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Objective: To determine the efficacy and safety of nonpharmacologic interventions for orthostatic hypotension (OH) secondary to aging., Methods: A total of 150 orthostatic challenges were performed in 25 older people (age 60-92 years) to determine cardiovascular responses to bolus water drinking, compression stockings, abdominal compression, and physical countermaneuvers. Primary outcome was response rate as assessed by proportion of participants whose systolic blood pressure (SBP) drop improved by ≥10 mm Hg., Results: The response rate to bolus water drinking was 56% (95% confidence interval [CI] 36.7-74.2), with standing SBP increasing by 12 mm Hg (95% CI 4-20). Physical countermaneuvers were efficacious in 44% (95% CI 25.8-63.3) but had little effect on standing SBP (+7.5 mm Hg [95% CI -1 to 16]). Abdominal compression was efficacious in 52% (95% CI 32.9-70.7) and improved standing SBP (+10 mm Hg [95% CI 2-18]). Compression stockings were the least efficacious therapy (32% [95% CI 16.1-51.4]) and had little effect on standing SBP (+6 mm Hg [95% CI -1, 13]). No intervention improved symptoms during standing. There were no adverse events., Conclusions: Bolus water drinking should become the standard first-line nonpharmacologic intervention, whereas compression stockings should be disregarded in this population., Classification of Evidence: This study provides Class III evidence that for older people with OH, bolus water drinking is superior to other nonpharmacologic interventions in decreasing SBP drop., (Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The aim of this study was to comprehensively determine hemodynamic and autonomic responses during-head up tilt test (HUT) in the acute and recovery phase of ischemic stroke., Methods: Cardiovascular parameters, baroreflex sensitivity (BRS), spectral-indices of heart rate (HRV), systolic (sBPV) and diastolic blood pressure variability (dBPV) were measured at rest in ischemic stroke patients (N.=17) and control group (N.=34). Dynamic cardiac autonomic function was assessed using HUT (Delta [rest-tilt]. Controls were examined once whereas stroke group at two timepoints: on admission and in day 10 (recovery period)., Results: After a recovery period the stroke group showed significantly higher resting values of systolic blood pressure (sBP, P=0.028), systolic time ratio (STR, P=0.023), high frequency sBPV (HF-sBP, P=0.027), high frequency R-R interval (HF-RRI, P=0.048), power spectral density of sBPV (PSD-sBP, P=0.004) and lower sympathovagal ratio (LF/HF, P=0.005), low frequency R-R interval (LF-RRI, P=0.045), BRS and significantly lower increase in post tilt changes in systolic blood pressure (Delta sBP), total peripheral resistance (Delta TPR) compared to controls. No significant differences were observed for post-tilt in all hemodynamic changes compared to admission. After the recovery period the patient group showed an improved blood pressure profile, left ventricular work index, systolic time ratio and BRS compared to admission., Conclusions: Patients with acute ischemic stroke after a recovery period presented autonomic imbalance and impaired cardiac sympathetic modulation at rest and in response to orthostatic challenge compared to a control group. Furthermore, there was a statistically significant decrease in baroreflex sensitivity, suggesting parasympathetic deficiency.

Background: Arterial stiffness (AS) is a reduction in the ability of large arteries to readily accommodate the increase in blood ejected from the heart during systole related with aging. Physical exercise is associated with AS reduction. However, it remains controversial as to which modality and intensity (resistance vs aerobic, high vs low) would be the most effective. The aim of these studies is to examine the effects of 3-months sitting callisthenic balance (SCB) and resistance exercise (RET) on aerobic capacity, aortic stiffness and body composition in older participants., Material and Methods: Aortic pulse wave velocity (PWVao), return time (RT), diastolic reflection area (DRA) and blood pressure (BP) level changes were measured with Arteriograph. Aerobic capacity was examined with 6-min walk test (6-MWT) and spiroergometry (VO2max). Body composition was analyzed by Bioelectric Impedance Analysis using Tanita., Results: Significant improvements of BP, PWVao, RT and DRA were observed in the SCB group (p = 0.018, p = 0.017 and p = 0.012, respectively). % of fat mass improved in RET and SCB group (p = 0.003, p = 0.012, respectively). Visceral fat significantly improved in SCB group (p = 0.03)., Conclusions: Despite no significant changes in indicators of aerobic capacity (VO2max and 6MWT result) in both groups, significant improvement in all measures of AS, except SBPao were observed in the SCB group, while no AS improvement in the RET group was noted. There were some differences in pattern of body compositions improvement between two groups., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

Objective: Functional ability and participation in life situations are compromised in many primary Sjögren's syndrome (SS) patients. This study aimed to identify the key barriers and priorities to participation in daily living activities, in order to develop potential future interventions., Methods: Group concept mapping, a semiquantitative, mixed-methods approach was used to identify and structure ideas from UK primary SS patients, adult household members living with a primary SS patient, and health care professionals. Brainstorming generated ideas, which were summarized into a final set of statements. Participants individually arranged these statements into themes and rated each statement for importance. Multidimensional scaling and hierarchical cluster analysis were applied to sorted and rated data to produce visual representations of the ideas (concept maps), enabling identification of agreed priority areas for interventions., Results: A total of 121 patients, 43 adult household members, and 67 health care professionals took part. In sum, 463 ideas were distilled down to 94 statements. These statements were grouped into 7 clusters: Patient Empowerment, Symptoms, Wellbeing, Access and Coordination of Health Care, Knowledge and Support, Public Awareness and Support, and Friends and Family. Patient Empowerment and Symptoms were rated as priority conceptual themes. Important statements within priority clusters indicate patients should be taken seriously and supported to self-manage symptoms of oral and ocular dryness, fatigue, pain, and poor sleep., Conclusion: Our data highlighted the fact that in addition to managing primary SS symptoms, interventions aiming to improve patient empowerment, general wellbeing, access to health care, patient education, and social support are important to facilitate improved participation in daily living activities., (© 2018 The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Background: The purpose of this study was to compare cardiovascular and autonomic adaptation changes in athletes exposed to high intensity and uninterrupted training for extended periods of time., Methods: We assessed hemodynamic profile and cardiac function in 22 international master-level athletes free of cardiovascular disease who experienced particularly intensive and uninterrupted training over an 8- to 21-year-period., Results: One-way ANOVA revealed that in athletes, extreme and uninterrupted strength and endurance training over long periods of time (up to 21 years) causes an increase in resting heart rate (50.3±7.1 vs. 63.0±10.7, P=0.0429), diastolic (65.8±5.2 vs. 75.2±5.7, P=0.0222) and mean blood pressure (85.4±6.0 vs. 95.6±6.4, P=0.0166). On multiple regression, increasing training experience was related to decrease in RRI (R2=0.18, P=0.0481) and increase in dBP (R2=0.32, P=0.0064) and mBP (R2=0.31, P=0.0075) although the effect was small. A negative correlation was observed between the training age and the parameters describing parasympathetic function: HF-RRI (R=-0.54, P=0.0321), HF-dBP (R=-0.52, P=0.0401) and PSD-RRI (R=-0.51, P=0.0414)., Conclusions: Long-term sport practice at a world class level causes an increase in resting heart rate, diastolic and mean blood pressure, and decrease of the parasympathetic dominance and this may result from decreasing adjustment to large training loads.

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 (TNF α , 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 TNF α production compared to both control groups and reduced suppression of TNF α 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.

