Publications
121 results found
Howell TA, Matza LS, Mallya UG, et al., 2023, Health state utilities associated with hyperphagia: data for use in cost-utility models, Obesity Science and Practice, Pages: 1-7, ISSN: 2055-2238
ObjectiveRare genetic diseases of obesity typically present with hyperphagia, a pathologic desire to consume food. Cost-utility models assessing the value of treatments for these rare diseases will require health state utilities representing hyperphagia. This study estimated utilities associated with various hyperphagia severity levels.MethodsFour health state vignettes were developed using published literature and clinician input to represent various severity levels of hyperphagia. Utilities were estimated for these health states in a time trade-off elicitation study in a UK general population sample.ResultsIn total, 215 participants completed interviews (39.5% male; mean age 39.1 years). Mean (SD) utilities were 0.98 (0.02) for no hyperphagia, 0.91 (0.10) for mild hyperphagia, 0.70 (0.30) for moderate hyperphagia, and 0.22 (0.59) for severe hyperphagia. Mean (SD) disutilities were −0.08 (0.10) for mild, −0.28 (0.30) for moderate, and −0.77 (0.58) for severe hyperphagia.ConclusionsThese data show increasing severity of hyperphagia is associated with decreased utility. Utilities associated with severe hyperphagia are similar to those of other health conditions severely impacting quality of life (QoL). These findings highlight that treatments addressing substantial QoL impacts of severe hyperphagia are needed. Utilities estimated here may be useful in cost-utility models of treatments for rare genetic diseases of obesity.
Kharbanda KK, Farokhnia M, Deschaine SL, et al., 2022, Role of the ghrelin system in alcohol use disorder and alcohol-associated liver disease: A narrative review, ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, Vol: 46, Pages: 2149-2159, ISSN: 0145-6008
Goldstone AP, Ling YY, Nestor LJ, et al., 2022, Effect of acute desacyl ghrelin administration on eating and addictive behaviours: The gut hormone in addiction study, 2nd World Congress on Alcohol and Alcoholism Joint meeting of ISBRA and ESBRA, Publisher: Wiley, Pages: 72-73, ISSN: 0145-6008
Aldhwayan MM, Al-Najim W, Ruban A, et al., 2022, Does bypass of the proximal small intestine impact food intake, preference, and taste function in humans? An experimental medicine study using the duodenal-jejunal bypass liner, Nutrients, Vol: 14, ISSN: 2072-6643
The duodenal-jejunal bypass liner (Endobarrier) is an endoscopic treatment for obesity and type 2 diabetes mellitus (T2DM). It creates exclusion of the proximal small intestine similar to that after Roux-en-Y Gastric Bypass (RYGB) surgery. The objective of this study was to employ a reductionist approach to determine whether bypass of the proximal intestine is the component conferring the effects of RYGB on food intake and sweet taste preference using the Endobarrier as a research tool. A nested mechanistic study within a large randomised controlled trial compared the impact of lifestyle modification with vs. without Endobarrier insertion in patients with obesity and T2DM. Forty-seven participants were randomised and assessed at several timepoints using direct and indirect assessments of food intake, food preference and taste function. Patients within the Endobarrier group lost numerically more weight compared to the control group. Using food diaries, our results demonstrated similar reductions of food intake in both groups. There were no significant differences in food preference and sensory, appetitive reward, or consummatory reward domain of sweet taste function between groups or changes within groups. In conclusion, the superior weight loss seen in patients with obesity and T2DM who underwent the Endobarrier insertion was not due to a reduction in energy intake or change in food preferences.
