Neural correlates of the DMT experience assessed with multivariate EEG.

Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) N,N-Dimethyltryptamine (DMT - a fast-acting tryptamine psychedelic) offers a safe and powerful means of advancing knowledge on the neurobiology of conscious states. Here we sought to investigate the effects of IV DMT on the power spectrum and signal diversity of human brain activity (6 female, 7 male) recorded via multivariate EEG, and plot relationships between subjective experience, brain activity and drug plasma concentrations across time. Compared with placebo, DMT markedly reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Time-referenced and neurophenomenological analyses revealed close relationships between changes in various aspects of subjective experience and changes in brain activity. Importantly, the emergence of oscillatory activity within the delta and theta frequency bands was found to correlate with the peak of the experience - particularly its eyes-closed visual component. These findings highlight marked changes in oscillatory activity and signal diversity with DMT that parallel broad and specific components of the subjective experience, thus advancing our understanding of the neurobiological underpinnings of immersive states of consciousness.

The Associations of Muscle Strength, Muscle Mass, and Adiposity With Clinical Outcomes and Quality of Life in Prevalent Kidney Transplant Recipients.

OBJECTIVE: Sarcopenia, defined as loss of both muscle strength and mass, is associated with inferior clinical outcomes and quality of life (QoL) in chronic kidney disease, but its effects are unknown in kidney transplantation. Obesity confers increased mortality risk and compromises QoL in kidney transplant recipients (KTRs), but the impacts of sarcopenic obesity remain unexplored. This study aimed to evaluate the associations of muscle strength and mass, sarcopenia, and sarcopenic obesity with clinical outcomes and QoL in KTRs. METHODS: This prospective longitudinal study enrolled 128 KTRs ≥1-year posttransplantation. Low muscle strength (by handgrip strength) and mass (by bioimpedance analysis), and a combination of both (sarcopenia) were defined as < reference cutoffs for corresponding indices. Sarcopenic obesity was defined as sarcopenia combined with fulfillment of ≥2 out of 3 criteria from (1) body mass index ≥30 kg/m2, (2) bioimpedance analysis-derived fat mass > reference cutoffs, and (3) waist circumference > World Health Organization cutoffs. Prospective follow-up data on mortality and hospitalization were collected. QoL was evaluated using Medical Outcomes Study Short Form-36 questionnaire. RESULTS: Median follow-up duration was 64 (60-72) months. Low muscle strength was independently associated with the composite endpoint of mortality and hospitalization (hazard ratio = 2.45; P = .006), and QoL (physical-related: ß = -12.2; P = .04; mental-related: ß = -9.9; P = .04). Low muscle mass (ß = -8.8; P = .04) and sarcopenia (ß = -14.7; P = .03) were associated with physical-related QoL only. No independent associations were found between muscle mass, sarcopenia, and sarcopenic obesity with the composite outcome of mortality and hospitalization. CONCLUSION: Low muscle strength is common among KTRs, conferring poor prognosis in the medium term. Future research on strength training may prove valuable in improving kidney transplantation outcomes.

The Associations of Endotoxemia With Systemic Inflammation, Endothelial Activation, and Cardiovascular Outcome in Kidney Transplantation.

OBJECTIVE: Cardiovascular disease is the leading cause of death in kidney transplant recipients (KTRs), yet incompletely accountable by traditional risk factors. Inflammation is an unconventional cardiovascular risk factor, with gut-derived endotoxemia potentially driving inflammation and endothelial disease. Comparable data are lacking in kidney transplantation. This study investigated the associations of endotoxemia with inflammation, endothelial activation, and 5-year cardiovascular events in KTRs. Determinants of endotoxemia were also explored. DESIGN AND METHODS: This is a single-center cross-sectional study with prospective follow-up from a prevalent cohort of 128 KTRs. MAIN OUTCOME MEASURES: Demographic, nutritional and clinical predictors of inflammation (high-sensitivity C-reactive protein [hsCRP]), endothelial activation (sE-selectin), and endotoxemia (endotoxin) were assessed. Follow-up data on 5-year cardiovascular event rates were collected. RESULTS: Endotoxemia (P = .03), reduced 25-hydroxyvitamin D (P = .04), high fructose intake (P < .001), decreased fiber intake (P < .001), and abdominal obesity (P = .002) were independently associated with elevated hsCRP. In turn, endotoxemia (P = .007) and increasing hsCRP (P = .02) were both independently associated with raised sE-selectin. Furthermore, endotoxemia predicted increased cardiovascular event rate (P = .02), independent of hsCRP and a global measure of cardiovascular risk estimated by a validated algorithm of 7-year risk for major adverse cardiac events in kidney transplantation. Determinants of endotoxemia included reduced 25-hydroxyvitamin D (P < .001), hypertriglyceridemia (P < .001), increased fructose intake (P = .01), and abdominal obesity (P = .01). CONCLUSIONS: Endotoxemia in KTRs contributes to inflammation, endothelial activation, and increased cardiovascular events. This study highlights the clinical relevance of endotoxemia in KTRs, suggesting future interventional targets.