Objectives: This study aimed to describe the prevalence and risk of chronic conditions in former elite cricketers compared to a normal population, and describe wellbeing in former elite cricketers., Design: Cross-sectional study., Methods: Former elite cricketers, recruited from the Professional Cricketers' Association, completed a self-report cross-sectional questionnaire. The English Longitudinal Study of Ageing (ELSA) served as the normal population. The prevalence of self-reported, GP-diagnosed conditions (heart problems, hypertension, stroke, diabetes, asthma, dementia, osteoarthritis (OA), total hip replacement (THR), total knee replacement (TKR), anxiety, depression) were reported for both population samples. Standardised morbidity ratios (SMRs) compared chronic conditions in sex-, age- and BMI-matched former cricketers (n=113) and normal population (n=4496)., Results: Heart problems were reported by 13.3% of former cricketers, significantly lower than the normal population, SMR 0.55 (0.33-0.91). Former cricketers reported 31.9% hypertension, 1.8% stroke, 6.2% diabetes, 15.0% asthma, and no dementia, none significantly different to the normal population. OA, THR, and TKR were reported by 51.3%, 14.7% and 10.7% of former cricketers, respectively, significantly higher than the normal population, SMRs 3.64 (2.81-4.71), 3.99 (2.21-7.20) and 3.84 (1.92-7.68). Anxiety and depression were reported by 12.4% and 8.8% of former cricketers, respectively, SMRs 3.95 (2.34-6.67) and 2.22 (1.20-4.14). 97% of former cricketers reflected they would undertake their cricket career again, 98% agreed that cricket enriched their lives., Conclusions: Heart problems were significantly lower, while OA, THR, TKR, anxiety, and depression were significantly higher in the former cricketers compared to the normal population (ELSA). Most former cricketers reflected positively on their career., (Copyright © 2017 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

The aim of this study was to explore the effect of a hyperbaric environment alone on the cardiovascular system by ensuring elimination of factors that may mask the effect on hyperbaria. The research was performed in a hyperbaric chamber to eliminate the effect of physical activity and the temperature of the aquatic environment. Biochemical analysis and examination with the Task Force Monitor device were performed before and immediately after exposure. TFM was used for noninvasive examination of the cardiovascular system and the functional evaluation of the autonomic nervous system. Natriuretic peptides were measured as biochemical markers which were involved in the regulation of haemodynamic circulation vasoconstriction (urotensin II). L-arginine acted as a precursor of the level of the nitric oxide whereas angiotensin II and angiotensin (1-7) were involved in cardiac remodeling. The study group is comprised of 18 volunteers who were professional divers of similar age and experience. The results shown in our biochemical studies do not exceed reference ranges but a statistically significant increase indicates the hyperbaric environment is not without impact upon the human body. A decrease in HR, an increase in mBP, dBP, and TPR, and increase in parasympathetic heart nerves activity suggest an increase in heart afterload with a decrease in heart activity within almost one hour after hyperbaric exposure. Results confirm that exposure to a hyperbaric environment has significant impact on the cardiovascular system. This is confirmed both by changes in peptides associated with poorer cardiovascular outcomes, where a significant increase in the studied parameters was observed, and by noninvasive examination.

Skeletal muscle fatigue and post-exertional malaise are key symptoms of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (ME/CFS). We have previously shown that AMP-activated protein kinase (AMPK) activation and glucose uptake are impaired in primary human skeletal muscle cell cultures derived from patients with ME/CFS in response to electrical pulse stimulation (EPS), a method which induces contraction of muscle cells in vitro The aim of the present study was to assess if AMPK could be activated pharmacologically in ME/CFS. Primary skeletal muscle cell cultures from patients with ME/CFS and healthy controls were treated with either metformin or compound 991. AMPK activation was assessed by Western blot and glucose uptake measured. Both metformin and 991 treatment significantly increased AMPK activation and glucose uptake in muscle cell cultures from both controls and ME/CFS. Cellular ATP content was unaffected by treatment although ATP content was significantly decreased in ME/CFS compared with controls. Pharmacological activation of AMPK can improve glucose uptake in muscle cell cultures from patients with ME/CFS. This suggests that the failure of EPS to activate AMPK in these muscle cultures is due to a defect proximal to AMPK. Further work is required to delineate the defect and determine whether pharmacological activation of AMPK improves muscle function in patients with ME/CFS., (© 2018 The Author(s).)

Introduction: Primary Sjögren's syndrome is the third most common systemic autoimmune rheumatic disease, following rheumatoid arthritis and systemic lupus erythematosus, and results in dryness, fatigue, discomfort and sleep disturbances. Sleep is relatively unexplored in primary Sjögren's syndrome. We investigated the experiences of sleep disturbances from the viewpoint of primary Sjögren's syndrome patients and their partners and explored the acceptability of cognitive behavioural therapy for insomnia., Method: We used focus groups to collect qualitative data from 10 patients with primary Sjögren's syndrome and three partners of patients. The data were recorded, transcribed verbatim and analysed using thematic analysis., Results: Five themes emerged from the data: (a) Experience of sleep disturbances; (b) variation and inconsistency in sleep disturbances; (c) the domino effect of primary Sjögren's syndrome symptoms; (d) strategies to manage sleep; (e) acceptability of evidence-based techniques. Sleep disturbances were problematic for all patients, but specific disturbances varied between participants. These included prolonged sleep onset time and frequent night awakenings and were aggravated by pain and discomfort. Patients deployed a range of strategies to try and self-manage. Cognitive behavioural therapy for insomnia was seen as an acceptable intervention, as long as a rationale for its use is given and it is tailored for primary Sjögren's syndrome., Conclusion: Primary Sjögren's syndrome patients described a range of sleep disturbances. Applying tailored, evidence-based sleep therapy interventions may improve sleep, severity of other primary Sjögren's syndrome symptoms and functional ability.

Objectives: To explore levels of the brain natriuretic peptide (BNP) and how these associate with the cardiac abnormalities recently identified in chronic fatigue syndrome (CFS)., Methods: Cardiac magnetic resonance examinations were performed using 3T Philips Intera Achieva scanner (Best, Netherlands) in CFS (Fukuda) participants and sedentary controls matched group wise for age and sex. BNP was also measured by using an enzyme immunoassay in plasma from 42 patients with CFS and 10 controls., Results: BNP levels were significantly higher in the CFS cohort compared with the matched controls (P=0.013). When we compared cardiac volumes (end-diastolic and end-systolic) between those with high BNP levels (BNP >400 pg/mL) and low BNP (<400 pg/mL), there were significantly lower cardiac volumes in those with the higher BNP levels in both end-systolic and end-diastolic volumes (P=0.05). There were no relationships between fatigue severity, length of disease and BNP levels (P=0.2) suggesting that our findings are unlikely to be related to deconditioning., Conclusion: This study confirms an association between reduced cardiac volumes and BNP in CFS. Lack of relationship between length of disease suggests that findings are not secondary to deconditioning. Further studies are needed to explore the utility of BNP to act as a stratification paradigm in CFS that directs targeted treatments., Trail Registration Number: Registered with NIHR Portfolio CLRN ID 97805., Competing Interests: Competing interests: None declared.

