Duodenal-Jejunal Bypass Liner for the management of Type 2 Diabetes Mellitus and Obesity: A Multicenter Randomized Controlled Trial.

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 Council and National Institute for Health Research (NIHR) partnership reference 12/10/04.

Role of the ghrelin system in alcohol use disorder and alcohol-associated liver disease: A narrative review.

Unhealthy alcohol consumption is a global health problem. Adverse individual, public health, and socioeconomic consequences are attributable to harmful alcohol use. Epidemiological studies have shown that alcohol use disorder (AUD) and alcohol-associated liver disease (ALD) are the top two pathologies among alcohol-related diseases. Consistent with the major role that the liver plays in alcohol metabolism, uncontrolled drinking may cause significant damage to the liver. This damage is initiated by excessive fat accumulation in the liver, which can further progress to advanced liver disease. The only effective therapeutic strategies currently available for ALD are alcohol abstinence or liver transplantation. Any molecule with dual-pronged effects at the central and peripheral organs controlling addictive behaviors and associated metabolic pathways are a potentially important therapeutic target for treating AUD and ALD. Ghrelin, a hormone primarily derived from the stomach, has such properties, and regulates both behavioral and metabolic functions. In this review, we highlight recent advances in understanding the peripheral and central functions of the ghrelin system and its role in AUD and ALD pathogenesis. We first discuss the correlation between blood ghrelin concentrations and alcohol use or abstinence. Next, we discuss the role of ghrelin in alcohol-seeking behaviors and finally its role in the development of fatty liver by metabolic regulations and organ crosstalk. We propose that a better understanding of the ghrelin system could open an innovative avenue for improved treatments for AUD and associated medical consequences, including ALD.

Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration.

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.

Serum insulin-like growth factor-I levels are associated with improved white matter recovery after traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin-like growth factor-I (IGF-I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF-I concentrations on WM tract and neuropsychological recovery after TBI. METHODS: Thirty-nine adults after TBI (84.6% male, median age = 30.5 years, 87.2% moderate-severe, median time since TBI = 16.3 months, n = 4 with GHD) were scanned twice, 13.3 months (range = 12.1-14.9) apart, and 35 healthy controls were scanned once. Symptom and quality of life questionnaires and cognitive assessments were completed at both visits (n = 33). Our main outcome measure was fractional anisotropy (FA), a measure of WM tract integrity, in a priori regions of interest: splenium of corpus callosum (SPCC) and posterior limb of internal capsule (PLIC). RESULTS: At baseline, FA was reduced in many WM tracts including SPCC and PLIC following TBI compared to controls, indicating axonal injury, with longitudinal increases indicating axonal recovery. There was a significantly greater increase in SPCC FA over time in patients with serum IGF-I above versus below the median for age. Only the higher IGF-I group had significant improvements in immediate verbal memory recall over time. INTERPRETATION: WM recovery and memory improvements after TBI were greater in patients with higher serum IGF-I at baseline. These findings suggest that the growth hormone/IGF-I system may be a potential therapeutic target following TBI. Ann Neurol 2017;82:30-43.

The screening and management of pituitary dysfunction following traumatic brain injury in adults: British Neurotrauma Group guidance.

Pituitary dysfunction is a recognised, but potentially underdiagnosed complication of traumatic brain injury (TBI). Post-traumatic hypopituitarism (PTHP) can have major consequences for patients physically, psychologically, emotionally and socially, leading to reduced quality of life, depression and poor rehabilitation outcome. However, studies on the incidence of PTHP have yielded highly variable findings. The risk factors and pathophysiology of this condition are also not yet fully understood. There is currently no national consensus for the screening and detection of PTHP in patients with TBI, with practice likely varying significantly between centres. In view of this, a guidance development group consisting of expert clinicians involved in the care of patients with TBI, including neurosurgeons, neurologists, neurointensivists and endocrinologists, was convened to formulate national guidance with the aim of facilitating consistency and uniformity in the care of patients with TBI, and ensuring timely detection or exclusion of PTHP where appropriate. This article summarises the current literature on PTHP, and sets out guidance for the screening and management of pituitary dysfunction in adult patients with TBI. It is hoped that future research will lead to more definitive recommendations in the form of guidelines.