Cardiovascular, muscular and perceptual contributions to physical fatigue in prevalent kidney transplant recipients.

Physical fatigue is debilitating and common among kidney transplant recipients (KTRs). This study investigated the mechanistic aetiology of physical fatigue in this setting through examinations of muscle mass, muscular and cardiovascular function, and perceived exertion. The incidence of physical fatigue, its association with quality of life (QoL), and the predictors of perceived exertion, were evaluated. This single-centre observational cross-sectional study enrolled 55 KTRs. Muscle mass was quantified using dual-energy x-ray absorptiometry. Muscular function was assessed by jumping mechanography. Cardiovascular function (maximal oxygen consumption and oxygen pulse) was estimated during submaximal exercise testing, with perceived exertion determined using age-adjusted Borg scale-ratings. Physical fatigue was measured using Multi-Dimensional Fatigue Inventory-20. QoL was assessed using Medical Outcomes Study Short Form-36. Demographic, clinical, nutritional, psychosocial and behavioural predictors of perceived exertion were assessed. Of clinical importance, increased perceived exertion was the only independent predictor of physical fatigue (P = 0.001), with no association found between physical fatigue and muscular or cardiovascular parameters. Physical fatigue occurred in 22% of KTRs, and negatively impacted on QoL (P < 0.001). Predictors of heightened perception included anxiety (P < 0.05) and mental fatigue (P < 0.05). Perception is a key determinant of physical fatigue in KTRs, paving the way for future interventions.

Hypervolemia and blood pressure in prevalent kidney transplant recipients.

BACKGROUND: The prevalence and consequences of hypervolemia in kidney transplant recipients (KTRs) have not been investigated. Specifically, its impact on blood pressure (BP) and relationship with N-terminal fragment of prohormone B-type natriuretic peptide (NT-proBNP) are unknown. The objectives of this study were to establish the prevalence of hypervolemia among clinically stable KTRs, investigate the predictors of posttransplant hypervolemia, assess its impact on blood pressure, and determine its relationship with NT-proBNP. METHODS: This single-center cross-sectional study enrolled 123 clinically stable KTRs. Extracellular volume status was determined by multifrequency bioimpedance analysis. Mild and severe hypervolemia were defined as percentage volume expansion of greater than 7% and greater than 15%, respectively. Systolic BP (SBP) and diastolic BP (DBP) were measured, with mean arterial pressure (MAP) calculated. Serum NT-proBNP was quantified using a noncompetitive immunoluminometric assay. Potential demographic, nutritional, and clinical predictors of extracellular volume status, BP, and NT-proBNP levels were assessed. RESULTS: Hypervolemia was present in 30% of KTRs, with 5% classified as severe hypervolemia. Significant predictors of volume expansion were increased sodium intake, advancing age, and reduced fat mass (P<0.01 for all associations). Hypervolemia was the only independent predictor of elevated MAP, SBP, and DBP (P<0.001 for all associations). Raised NT-proBNP levels were independently associated with both hypervolemia (P=0.01) and allograft dysfunction (P=0.03). CONCLUSIONS: Hypervolemia is unexpectedly common among clinically stable KTRs. It is closely associated with elevated BP. The relationship with increased sodium intake signals potential therapeutic focus. Further study is warranted to prospectively investigate objective measures of extracellular volume status among KTRs.

The periodontal health component of the Renal Impairment In Secondary Care (RIISC) cohort study: a description of the rationale, methodology and initial baseline results.

INTRODUCTION: Chronic kidney disease (CKD) is associated with significant morbidity and mortality. There is a need to identify novel and modifiable risk factors in such patients. The periodontal component of the Renal Impairment In Secondary Care (RIISC) study aims to evaluate the association between chronic periodontitis and CKD progression. METHODS: The RIISC study is a prospective, observational cohort study of patients with CKD from a renal clinic at a hospital in the West Midlands region of the UK. Patients undergo a periodontal examination and plaque and saliva sampling. To benchmark the oral health status of the RIISC cohort, we compared it to the Adult Dental Health Survey 2009 (ADHS), a representative survey of the oral health of community dwelling adults in the UK. RESULTS: Of the first 500 patients recruited into the RIISC study, 469 patients underwent a dental examination and 80 (17%) were edentulous. Among dentate subjects, patients within RIISC were significantly more likely to have any (OR 4.0 95% CI 2.7-5.9) or severe (OR 3.8 95% CI 2.5-5.6) periodontitis compared to the ADHS sample. CONCLUSION: The prevalence and severity of chronic periodontitis in this cohort of CKD patients is markedly higher than a geographically matched control population.

Predictors and consequences of fatigue in prevalent kidney transplant recipients.

