand (AS) test in 205 older subjects (> 60 years old) at baseline and 2-year follow-up. OH was found in 24 subjects (11.71%) at baseline and 20 subjects (9.76%) after 2 years, with a significant degree of variability in the occurrence of OH after 2 years. Twenty-two subjects who had OH at baseline were free of it after 2 years, two subjects had persistent OH at baseline and after 2 years. After 2 years, adults with occupational PA showed no significant decrease of blood pressure in response to AS test, while lack of undertaking an occupation-related PA was significantly related with a greater decrease in sBP and mBP in response to AS testing in the 1st min. Occupation-related PA and leisure-time-related PE were related to an increase in the response of BP on AS in change between baseline and after 2 years. High between-subjects variance in OH over 2 years was noted. Occupations that involved continuous physical activity and leisure-time physical exercise in middle age were both protective for BP decline on orthostatic stress test within 2 years.

Objectives To identify, synthesise and appraise evidence relating to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and pregnancy.Design Mixed-methods systematic review, using convergent segregated design.Data sources MEDLINE, EMBASE, Scopus, PsycINFO, CINAHL, MedRxiv, PROSPERO and grey literature sources through 6 August 2023.Eligibility criteria We included original research studies, expert opinion and grey literature reporting on ME/CFS and pregnancy/post partum (up to 2 years), risk of pregnancy outcomes with ME/CFS or experiences during pregnancy for mother, partner or health and social care professionals following ME/CFS during pregnancy, all where the evidence was relevant to a confirmed ME/CFS diagnosis prior to pregnancy.Data extraction and synthesis Three independent reviewers completed all screening, data extraction and quality assessment. Risk of bias was assessed using the mixed-methods appraisal tool V.2018. Qualitative and quantitative literature was analysed separately using thematic and descriptive syntheses. Findings were integrated through configuration.Results Searches identified 3675 articles, 16 met the inclusion criteria: 4 quantitative (1 grey), 11 qualitative (9 grey) and 1 grey mixed-methods study. Of the four quantitative studies that reported on ME/CFS severity during pregnancy, two suggested pregnancy negatively impacted on ME/CFS, one found most women had no change in ME/CFS symptoms and one found ME/CFS improved; this difference in symptom severity across studies was supported by the qualitative evidence. The qualitative literature also highlighted the importance of individualised care throughout pregnancy and birth, and the need for additional support during family planning, pregnancy and with childcare. Only one quantitative study reported on pregnancy outcomes, finding decreased vaginal births and higher rates of spontaneous abortions and developmental and learning delays associated with pregnancies in those with ME/CFS.Conclusions Current evidence on ME/CFS in pregnancy is limited and findings inconclusive. More high-quality research is urgently needed to support the development of evidence-based guidelines on ME/CFS and pregnancy.

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Abstract Background The aim of this study was to explore the tolerability and effect of static stretching (SS) and whole body cryotherapy (WBC) upon fatigue, daytime sleepiness, cognitive functioning and objective and subjective autonomic nervous system functioning in those with Chronic Fatigue Syndrome (CFS) compared to a control population. Methods Thirty-two CFS and eighteen healthy controls (HC) participated in 2 weeks of a SS + WBC programme. This programme was composed of five sessions per week, 10 sessions in total. Results A significant decrease in fatigue was noted in the CFS group in response to SS + WBC. Some domains of cognitive functioning (speed of processing visual information and set-shifting) also improved in response to SS + WBC in both CFS and HC groups. Our study has confirmed that WBC is well tolerated by those with CFS and leads to symptomatic improvements associated with changes in cardiovascular and autonomic function. Conclusions Given the preliminary data showing the beneficial effect of cryotherapy, its relative ease of application, good tolerability, and proven safety, therapy with cold exposure appears to be an approach worth attention. Further studies of cryotherapy as a potential treatment in CFS is important in the light of the lack of effective therapeutic options for these common and often disabling symptoms.

Introduction Opioid prescribing rates are disproportionately high in the North of England. In addition to patients’ complex health needs, clinician prescribing behaviour is also a key driver. Although strategies have been initiated to reduce opioid prescribing nationally, the COVID-19 pandemic has interrupted service provision and created challenges for the system and health professionals to tackle this complex issue. A pilot intervention using smartphone video messaging has been developed to remotely explain the rationale for opioid reduction and facilitate self-initiation of support. The aim of this study is to evaluate the potential benefits, risks and economic consequences of ‘at scale’ implementation.Methods and analysis This will be a mixed-methods study comprising a quasi-experimental non-randomised before-and-after study and qualitative interviews. The intervention arm will comprise 50 General Practitioner (GP) Practices using System 1 (a clinical computer system hosting the intervention) who will deliver the video to their patients via text message. The control arm will comprise 50 practices using EMIS (a different computer system) who will continue usual care. Monthly practice level prescribing and consultation data will be observed for 6 months postintervention. A general linear model will be used to estimate the association between the exposure and the main outcome (opioid prescribing; average daily quantity (ADQ)/1000 specific therapeutic group age-sex related prescribing unit). Semi-structured interviews will be undertaken remotely with purposively selected participants including patients who received the video, and health professionals involved in sending out the videos and providing additional support. Interviews will be audio recorded, transcribed and analysed thematically.Ethics and dissemination Ethics approval has been granted by the NHS Health Research Authority Research Ethics Committee (22/PR/0296). Findings will be disseminated to the participating sites, participants, and commissioners, and in peer-reviewed journals and academic conferences.Trial registration number NCT05276089.