Anterior mid-tibial cortex stress fractures (ATCSF) are uncommon and notoriously challenging to treat. They are termed high risk due to their predilection to prolonged recovery, nonunion and complete fracture. Early diagnosis is essential to avoid progression and reduce fracture complications. Imaging plays a key role in confirming the diagnosis. Magnetic resonance imaging (MRI) is accepted as the gold standard modality due to its high accuracy and nonionizing properties. This report describes three cases of ATCSFs in recreational athletes who had positive radiographic findings with no significant MRI changes. Two athletes had multiple striations within their tibias. Despite the radiographic findings, their severity of symptoms were low with mild or no tenderness on examination. Clinicians should be mindful that the ATCSFs may not present with typical acute stress fracture symptoms. We recommend that plain radiographs should be used as the first line investigation when suspecting ATCSFs. Clinicians should be aware that despite MRI being considered the gold standard imaging modality, we report three cases where the MRI was unremarkable, whilst radiographs and computed tomography confirmed the diagnosis. We urge clinicians to continue to use radiographs as the first line imaging modality for ATCSFs and not to directly rely on MRI. Those who opt directly for MRI may be falsely reassured causing a delay in diagnosis.

The aim of this study was to evaluate cardiovascular autonomic modulation in response to an orthostatic stress in healthy subjects and Parkinson's disease (PD). The study included 47 controls and 56 PD patients divided into groups (vasoconstrictor PD, vasodilator PD, control) according to vasodilation/vasoconstriction response during 70° head up tilt test. Using impedance cardiography (ICG) and electrocardiography (ECG) we measured stroke volume, cardiac output, left ventricular work index, left ventricular ejection time, acceleration index, index of contractility, Heather index, thoracic fluid content, total peripheral resistance, total arterial compliance. We also analyzed heart rate variability (HRV), using spectral analysis and continuous blood pressure (contBP). At rest, the vasodilator PD group showed significantly higher values of total peripheral resistance and lower values of stroke volume and cardiac output, compared to the vasoconstrictor PD and the control groups. A post-tilt drop in ∆ (change rest - tilt) systolic blood pressure, ∆mean blood pressure, ∆total peripheral resistance and ∆Heather index, and a significantly lower increase in ∆diastolic blood pressure was observed in subjects from the vasodilator PD group compared to the vasoconstrictor PD and the control groups. No statistically significant differences were observed for HRV parameters between the vasoconstrictor and vasodilator PD groups, P > .05. Longer duration and higher disease stage of PD correlated with a reduction in post-tilt systolic blood pressure changes in vasodilator group. Positive inotropy of the cardiac muscle represents a significant factor preventing orthostatic hypotension in PD subjects with a concurrent drop in peripheral vascular resistance during orthostatic stress., (© 2017 John Wiley & Sons Australia, Ltd.)

Importance: 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)., Objective: To examine whether current CFS diagnostic criteria are identifying different disease phenotypes using the DSQ., Design: Case control study., Setting: Clinical Research Facility of the Royal Victoria Infirmary, Newcastle upon Tyne, UK., Participants: 49 CFS subjects and ten matched, sedentary community controls, excluded for co-morbid depression., Main Outcomes and Measures: 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., Results: 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., Conclusions and Relevance: 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.

Background: Previous studies have consistently shown increased rates of childhood adversity in chronic fatigue syndrome (CFS). However, such aetiopathogenic studies of CFS are potentially confounded by co-morbidity and misdiagnosis particularly with depression. Purpose: We examined the relationship between rates of childhood adversity using two complimentary approaches (1) a sample of CFS patients who had no lifetime history of depression and (2) a modelling approach. Methods: Childhood trauma questionnaire (CTQ) administered to a sample of 52 participants with chronic fatigue syndrome and 19 controls who did not meet criteria for a psychiatric disorder (confirmed using the Structured Clinical Interview for DSM-IV). Subsequently, Mediation Analysis (Baye's Rules) was used to establish the risk childhood adversity poses for CFS with and without depression. Results: In a cohort of CFS patients with depression comprehensively excluded, CTQ scores were markedly lower than in all previous studies and, in contrast to these previous studies, not increased compared with healthy controls. Post-hoc analysis showed that CTQ scores correlated with the number of depressive symptoms during the lifetime worst period of low mood. The probability of developing CFS given a history of childhood trauma is 4%, a two-fold increased risk compared to the general population. However, much of this risk is mediated by the concomitant development of major depression. Conclusions: The data suggests that previous studies showing a relationship between childhood adversity and CFS may be attributable to the confounding effects of co-morbid or misdiagnosed depressive disorder. Abbreviations: CFS: Chronic fatigue syndrome; CTQ: Childhood trauma questionnaire; MDD: Major depressive disorder; CA: Childhood adversity; P : Probability., Competing Interests: No potential conflict of interest was reported by the authors.

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.

In the general population, physical activity is associated with improved health outcomes. However, long-term sports participation may be associated with adverse outcomes, particularly at the elite level. The aims of this study were to assess morbidity and health-related quality of life (HrQoL) amongst former rugby players, compared to an age-standardised general population sample. A cross-sectional study of former elite, male, rugby players (n = 259) was undertaken, and standardised morbidity ratios (SMR) calculated, assessing morbidity prevalence relative to English Longitudinal Study of Aging participants (ELSA, n = 5186). HrQoL, measured using the EQ-5D, was compared to a Health Survey for England (HSE, n = 2981) sample. In SMR analyses of participants aged 50+, diabetes was significantly lower amongst former players, (0.28, 95% CI 0.11-0.66), whereas osteoarthritis (4.00, 95% CI 3.32-4.81), joint replacement (6.02, 95% CI 4.66-7.77), osteoporosis (2.69, 95% CI 1.35-5.38), and anxiety (2.00, 95% CI 1.11-3.61) were significantly higher. More problems in HrQoL were reported amongst former players within the domains of mobility (p < 0.001), self-care (p = 0.041), usual activities (p < 0.001) and pain/discomfort (p < 0.001). Morbidity and HrQoL differ between players and the general population, with higher musculoskeletal morbidity and lower diabetes amongst former players. The magnitude of musculoskeletal morbidity may warrant proactive osteoarthritis management within this population.

Objectives: Although fatigue is a common symptom for people with rheumatic diseases, limited support is available. This study explored the impact of written information about fatigue, focusing on a booklet, Fatigue and arthritis., Methods: Thirteen patients with rheumatic disease and fatigue were recruited purposively from a rheumatology outpatient service. They were interviewed before and after receiving the fatigue booklet. Two patients, plus six professionals with relevant interests, participated in a focus group. Transcripts were analysed thematically and a descriptive summary was produced., Results: Interviewees consistently reported that fatigue made life more challenging, and none had previously received any support to manage it. Reflecting on the booklet, most said that it had made a difference to how they thought about fatigue, and that this had been valuable. Around half also said that it had affected, or would affect, how they managed fatigue. No one reported any impact on fatigue itself. Comments from interviewees and focus group members alike suggested that the research process may have contributed to the changes in thought and behaviour reported. Its key contributions appear to have been: clarifying the booklet's relevance; prompting reflection on current management; and introducing accountability., Conclusions: This study indicated that written information can make a difference to how people think about fatigue and may also prompt behaviour change. However, context appeared to be important: it seems likely that the research process played a part and that the impact of the booklet may have been less if read in isolation. Aspects of the research appearing to facilitate impact could be integrated into routine care, providing a pragmatic (relatively low-cost) response to an unmet need., (© 2016 The Authors Musculoskeletal Care Published by John Wiley & Sons Ltd.)