Prevalence and correlates of vitamin D deficiency in adults after traumatic brain injury.

OBJECTIVES: Traumatic brain injury (TBI) is a major cause of long-term disability with variable recovery. Preclinical studies suggest that vitamin D status influences the recovery after TBI. However, there is no published clinical data on links between vitamin D status and TBI outcomes. The aim was to determine the (i) prevalence of vitamin D deficiency/insufficiency, and associations of vitamin D status with (ii) demographic factors and TBI severity, and with (iii) cognitive function, symptoms and quality of life, in adults after TBI. DESIGN: Retrospective audit of patients seen between July 2009 and March 2015. Serum vitamin D (25-hydroxy-cholecalciferol) was categorized as deficient (<40 nmol/l), insufficient (40-70 nmol/l) or replete (>70 nmol/l). PATIENTS: A total of 353 adults seen in tertiary hospital clinic (75·4% lighter skinned, 74·8% male, age median 35·1 year, range 26·6-48·3 year), 0·3-56·5 months after TBI (74·5% moderate-severe). MEASUREMENTS: Serum vitamin D concentrations; Addenbrooke's Cognitive Examination (ACE-R), Beck Depression Inventory-II (BDI-II), SF-36 Quality of Life, Pittsburgh Sleep Quality Index. RESULTS: In total, 46·5% of patients after TBI had vitamin D deficiency and 80·2% insufficiency/deficiency. Patients with vitamin D deficiency had lower ACE-R scores than those of vitamin D replete (mean effect size ± SEM 4·5 ± 2·1, P = 0·034), and higher BDI-II scores than those of vitamin D insufficient (4·5 ± 1·6, P = 0·003), correcting for age, gender, time since TBI and TBI severity. There was no association between vitamin D status and markers of TBI severity, sleep or quality of life. CONCLUSION: Vitamin D deficiency is common in patients after TBI and associated with impaired cognitive function and more severe depressive symptoms.

Changes in Reward after Gastric Bypass: the Advantages and Disadvantages.

Gastric bypass surgery is an effective long-term weight loss intervention. Key to its success appears a putative shift in food preference away from high-energy-density foods associated with a reduced appetitive drive and loss of neural reactivity in the reward system of the brain towards food. Post-prandial exaggerated satiety gut hormone responses have been implicated as mediators. Whilst the positive impact of bariatric surgery on both physical and psychological outcomes for many patients is clearly evident, a subset of patients appear to be detrimentally affected by this loss of reward from food and by a lack of alternative strategies for regulating affect after surgery. Mindfulness training has emerged as a potential tool in reducing the need for immediate reward that underpins much of eating behaviour. Further research is needed to help identify patients who may be more vulnerable after gastric bypass and which forms of support may be most beneficial.

Hyperghrelinemia in Prader-Willi syndrome begins in early infancy long before the onset of hyperphagia.

Circulating total ghrelin levels are elevated in older children and adults with Prader-Willi syndrome (PWS). However, the presence or absence of hyperghrelinemia in young children with PWS remains controversial. We hypothesized that a more robust way to analyze appetite-regulating hormones in PWS would be by nutritional phases rather than age alone. Our objectives were to compare total serum ghrelin levels in children with PWS by nutritional phase as well as to compare total ghrelin levels in PWS (5 weeks to 21 years of age) to normal weight controls and individuals with early-onset morbid obesity (EMO) without PWS. Fasting serum total ghrelin levels were measured in 60 subjects with PWS, 39 subjects with EMO of unknown etiology, and in 95 normal non-obese sibling controls of PWS or EMO subjects (SibC) in this 12 year longitudinal study. Within PWS, total ghrelin levels were significantly (P < 0.001) higher in earlier nutritional phases: phase 1a (7,906 ± 5,887); 1b (5,057 ± 2,624); 2a (2,905 ± 1,521); 2b (2,615 ± 1,370) and 3 (2,423 ± 1,350). Young infants with PWS also had significantly (P = 0.009) higher total ghrelin levels than did the sibling controls. Nutritional phase is an important independent prognostic factor of total ghrelin levels in individuals with PWS. Circulating ghrelin levels are elevated in young children with PWS long before the onset of hyperphagia, especially during the early phase of poor appetite and feeding. Therefore, it seems unlikely that high ghrelin levels are directly responsible for the switch to the hyperphagic nutritional phases in PWS.

Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than after gastric banding.

OBJECTIVES: Roux-en-Y gastric bypass (RYGB) has greater efficacy for weight loss in obese patients than gastric banding (BAND) surgery. We hypothesise that this may result from different effects on food hedonics via physiological changes secondary to distinct gut anatomy manipulations. DESIGN: We used functional MRI, eating behaviour and hormonal phenotyping to compare body mass index (BMI)-matched unoperated controls and patients after RYGB and BAND surgery for obesity. RESULTS: Obese patients after RYGB had lower brain-hedonic responses to food than patients after BAND surgery. RYGB patients had lower activation than BAND patients in brain reward systems, particularly to high-calorie foods, including the orbitofrontal cortex, amygdala, caudate nucleus, nucleus accumbens and hippocampus. This was associated with lower palatability and appeal of high-calorie foods and healthier eating behaviour, including less fat intake, in RYGB compared with BAND patients and/or BMI-matched unoperated controls. These differences were not explicable by differences in hunger or psychological traits between the surgical groups, but anorexigenic plasma gut hormones (GLP-1 and PYY), plasma bile acids and symptoms of dumping syndrome were increased in RYGB patients. CONCLUSIONS: The identification of these differences in food hedonic responses as a result of altered gut anatomy/physiology provides a novel explanation for the more favourable long-term weight loss seen after RYGB than after BAND surgery, highlighting the importance of the gut-brain axis in the control of reward-based eating behaviour.

Pituitary dysfunction after blast traumatic brain injury: The UK BIOSAP study.

OBJECTIVE: Pituitary dysfunction is a recognized consequence of traumatic brain injury (TBI) that causes cognitive, psychological, and metabolic impairment. Hormone replacement offers a therapeutic opportunity. Blast TBI (bTBI) from improvised explosive devices is commonly seen in soldiers returning from recent conflicts. We investigated: (1) the prevalence and consequences of pituitary dysfunction following moderate to severe bTBI and (2) whether it is associated with particular patterns of brain injury. METHODS: Nineteen male soldiers with moderate to severe bTBI (median age = 28.3 years) and 39 male controls with moderate to severe nonblast TBI (nbTBI; median age = 32.3 years) underwent full dynamic endocrine assessment between 2 and 48 months after injury. In addition, soldiers had structural brain magnetic resonance imaging, including diffusion tensor imaging (DTI), and cognitive assessment. RESULTS: Six of 19 (32.0%) soldiers with bTBI, but only 1 of 39 (2.6%) nbTBI controls, had anterior pituitary dysfunction (p = 0.004). Two soldiers had hyperprolactinemia, 2 had growth hormone (GH) deficiency, 1 had adrenocorticotropic hormone (ACTH) deficiency, and 1 had combined GH/ACTH/gonadotrophin deficiency. DTI measures of white matter structure showed greater traumatic axonal injury in the cerebellum and corpus callosum in those soldiers with pituitary dysfunction than in those without. Soldiers with pituitary dysfunction after bTBI also had a higher prevalence of skull/facial fractures and worse cognitive function. Four soldiers (21.1%) commenced hormone replacement(s) for hypopituitarism. INTERPRETATION: We reveal a high prevalence of anterior pituitary dysfunction in soldiers suffering moderate to severe bTBI, which was more frequent than in a matched group of civilian moderate to severe nbTBI subjects. We recommend that all patients with moderate to severe bTBI should routinely have comprehensive assessment of endocrine function.

Obesity surgery and neural correlates of human eating behaviour: A systematic review of functional MRI studies.