Objectives The North East of England, ranked as having the highest poverty levels and the lowest health outcomes, has the highest cardiovascular disease (CVD) premature mortality. This study aimed to compare CVD-related conditions and risk factors for deprived practice populations with other general practice (GP) populations in Northern England to England overall, before and during COVID-19 to identify changes in recorded CVD-related risk factors and conditions and evidence-based lipid prescribing behaviour.Design A population-based observational study of aggregated practice-level data obtained from publicly accessible data sets.Setting 34 practices that fall into the 15% most deprived practice populations in England were identified as the most deprived communities in the North East and North Cumbria (Deep End).Participants Patients aged ≥16 registered with GP and diagnosed with any form of CVD.Primary and secondary outcome measures CVD-related conditions and risk factors, statin prescribing.Results Deep End (n=263 830) had a smaller, younger and more deprived population with lower levels of employment and full-time education and higher smoking prevalence. They had some higher recorded CVD-related conditions than England but lower than the non-Deep End. Atrial fibrillation (−0.9, –0.5), hypertension (−3.7, –1.3) and stroke and transient ischaemic attack rates (−0.5, –0.1) appeared to be lower in the Deep End than in the non-Deep End but the optimal statin prescribing rate was higher (3.1, 8.2) than in England.Conclusion Recorded CVD-related risk factors and conditions remained comparable before and during COVID-19. These are higher in the Deep End than in England and similar or lower than the non-Deep End, with a higher optimal statin prescribing rate. However, it was not possible to control for age and sex. More work is needed to estimate the consequences of the pandemic on disadvantaged communities and to compare whether the findings are replicated in other areas of deprivation.

Introduction Hyperlipidaemia contributes a significant proportion of modifiable cardiovascular disease (CVD) risk, which is a condition that disproportionally affects disadvantaged socioeconomic communities, with death rates in the most deprived areas being four times higher than those in the least deprived. With the national CVD Prevention programme being delivered to minimise risk factors, no evidence is available on what has been implemented in primary care for deprived populations. This study describes the protocol for the development of a tailored intervention aiming to optimise lipid management in primary care settings to help reduce inequalities in CVD risks and improve outcomes in deprived communities.Methods and analysis A mixed-methods approach will be employed consisting of four work packages: (1) rapid review and logic model; (2) assessment and comparison of CVD risk management for deprived with non-deprived populations in Northern England to England overall; (3) interviews with health professionals; and (4) intervention development. A systematic search and narrative synthesis will be undertaken to identify evidence-based interventions and targeted outcomes in deprived areas. General practice-level data will be assessed to establish the profile of lipid management, compared with the regional and national levels. Health professionals involved in the organisation and delivery of routine lipid management to deprived populations will be interviewed to understand the implementation and delivery of current lipid management and associated challenges. The prototype intervention will be informed by the evidence generated from workpackages 1–3, which will be reviewed and assessed using the nominal group technique to reach consensus. Training and skills development materials will also be developed as needed.Ethics and dissemination Ethics approval has been obtained from the Faculty of Medical Sciences Research Ethics Committee at Newcastle University, UK. Findings will be disseminated to the participating sites, participants, commissioners, and in peer-reviewed journals and academic conferences.

Introduction There are limited injury data in professional horse racing, particularly by sex.Objectives To describe injury incidence, characteristics and falls in male and female, flat and jump jockeys in Great Britain.Design and setting Retrospective cohort study of professional jockeys in Britain.Participants 245 jockeys licensed between 2007 and 2017.Primary and secondary outcome measures The primary outcome measure was injury on a race day. Injury incidence (per 1000 rides; per 1000 falls) was derived. Incidence-rate ratios (IRR) were calculated to compare incidence between flat and jump racing, male and female jockeys, and male flat and male jump jockeys for: (i) injury incidence, (ii) fall incidence and (iii) injuries per fall.Results 234 British professional jockeys were included. Jockeys were on average 19.5±2.0 years old at licence date, 79.9% male and 58.1% flat. The time of follow-up (racing in the study) was 3.7 (SD=2.3) years. There were 278 injuries, occurring in-race (81.7%), in the stalls (10.8%) or parade ring (6.1%). After one injury was removed to preserve anonymity, 57.2% were soft tissue injuries, 25.3% fractures and 10.5% concussion. There were 1634 falls, with 92% in male jump racing. The injury incidence was higher in jump racing (5.1 vs 1.0/1000 jockey rides). The falls incidence was 1.8/1000 rides in flat and 46.2/1000 rides in jump racing (IRR 0.04, 95% CI 0.03 to 0.04). There were over five times higher injuries/1000 falls in flat than jump racing (IRR 5.56, 95% CI 4.05 to 7.53). Male flat jockeys fell less than female flat (IRR 0.57, 95% CI 0.35 to 0.97).Conclusion Most injuries occurred in-race and were soft tissue injuries. Jump jockeys fell more often than flat, and female flat jockeys fell more often than male flat. Flat jockeys injured more frequently when falling. No sex differences were seen for injuries per fall.

BackgroundCognitive reserve explains why subjects with more years of education, professional achievement, or participation in recreational activities show less cognitive decline with aging. We hypothesize that levels of recreational travel, education, occupation, systemic health, physical performance, and current cognitive activity levels affect the trajectory of cognitive function in older, healthy people in Poland.Materials and MethodsHealthy, older people (N = 205) were examined and followed-up at 2 years. Participants completed physical and cognitive function assessments: including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and its two subtests Delayed Recall (DR) and Verbal Fluency (VF), and Trail Making Test Part B (TMT B). Factors associated with cognitive functioning were also examined.ResultsThe MMSE result significantly decreased over 2 years. No significant decrease in other cognitive tests was noted. However, the trajectory of cognitive tests results varied between individual participants. Percentage of variance of change was explained by the following predictors: 21 in MMSE, 24 in MoCA, 8 in DR, 25 in VF, and 24 in TMT B. Age and the presence of varicose veins were significantly linked to negative changes in MMSE and MoCA scores, while working in a professional occupational status associated with a higher score. The subgroup with varicose veins did worse on the Delayed Recall subtest of MoCA.ConclusionCognitive reserve could be extended by proxies of reserve that are related to systemic health and travel activity. The latter is a combination of social, physical, and cognitive activity and potentially might serve as an intervention to improve cognitive function in older people. However, due to the limitations of this study, results should be interpreted with caution and needs to be replicated in the further studies.