The primary objective is the description of bone mineral density (BMD) and body composition in newly licensed jockeys. One in three male, flat jockeys has a very low bone mineral density. Further research is needed to assess the short-term risk of fractures and long-term health implications of these findings., Introduction: Describe bone mineral density (BMD) and body composition in entry-level male and female, flat and jump jockeys in Great Britain., Methods: Data was collected on jockeys applying for a professional jockey license between 2013 and 2015. Areal BMD at the spine, femoral neck (FN), total hip and body composition were assessed by dual-energy X-ray absorptiometry (DXA) scan. We examined differences between BMD and body composition by gender and race type (flat or jump). Volumetric bone mineral apparent density (BMAD) of the spine and FN was also calculated to account for group differences in bone size., Results: Seventy-nine male flat jockeys (age 18.5 ± 1.9, BMI 19.0 ± 1.4), 69 male jump (age 20.7 ± 2.0, BMI 20.6 ± 1.3) and 37 female flat jockeys (age 19.3 ± 2.0, BMI 20.8 ± 1.7) took part in this study. Spine BMD Z-scores ≤-2 for male flat, male jump and female flat jockeys were 29, 13 and 2.7%, respectively. Spine BMD was lower in male than female flat jockeys (p<0.001). All BMD scores were lower in male flat compared to male jump jockeys (p<0.001). Body fat percent (BF %) was lower in male flat jockeys compared to male jump and female flat jockeys (p<0.05). Lean mass index (LMI) was lower in male flat compared to male jump jockeys (p<0.001)., Conclusions: Male flat jockeys had a significantly lower BMD, LMI and BF% compared to jump jockeys and female flat jockeys. Male flat jockeys had lower spine BMD scores than females. Individual bone maturation may influence these findings. Further investigation into the relevance of low BMD and altered body composition on jockey health is required.

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.

Objectives: To identify whether sleep disturbances are more prevalent in primary SS (pSS) patients compared with the general population and to recognize which specific sleep symptoms are particularly problematic in this population., Methods: Electronic searches of the literature were conducted in PubMed, Medline (Ovid), Embase (Ovid), PsychINFO (Ovid) and Web of Science and the search strategy registered a priori . Titles and abstracts were reviewed by two authors independently against a set of prespecified inclusion/exclusion criteria, reference lists were examined and a narrative synthesis of the included articles was conducted., Results: Eight whole-text papers containing nine separate studies met the inclusion criteria and were included in the narrative analysis. Few of these studies met all of the quality assessment criteria. The studies used a range of self-reported measures and objective measures, including polysomnography. Mixed evidence was obtained for some of the individual sleep outcomes, but overall compared with controls, pSS patients reported greater subjective sleep disturbances and daytime somnolence and demonstrated more night awakenings and pre-existing obstructive sleep apnoea., Conclusions: A range of sleep disturbances are commonly reported in pSS patients. Further polysomnography studies are recommended to confirm the increased prevalence of night awakenings and obstructive sleep apnoea in this patient group. pSS patients with excessive daytime somnolence should be screened for co-morbid sleep disorders and treated appropriately. Interventions targeted at sleep difficulties in pSS, such as cognitive behavioural therapy for insomnia and nocturnal humidification devices, have the potential to improve quality of life in this patient group and warrant further investigation., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.)

Physical activity (PA) is increasingly recognised as an important factor within studies of osteoarthritis (OA). However, subjective methods used to assess PA are highly variable and have not been developed for use within studies of OA, which creates difficulties when comparing and interpreting PA data in OA research. The aim of this study was, therefore, to gain expert agreement on the appropriate methods to harmonise PA data among existing population cohorts to enable the investigation of the association of PA and OA. The definition of PA in an OA context and methods of harmonization were established via an international expert consensus meeting and modified Delphi exercise using a geographically diverse committee selected on the basis of individual expertise in physical activity, exercise medicine, and OA. Agreement was met for all aims of study: (1) The use of Metabolic Equivalent of Task (MET) minutes per week (MET-min/week) as a method for harmonising PA variables among cohorts; (2) The determination of methods for treating missing components of MET-min/week calculation; a value will be produced from comparable activities within a representative cohort; (3) Exclusion of the domain of occupation from total MET-min/week; (4) The need for a specific measure of joint loading of an activity in addition to intensity and time, in studies of diseases, such as OA. This study has developed a systematic method to classify and harmonise PA in existing OA cohorts. It also provides minimum requirements for future studies intending to include subjective PA measures.

Background: Chronic Fatigue Syndrome (CFS) is a prevalent debilitating condition that affects approximately 250,000 people in the UK. There is growing interest in the role of mitochondrial function and mitochondrial DNA (mtDNA) variation in CFS. It is now known that fatigue is common and often severe in patients with mitochondrial disease irrespective of their age, gender or mtDNA genotype. More recently, it has been suggested that some CFS patients harbour clinically proven mtDNA mutations., Methods: MtDNA sequencing of 93 CFS patients from the United Kingdom (UK) and South Africa (RSA) was performed using an Ion Torrent Personal Genome Machine. The sequence data was examined for any evidence of clinically proven mutations, currently; more than 200 clinically proven mtDNA mutations point mutations have been identified., Results: We report the complete mtDNA sequence of 93 CFS patients from the UK and RSA, without finding evidence of clinically proven mtDNA mutations. This finding demonstrates that clinically proven mtDNA mutations are not a common element in the aetiology of disease in CFS patients. That is patients having a clinically proven mtDNA mutation and subsequently being misdiagnosed with CFS are likely to be rare., Conclusion: The work supports the assertion that CFS should not be considered to fall within the spectrum of mtDNA disease. However, the current study cannot exclude a role for nuclear genes with a mitochondrial function, nor a role of mtDNA population variants in susceptibility to disease. This study highlights the need for more to be done to understand the pathophysiology of CFS.

The Institute of Medicine (IOM) recently developed clinical criteria for chronic fatigue syndrome (CFS). There might be additional criteria that could select a more homogenous and impaired group of patients, particularly those with pain. The current study focused on criteria which involved meeting the four IOM criteria, excluding medical and psychiatric co-morbidities, along with having fibromyalgia (FM). Findings indicated that those meeting the IOM clinical criteria plus FM were more impaired on a wide variety of symptoms and functional areas than those meeting on the IOM criteria or those with just 6 months of fatigue. The implications of using such research criteria are discussed.

Background: The Institute of Medicine (IOM) recently developed clinical criteria for what had been known as chronic fatigue syndrome (CFS). Given the broad nature of the clinical IOM criteria, there is a need for a research definition that would select a more homogenous and impaired group of patients than the IOM clinical criteria. At the present time, it is unclear what will serve as the research definition., Purpose: The current study focused on a research definition which selected homebound individuals who met the four IOM criteria, excluding medical and psychiatric co-morbidities., Methods: Our research criteria were compared to those participants meeting the IOM criteria. Those not meeting either of these criteria sets were placed in a separate group defined by 6 or more months of fatigue. Data analyzed were from the DePaul Symptom Questionnaire and the SF-36. Due to unequal sample sizes and variances, Welch's F tests and Games-Howell post hoc tests were conducted., Results: Using a large database of over 1,000 patients from several countries, we found that those meeting a more restrictive research definition were even more impaired and more symptomatic than those meeting criteria for the other two groups., Conclusion: Deciding on a particular research case definition would allow researchers to select more comparable patient samples across settings, and this would represent one of the most significant methodologic advances for this field of study.