Ruban A, Miras A, glaysher M, et al., 2022, Duodenal-jejunal bypass liner for the management of Type 2 diabetes and obesity: a multicenter randomized controlled trial, Annals of Surgery, Vol: 275, Pages: 440-447, ISSN: 0003-4932
Objective: The aim of this study was to examine the clinical efficacy and safety of the duodenal-jejunal bypass liner (DJBL) while in situ for 12 months and for 12 months after explantation.Summary Background Data: This is the largest randomized controlled trial (RCT) of the DJBL, a medical device used for the treatment of people with type 2 diabetes mellitus (T2DM) and obesity. Endoscopic interventions have been developed as potential alternatives to those not eligible or fearful of the risks of metabolic surgery.Methods: In this multicenter open-label RCT, 170 adults with inadequately controlled T2DM and obesity were randomized to intensive medical care with or without the DJBL. Primary outcome was the percentage of participants achieving a glycated hemoglobin reduction of ≥20% at 12 months. Secondary outcomes included weight loss and cardiometabolic risk factors at 12 and 24 months.Results: There were no significant differences in the percentage of patients achieving the primary outcome between both groups at 12 months [DJBL 54.6% (n = 30) vs control 55.2% (n = 32); odds ratio (OR) 0.93, 95% confidence interval (CI): 0.44–2.0; P = 0.85]. Twenty-four percent (n = 16) patients achieved ≥15% weight loss in the DJBL group compared to 4% (n = 2) in the controls at 12 months (OR 8.3, 95% CI: 1.8–39; P = .007). The DJBL group experienced superior reductions in systolic blood pressure, serum cholesterol, and alanine transaminase at 12 months. There were more adverse events in the DJBL group.Conclusions: The addition of the DJBL to intensive medical care was associated with superior weight loss, improvements in cardiometabolic risk factors, and fatty liver disease markers, but not glycemia, only while the device was in situ. The benefits of the devices need to be balanced against the higher rate of adverse events when making clinical decisions.Trial Registration: ISRCTN30845205. isrctn.org; Efficacy and Mechanism Evaluation Programme, a Medical Research
Ruban A, Miras AD, Glaysher MA, et al., 2022, Duodenal-Jejunal Bypass Liner for the management of Type 2 Diabetes Mellitus and Obesity, Annals of Surgery, Vol: 275, Pages: 440-447, ISSN: 0003-4932
Al-Alsheikh AS, Alabdulkader S, Johnson B, et al., 2022, Effect of obesity surgery on taste, Nutrients, Vol: 14, Pages: 1-24, ISSN: 2072-6643
Obesity surgery is a highly efficacious treatment for obesity and its comorbidities. The underlying mechanisms of weight loss after obesity surgery are not yet fully understood. Changes to taste function could be a contributing factor. However, the pattern of change in different taste domains and among obesity surgery operations is not consistent in the literature. A systematic search was performed to identify all articles investigating gustation in human studies following bariatric procedures. A total of 3323 articles were identified after database searches, searching references and deduplication, and 17 articles were included. These articles provided evidence of changes in the sensory and reward domains of taste following obesity procedures. No study investigated the effect of obesity surgery on the physiological domain of taste. Taste detection sensitivity for sweetness increases shortly after Roux-en-Y gastric bypass. Additionally, patients have a reduced appetitive reward value to sweet stimuli. For the subgroup of patients who experience changes in their food preferences after Roux-en-Y gastric bypass or vertical sleeve gastrectomy, changes in taste function may be underlying mechanisms for changing food preferences which may lead to weight loss and its maintenance. However, data are heterogeneous; the potential effect dilutes over time and varies significantly between different procedures.