The purpose of this study is to assess the cardiovascular system response to orthostatic stress in a group of 133 healthy men using heart rate asymmetry (HRA) methods. HRA is a feature of variability in human heart rate which is dependent upon external and internal body conditions. The initial phases of head-up tilt test (HUTT), namely, supine and tilt, were chosen as the external body affecting factors. Various calculation methods of HRA, such as Porta’s index (PI), Guzik’s index (GI), and its variance based components, were used to assess the heart rate variability (HRV) and its asymmetry. We compared 5-min ECG recordings from both supine and tilt phases of HUT test. Short-term HRA was observed in 54.1% of men in supine phase and 65.4% of men in tilt phase. The study revealed significant increase of GI (from 0.50 to 0.52, p < 0.001) in the tilt phase as well as significant changes in HRV descriptors between HUTT phases. Our results showed that the variability of human heart rate and its asymmetry are sensitive to orthostatic stress. The study of short-term HRA is a potential additional tool to increase sensitivity in conditions where HUTT is a diagnostic tool, such as vasovagal syncope.

Myalgic encephalomyelitis/ Chronic fatigue syndrome (ME/CFS) has been associated with abnormalities in mitochondrial function. In this study we have analysed previous bioenergetics data in peripheral blood mononuclear cells (PBMCs) using new techniques in order to further elucidate differences between ME/CFS and healthy control cohorts. We stratified our ME/CFS cohort into two individual cohorts representing moderately and severely affected patients in order to determine if disease severity is associated with bioenergetic function in PBMCs. Both ME/CFS cohorts showed reduced mitochondrial function when compared to a healthy control cohort. This shows that disease severity does not correlate with mitochondrial function and even those with a moderate form of the disease show evidence of mitochondrial dysfunction. Equations devised by another research group have enabled us to calculate ATP-linked respiration rates and glycolytic parameters. Parameters of glycolytic function were calculated by taking into account respiratory acidification. This revealed severely affected ME/CFS patients to have higher rates of respiratory acidification and showed the importance of accounting for respiratory acidification when calculating parameters of glycolytic function. Analysis of previously published glycolysis data, after taking into account respiratory acidification, showed severely affected patients have reduced glycolysis compared to moderately affected patients and healthy controls. Rates of ATP-linked respiration were also calculated and shown to be lower in both ME/CFS cohorts. This study shows that severely affected patients have mitochondrial and glycolytic impairments, which sets them apart from moderately affected patients who only have mitochondrial impairment. This may explain why these patients present with a more severe phenotype.

Objective: Investigate global and regional grey and white matter volumes in patients with Chronic Fatigue Syndrome (CFS) using magnetic resonance imaging (MRI) and recent voxel-based morphometry (VBM) methods. Methods: Forty-two patients with CFS and thirty healthy volunteers were scanned on a 3-Tesla MRI scanner. Anatomical MRI scans were segmented, normalized and submitted to a VBM analysis using randomisation methods. Group differences were identified in overall segment volumes and voxel-wise in spatially normalized grey matter (GM) and white matter (WM) segments. Results: Accounting for total intracranial volume, patients had larger GM volume and lower WM volume. The voxel-wise analysis showed increased GM volume in several structures including the amygdala and insula in the patient group. Reductions in WM volume in the patient group were seen primarily in the midbrain, pons and right temporal lobe. Conclusion: Elevated GM volume in CFS is seen in areas related to processing of interoceptive signals and stress. Reduced WM volume in the patient group partially supports earlier findings of WM abnormalities in regions of the midbrain and brainstem. Keywords: Chronic Fatigue Syndrome, Voxel-based morphometry, Insula, Amygdala, Midbrain

Plain English summary Many funding bodies within the United Kingdom and globally have encouraged public involvement in research. The Department of Health has also called public involvement a sign of good research. Despite the wide acceptance of public involvement improving many aspects of research, from its design to its communication, involvement has varied levels of implementation across different fields of research. Sports people have rarely been involved in research, partly as this research tends not to be funded by mainstream funding bodies. This may lead to a lower research quality, not founded in player (‘service user’) experiences. When creating a study of former rugby player health, we were very keen to involve rugby players, understand their thoughts on player health, and their playing experiences. This article explains how rugby players were involved in several ways, but mainly in group discussions during the design stage. These groups helped to inform our study’s aims and questionnaire, ensure the questionnaire would capture player experiences and answer questions relevant to players, that they would like to understand after their participation in rugby. We found that these groups were easy to arrange, and that in only one session with each group, we were given many ideas of how to improve the questionnaire and study. We believe that other studies in sports should involve sports people, and that this is a useful activity that will change data collection forms and processes, improving the research, helping researchers, and making studies more suitable for players who take part in them. Abstract Background Patient and public involvement (‘involvement’) in the UK has increased in accordance with funding requirements, patient-centered health policy initiatives and reporting of the positive impact of involvement for those involved, research and researchers. However, involvement has not been implemented equally across all disease areas and populations. The aim of this process was to involve rugby players across the research cycle of a player health study, ensure the study is player-centred, and that players had approved and informed the design of the study and its questionnaire from their playing experiences. Methods Two group discussions were undertaken with current students who were playing rugby at a Collegiate University. All male and female University rugby players and two College rugby teams were approached to become involved. Sessions were chaired by a player-lead using a topic guide and were audio-recorded and transcribed. Player suggestions were extracted by the player-lead and discussed within the study team for inclusion in the player health study and its questionnaire. Results Players readily engaged with the sessions and made many contributions to the development of the study and the questionnaire. Players discussed whether certain topics were being collected satisfactorily, and whether the questionnaire would encompass their playing experiences or that of other players. Players suggested where answers might be less reliable, and ways in which this could be improved. Players recommended additions to the questionnaire, and questioned researchers on the choice of language, motivation for question inclusion and if measures were standardised or novel. Alterations were made to the questionnaire based on suggestions, where these were agreed by the study team. Conclusions Involving a group of players in the design of a player health study and questionnaire was not an arduous process and was rewarding for researchers. The process resulted in numerous alterations to the questionnaire and its functionality, which may improve response rate, the experience of players participating in the player health study, and their ability to report relevant information aligned with their previous experience. Player involvement in research was feasible to implement and improved not only the questionnaire, but also researcher confidence in the project and player experiences being accurately captured and leading a reliable data collection processes in a population with the potential for cultural bias to affect the ascertainment of health, pain and injury.