Background: Cognitive impairment is common in later life. Identifying potential modifiable risk factors for cognitive decline may ameliorate the burden of disease. Cross-sectional studies show an association between blood pressure (BP) variability and impaired cognitive function in patients with hypertension and/or dementia. However, research examining the association between BP variability and cognitive function in the general older population is scarce., Objective: In this study, we examined the association between BP variability and cognitive function over 5-year follow-up in an unselected community-dwelling cohort., Methods: Ambulatory BP monitoring was performed in 353 community-dwelling people aged at least 65 years. Cognitive assessment, using the Mini Mental State Examination (MMSE) and Cambridge Cognitive Examination (CAMCOG), was performed at baseline and at 5-year follow-up. BP variability was calculated using the coefficient of variation. Cognitive change over 5 years was defined as baseline score minus follow-up score., Results: Increased daytime systolic variability was associated with poorer performance on the CAMCOG total score and subscores. Daytime diastolic variability was associated with poorer performance on total CAMCOG, CAMCOG executive score, and MMSE. These findings were independent of demographic and cardiovascular risk factors. Daytime systolic variability was also independently associated with greater decline in total CAMCOG and MMSE scores over 5-year follow-up., Conclusion: Increased BP variability is associated with poorer cognitive function in older people and may represent a novel modifiable risk factor for cognitive decline.

Objectives: The objective of this study was to examine individuals with myalgic encephalomyelitis and chronic fatigue syndrome who are confined to their homes due to severe symptomatology. The existing literature fails to address differences between this group, and less severe, nonhousebound patient populations., Methods: Participants completed the DePaul Symptom Questionnaire, a measure of myalgic encephalomyelitis and chronic fatigue syndrome symptomology, and the SF-36, a measure of health impact on physical/mental functioning. ANOVAs and, where appropriate, MANCOVAS were used to compare housebound and nonhousebound patients with myalgic encephalomyelitis and chronic fatigue syndrome across areas of functioning, symptomatology, and illness onset characteristics., Results: Findings indicated that the housebound group represented one quarter of the sample, and were significantly more impaired with regards to physical functioning, bodily pain, vitality, social functioning, fatigue, postexertional malaise, sleep, pain, neurocognitive, autonomic, neuroendocrine, and immune functioning compared to individuals who were not housebound., Discussion: Findings indicated that housebound patients have more impairment on functional and symptom outcomes compared to those who were not housebound. Understanding the differences between housebound and not housebound groups holds implications for physicians and researchers as they develop interventions intended for patients who are most severely affected by this chronic illness., (© The Author(s) 2016.)

Introduction: good oral hygiene is important for eating, talking and improved quality of life, and is part of basic patient care, but there are few observational studies in hospitalised older patients. The aim of this study is to investigate dental plaque load in older patients over time in hospital., Methods: we examined the mouths of 93 patients with lower limb fracture prospectively at day 1, 7 and 14 after admission in a Newcastle upon Tyne Hospital. We assessed dental and denture plaque load, dry mouth symptoms and tooth number, along with demographic and frailty variables. We used univariate generalised linear modelling and mixed effects models to investigate associations between increased plaque and patient characteristics., Results: in dentate patients, plaque score increased with time in hospital (P = 0.007, odds ratio (OR): 1.02; 95% confidence of interval (CI): 1.01-1.04). Frailty (P = 0.015, OR: 1.19; 95% CI: 1.04-1.37), dementia (P < 0.001, OR: 4.30; 95% CI: 2.03-9.12), residence in an institution (P < 0.001, OR: 4.61; 95% CI: 2.18-9.74), decreased mobility (P = 0.013, OR: 0.97; 95% CI: 0.96-0.99), but not Charlson comorbidity index (P = 0.102, OR: 1.08; 95% CI: 0.99-1.19), were associated with increased plaque scores at every time point., Conclusions: oral hygiene deteriorated in dentate patients in hospital. Plaque scores were significantly higher in patients who were more likely to be dependent on others for their oral hygiene., (© The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Importance: Fatigue is a significant and debilitating symptom affecting 25% of the population. It occurs in those with a range of chronic diseases, can be idiopathic and in 0.2-0.4% of the UK population occurs in combination with other symptoms that together constitute chronic fatigue syndrome (CFS). Until recently, NHS clinical services only focussed upon CFS and excluded the majority of fatigued patients who did not meet the CFS diagnostic criteria. The CRESTA Fatigue interdisciplinary clinic was established in 2013 in response to this unmet need., Objective: To identify the service needs of the heterogeneous group of patients accessing the CRESTA Fatigue Clinic, to prioritize these needs, to determine whether each is being met and to plan targeted service enhancements., Design: Using a group concept mapping approach, we objectively identified the shared understanding of service users accessing this novel clinic., Setting: NHS Clinics for Research & Service in Themed Assessment (CRESTA) Fatigue Clinic, Newcastle Upon Tyne, UK., Participants: Patients (n = 30) and referrers (n = 10) to the CRESTA Fatigue Clinic contributed towards a statement generation exercise to identify ways the clinic could support service users to improve their quality of life. Patients (n = 46) participated in the sorting and rating task where resulting statements were sorted into groups similar in meaning and rated for 'importance' and 'current success'., Main Outcome and Measure: We mapped the needs of patients attending the CRESTA Fatigue Clinic and identified which high-priority needs were being successfully met and which were not., Results: Multidimensional scaling and hierarchical cluster analysis depicted the following eight themed clusters from the data which related to various service-user requirements: 'clinic ethos', 'communication', 'support to self-manage', 'peer support', 'allied health services', 'telemedicine', 'written information' and 'service operation'. Service improvement targets were identified within value bivariate plots of the statements., Conclusion and Relevance: Service development concepts were grouped into thematic clusters and prioritized for both importance and current success. The resulting concept maps depict where the CRESTA Fatigue Clinic successfully addresses issues which matter to patients and highlights areas for service enhancement. Unmet needs of patients have been identified in a rigorous service evaluation, and these are currently being addressed in collaboration with a service-user group., (© 2015 The Authors. Health Expectations. Published by John Wiley & Sons Ltd.)

Objective: The systematic review and meta-analysis aims to determine the efficacy and safety of droxidopa in the treatment of orthostatic hypotension, following its recent approvals in the United States., Methods: MEDLINE, EMBASE, PubMed, Cochrane Controlled Trials Register, Web of Science, ProQuest, and the WHO Clinical Trials Registry were searched. Studies were included if they randomized adults with orthostatic hypotension to droxidopa or to control, and outcomes related to symptoms, daily activity, blood pressure, or adverse events. Data were extracted independently by two reviewers. Risk of bias was judged against the Cochrane risk of bias tool and quality of evidence measured using Grading of Recommendations Assessment, Development and Evaluation criteria. A fixed-effects model was used for pooled analysis., Results: Of 224 identified records, four studies met eligibility, with a pooled sample size of 494. Study duration was between 1 and 8 weeks. Droxidopa was effective at reducing dizziness [mean difference -0.97 (95% confidence interval -1.51, -0.42)], overall symptoms [-0.52 (-0.98, -0.06)] and difficulty with activity [-0.86 (-1.34, -0.38)]. Droxidopa was also effective at improving standing SBP [3.9 (0.1, 7.69)]. Rates of adverse events were similar between droxidopa and control groups, including supine hypertension [odds ratio 1.93 (0.87, 4.25)]., Conclusion: Droxidopa is well tolerated and effective at reducing the symptoms associated with neurogenic orthostatic hypotension without increasing the risk of supine hypertension., Registration: PROSPERO ID CRD42015024612.