Changes in eating behaviour including reductions in appetite and food intake, and healthier food cue reactivity, reward, hedonics and potentially also preference, contribute to weight loss and its health benefits after obesity surgery. Functional magnetic resonance imaging (fMRI) has been increasingly used to interrogate the neural correlates of eating behaviour in obesity, including brain reward-cognitive systems, changes after obesity surgery, and links with alterations in the gut-hormone-brain axis. Neural responses to food cues can be measured by changes in blood oxygen level dependent (BOLD) signal in brain regions involved in reward processing, including caudate, putamen, nucleus accumbens, insula, amygdala, orbitofrontal cortex, and top-down inhibitory control, including dorsolateral prefrontal cortex (dlPFC). This systematic review aimed to examine: (i) results of human fMRI studies involving obesity surgery, (ii) important methodological differences in study design across studies, and (iii) correlations and associations of fMRI findings with clinical outcomes, other eating behaviour measures and mechanistic measures. Of 741 articles identified, 23 were eligible for inclusion: 16 (69.6%) longitudinal, two (8.7%) predictive, and five (21.7%) cross-sectional studies. Seventeen studies (77.3%) included patients having Roux-en-Y gastric bypass (RYGB) surgery, six (26.1%) vertical sleeve gastrectomy (VSG), and five (21.7%) laparoscopic adjustable gastric banding (LAGB). The majority of studies (86.0%) were identified as having a very low risk of bias, though only six (27.3%) were controlled interventional studies, with none including randomisation to surgical and control interventions. The remaining studies (14.0%) had a low risk of bias driven by their control groups not having an active treatment. After RYGB surgery, food cue reactivity often decreased or was unchanged in brain reward systems, and there were inconsistent findings as to whether reductions in food cue reactivity was greater for high-energy than low-energy foods. There was minimal evidence from studies of VSG and LAGB surgeries for changes in food cue reactivity in brain reward systems, though effects of VSG surgery on food cue reactivity in the dlPFC were more consistently found. There was consistent evidence for post-operative increases in satiety gut hormones glucagon-like-peptide 1 (GLP-1) and peptide YY (PYY) mediating reduced food cue reactivity after RYGB surgery, including two interventional studies. Methodological heterogeneity across studies, including nutritional state, nature of food cues, post-operative timing, lack of control groups for order effects and weight loss or dietary/psychological advice, and often small sample sizes, limited the conclusions that could be drawn, especially for correlational analyses with clinical outcomes, other eating behaviour measures and potential mediators. This systematic review provides a detailed data resource for those performing or analysing fMRI studies of obesity surgery and makes suggestions to help improve reporting and design of such studies, as well as future directions.

Body weight, behaviours of concern, and social contact in adults and adolescents with Prader-Willi syndrome in full-time care services: Findings from pooled international archival data.

BACKGROUND: Prader-Willi syndrome (PWS) is a complex genetic neurodevelopmental condition characterised by a range of debilitating and lifelong symptoms. The many physical and behavioural challenges that arise with adults with PWS often necessitate full-time (i.e., 24-hour) professional care support. However, despite the fact that many clinicians regard full-time PWS-specific care to represent best practice, relatively few studies have directly examined the benefits of such services. The purpose of this paper is to use archival data to investigate the impact of full-time care services on people with PWS, and to assemble a large statistical dataset on which robust analyses of improvements in weight, BMI, and behavioural outcomes can be based. METHODS: Information collated by the International PWS Organisation (IPWSO), an international non-profit membership organisation supporting national PWS associations around the world, was combined into a single anonymised dataset for statistical analysis. Data were supplied by service-providers from several countries who provide full-time support to people with PWS. The dataset included details on the specific services provided, basic demographic information on service recipients, including weight, body mass index (BMI), and observational records relating to behaviours of concern (BOC; consisting of temper outbursts, skin-picking, egocentrism, inflexibility, and striving for dominance). RESULTS: A total of 193 people with PWS (ranging in age from < 10 yrs to > 50 yrs; 93% of whom were > 18 yrs), residing in 11 services across 6 countries, were represented in the dataset. On average, people with PWS showed significant reductions in weight and BMI after joining a full-time care service, with improvements within one year of entering, which were cumulative over time and independent of age or initial weight at entry. Similar cumulative improvements over time were seen for BOC within one year and were unrelated to age or severity of BOC at entry. The degree to which services are specialised for residents with PWS appeared to confer particular benefits, with people living in PWS-exclusive services showing the greatest improvements in weight, BMI, and BOC. Reductions in BOC were associated with greater, rather than less, social contact, suggesting that these improvements were not achieved at the expense of broader freedoms, such as the opportunity to meet with families and friends. CONCLUSIONS: We conclude that full-time care services have a high likelihood of enhancing the lives of people with PWS within one year with long-lasting benefits, especially if those services are exclusive and specialised around the particular needs of PWS.