Abnormalities in mitochondrial function have previously been shown in chronic fatigue syndrome (CFS) patients, implying that mitochondrial dysfunction may contribute to the pathogenesis of disease. This study builds on previous work showing that mitochondrial respiratory parameters are impaired in whole cells from CFS patients by investigating the activity of individual mitochondrial respiratory chain complexes. Two different cell types were used in these studies in order to assess individual complex activity locally in the skeletal muscle (myotubes) (n = 6) and systemically (peripheral blood mononuclear cells (PBMCs)) (control n = 6; CFS n = 13). Complex I, II and IV activity and respiratory activitysupported by fatty acid oxidation and glutaminolysis were measured usingextracellular flux analysis. Cells were permeabilised and combinations of substrates and inhibitors were added throughout the assays to allow states of mitochondrial respiration to be calculated and the activity of specific aspects of respiratory activity to be measured. Results showed there to be no significant differences in individual mitochondrial complex activity or respiratory activity supported by fatty acid oxidation or glutaminolysis between healthy control and CFS cohorts in either skeletal muscle (p ≥ 0.190) or PBMCs (p ≥ 0.065). This is the first study to use extracellular flux analysisto investigate individual mitochondrial complex activity in permeabilised cells in the context of CFS. The lack of difference in complex activity in CFS PBMCs suggests that the previously observed mitochondrial dysfunction in whole PBMCs is due to causes upstream of the mitochondrial respiratory chain.

Aim: The paper presents a meta-analysis of studies comparing hemodynamic parameters: heart rate (HR), systolic blood pressure (sBP), diastolic blood pressure (dBP), and stroke volume (SV) measured during head-up tilt table test (HUTT) in patients with positive and negative HUT test outcome.Methods: Pubmed and Clinical Key databases were searched for English-only articles presenting results of biosignals measurements during tilt test in patients suffering from syncope. From 3,289 articles 13 articles published between 1997 and 2015 investigating 892 patients (467 with positive HUTT outcome and 401 with negative one) were selected.Results: There were not statistically significant differences observed between the parameters measured in supine position in patients with positive and negative test outcome [HR (p = 0.86), sBP (p = 0.32), dBP (p = 0.21), SV (p = 0.71)]. In tilt position the parameters HR and SV were significantly different when compared between the two groups of patients [HR (p = 0.02), sBP (p = 0.10), dBP (p = 0.59), SV (p = 0.0004)].Conclusions: Changes in HR and SV parameters in response to tilt test turned out to be statistically significant. In supine position the differences between patients with positive and negative test outcome were not significant, hence tilt test can be considered as necessary in the diagnosis of vasovagal syndrome.

OBJECTIVES:To explore cognitive performance in chronic fatigue syndrome (CFS) examining two cohorts. To establish findings associated with CFS and those related to co-morbid depression or autonomic dysfunction. METHODS:Identification and recruitment of participants was identical in both phases, all CFS patients fulfilled Fukuda criteria. In Phase 1 (n = 48) we explored cognitive function in a heterogeneous cohort of CFS patients, investigating links with depressive symptoms (HADS). In phase 2 (n = 51 CFS & n = 20 controls) participants with co-morbid major depression were excluded (SCID). Furthermore, we investigated relationships between cognitive performance and heart rate variability (HRV). RESULTS:Cognitive performance in unselected CFS patients is in average range on most measures. However, 0-23% of the CFS sample fell below the 5th percentile. Negative correlations occurred between depressive symptoms (HAD-S) with Digit-Symbol-Coding (r = -.507, p = .006) and TMT-A (r = -.382, p = .049). In CFS without depression, impairments of cognitive performance remained with significant differences in indices of psychomotor speed (TMT-A: p = 0.027; digit-symbol substitution: p = 0.004; digit-symbol copy: p = 0.007; scanning: p = .034) Stroop test suggested differences due to processing speed rather than inhibition. Both cohorts confirmed relationships between cognitive performance and HRV (digit-symbol copy (r = .330, p = .018), digit-symbol substitution (r = .313, p = .025), colour-naming trials Stroop task (r = .279, p = .050). CONCLUSION:Cognitive difficulties in CFS may not be as broad as suggested and may be restricted to slowing in basic processing speed. While depressive symptoms can be associated with impairments, co-morbidity with major depression is not itself responsible for reductions in cognitive performance. Impaired autonomic control of heart-rate associates with reductions in basic processing speed.

IntroductionA large body of evidence has established a pattern of altered functioning in the immune system, autonomic nervous system and hypothalamic pituitary adrenal axis in chronic fatigue syndrome. However, the relationship between components within and between these systems is unclear. In this paper we investigated the underlying network structure of the autonomic system in patients and controls, and a larger network comprising all three systems in patients alone.MethodsIn a sample of patients and controls we took several measures of autonomic nervous system output during 10 minutes of supine rest covering tests of blood pressure variability, heart rate variability and cardiac output. Awakening salivary cortisol was measured on each of two days with participants receiving 0.5mg dexamethasone during the afternoon of the first day. Basal plasma cytokine levels and the in vitro cytokine response to dexamethasone were also measured. Symptom outcome measures used were the fatigue impact scale and cognitive failures questionnaire. Mutual information criteria were used to construct networks describing the dependency amongst variables. Data from 42 patients and 9 controls were used in constructing autonomic networks, and 15 patients in constructing the combined network.ResultsThe autonomic network in patients showed a more uneven distribution of information, with two distinct modules emerging dominated by systolic blood pressure during active stand and end diastolic volume and stroke volume respectively. The combined network revealed strong links between elements of each of the three regulatory systems, characterised by three higher modules the centres of which were systolic blood pressure during active stand, stroke volume and ejection fraction respectively.ConclusionsCFS is a complex condition affecting physiological systems. It is important that novel analytical techniques are used to understand the abnormalities that lead to CFS. The underlying network structure of the autonomic system is significantly different to that of controls, with a small number of individual nodes being highly influential. The combined network suggests links across regulatory systems which shows how alterations in single nodes might spread throughout the network to produce alterations in other, even distant, nodes. Replication in a larger cohort is warranted.