Aims: Carotid sinus hypersensitivity (CSH) is arbitrarily defined as ≥3 s asystole or vasodepression of ≥50 mmHg in response to carotid sinus massage (CSM). Using this definition, 39% of older people meet the criteria for CSH. It has been suggested that current criteria are too sensitive. Krediet et al. [The history of diagnosing carotid sinus hypersensitivity: why are the current criteria too sensitive? Europace 2011;13:14-22] and Kerr et al. [Carotid sinus hypersensitivity in asymptomatic older persons: implications for diagnosis of syncope and falls. Arch Intern Med 2006;166:515-20] have proposed modified criteria. This population-based study aimed to compare the prevalence of CSH defined according to standard, Krediet and Kerr criteria, and to establish if CSH defined according these criteria is associated with all-cause mortality., Methods and Results: A total of 272 community-dwelling people aged ≥65 were recruited at random. Carotid sinus massage was performed for 5 s in supine and head-up positions. Heart rate and blood pressure response were recorded using an electrocardiogram and photoplethysmography. Cox regression analysis was used to examine the association between each definition of CSH and all-cause mortality. The prevalence of CSH defined according to standard, Krediet, and Kerr criteria was 39, 52, and 10%, respectively. Seventy-one participants died over a mean follow-up of 8.6 years (SD 2.1). Carotid sinus hypersensitivity defined according to standard and Krediet criteria was not associated with survival. Carotid sinus hypersensitivity defined according to Kerr criteria was associated with all-cause mortality independent of age and sex [hazard ratio (HR) 2.023 (95% confidence interval (95% CI) 1.131-3.618) P = 0.018)]. This remained significant after adjusting for cardiovascular risk factors [HR 2.174 (1.075-3.900) P = 0.009]., Conclusion: Carotid sinus hypersensitivity defined according to Kerr criteria is associated with increased mortality. This raises an interesting question as to the suitability of the current criteria used to define CSH., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Aim: To validate a new patient-reported outcome measure for routine clinical use., Methods: A total of 50 older individuals with orthostatic hypotension who attended a falls and syncope clinic completed three questionnaires, the recently developed Orthostatic Hypotension Questionnaire, the existing Orthostatic Grading Scale and the quality of life measure EQ-5D-5L. Validity of the Orthostatic Hypotension Questionnaire was tested against the aforementioned questionnaires for symptoms and for quality of life. Comorbidity was quantified using the Charlson Comorbidity Index., Results: The cohort of 50 individuals had a median age of 67 years (interquartile range 26-89 years) with a median Charlson Comorbidity Index of 3 (interquartile range 2-5). The total Orthostatic Hypotension Questionnaire Symptom Assessment score correlated strongly with the Orthostatic Grading Scale (0.616, P < 0.001) and the Orthostatic Hypotension Questionnaire Daily Activity Scale correlated strongly with daily activity on the EQ-5D-5L (0.61, P < 0.001). Using the Orthostatic Grading Scale, individuals' symptoms were categorized as mild, moderate or severe, the Orthostatic Hypotension Questionnaire scores were significantly different between these groups (P < 0.001). Internal consistency was high (Cronbach's apha 0.882), and ceiling or floor effects did not limit the total scores., Conclusion: The Orthostatic Hypotension Questionnaire is a valid patient report tool to quantify the symptom burden of people with orthostatic hypotension. Because the symptoms associated with orthostatic hypotension are frequently non-specific, it will be a clinically useful tool to measure and quantify symptom load in people with orthostatic hypotension. Geriatr Gerontol Int 2016; 16: 785-790., (© 2015 Japan Geriatrics Society.)

Orthostatic hypotension and cognitive impairment are common in Parkinson's disease (PD) and significantly impair quality of life. Orthostatic hypotension and cognitive impairment appear to be interrelated. Whether the relationship is causative or associative remains unclear. The vascular hypothesis proposes that recurrent episodic hypotension results in cerebral hypoperfusion, in turn causing anoxic damage to vulnerable areas of the brain and impaired cognitive function. Support for this hypothesis has come from brain MRI studies showing an association between white matter hyperintensities and a postural drop in blood pressure among PD patients. Alternatively, the association between orthostatic hypotension and cognitive decline in PD may reflect shared underlying synuclein-related pathology affecting common neuroanatomical and neurochemical substrates. Cardiac imaging studies demonstrate noradrenergic denervation early in PD, and cardiac denervation has been associated with poorer cognition. Neurogenic orthostatic hypotension occurs as a result of defective norepinephrine release from sympathetic terminals upon standing. Neuropathological studies have also demonstrated Lewy body pathology in the locus coeruleus; the main source of noradrenaline in the brain. Locus coeruleus norepinephrine levels are reduced in PD patients with dementia when compared with PD patients without. In this review, we examine the evidence for an association between orthostatic hypotension and cognitive impairment in PD. We evaluate the literature supporting the hypothesis that progressive noradrenergic denervation underlies both orthostatic hypotension and cognitive impairment, and we examine studies suggesting that recurrent cerebral hypoperfusion results in cognitive decline in PD. Finally, we explore how modulation of blood pressure and the noradrenergic nervous system may improve cognition in PD. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Objectives: To explore potential mechanisms that underpin the cardiac abnormalities seen in chronic fatigue syndrome (CFS) using non-invasive cardiac impedance, red cell mass and plasma volume measurements., Methods: Cardiac MR (MR) examinations were performed using 3 T Philips Intera Achieva scanner (Best, NL) in participants with CFS (Fukuda; n=47) and matched case-by-case controls. Total volume (TV), red cell volume (RCV) and plasma volume (PV) measurements were performed (41 CFS and 10 controls) using the indicator dilution technique using simultaneous 51-chromium labelling of red blood cells and 125-iodine labelling of serum albumin., Results: The CFS group length of history (mean±SD) was 14±10 years. Patients with CFS had significantly reduced end-systolic and end-diastolic volumes together with reduced end-diastolic wall masses (all p<0.0001). Mean±SD RCV was 1565±443 mL with 26/41 (63%) having values below 95% of expected. PV was 2659±529 mL with 13/41 (32%) <95% expected. There were strong positive correlations between TV, RCV and PV and cardiac end-diastolic wall mass (all p<0.0001; r(2)=0.5). Increasing fatigue severity correlated negatively with lower PV (p=0.04; r(2)=0.2). There were no relationships between any MR or volume measurements and length of history, suggesting that deconditioning was unlikely to be the cause of these abnormalities., Conclusions: This study confirms an association between reduced cardiac volumes and blood volume in CFS. Lack of relationship between length of disease, cardiac and plasma volumes suggests findings are not secondary to deconditioning. The relationship between plasma volume and severity of fatigue symptoms suggests a potential therapeutic target in CFS.

Background: Greater ambulatory blood pressure variability (ABPV) is associated with end-organ damage and increased mortality. Age-related changes in the cardiovascular and autonomic nervous systems make age-associated increases in ABPV likely. Cross-sectional studies support this hypothesis, showing greater ABPV among older compared to younger adults. The only longitudinal study to examine changes in ABPV, however, found ABPV decreased over 5 years follow-up. This unexpected observation probably reflected the highly selected nature of the study participants., Methods: In this longitudinal study, we assessed changes in ABPV over 10 years in a community-cohort of older people. In addition, we examined the extent to which ABPV was predicted by demographics, cardiovascular risk factors, and medication. Clinical examination and 24-hour ambulatory blood pressure monitoring were carried out at baseline and at 10 years follow-up in 83 people, median age 70 years. ABPV was calculated using SD and coefficient of variation (Cv). Three time periods were examined: daytime, nighttime, and 24 hours., Results: Daytime and 24-hour, systolic and diastolic, SD, and Cv were significantly greater at follow-up than at baseline (P < 0.001 in all cases). Mean BP did not change., Conclusions: Multilevel modeling showed follow-up interval had a significant, positive effect on SD and Cv (P < 0.004), independent of age, sex, and medication.ABPV increased over a 10-year follow-up despite stable mean BP. ABPV may therefore be an additional target for treatment in older people. Future studies should examine what degree of ABPV is harmful and if control of ABPV reduces adverse outcome., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Chronic fatigue syndrome (CFS) is a debilitating illness, but it is unclear if patient age and illness duration might affect symptoms and functioning of patients. In the current study, participants were categorized into four groups based upon age (under or over age 55) and illness duration (more or less than 10 years). The groups were compared on functioning and symptoms. Findings indicated that those who were older with a longer illness duration had significantly higher levels of mental health functioning than those who were younger with a shorter or longer illness duration and the older group with a shorter illness duration. The results suggest that older patients with an illness duration of over 10 years have significantly higher levels of mental health functioning than the three other groups. For symptoms, the younger/longer illness duration group had significantly worse immune and autonomic domains than the older/longer illness group. In addition, the younger patients with a longer illness duration displayed greater autonomic and immune symptoms in comparison to the older group with a longer illness duration. These findings suggest that both age and illness duration need to be considered when trying to understand the influence of these factors on patients.