Howell TA, Matza L, Mallya UG, et al., 2022, HEALTH STATE UTILITIES ASSOCIATED WITH HYPERPHAGIA, Publisher: ELSEVIER SCIENCE INC, Pages: S234-S235, ISSN: 1098-3015
Pellikaan K, Ben Brahim Y, Rosenberg AGW, et al., 2021, Hypogonadism in Women with Prader-Willi Syndrome-Clinical Recommendations Based on a Dutch Cohort Study, Review of the Literature and an International Expert Panel Discussion, JOURNAL OF CLINICAL MEDICINE, Vol: 10
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Pellikaan K, Ben Brahim Y, Rosenberg AGW, et al., 2021, Hypogonadism in Adult Males with Prader-Willi Syndrome-Clinical Recommendations Based on a Dutch Cohort Study, Review of the Literature and an International Expert Panel Discussion, JOURNAL OF CLINICAL MEDICINE, Vol: 10
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Guerrero-Hreins E, Goldstone AP, Brown RM, et al., 2021, The therapeutic potential of GLP-1 analogues for stress-related eating and role of GLP-1 in stress, emotion and mood: a review, Progress in Neuro-Psychopharmacology and Biological Psychiatry, Vol: 110, ISSN: 0278-5846
Stress and low mood are powerful triggers for compulsive overeating, a maladaptive form of eating leading to negative physical and mental health consequences. Stress-vulnerable individuals, such as people with obesity, are particularly prone to overconsumption of high energy foods and may use it as a coping mechanism for general life stressors. Recent advances in the treatment of obesity and related co-morbidities have focused on the therapeutic potential of anorexigenic gut hormones, such as glucagon-like peptide 1 (GLP-1), which acts both peripherally and centrally to reduce energy intake. Besides its appetite suppressing effect, GLP-1 acts on areas of the brain involved in stress response and emotion regulation. However, the role of GLP-1 in emotion and stress regulation, and whether it is a viable treatment for stress-induced compulsive overeating, has yet to be established. A thorough review of the pre-clinical literature measuring markers of stress, anxiety and mood after GLP-1 exposure points to potential divergent effects based on temporality. Specifically, acute GLP-1 injection consistently stimulates the physiological stress response in rodents whereas long-term exposure indicates anxiolytic and anti-depressive benefits. However, the limited clinical evidence is not as clear cut. While prolonged GLP-1 analogue treatment in people with type 2 diabetes improved measures of mood and general psychological wellbeing, the mechanisms underlying this may be confounded by associated weight loss and improved blood glucose control. There is a paucity of longitudinal clinical literature on mechanistic pathways by which stress influences eating behavior and how centrally-acting gut hormones such as GLP-1, can modify these. (250).
Sjostrom A, Pellikaan K, Sjostrom H, et al., 2021, Hyperprolactinemia in adults with Prader-Willi syndrome, Journal of Clinical Medicine, Vol: 10, ISSN: 2077-0383
Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder typically characterized by body composition abnormalities, hyperphagia, behavioural challenges, cognitive dysfunction, and hypogonadism. Psychotic illness is common, particularly in patients with maternal uniparental disomy (mUPD), and antipsychotic medications can result in hyperprolactinemia. Information about hyperprolactinemia and its potential clinical consequences in PWS is sparse. Here, we present data from an international, observational study of 45 adults with PWS and hyperprolactinemia. Estimated prevalence of hyperprolactinemia in a subset of centres with available data was 22%, with 66% of those related to medication and 55% due to antipsychotics. Thirty-three patients were men, 12 women. Median age was 29 years, median BMI 29.8 kg/m2, 13 had mUPD. Median prolactin was 680 mIU/L (range 329–5702). Prolactin levels were higher in women and patients with mUPD, with only 3 patients having severe hyperprolactinemia. Thyroid function tests were normal, 24 were treated with growth hormone, 29 with sex steroids, and 20 with antipsychotic medications. One patient had kidney insufficiency, and one a microprolactinoma. In conclusion, severe hyperprolactinemia was rare, and the most common aetiology of hyperprolactinemia was treatment with antipsychotic medications. Although significant clinical consequences could not be determined, potential negative long-term effects of moderate or severe hyperprolactinemia cannot be excluded. Our results suggest including measurements of prolactin in the follow-up of adults with PWS, especially in those on treatment with antipsychotics