Background and objective: This is the first study to investigate the effect of high-flow oxygen therapy, using a normobaric chamber on cognitive, biochemical (oxidative stress parameters and the level of neurotrophins), cardiovascular and autonomic functioning. Materials and methods: 17 healthy volunteers, eight males and nine females, with a mean age of 37.5 years, were examined. The experimental study involved ten two-hour exposures in a normobaric chamber with a total pressure of 1500 hPa, in air adjusted to 37% oxygen, 1.079% carbon dioxide and 0.44% hydrogen. Cognitive function was assessed by using Trail Making Test parts A, B and difference in results of these tests (TMT A, TMT B and TMT B-A); California Verbal Learning Test (CVLT); Digit symbol substitution test (DSST); and Digit Span (DS). Fatigue (Fatigue Severity Scale (FSS)), cardiovascular, autonomic and baroreceptor functioning (Task Force Monitor) and biochemical parameters were measured before and after intervention. Results: After 10 sessions in the normobaric chamber, significant decreases in weight, caused mainly by body fat % decrease (24.86 vs. 23.93%, p = 0.04 were observed. TMT part A and B results improved (p = 0.0007 and p = 0.001, respectively). In contrast, there was no statistically significant influence on TMT B-A. Moreover, decrease in the number of symbols left after a one-minute test in DSST was noted (p = 0.0001). The mean number of words correctly recalled in the CVLT Long Delay Free Recall test improved (p = 0.002), and a reduction in fatigue was observed (p = 0.001). Biochemical tests showed a reduction in levels of malondialdehyde (p < 0.001), with increased levels of Cu Zn superoxide dismutase (p < 0.001), Neurotrophin 4 (p = 0.0001) and brain-derived neurotrophic factor (p = 0.001). A significant increase in nitric oxide synthase 2 (Z = 2.29, p = 0.02) and Club cell secretory protein (p = 0.015) was also noted. Baroreceptor function was significantly improved after normobaric exposures (p = 0.003). Significant effect of normobaric exposures and BDNF in CVLT Long Delay Free Recall was noted. Conclusions: This study demonstrates that 10 exposures in a normobaric chamber have a positive impact on visual information and set-shifting processing speed and increase auditory-verbal short-term memory, neurotrophic levels and baroreceptor function. A response of the respiratory tract to oxidative stress was also noted. There is a need to rigorously examine the safety of normobaric therapy. Further studies should be carried out with physician examination, both pre and post treatment.

Background: Cognitive reserve is a way of explaining why some individuals with a high degree of brain pathology are without clinical manifestations. In this study, factors related to systemic diseases, body composition, aerobic capacity, past and current behavior were examined and included as predictors of cognitive function.Materials and Methods: 407 subjects (60–88 years old) underwent physical examination and cognitive function assessment [Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Trail Making Test Part B (TMT B)]. Predictors of cognitive functioning were evaluated: occupational status (OS), diet, mental and touristic activities were assessed using an ad hoc questionnaire. Aerobic capacity was measured using a six-minute walk test (6MWT).Results: With each year of age there is a decrease in MMSE score by 0.18 points. Varicose veins on lower extremities and low OS were also significantly associated with MMSE result. For every year of having hypertension, low OS and not being abroad in the last 3 years, there was 0.17, 0.30, and 0.16 less points, respectively, and 0.15 more point per one additional meter walked in 6MWT in the MoCA score. With each year of age and for low OS there was there were 0.31 and 0.21 s more to complete TMT B, respectively.Conclusion: Education, OS, presence of systemic diseases and social and tourist activities, aerobic capacity and body composition could be considered as factors contributing to cognitive functioning in older people. However, the relationship of above mentioned factors with education level and cognitive function may be not fully orthogonal.

The main objective of the study was to analyze the impact of sleep deprivation upon hemodynamic and autonomic parameters in subjects with normal blood pressure (BP) compared to prehypertension and hypertension at 24, 28, and 32 h of total sleep deprivation (TSD). Thirty volunteers, healthy men with current medical tests indicating the absence of disease took part in the study. After physical examination (basic neurological, clinical examination, echocardiography and doppler ultrasound of the renal arteries, evaluation of the autonomic nervous system) subjects were divided into three groups: I – normotensive, II – pre-hypertensive, III – hypertensive (age: 31.2 ± 2.1 vs. 33.5 ± 2.7 vs. 36.8 ± 2.7 years, p > 0.05; BMI: 25.2 ± 0.8 vs. 29.0 ± 1.5 vs. 26.4 ± 1.0 kg/m2, p > 0.05). Hemodynamic and autonomic parameters were automatically measured at rest and in a tilted position with a Task Force Monitor. The Task Force Monitor consists of electrocardiography, impedance cardiography, oscillometric, and continuous BP measurement. Mixed models with random effects was applied in order to analyze the parameters’ dependence on the time and the group of patients. One-way ANOVA or Kruskal–Wallis test were used to detect differences between normotensive, pre-hypertensive and hypertensive groups in each time point. In the pre-hypertensive group 28-h TSD resulted in increased vagal outflow [changes in high frequency heart rate (HR) variability, p = 0.0189], as evidenced by decreased HR (p = 0.0293). Moreover after 24-h TSD and 28-h TSD we observed changes in BP parameters. In hypertensive group, the most important changes in hemodynamic parameters: systolic blood pressure (sBP, p = 0.0031), diastolic blood pressure (dBP, p = 0.0136), cardiac output (CO, p = 0.0439) and changes in HR (p = 0.0063) after tilt test were observed after 32-h TSD. In conclusion, our results show that changes in hemodynamic parameters during sleep deprivation depend on the baseline BP and duration of TSD. What is important, both groups reported a decrease of sBP and dBP during the TSD (pre-hypertensive group after 24, 28-h TSD; hypertensive group after 32-h TSD. In our opinion, this is the first study which considers three homogenous groups in terms of gender: only men, during different points of acute TSD: 24, 28, and 32 h of TSD in laboratory condition.