Unlabelled: The most common cause of chronic oro-facial pain is a group of disorders collectively termed temporomandibular disorders (TMDs). Chronic painful TMD is thought to be a 'central sensitivity syndrome' related to hypersensitivity of the nervous system, but the cause is unknown. A similar understanding is proposed for other unexplained conditions, including chronic fatigue syndrome (CFS). Exploring the comorbidity of the two conditions is a valuable first step in identifying potential common aetiological mechanisms or treatment targets., Method: Systematic literature review. Studies were included if they recruited community or control samples and identified how many reported having both TMD and CFS, or if they recruited a sample of patients with either TMD or CFS and measured the presence of the other condition., Results: Six papers met inclusion criteria. In studies of patients with CFS (n = 3), 21-32% reported having TMD. In a sample of people with CFS and fibromyalgia, 50% reported having TMD. Studies in people with TMD (n = 3) reported 0-43% having CFS. Studies in samples recruited from oro-facial pain clinics (n = 2) reported a lower comorbidity with CFS (0-10%) than a study that recruited individuals from a TMD self-help organisation (43%)., Conclusion: The review highlights the limited standard of evidence addressing the comorbidity between oro-facial pain and CFS. There is a valuable signal that the potential overlap in these two conditions could be high; however, studies employing more rigorous methodology including standardised clinical assessments rather than self-report of prior diagnosis are needed., (© 2015 John Wiley & Sons Ltd.)

Background: Orthostatic hypotension (OH) affects 6% of community-dwelling older people. This increases to 60% when non-invasive, continuous blood pressure (BP) monitoring is used, due to identification of transient drops in BP which recover rapidly., Aim: To determine the clinical relevance of these transient orthostatic BP drops., Design: Five-year clinical observational study., Methods: One hundred three consecutive new patients attending a Falls and Syncope Clinic in the UK from 1 February 2009 underwent continuous BP monitoring during an active stand. BP profiles were analysed to quantify all reductions in BP, measuring the duration of any drop below diagnostic criteria. Five-year follow-up data were extracted from hospital clinical records to assess clinical outcomes., Results: Systolic BP (sBP) dropped ≥20 mmHg in 76 (74%) individuals, with 65 (63%) having ≥10 mmHg drop in diastolic BP. However, only 22 (21%) cases were diagnosed clinically with OH. A sustained reduction in BP (≥30 s) had a sensitivity of 0.91 and specificity of 0.88 for a clinical diagnosis of OH, being more accurate than absolute BP reduction alone. A sustained reduction in sBP was associated with greater use of vasopressors (36%,P0.001) and an independent, significantly greater risk of death (45% at 5 years,P0.009)., Conclusion: An orthostatic reduction in sBP lasting ≥30 s improves accuracy of diagnosis. Moreover, given the significant adverse outcomes with a sustained reduction, clinicians should consider this when diagnosing and treating patients, as transient OH does not appear to be clinically significant., (© The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Chronic fatigue syndrome is a common condition characterized by severe fatigue with post-exertional malaise, impaired cognitive ability, poor sleep quality, muscle pain, multi-joint pain, tender lymph nodes, sore throat or headache. Its defining symptom, fatigue is common to several diseases., Areas of Agreement: Research has established a broad picture of impairment across autonomic, endocrine and inflammatory systems though progress seems to have reached an impasse., Areas of Controversy: The absence of a clear consensus view of the pathophysiology of fatigue suggests the need to switch from a focus on abnormalities in one system to an experimental and clinical approach which integrates findings across multiple systems and their constituent parts and to consider multiple environmental factors., Growing Points: We discuss this with reference to three key factors, non-determinism, non-reductionism and self-organization and suggest that an approach based on these principles may afford a coherent explanatory framework for much of the observed phenomena in fatigue and offers promising avenues for future research., Areas Timely for Developing Research: By adopting this approach, the field can examine issues regarding aetiopathogenesis and treatment, with relevance for future research and clinical practice., (© The Author 2016. Published by Oxford University Press.)

Objectives: Sleep disturbances are common in chronic fatigue syndrome (CFS), and one of the key symptom complaints, yet it has been neglected by previous qualitative research. The aim was to explore the specific role of sleep in patients' experience of their illness., Design: A qualitative semi-structured interview format facilitated a detailed and open exploration of sleep, and the extent to which its management and problems were linked to the lived experience of CFS., Methods: Eleven semi-structured interviews were conducted with individuals with CFS. Data were transcribed verbatim and analysed thematically, to explore and describe patients' experience of their sleep, and its impact on their condition., Results: Sleep emerged as a key aspect of the illness experience, and its management and effect on daytime functioning was a central pre-occupation for all 11 participants; all of them saw sleep as playing a critical role in their illness through either maintaining or exacerbating existing symptoms. Exploration of individual experiences presented three overarching themes: (1) sleep pattern variability over illness course and from day to day; (2) effect of sleep on daytime functioning; and (3) attempts at coping and sleep management., Conclusions: Each patient with CFS has a unique experience of sleep. Despite the differing narratives regarding the role of sleep in CFS, all participants held the belief that sleep is a vital process for health and well-being which has had a direct bearing on the course and progression of their CFS. Also, every participant regarded their sleep as in some way 'broken' and in need of management/repair. Patients' insights demonstrate sleep-specific influences on their CFS, and the impact of disturbed sleep should be a consideration for clinical and research work., Statement of Contribution: What is already known on this subject? Sleep disturbances are common in CFS, and one of the key symptom complaints, yet it has been neglected by previous qualitative research. Ontology of CFS is a matter of dispute, with models ranging from the biological to the psychological competing to explain symptomatology in this illness. A qualitative study has the potential to add some clarity to the debate by making the patients' lived experience of the condition, and their own understanding of it, the focus of research. What this study adds? Coping and attempts at managing sleep problems in CFS adds to the 'illness burden' experienced by patients. Disturbed sleep is universally seen by patients with CFS as impacting on other daytime symptoms. Broken sleep may contribute to a biopsychosocial cycle that serves to maintain this illness., (© 2015 The British Psychological Society.)