Coupaye M, Pellikaan K, Goldstone AP, et al., 2021, Hyponatremia in Children and Adults with Prader-Willi Syndrome: A Survey Involving Seven Countries, JOURNAL OF CLINICAL MEDICINE, Vol: 10
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Herlinger KE, Ling YY, Nestor LJ, et al., 2021, Comparison of monetary reward anticipation and negative emotional processing in obesity, ex-smokers and abstinent alcohol dependence, 44th Annual Meeting Research Society on Alcoholism / International Society for Behavioral Research on Alcoholism, Publisher: Wiley, Pages: 241A-241A, ISSN: 0145-6008
Goldstone AP, Ling YY, Nestor LJ, et al., 2021, EFFECT OF ACUTE DESACYL GHRELIN ADMINISTRATION ON EATING AND ADDICTIVE BEHAVIOURS: THE GUT HORMONE IN ADDICTION STUDY, Publisher: WILEY, Pages: 51A-51A, ISSN: 0145-6008
Glaysher M, Ward J, Aldhwayan M, et al., 2021, The effect of a duodenal-jejunal bypass liner on lipid profile and blood concentrations of long chain polyunsaturated fatty acids, Clinical Nutrition, Vol: 40, Pages: 2343-2354, ISSN: 0261-5614
Background & aimsDuodenal-jejunal bypass liners (DJBLs) prevent absorption in the proximal small intestine, the site of fatty acid absorption. We sought to investigate the effects of a DJBL on blood concentrations of essential fatty acids (EFAs) and bioactive polyunsaturated fatty acids (PUFAs).MethodsSub-study of a multicentre, randomised, controlled trial with two treatment groups. Patients aged 18–65 years with type-2 diabetes mellitus and body mass index 30–50 kg/m2 were randomised to receive a DJBL for 12 months or best medical therapy, diet and exercise. Whole plasma PUFA concentrations were determined at baseline, 10 days, 6 and 11.5 months; data were available for n = 70 patients per group.ResultsWeight loss was significantly greater in the DJBL group compared to controls after 11.5 months: total body weight loss 11.3 ± 5.3% versus 6.0 ± 5.7% (mean difference [95% CI] = 5.27% [3.75, 6.80], p < 0.001). Absolute concentrations of both EFAs, linoleic acid and α-linolenic acid, and their bioactive derivatives, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid, were significantly lower in the DJBL group than in the control group at 6 and 11.5 months follow-up. Total serum cholesterol, LDL-cholesterol and HDL-cholesterol were also significantly lower in the DJBL group.ConclusionOne year of DJBL therapy is associated with superior weight loss and greater reductions in total serum cholesterol and LDL-cholesterol, but also depletion of EFAs and their longer chain derivatives. DJBL therapy may need to be offset by maintaining an adequate dietary intake of PUFAs or by supplementation.
Herlinger K, Ling YY, Nestor LJ, et al., 2020, Comparison of food cue reactivity, eating behaviours, mood and impulsivity in obesity, ex-smokers and abstinent alcohol dependence, 33rd Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER, Pages: S15-S15, ISSN: 0924-977X
Ruban A, Glaysher MA, Miras AD, et al., 2020, A duodenal sleeve bypass device added to intensive medical therapy for obesity with type 2 diabetes: a RCT, Efficacy and Mechanism Evaluation, Vol: 7, Pages: 1-130, ISSN: 2050-4365
BackgroundThe EndoBarrier® (GI Dynamics Inc., Boston, MA, USA) is an endoluminal duodenal–jejunal bypass liner developed for the treatment of patients with obesity and type 2 diabetes mellitus. Meta-analyses of its effects on glycaemia and weight have called for larger randomised controlled trials with longer follow-up.ObjectivesThe primary objective was to compare intensive medical therapy with a duodenal–jejunal bypass liner with intensive medical therapy without a duodenal–jejunal bypass liner, comparing effectiveness on the metabolic state as defined by the International Diabetes Federation as a glycated haemoglobin level reduction of ≥ 20%. The secondary objectives were to compare intensive medical therapy with a duodenal–jejunal bypass liner with intensive medical therapy without a duodenal–jejunal bypass liner, comparing effectiveness on the metabolic state as defined by the International Diabetes Federation as a glycated haemoglobin level of < 42 mmol/mol, blood pressure of < 135/85 mmHg, and the effectiveness on total body weight loss. Additional secondary outcomes were to investigate the cost-effectiveness