Background: Primary biliary cirrhosis (PBC) is an autoimmune liver disease, and 50% of patients with this disease experience fatigue. This is a debilitating symptom affecting quality of life and resulting in social isolation, which is highlighted by patients as a research priority. PBC is characterised immunologically by the presence of high-titre autoantibodies that are directed at the pyruvate dehydrogenase complex (PDC) and are highly effective at blocking its energy generation function. We hypothesised that if anti-PDC antibodies were a driver of fatigue through bioenergetic dysfunction, then the B-cell-targeting biological agent rituximab (MabThera®, Roche Products Ltd, Welwyn Garden City, UK) might be a therapeutic option. Objective: To assess whether or not rituximab safely improved moderate or severe fatigue in PBC patients. Design: A Phase II, double-blind, randomised controlled trial comparing rituximab with placebo in fatigued PBC patients. Randomisation was conducted using a web-based system. Participants received two infusions on days 1 and 15 and were followed up at 3, 6, 9 and 12 months. Setting: A single-centre UK study in Newcastle upon Tyne Hospitals NHS Foundation Trust. Participants: Seventy-one participants aged ≥ 18 years with PBC and moderate or severe fatigue (score of > 33 on the PBC-40 fatigue domain) were screened. The PBC-40 questionnaire is a fully validated disease-specific health-related quality-of-life measure for use in patients with PBC. Fatigue, with a maximum score of 55, is one of its six domains. Fifty-seven participants were randomised to the trial, 55 of whom reached the primary end-point assessment. Intervention: Participants were randomised in a 1 : 1 ratio to receive either rituximab (1000 mg) or a saline intravenous infusion (placebo) on days 1 and 15. The infusions were delivered in a double-blind manner using the same protocol. Main outcome measures: The primary outcome measure was the PBC-40 fatigue domain at 3 months, assessed on an intention-to-treat basis. Secondary outcome measures included markers of bioenergetics function (anaerobic threshold and post-exercise muscle pH assessed using magnetic resonance imaging) and physical activity levels. Impact on biochemical markers of liver disease severity was assessed as an experimental outcome. Results: Rituximab therapy was safe, with no serious adverse events linked to the drug. There was no statistically significant difference in fatigue score at 3 months between the rituximab and placebo arms [adjusted mean difference –0.9, 95% confidence interval (CI) –4.6 to 3.1]. However, improvement in fatigue was observed in both arms {mean score decreasing from 41.2 [standard deviation (SD) 5.5] to 36.2 (SD 8.4) in the rituximab arm and from 43.0 (SD 5.9) to 38.1 (SD 8.7) in the placebo arm}. There was little difference in any of the secondary outcomes between arms. However, anaerobic threshold improved significantly in the rituximab arm (adjusted mean difference at 3 months 1.41, 95% CI 0.03 to 2.80). No change in muscle bioenergetics characteristics was seen. A suggestive improvement in liver biochemistry was observed. Limitations: Recruitment was lower than the original target, leading to a reduction in study power. A clinically significant placebo effect on PBC-40 fatigue scores was seen. Conclusions: Rituximab is ineffective for the treatment of fatigue in unselected PBC patients despite metabolic modulation through improvement of anaerobic threshold. Future work: Results from the trial demonstrate that metabolic effect of rituximab is not translated into clinical benefit. This will help to guide us to design future trials and when looking at completely different targets. Trial registration: Current Controlled Trials ISRCTN03978701, ClinicalTrials.gov identifier NCT02376335 and EudraCT number 2012-000145-12. Funding: This project was funded by the National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation programme and will be published in full in Efficacy and Mechanism Evaluation; Vol. 5, No. 2. See the NIHR Journals Library website for further project information. Additional funding was received from the Medical Research Council and a Department of Health and Social Care subvention.

Glucocorticoid receptor (GR) function may have aetiopathogenic significance in chronic fatigue syndrome (CFS), via its essential role in mediating inflammatory responses as well as in hypothalamic-pituitary-adrenal axis regulation. GR function can be estimated ex vivo by measuring dexamethasone (dex) modulation of cytokine response to lipopolysaccharide (LPS), and in vivo using the impact of dex on cortisol levels. This study aimed to compare the GR function between CFS (n=48), primary Sjögren’s syndrome (a disease group control) (n=27), and sedentary healthy controls (HCs) (n=20), and to investigate its relationship with clinical measures. In the GR ex vivo response assay, whole blood was diluted and incubated with LPS (to stimulate cytokine production), with or without 10 or 100 nanomolar concentrations of dex. Cytometric bead array (CBA) and flow cytometry enabled quantification of cytokine levels (TNFα, interleukin- (IL-) 6, and IL-10) in the supernatants. In the in vivo response assay, five plasma samples were taken for determination of total cortisol concentration using ELISA at half-hourly intervals on two consecutive mornings separated by ingestion of 0.5 mg of dex at 11 pm. The association of the data from the in vivo and ex vivo analyses with reported childhood adversity was also examined. CFS patients had reduced LPS-induced IL-6 and TNFα production compared to both control groups and reduced suppression of TNFα by the higher dose of dex compared to HCs. Cortisol levels, before or after dex, did not differ between CFS and HCs. Cortisol levels were more variable in CFS than HCs. In the combined group (CFS plus HC), cortisol concentrations positively and ex vivo GR function (determined by dex-mediated suppression of IL-10) negatively correlated with childhood adversity score. The results do not support the hypothesis that GR dysregulation is aetiopathogenic in CFS and suggest that current and future endocrine cross-sectional studies in CFS may be vulnerable to the confounding influence of childhood trauma which is likely increased by comorbid depression.