Prader-Willi syndrome: guidance for children and transition into adulthood.

Prader-Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000. Management of people with PWS requires a multi-disciplinary approach, ideally through a multi-disciplinary team (MDT) clinic with community support. Hypotonia, poor feeding and faltering growth are characteristic features in the neonatal period, followed by hyperphagia and risk of rapid weight gain later in childhood. Children and adolescents (CA) with PWS usually display developmental delay and mild learning disability and can develop endocrinopathies, scoliosis, respiratory difficulties (both central and obstructive sleep apnoea), challenging behaviours, skin picking, and mental health issues, especially into adulthood. This consensus statement is intended to be a reference document for clinicians managing children and adolescents (up to 18 years of age) with PWS. It considers the bio-psycho-social domains of diagnosis, clinical assessment, and management in the paediatric setting as well as during and after transition to adult services. The guidance has been developed from information gathered from peer-reviewed scientific reports and from the expertise of a range of experienced clinicians in the United Kingdom and Ireland involved in the care of patients with PWS.

Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study.

OBJECTIVE: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). METHODS: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. RESULTS: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). CONCLUSIONS: DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.

Comparison of the overnight metyrapone and glucagon stimulation tests in the assessment of secondary hypoadrenalism.

OBJECTIVE: The insulin tolerance test (ITT) is contraindicated in a proportion of patients with suspected ACTH deficiency. The aim of this study was to investigate the diagnostic accuracy of the glucagon stress test (GST) compared with the overnight metyrapone test (OMT) in patients with contraindications to ITT. DESIGN: This was a prospective comparison of the GST to the OMT in patients with suspected ACTH deficiency and contraindications to the ITT. The OMT was used as the standard for comparison. The study was conducted at two tertiary referral centres for pituitary disease. PATIENTS: Seventy-eight patients underwent contemporaneous OMT and GST of whom 61 had sufficient suppression of cortisol during the OMT to be included in the comparison. Forty had suffered traumatic brain injury, 36 had organic pituitary disorders and two were classified as 'other'. MEASUREMENTS: ACTH sufficiency was defined as 0800h 11-deoxycortisol ≥ 200 nmol/l on OMT and peak cortisol ≥ 440 nmol/l on GST, as per local reference ranges. RESULTS: There was significant discrepancy between the proportion of patients diagnosed with ACTH deficiency using the OMT (39%) and GST (89%). From our data, a GST peak cortisol cut-off of ≥350 nm provides the combination of optimal sensitivity (71%) and specificity (57%), compared with a higher sensitivity (88%) but poor specificity (11%) using a cut-off of ≥440 nm. CONCLUSIONS: The GST should be used with caution as a diagnostic test of ACTH reserve. The OMT should be used in preference to the GST to assess the hypothalamic pituitary adrenal axis where ITT is contraindicated.

Effects of bariatric surgery and dietary interventions for obesity on brain neurotransmitter systems and metabolism: A systematic review of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies.

This systematic review collates studies of dietary or bariatric surgery interventions for obesity using positron emission tomography and single-photon emission computed tomography. Of 604 publications identified, 22 met inclusion criteria. Twelve studies assessed bariatric surgery (seven gastric bypass, five gastric bypass/sleeve gastrectomy), and ten dietary interventions (six low-calorie diet, three very low-calorie diet, one prolonged fasting). Thirteen studies examined neurotransmitter systems (six used tracers for dopamine DRD2/3 receptors: two each for 11 C-raclopride, 18 F-fallypride, 123 I-IBZM; one for dopamine transporter, 123 I-FP-CIT; one used tracer for serotonin 5-HT2A receptor, 18 F-altanserin; two used tracers for serotonin transporter, 11 C-DASB or 123 I-FP-CIT; two used tracer for µ-opioid receptor, 11 C-carfentanil; one used tracer for noradrenaline transporter, 11 C-MRB); seven studies assessed glucose uptake using 18 F-fluorodeoxyglucose; four studies assessed regional cerebral blood flow using 15 O-H2 O (one study also used arterial spin labeling); and two studies measured fatty acid uptake using 18 F-FTHA and one using 11 C-palmitate. The review summarizes findings and correlations with clinical outcomes, eating behavior, and mechanistic mediators. The small number of studies using each tracer and intervention, lack of dietary intervention control groups in any surgical studies, heterogeneity in time since intervention and degree of weight loss, and small sample sizes hindered the drawing of robust conclusions across studies.