and mechanism of action of the effect of a duodenal–jejunal bypass liner on brain reward system responses, insulin sensitivity, eating behaviour and metabonomics.DesignA multicentre, open-label, randomised controlled trial.SettingImperial College Healthcare NHS Trust and University Hospital Southampton NHS Foundation Trust.ParticipantsPatients aged 18–65 years with a body mass index of 30–50 kg/m2 and with inadequately controlled type 2 diabetes mellitus who were on oral glucose-lowering medications.InterventionsParticipants were randomised equally to receive intensive medical therapy alongside a duodenal–jejunal bypass liner device (n = 85) or intensive medical therapy alone for 12 months (n = 85), and were followed up
Alenaini W, Parkinson JRC, McCarthy JP, et al., 2020, Ethnic differences in body fat deposition and liver fat content in two UK-based cohorts, Obesity (Silver Spring, Md.), Vol: 28, Pages: 2142-2152, ISSN: 1071-7323
OBJECTIVE: Differences in the content and distribution of body fat and ectopic lipids may be responsible for ethnic variations in metabolic disease susceptibility. The aim of this study was to examine the ethnic distribution of body fat in two separate UK-based populations. METHODS: Anthropometry and body composition were assessed in two separate UK cohorts: the Hammersmith cohort and the UK Biobank, both comprising individuals of South Asian descent (SA), individuals of Afro-Caribbean descent (AC), and individuals of European descent (EUR). Regional adipose tissue stores and liver fat were measured by magnetic resonance techniques. RESULTS: The Hammersmith cohort (n = 747) had a mean (SD) age of 41.1 (14.5) years (EUR: 374 men, 240 women; SA: 68 men, 22 women; AC: 14 men, 29 women), and the UK Biobank (n = 9,533) had a mean (SD) age of 55.5 (7.5) years (EUR: 4,483 men, 4,873 women; SA: 80 men, 43 women, AC: 31 men, 25 women). Following adjustment for age and BMI, no significant differences in visceral adipose tissue or liver fat were observed between SA and EUR individuals in the either cohort. CONCLUSIONS: Our data, consistent across two independent UK-based cohorts, present a limited number of ethnic differences in the distribution of body fat depots associated with metabolic disease. These results suggest that the ethnic variation in susceptibility to features of the metabolic syndrome may not arise from differences in body fat.
Murphy CF, Stratford N, Docherty NG, et al., 2020, A Pilot Study of Gut-Brain Signaling After Octreotide Therapy for Unintentional Weight Loss After Esophagectomy., J Clin Endocrinol Metab
BACKGROUND: Recurrence-free patients after esophageal cancer surgery face long-term nutritional consequences, occurring in the context of an exaggerated post-prandial gut hormone response. Acute gut hormone suppression influences brain reward signaling and eating behavior. This study aimed to suppress gut hormone secretion and characterize reward responses and eating behavior among post-esophagectomy patients with unintentional weight loss. METHODS: This pilot study prospectively studied post-operative patients with ≥10% body weight loss (BWL) beyond one year who were candidates for clinical treatment with long-acting Octreotide (LAR). Before and after four weeks of treatment, gut hormone secretion, food cue reactivity (functional MRI), eating motivation (progressive ratio task), ad libitum food intake, body composition, and symptom burden were assessed. RESULTS: 8 patients (7 male, age: mean±SD 62.8±9.4 years, post-operative BWL: 15.5±5.8%) participated. Octreotide LAR did not significantly suppress total post-prandial plasma GLP-1 response at four weeks (P=0.08). Post-prandial symptom burden improved after treatment (Sigstad score median(range): 12(2-28) vs. 8(3-18), P=0.04), but weight remained stable (Pre:68.6±12.8kg vs. Post:69.2±13.4kg, P=0.13). There was no significant change in brain reward system responses, during evaluation of high-energy or low-energy food pictures, nor their appeal rating. Moreover, treatment did not alter motivation to eat (P=0.41) nor ad libitum food intake(P=0.46). CONCLUSION: The protocol used made it feasible to characterize the gut-brain axis and eating behavior in this cohort. Inadequate suppression of gut hormone responses four weeks after Octreotide LAR administration may explain the lack of gut-brain pathway alterations. A higher dose or shorter inter-dose interval may be required to optimize the intervention.