Symptoms of orthostatic intolerance (OI) are common in Chronic Fatigue Syndrome (CFS) and similar disorders. These symptoms may relate to individual differences in intracranial compliance and cerebral blood perfusion. The present study used phase-contrast, quantitative flow magnetic resonance imaging (MRI) to determine intracranial compliance based on arterial inflow, venous outflow and cerebrospinal fluid flow along the spinal canal into and out of the cranial cavity. Flow-sensitive Alternating Inversion Recovery (FAIR) Arterial Spin Labelling was used to measure cerebral blood perfusion at rest. Forty patients with CFS and 10 age and gender matched controls were scanned. Severity of symptoms of OI was determined from self-report using the Autonomic Symptom Profile. CFS patients reported significantly higher levels of OI (p < .001). Within the patient group, higher severity of OI symptoms were associated with lower intracranial compliance (r = -.346, p = .033) and higher resting perfusion (r = .337, p = .038). In both groups intracranial compliance was negatively correlated with cerebral perfusion. There were no significant differences between the groups in intracranial compliance or perfusion. In patients with CFS, low intracranial compliance and high resting cerebral perfusion appear to be associated with an increased severity of symptoms of OI. This may signify alterations in the ability of the cerebral vasculature to cope with changes to systemic blood pressure due to orthostatic stress, but this may not be specific to CFS.

Chronic fatigue syndrome (CFS) is characterised by a constellation of symptoms diagnosed with a number of different polythetic criteria. Heterogeneity across these diagnostic criteria is likely to be confounding research into the as-yet-unknown pathophysiology underlying this stigmatised and debilitating condition and may diagnose a disease spectrum with significant implications for clinical management. No studies to date have objectively investigated this possibility using a validated measure of CFS symptoms-the DePaul Symptom Questionnaire (DSQ).To examine whether current CFS diagnostic criteria are identifying different disease phenotypes using the DSQ.Case control study.Clinical Research Facility of the Royal Victoria Infirmary, Newcastle upon Tyne, UK.49 CFS subjects and ten matched, sedentary community controls, excluded for co-morbid depression.Self-reported autonomic and cognitive features were assessed with the Composite Autonomic Symptom Score (COMPASS) and Cognitive Failures Questionnaire (COGFAIL) respectively. Objective autonomic cardiovascular parameters were examined using the Task Force® Monitor and a battery of neuropsychological tests administered for objective cognitive assessment.Self-reported autonomic and cognitive symptoms were significantly greater in CFS subjects compared to controls. There were no statistically significant differences in objective autonomic measures between CFS and controls. There were clinically significant differences between DSQ subgroups on objective autonomic testing. Visuospatial memory, verbal memory and psychomotor speed were significantly different between DSQ subgroups.The finding of no significant differences in objective autonomic testing between CFS and control subjects may reflect the inclusion of sedentary controls or exclusion for co-morbid depression. Consistent exclusion criteria would enable better delineation of these two conditions and their presenting symptoms. Findings across CFS subgroups suggest subjects have a different disease burden on subjective and objective measures of function, autonomic parameters and cognitive impairment when categorised using the DSQ. Different CFS criteria may at best be diagnosing a spectrum of disease severities and at worst different CFS phenotypes or even different diseases. This complicates research and disease management and may contribute to the significant stigma associated with the condition.

Our objective was to explore the implementation of a novel NHS England (NHSE)-funded pilot project aimed at deploying clinical pharmacists in an integrated urgent care (IUC) setting including the NHS 111 service. Eight integrated urgent care clinical pharmacists (IUCCPs) within the participating North East of England Trusts. Individuals participated in semi-structured 1-to-1 interviews by an experienced qualitative researcher, either face-to-face or via the telephone. Each recording was transcribed, and the five stages of framework analysis (familiarisation, identifying a thematic framework, indexing, charting, mapping and interpretation) took place to establish emerging themes. All interviews took place between November 2018−February 2019. Four higher-order themes were identified: 1. Personality Traits, 2. Integration, 3. Benefits, 4. Training. The IUCCP programme is an innovative NHSE initiative. It provides an opportunity to extend the role of clinical pharmacists into the hard-pressed clinical environment of urgent and emergency care. Our evaluation has highlighted the potential for this professional group to contribute clinically in this area. Better communications, standard operating procedures and induction will improve how individuals develop in these novel roles.

Background and Objectives: Determining the clinical course of multiple sclerosis (MS) and prediction of long-term disability can be a big challenge. To determine early clinical features of MS, their influence on long-term disability progression, and time to transition from relapsing-remitting MS (RRMS) to secondary progressive MS (SPMS), a cohort of Polish patients was studied. Materials and Methods: We retrospectively evaluated 375 Polish MS patients based on data from available medical records. We assessed early clinical MS features and the relationship between demographics and time from disease onset to attainment of 4 and 6 points on the Expanded Disability Status Scale (EDSS), as well as time to conversion from RRMS to SPMS. Results: The differences between initial MS variants were significantly associated with gender, age at disease onset, number and type of the first symptoms, and rate of the disability accrual. Mean times from disease onset to attainment of EDSS 4 and 6 were significantly influenced by the disease variant, age at onset, gender, degree of recovery from the initial symptoms, and first inter-bouts interval. The mean time to secondary progression was significantly influenced by the number and type of the first symptoms of RRMS. Conclusions: Early clinical features of MS are important in determining the disease variant, the time to transition from RRMS to SPMS, as well as predicting the disability accumulation of patients. Despite the small differences regarding the first MS symptoms, the disability outcomes in the cohort of Polish patients are similar to other regions of the world.