Postprandial Increases in Liver-Gut Hormone LEAP2 Correlate with Attenuated Eating Behavior in Adults Without Obesity.

Background: The novel liver-gut hormone liver-expressed antimicrobial peptide-2 (LEAP2) is a centrally acting inverse agonist, and competitive antagonist of orexigenic acyl ghrelin (AG), at the GH secretagogue receptor, reducing food intake in rodents. In humans, the effects of LEAP2 on eating behavior and mechanisms behind the postprandial increase in LEAP2 are unclear, though this is reciprocal to the postprandial decrease in plasma AG. Methods: Plasma LEAP2 was measured in a secondary analysis of a previous study. Twenty-two adults without obesity attended after an overnight fast, consuming a 730-kcal meal without or with subcutaneous AG administration. Postprandial changes in plasma LEAP2 were correlated with postprandial changes in appetite, high-energy (HE) or low-energy (LE) food cue reactivity using functional magnetic resonance imaging, ad libitum food intake, and plasma/serum AG, glucose, insulin, and triglycerides. Results: Postprandial plasma LEAP2 increased by 24.5% to 52.2% at 70 to 150 minutes, but was unchanged by exogenous AG administration. Postprandial increases in LEAP2 correlated positively with postprandial decreases in appetite, and cue reactivity to HE/LE and HE food in anteroposterior cingulate cortex, paracingulate cortex, frontal pole, and middle frontal gyrus, with similar trend for food intake. Postprandial increases in LEAP2 correlated negatively with body mass index, but did not correlate positively with increases in glucose, insulin, or triglycerides, nor decreases in AG. Conclusions: These correlational findings are consistent with a role for postprandial increases in plasma LEAP2 in suppressing human eating behavior in adults without obesity. Postprandial increases in plasma LEAP2 are unrelated to changes in plasma AG and the mediator(s) remain uncertain.

Health state utilities associated with hyperphagia: Data for use in cost-utility models.

Objective: Rare 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. Methods: Four 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. Results: In 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. Conclusions: These 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.

Malignancies in Prader-Willi Syndrome: Results From a Large International Cohort and Literature Review.

CONTEXT: Prader-Willi syndrome (PWS) is a complex disorder combining hypothalamic dysfunction, neurodevelopmental delay, hypotonia, and hyperphagia with risk of obesity and its complications. PWS is caused by the loss of expression of the PWS critical region, a cluster of paternally expressed genes on chromosome 15q11.2-q13. As life expectancy of patients with PWS increases, age-related diseases like malignancies might pose a new threat to health. OBJECTIVE: To investigate the prevalence and risk factors of malignancies in patients with PWS and to provide clinical recommendations for cancer screening. METHODS: We included 706 patients with PWS (160 children, 546 adults). We retrospectively collected data from medical records on past or current malignancies, the type of malignancy, and risk factors for malignancy. Additionally, we searched the literature for information about the relationship between genes on chromosome 15q11.2-q13 and malignancies. RESULTS: Seven adults (age range, 18-55 years) had been diagnosed with a malignancy (acute lymphoblastic leukemia, intracranial hemangiopericytoma, melanoma, stomach adenocarcinoma, biliary cancer, parotid adenocarcinoma, and colon cancer). All patients with a malignancy had a paternal 15q11-13 deletion. The literature review showed that several genes on chromosome 15q11.2-q13 are related to malignancies. CONCLUSION: Malignancies are rare in patients with PWS. Therefore, screening for malignancies is only indicated when clinically relevant symptoms are present, such as unexplained weight loss, loss of appetite, symptoms suggestive of paraneoplastic syndrome, or localizing symptoms. Given the increased cancer risk associated with obesity, which is common in PWS, participation in national screening programs should be encouraged.