Rosenberg AGW, Pellikaan K, Poitou C, et al., 2020, Central adrenal insufficiency is rare in adults with prader-willi syndrome (vol 105, pg 1, 2020), Journal of Clinical Endocrinology and Metabolism, Vol: 105, Pages: E3052-E3052, ISSN: 0021-972X
Foss L, Belli A, Brody D, et al., 2020, Setting a national consensus for managing mild and blast traumatic brain injury: post-meeting consensus report
A meeting was held on Wednesday 15 January 2020 to examine the current evidence for non-routine imaging and for neuroendocrine screening in the management of military personnel with brain injury and overlapping symptom domains. The Summit aimed to specifically address the relative utility of magnetoencephalography (MEG), diffusion tensor imaging (DTI) and susceptibility weighted imaging (SWI) in the UK context. This Consensus Report discusses points of consensus, points for further discussion/points of equipoise and recommendations that arose during, and following, the meeting.
Rosenberg AGW, Pellikaan K, Poitou C, et al., 2020, Central adrenal insufficiency is rare in adults with Prader-Willi syndrome, Journal of Clinical Endocrinology and Metabolism, Vol: 105, Pages: e2563-e2571, ISSN: 0021-972X
CONTEXT: Prader-Willi syndrome (PWS) is associated with several hypothalamic-pituitary hormone deficiencies. There is no agreement on the prevalence of central adrenal insufficiency (CAI) in adults with PWS. In some countries, it is general practice to prescribe stress-dose hydrocortisone during physical or psychological stress in patients with PWS. Side effects of frequent hydrocortisone use are weight gain, osteoporosis, diabetes mellitus, and hypertension-already major problems in adults with PWS. However, undertreatment of CAI can cause significant morbidity-or even mortality. OBJECTIVE: To prevent both over- and undertreatment with hydrocortisone, we assessed the prevalence of CAI in a large international cohort of adults with PWS. As the synacthen test shows variable results in PWS, we only use the metyrapone test (MTP) and insulin tolerance test (ITT). DESIGN: Metyrapone test or ITT in adults with PWS (N = 82) and review of medical files for symptoms of hypocortisolism related to surgery (N = 645). SETTING: Outpatient clinic. PATIENTS OR OTHER PARTICIPANTS: Eighty-two adults with genetically confirmed PWS. MAIN OUTCOME MEASURE: For MTP, 11-deoxycortisol > 230 nmol/L was considered sufficient. For ITT, cortisol > 500 nmol/L (Dutch, French, and Swedish patients) or > 450 nmol/L (British patients) was considered sufficient. RESULTS: Central adrenal insufficiency was excluded in 81 of 82 patients. Among the 645 patients whose medical files were reviewed, 200 had undergone surgery without perioperative hydrocortisone treatment. None of them had displayed any features of hypocortisolism. CONCLUSIONS: Central adrenal insufficiency is rare (1.2%) in adults with PWS. Based on these results, we recommend against routinely prescribing hydrocortisone stress-doses in adults with PWS.