BACKGROUND: Fatigue has been underinvestigated in stable kidney transplant recipients (KTRs). The objectives of this study were to investigate the nature, severity, prevalence, and clinical awareness of fatigue in medically stable KTRs, examine the impact of fatigue on quality of life (QoL), and explore the underlying causes of posttransplantation fatigue. METHODS: This single-center cross-sectional study enrolled 106 stable KTRs. Multi-dimensional Fatigue Inventory-20 was used to measure five fatigue dimensions: General Fatigue, Physical Fatigue, Reduced Activity, Reduced Motivation, and Mental Fatigue. Clinical awareness of fatigue was determined by reviewing medical records. QoL was assessed by Medical Outcomes Study Short Form-36 Questionnaire. Demographic, clinical, psychosocial, and behavioral parameters were evaluated as fatigue predictors. RESULTS: Fatigue was found in 59% of KTRs. Only 13% had this symptom documented in medical records. Fatigue in KTRs was in the same range as chronically unwell patients, with Physical Fatigue, Reduced Activity, and Reduced Motivation approached levels observed in chronic fatigue syndrome. All fatigue dimensions significantly and inversely correlated with QoL (P<0.001 for all associations). Demographic predictors were male, older age, and non-Caucasian ethnicity (P≤0.05 for all associations). Clinical predictors included elevated highly sensitive C-reactive protein (inflammation), decreased estimated glomerular filtration rate (graft dysfunction), and reduced lean tissue index (P≤0.05 for all associations). Psychosocial and behavioral predictors were inferior sleep quality, anxiety, and depression (P<0.01 for all associations). CONCLUSIONS: Fatigue is common and pervasive in clinically stable KTRs. It is strongly associated with reduced QoL. This study identified modifiable fatigue predictors and sets the scene for future interventional studies.

The role of hepcidin-25 in kidney transplantation.

BACKGROUND: Hepcidin-25 is a peptide hormone involved in iron absorption and homeostasis and found at increased serum levels in conditions involving systemic inflammation, renal dysfunction, and increased adiposity. Hepcidin may play a role in the pathogenesis of anemia, but its role in kidney transplantation is undefined. METHODS: This study enrolled 100 stable patients beyond 12 months after transplantation, from a large single United Kingdom center. Serum hepcidin-25 level, and relevant demographic and laboratory data pertinent to posttransplantation anemia, were measured and collected. Independent predictors of serum hepcidin were evaluated, and the relationship between hepcidin and hemoglobin, assessed. RESULTS: Independent associations were seen between higher hepcidin levels and allograft dysfunction (estimated glomerular filtration rate), increased inflammation (high-sensitivity C-reactive peptide), higher transferrin saturation (a marker of iron stores), and the use of marrow-suppressive medication (P<0.05 for all). Higher fat tissue index (whole-body multifrequency bioimpedance measurement) was also associated with higher hepcidin levels, but this relationship did not persist after adjustment for inflammation (high-sensitivity C-reactive peptide). In turn, inflammation was associated with increased fat tissue index (P=0.01) and male gender (P=0.04). A nonlinear association between serum hepcidin level and hemoglobin was seen, with a progressive fall in hemoglobin as hepcidin levels rose to 100 ng/mL, but little effect thereafter (P=0.009). This association was independent of renal dysfunction and female gender, both of which were also independently associated with a lower hemoglobin level. CONCLUSIONS: These results highlight possible mechanisms of hemoglobin reduction in kidney transplantation patients, and the therapeutic opportunities from understanding the role of hepcidin in this context.

The natural history of, and risk factors for, progressive chronic kidney disease (CKD): the Renal Impairment in Secondary care (RIISC) study; rationale and protocol.

BACKGROUND: Chronic kidney disease (CKD) affects up to 16% of the adult population and is associated with significant morbidity and mortality. People at highest risk from progressive CKD are defined by a sustained decline in estimated glomerular filtration rate (eGFR) and/or the presence of significant albuminuria/proteinuria and/or more advanced CKD. Accurate mapping of the bio-clinical determinants of this group will enable improved risk stratification and direct the development of better targeted management for people with CKD. METHODS/DESIGN: The Renal Impairment In Secondary Care study is a prospective, observational cohort study, patients with CKD 4 and 5 or CKD 3 and either accelerated progression and/or proteinuria who are managed in secondary care are eligible to participate. Participants undergo a detailed bio-clinical assessment that includes measures of vascular health, periodontal health, quality of life and socio-economic status, clinical assessment and collection of samples for biomarker analysis. The assessments take place at baseline, and at six, 18, 36, 60 and 120 months; the outcomes of interest include cardiovascular events, progression to end stage kidney disease and death. DISCUSSION: The determinants of progression of chronic kidney disease are not fully understood though there are a number of proposed risk factors for progression (both traditional and novel). This study will provide a detailed bio-clinical phenotype of patients with high-risk chronic kidney disease (high risk of both progression and cardiovascular events) and will repeatedly assess them over a prolonged follow up period. Recruitment commenced in Autumn 2010 and will provide many outputs that will add to the evidence base for progressive chronic kidney disease.