Patients' perspective on their drug therapy after bariatric surgery: A quantitative, cross-sectional interview study.

Drug therapy in patients who have undergone bariatric surgery is challenging. We aimed to investigate the patients' perspective on their drug therapy. This should allow deriving tailored measures to better support patients and their healthcare professionals with drug therapy after bariatric surgery. We conducted a quantitative telephone-based interview study with patients who have undergone bariatric surgery. The interview consisted of assessments in three parts: (i) current drug therapy: prescription, administration and adherence, (ii) changes after bariatric surgery and (iii) adverse events. (i) The 105 enrolled patients were taking a median of 10 (range: 3-30) drugs. In 1017 of 1080 drugs (94%), expectations in drug effectiveness were (rather) met. Of the 105 patients, 27% reported difficulties in drug administration, 44% forgot to take their drugs at least one time and 20% reported deviations from the prescription. (ii) Sixteen percent of the patients observed changes in drug effectiveness or tolerability-additionally to therapy adjustment by physicians. (iii) Seventy-four percent recognised at least one adverse event right before and/or after bariatric surgery, most frequently in gastrointestinal disorders. Patients who have undergone bariatric surgery have to deal with many difficulties in drug handling and adverse events. Our study emphasises the need for better and more individual support for patients with their drug therapy after bariatric surgery and, therefore, suggests a multidisciplinary approach that includes pharmacists. The stronger involvement of the patients' perspective seems to be a valuable source in research and practice.

Where in the brain is creativity? The fallacy of a creativity faculty in the brain.

The neuroscience of creativity is built on a tacit and near universal assumption that is false. Paradoxically, this is not contentious; once made explicit, the assumption is readily conceded as false. Psychology regards creativity as made up of many complex, multifaceted, and varied cognitive and emotional processes deployed across many different domains. But we instead think of, and treat, creativity as if it were a single, separate, cohesive, and discrete thing-as in, Einstein had it. In a straightforward extension of this fallacy, cognitive neuroscientists have looked for uniquely creative cognition that (1) is distinct from all other kinds of cognition and (2) has a proprietary neural substrate. In other words, a standalone and monolithic creativity faculty in the brain that manages only creativity and all creativity. First, this paper brings into sharp focus the nature and ubiquity of this fallacy. It then outlines the alternative theoretical position that is (1) based on fundamental neural principles and (2) predicated on taking seriously the concept of creativity as complex and diverse. Like morality or secretiveness, it holds that creativity does not exist as its own, specialized entity in the brain. Instead, its neurocognitive mechanisms are distributed, embedded, and varied; that is, creativity is everywhere and multiply realizable.

EMC10 modulates hepatic ER stress and steatosis in an isoform specific manner.

BACKGROUND & AIMS: Endoplasmic reticulum (ER) membrane protein complex subunit 10 (EMC10) has been implicated in obesity. Here we investigated the roles of the two isoforms of EMC10, including a secreted isoform (scEMC10) and an ER membrane-bound isoform (mEMC10), in MASLD. METHODS: Manifold steatotic mouse models and HepG2 cells were employed to investigate the role of EMC10 in the regulation of hepatic PERK-eIF2α-ATF4 signaling and hepatosteatosis. The therapeutic effect of scEMC10-neutralizing antibody on mouse hepatosteatosis was explored. Associations of MASLD with serum scEMC10 and hepatic mEMC10 were determined in two cohorts of participants with MASLD. RESULTS: scEMC10 promoted, while mEMC10 suppressed the activation of hepatocytic PERK-eIF2α-ATF4 signaling. Emc10 gene knockout exacerbated, while hepatic overexpression of mEMC10 ameliorated hepatic ER stress and steatosis in mice challenged with either a MCD diet or tunicamycin, highlighting a direct, suppressive role of mEMC10 in MASLD via modulation of hepatic ER stress. Overexpression of scEMC10 promoted, whereas neutralization of circulating scEMC10 prevented hepatosteatosis in mice with fatty liver, suggesting a progressive role of scEMC10 in MASLD. Clinically, serum scEMC10 increased, while hepatic mEMC10 decreased in participants with MASLD. Correlative analysis indicated serum scEMC10 positively, whereas hepatic mEMC10 negatively correlated with liver fat content and serum ALT, AST, and GGT. CONCLUSIONS: These findings demonstrate a novel, isoform specific role for EMC10 in the pathogenesis of MASLD and identify the secreted isoform as a tractable therapeutic target for MASLD via antibody-based neutralization. IMPACT AND IMPLICATIONS: We have shown the role of EMC10 in the regulation of energy homeostasis and obesity. In this study, we determine the distinct roles of the two isoforms of EMC10 in the regulation of hepatic ER stress and steatosis in mice, and associations of MASLD with different EMC10 isoforms in humans. Our findings delineate a novel regulatory axis for hepatosteatosis and identify EMC10 as a modulator of the PERK-eIF2α-ATF4 signaling cascade that may be of broad physiological significance. Moreover, our pre-clinical and clinical studies clearly provide the foundations for translation of scEMC10 modulation for the treatment of MASLD.