Background: There has been considerable controversy regarding how to name and define the illnesses known as myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). The IOM report has proposed a new clinical criteria and name for this illness, but aspects of these recommendations have been scrutinized by patients and scientists., Purpose: It is possible that both empiric and consensus approaches could be used to help settle some of these diagnostic challenges. Using patient samples collected in the United States, Great Britain, and Norway (N=556), the current study attempted to categorize patients using more general as well as more restricted case definitions., Results: Overall, the outcomes suggest that there might be four groupings of patients, with the broadest category involving those with chronic fatigue (N=62), defined by 6 or more months of fatigue which can be cannot be explained by medical or psychiatric conditions. A second category involves those patients that have chronic fatigue that can be explained by a medical or psychiatric condition (N=47). A third category involves more specific criteria that have been posited both by the IOM report, a Canadian Clinical Case criteria, a ME-ICC criteria and a more empiric approach. These efforts have specified domains of substantial reductions of activity, post-exertional malaise, neurocognitive impairment, and sleep dysfunction (N=346). Patients with these characteristics were more functionally impaired than those meeting just chronic fatigue criteria, p < .05. Finally, those meeting even more restrictive ME criteria proposed by Ramsay, identified a smaller and even more impaired group, p < .05., Discussion: The advantages of using such empirical and consensus approaches to develop reliable classification and diagnostic efforts are discussed.

Background: Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) have case definitions with varying criteria, but almost all criteria require an individual to have a substantial reduction in activity level. Unfortunately, a consensus has not been reached regarding what constitutes substantial reductions. One measure that has been used to measure substantial reduction is the Medical Outcomes Study Short Form-36 Health Survey (SF-36).[1]., Purpose: The current study examined the relationship between the SF-36, a measure of current functioning, and a self-report measure of the percent reduction in hours spent on activities., Results: Findings indicated that select subscales of the SF-36 accurately measure significant reductions in functioning. Further, this measure significantly differentiates patients from controls., Conclusion: Determining what constitutes a significant reduction in activity is difficult because it is subjective to the individual. However, certain subscales of the SF-36 could provide a uniform way to accurately measure and define substantial reductions in functioning.

Considerable discussion has transpired regarding whether chronic fatigue syndrome is a distinct illness from Myalgic Encephalomyelitis. A prior study contrasted the Myalgic Encephalomyelitis International Consensus Criteria with the Fukuda and colleagues' chronic fatigue syndrome criteria and found that the Myalgic Encephalomyelitis International Consensus Criteria identified a subset of patients with greater functional impairment and physical, mental, and cognitive problems than the larger group who met Fukuda and colleagues' criteria. The current study analyzed two discrete data sets and found that the Myalgic Encephalomyelitis International Consensus Criteria identified more impaired individuals with more severe symptomatology., (© The Author(s) 2014.)

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.

Objective: To evaluate the effects of non-pharmacological interventions for primary SS (pSS) on outcomes falling within the World Health Organization International Classification of Functioning Disability and Health domains., Methods: We searched the following databases from inception to September 2014: Cochrane Database of Systematic Reviews; Medline; Embase; PsychINFO; CINAHL; and clinical trials registers. We included randomized controlled trials of any non-pharmacological intervention. Two authors independently reviewed titles and abstracts against the inclusion/exclusion criteria and independently assessed trial quality and extracted data., Results: A total of 1463 studies were identified, from which 17 full text articles were screened and 5 studies were included in the review; a total of 130 participants were randomized. The included studies investigated the effectiveness of an oral lubricating device for dry mouth, acupuncture for dry mouth, lacrimal punctum plugs for dry eyes and psychodynamic group therapy for coping with symptoms. Overall, the studies were of low quality and at high risk of bias. Although one study showed punctum plugs to improve dry eyes, the sample size was relatively small., Conclusion: Further high-quality studies to evaluate non-pharmacological interventions for PSS are needed., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

In late age, the autonomic nervous system (ANS) has diminished ability to maintain physiological homeostasis in the brain in response to challenges such as to systemic blood pressure changes caused by standing. We devised an fMRI experiment aiming to map the cerebral effects of an ANS challenge (Valsalva manoeuvre (VM)). We used dual-echo fMRI to measure the effective transverse relaxation rate (R2*, which is inversely proportional to brain tissue oxygenation levels) in 45 elderly subjects (median age 80 years old, total range 75-89) during performance of the VM. In addition, we collected fluid-attenuated inversion recovery (FLAIR) data from which we quantified white matter hyperintensity (WMH) volumes. We conducted voxelwise analysis of the dynamic changes in R2* during the VM to determine the distribution of oxygenation changes due to the autonomic stressor. In white matter, we observed significant decreases in oxygenation levels. These effects were predominantly located in posterior white matter and to a lesser degree in the right anterior brain, both concentrated around the border zones (watersheds) between cerebral perfusion territories. These areas are known to be particularly vulnerable to hypoxia and are prone to formation of white matter hyperintensities. Although we observed overlap between localisation of WMH and triggered deoxygenation on the group level, we did not find significant association between these independent variables using subjectwise statistics. This could suggest other than recurrent transient hypoxia mechanisms causing/contributing to the formation of WMH.

Objective: Hip pain and injury as a result of activity can lead to the development of early hip osteoarthritis (OA) in susceptible individuals. Our understanding of the factors that increase susceptibility continues to evolve. The ability to clearly identify individuals (and cohorts) with activity-related hip pain who are at risk of early hip OA is currently lacking. The purpose of this study was to gain expert consensus on which key clinical measures might help predict the risk of early hip OA in individuals presenting with activity-related hip pain. The agreed measures would constitute a standardised approach to initial clinical assessment to help identify these individuals., Methods: This Dephi study used online surveys to gain concordance of expert opinion in a structured process of 'rounds'. In this study, we asked 'What outcome measures are useful in predicting hip OA in activity-related hip pain?' The Delphi panel consisted of experts from sport and exercise medicine, orthopaedics, rheumatology, physiotherapy and OA research., Results: The study identified key clinical measures in the history, examination and investigations (plain anteroposterior radiograph and femoroacetabular impingement views) that the panel agreed would be useful in predicting future risk of hip OA when assessing activity-related hip pain. The panel also agreed that certain investigations and tests (eg, MR angiography) did not currently have a role in routine assessment. There was a lack of consensus regarding the role of MRI, patient-reported outcome measures (PROMs) and certain biomechanical and functional assessments., Conclusions: We provide a standardised approach to the clinical assessment of patients with activity-related hip pain. Assessment measures rejected by the Delphi panel were newer, more expensive investigations that currently lack evidence. Assessment measures that did not reach consensus include MRI and PROMs. Their role remains ambiguous and would benefit from further research., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Myalgic encephalitis (M.E.) is a common condition, the cause of which is not known and there are no treatments available. In this study the national patient support group Action for M.E. sought the opinions of their members via an online survey as to what they felt should be future priorities for M.E., Research: Respondents were asked what they considered first, second and third research priorities to be from a list of 13 pre-defined options. Individuals were invited to provide additional free text comments about Action for M.E.'s research priorities in general. Of the 1144 respondents: 822 had M.E.; 94 were a supporting a member of Action for M.E. ; 66 were carers for someone with M.E.; 26 were professionals with an interest in M.E.; 136 had a family member or colleague with M.E. Individuals selected more than one category as applicable. The top five research priorities identified were: disease processes to achieve a better understanding of the causes of M.E.; more effective treatments; faster and more accurate diagnosis; clinical course of M.E.; outcomes and natural history; and severely affected patients. Least popular priorities were: sleep; economic research towards identifying the cost of ME; and psychological aspects. Much of the free text comments emphasised the importance of funding biomedical research into disease processes to achieve a better understanding of the causes of M.E. Three themes were identified in relation to this topic: accurate diagnosis and awareness; risk factors and causes; drug development and curative therapies. In conclusion; individuals affected by M.E. have clear views regarding priorities for research investment. These have informed Action for M.E.'s ongoing research strategy and ultimately will inform national and international research priorities.