Ruban A, Glaysher M, Miras A, et al., 2020, ONE YEAR OF DUODENAL-JEJUNAL BYPASS LINER THERAPY (ENDOBARRIER (R)) LEADS TO SIGNIFICANT CHANGES IN LIVER BIOCHEMISTRY ASSOCIATED WITH NON-ALCOHOLIC FATTY LIVER DISEASE, GI Fellows Sessions at Digestive Disease Week / 61st Annual Meeting of the Society-for-Surgery-of-the-Alimentary-Tract, Publisher: MOSBY-ELSEVIER, Pages: AB225-AB226, ISSN: 0016-5107
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Glaysher M, Ward J, Aldhwayan M, et al., 2020, The effect of a duodenal-jejunal bypass liner device (Endobarrier (R)) on lipid profile and blood concentrations of long chain polyunsaturated fatty acids, 11th Annual Scientific Meeting of the British-Obesity-and-Metabolic-Surgery-Society (BOMSS), Publisher: SPRINGER, Pages: S16-S17, ISSN: 0960-8923
Ruban A, Prechtl C, Glaysher M, et al., 2019, Effectiveness of different recruitment strategies in an RCT of a surgical device:;Experience from the Endobarrier trial, BMJ Open, Vol: 9, ISSN: 2044-6055
Recruiting participants into clinical trials is notoriously difficult and poses the greatest challenge when planning any investigative study. Poor recruitment may not only have financial ramifications owing to increased time and resources being spent but could adversely influence the clinical impact of a study if it becomes underpowered. Herein we present our own experience of recruiting into a nationally funded, multi-centre, randomised controlled trial (RCT) of the Endobarrier vs. standard medical therapy in obese patients with type 2 diabetes. Despite these both being highly prevalent conditions, there were considerable barriers to the effectiveness of different recruitment strategies across each study site. Although recruitment from primary care proved extremely successful at one study site, this largely failed at another site prompting the implementation of multimodal recruitment strategies including a successful media campaign to ensure sufficient participants were enrolled and the study was adequately powered. From this experience we propose where appropriate the early engagement and investment in media campaigns to enhance recruitment into clinical trials.
Mani B, Puzziferri N, He Z, et al., 2019, LEAP2 changes with body mass and food intake in humans and mice, Journal of Clinical Investigation, Vol: 129, Pages: 3909-3923, ISSN: 0021-9738
Acyl-ghrelin administration increases food intake, body weight, and blood glucose. In contrast, mice lacking ghrelin or ghrelin receptors (GHSRs) exhibit life-threatening hypoglycemia during starvation-like conditions, but do not consistently exhibit overt metabolic phenotypes when given ad libitum food access. These results, and findings of ghrelin resistance in obese states, imply nutritional state dependence of ghrelin’s metabolic actions. Here, we hypothesized that liver-enriched antimicrobial peptide-2 (LEAP2), a recently characterized endogenous GHSR antagonist, blunts ghrelin action during obese states and postprandially. To test this hypothesis, we determined changes in plasma LEAP2 and acyl-ghrelin due to fasting, eating, obesity, Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), oral glucose administration, and type 1 diabetes mellitus (T1DM) using humans and/or mice. Our results suggest that plasma LEAP2 is regulated by metabolic status: its levels increased with body mass and blood glucose and decreased with fasting, RYGB, and in postprandial states following VSG. These changes were mostly opposite of those of acyl-ghrelin. Furthermore, using electrophysiology, we showed that LEAP2 both hyperpolarizes and prevents acyl-ghrelin from activating arcuate NPY neurons. We predict that the plasma LEAP2/acyl-ghrelin molar ratio may be a key determinant modulating acyl-ghrelin activity in response to body mass, feeding status, and blood glucose.