Introduction. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a debilitating disorder of unknown aetiology, characterised by severe disabling fatigue in the absence of alternative diagnosis. Historically, there has been a tendency to draw psychological explanations for the origin of fatigue; however, this model is at odds with findings that fatigue and accompanying symptoms may be explained by central and peripheral pathophysiological mechanisms, including effects of the immune, oxidative, mitochondrial, and neuronal pathways. For example, patient descriptions of their fatigue regularly cite difficulty in maintaining muscle activity due to perceived lack of energy. This narrative review examined the literature for evidence of biochemical dysfunction in CFS/ME at the skeletal muscle level. Methods. Literature was examined following searches of PUB MED, MEDLINE, and Google Scholar, using key words such as CFS/ME, immune, autoimmune, mitochondria, muscle, and acidosis. Results. Studies show evidence for skeletal muscle biochemical abnormality in CFS/ME patients, particularly in relation to bioenergetic dysfunction. Discussion. Bioenergetic muscle dysfunction is evident in CFS/ME, with a tendency towards an overutilisation of the lactate dehydrogenase pathway following low-level exercise, in addition to slowed acid clearance after exercise. Potentially, these abnormalities may lead to the perception of severe fatigue in CFS/ME.

MethodsWe obtained a time series of tongue/throat swabs from 90 patients with lower limb fracture, aged 65-101 in a general hospital in the North East of England between April 2009-July 2010. We used novel real-time multiplex PCR assays to detect S. aureus, MRSA, E. coli, P. aeruginosa, S. pneumoniae, H. influenza and Acinetobacter spp. We collected data on dental/denture plaque (modified Quigley-Hein index) and outcomes of clinician-diagnosed HAP.ResultsThe crude incidence of HAP was 10% (n = 90), with mortality of 80% at 90 days post discharge. 50% of cases occurred within the first 25 days. HAP was not associated with being dentate, tooth number, or heavy dental/denture plaque. HAP was associated with prior oral carriage with E. coli/S. aureus/P.aeruginosa/MRSA (p = 0.002, OR 9.48 95% CI 2.28-38.78). The incidence of HAP in those with carriage was 35% (4% without), with relative risk 6.44 (95% CI 2.04-20.34, p = 0.002). HAP was associated with increased length of stay (Fishers exact test, p=0.01), with mean 30 excess days (range -11.5-115). Target organisms were first detected within 72 hours of admission in 90% participants, but HAP was significantly associated with S. aureus/MRSA/P. aeruginosa/E. coli being detected at days 5 (OR 4.39, 95%CI1.73-11.16) or 14 (OR 6.69, 95%CI 2.40-18.60).ConclusionsPatients with lower limb fracture who were colonised orally with E. coli/ S. aureus/MRSA/P. aeruginosa after 5 days in hospital were at significantly greater risk of HAP (p = 0.002).

OBJECTIVES:The precise relationship between sleep and physical and mental functioning in chronic fatigue syndrome (CFS) has not been examined directly, nor has the impact of daytime napping. This study aimed to examine self-reported sleep in patients with CFS and explore whether sleep quality and daytime napping, specific patient characteristics (gender, illness length) and levels of anxiety and depression, predicted daytime fatigue severity, levels of daytime sleepiness and cognitive functioning, all key dimensions of the illness experience. METHODS:118 adults meeting the 1994 CDC case criteria for CFS completed a standardised sleep diary over 14 days. Momentary functional assessments of fatigue, sleepiness, cognition and mood were completed by patients as part of usual care. Levels of daytime functioning and disability were quantified using symptom assessment tools, measuring fatigue (Chalder Fatigue Scale), sleepiness (Epworth Sleepiness Scale), cognitive functioning (Trail Making Test, Cognitive Failures Questionnaire), and mood (Hospital Anxiety and Depression Scale). RESULTS:Hierarchical Regressions demonstrated that a shorter time since diagnosis, higher depression and longer wake time after sleep onset predicted 23.4% of the variance in fatigue severity (p

Post exertional muscle fatigue is a key feature in Chronic Fatigue Syndrome (CFS). Abnormalities of skeletal muscle function have been identified in some but not all patients with CFS. To try to limit potential confounders that might contribute to this clinical heterogeneity, we developed a novel in vitro system that allows comparison of AMP kinase (AMPK) activation and metabolic responses to exercise in cultured skeletal muscle cells from CFS patients and control subjects.Skeletal muscle cell cultures were established from 10 subjects with CFS and 7 age-matched controls, subjected to electrical pulse stimulation (EPS) for up to 24h and examined for changes associated with exercise.In the basal state, CFS cultures showed increased myogenin expression but decreased IL6 secretion during differentiation compared with control cultures. Control cultures subjected to 16 h EPS showed a significant increase in both AMPK phosphorylation and glucose uptake compared with unstimulated cells. In contrast, CFS cultures showed no increase in AMPK phosphorylation or glucose uptake after 16 h EPS. However, glucose uptake remained responsive to insulin in the CFS cells pointing to an exercise-related defect. IL6 secretion in response to EPS was significantly reduced in CFS compared with control cultures at all time points measured.EPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells. We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6. The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets.

Syncope is a sudden transient loss of consciousness with loss of postural tone, followed by spontaneous recovery1. Around 30 percent of the general population have one syncopal event in their lifetime, with 3% having recurrent episodes2. Vasovagal syncope (VVS) is an exaggerated tendency towards the common faint that accounts for up to 29% of syncope3 and affects all age groups. VVS is characterised by profound hypotension with or without bradycardia. Those with VVS are at risk of injury during episodes and the long term implications of recurrent episodes of hypotension are unclear1. The underlying pathophysiology of VVS is uncertain and current treatments involve salt and fluid replacement and maintenance of blood pressure using mineralocorticoids or alpha agonists1. These treatments are largely symptomatic and may be associated with side effects that make their use in younger age groups inappropriate4.