Gorgoraptis N, Zaw-Linn J, Feeney C, et al., 2019, Cognitive impairment and health- related quality of life following traumatic brain injury, Journal of Alzheimer's Disease, Vol: 44, Pages: 321-331, ISSN: 1387-2877
BACKGROUNDCognitive impairment is a common and disabling consequence of traumatic brain injury (TBI) but its impact on health-related quality of life is not well understood.OBJECTIVETo investigate the relationship between cognitive impairment and health-related quality of life (HRQoL) after TBI.METHODSRetrospective, cross-sectional study of a specialist TBI outpatient clinic patient sample. Outcome measures: Addenbrooke's Cognitive Examination Tool - Revised (ACE-R), and SF-36 quality of life, Beck Depression Inventory II (BDI-II), Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) questionnaires.RESULTS240 adults were assessed: n = 172 (71.7% ) moderate-severe, 41 (23.8% ) mild, 27 (11.3% ) symptomatic TBI, 174 (72.5% ) male, median age (range): 44 (22-91) years. TBI patients reported poorer scores on all domains of SF-36 compared to age-matched UK normative data. Cognitively impaired patients reported poorer HRQoL on the physical, social role and emotional role functioning, and mental health domains. Cognitive impairment predicted poorer HRQoL on the social and emotional role functioning domains, independently of depressive symptoms, sleep disturbance, daytime sleepiness and TBI severity. Mediation analysis revealed that the effect of depressive symptoms on the emotional role functioning domain of HRQoL was partially mediated by cognitive dysfunction.CONCLUSIONCognitive impairment is associated with worse health-related quality of life after TBI and partially mediates the effect of depressive symptoms on emotional role functioning.
Azor AM, Cole JH, Holland AJ, et al., 2019, Increased brain age in adults with Prader-Willi syndrome, NeuroImage: Clinical, Vol: 21, ISSN: 2213-1582
Prader-Willi syndrome (PWS) is the most common genetic obesity syndrome, with associated learning difficulties, neuroendocrine deficits, and behavioural and psychiatric problems. As the life expectancy of individuals with PWS increases, there is concern that alterations in brain structure associated with the syndrome, as a direct result of absent expression of PWS genes, and its metabolic complications and hormonal deficits, might cause early onset of physiological and brain aging. In this study, a machine learning approach was used to predict brain age based on grey matter (GM) and white matter (WM) maps derived from structural neuroimaging data using T1-weighted magnetic resonance imaging (MRI) scans. Brain-predicted age difference (brain-PAD) scores, calculated as the difference between chronological age and brain-predicted age, are designed to reflect deviations from healthy brain aging, with higher brain-PAD scores indicating premature aging. Two separate adult cohorts underwent brain-predicted age calculation. The main cohort consisted of adults with PWS (n = 20; age mean 23.1 years, range 19.8-27.7; 70.0% male; body mass index (BMI) mean 30.1 kg/m2, 21.5-47.7; n = 19 paternal chromosome 15q11-13 deletion) and age- and sex-matched controls (n = 40; age 22.9 years, 19.6-29.0; 65.0% male; BMI 24.1 kg/m2, 19.2-34.2) adults (BMI PWS vs. control P = .002). Brain-PAD was significantly greater in PWS than controls (effect size mean ± SEM +7.24 ± 2.20 years [95% CI 2.83, 11.63], P = .002). Brain-PAD remained significantly greater in PWS than controls when restricting analysis to a sub-cohort matched for BMI consisting of n = 15 with PWS with BMI range 21.5-33.7 kg/m2, and n = 29 controls with BMI 21.7-34.2 kg/m2 (effect size +5.51 ± 2.56 years [95% CI 3.44, 10.38], P = .037). In the PWS group, brain-PAD scores were not associated with intelligence quotient (IQ), use of hormonal and psychotropic medications, nor severity of repetitive or disruptive
Scott GPT, Zetterberg H, Jolly A, et al., 2017, Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration, Brain, Vol: 141, Pages: 459-471, ISSN: 1460-2156
Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using 11C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, 11C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater 11C-PBR28 binding. Minocycline reduced 11C-PBR28 binding (mean Δwhite matter binding = −23.30%, 95% confidence interval −40.9 to −5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury.
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