Consequences of COVID-19 on Adipose Tissue Signatures.

Since the emergence of coronavirus disease-19 (COVID-19) in 2019, it has been crucial to investigate the causes of severe cases, particularly the higher rates of hospitalization and mortality in individuals with obesity. Previous findings suggest that adipocytes may play a role in adverse COVID-19 outcomes in people with obesity. The impact of COVID-19 vaccination and infection on adipose tissue (AT) is currently unclear. We therefore analyzed 27 paired biopsies of visceral and subcutaneous AT from donors of the Leipzig Obesity BioBank that have been categorized into three groups (1: no infection/no vaccination; 2: no infection but vaccinated; 3: infected and vaccinated) based on COVID-19 antibodies to spike (indicating vaccination) and/or nucleocapsid proteins. We provide additional insights into the impact of COVID-19 on AT biology through a comprehensive histological transcriptome and serum proteome analysis. This study demonstrates that COVID-19 infection is associated with smaller average adipocyte size. The impact of infection on gene expression was significantly more pronounced in subcutaneous than in visceral AT and mainly due to immune system-related processes. Serum proteome analysis revealed the effects of the infection on circulating adiponectin, interleukin 6 (IL-6), and carbonic anhydrase 5A (CA5A), which are all related to obesity and blood glucose abnormalities.

Psychometric properties of the WBIS/-M in a representative prebariatric sample - evidence for an improved 10-item version.

Introduction The Weight Bias Internalization Scale and the Modified Weight Bias Internalization Scale are well-established self-report questionnaires for assessing weight bias internalization, which is widespread among bariatric patients. However, among this group, psychometric properties of the Weight Bias Internalization Scale have only been examined in small samples showing unsatisfactory model fit and have not been explored for the modified questionnaire. Methods This study psychometrically evaluated and compared the Weight Bias Internalization Scale and Modified Weight Bias Internalization Scale in a large sample of prebariatric patients (N=825, mean age=46.75 years, SD=11.55) regarding item characteristics, model fit to unidimensionality, reliability, construct validity, and measurement invariance. Results Item 4 of both questionnaires showed low corrected item-total correlations (<.40) and was therefore removed from the scales. The new 10-item versions showed improved item characteristics, internal consistency, model fit to unidimensionality, and convergent and divergent validity when compared to the 11-item versions. The best psychometric properties were found for the 10-item version of the Modified Weight Bias Internalization Scale. Conclusion The 10-item version of the Modified Weight Bias Internalization Scale surpasses the other versions studied in all psychometric properties. Therefore, it should be used in prebariatric patients to detect weight bias internalization and provide them with psychological interventions that could improve bariatric surgery outcomes.

Depressive Symptoms among Bariatric Surgery Candidates: Associations with Stigmatization and Weight and Shape Concern.

Bariatric surgery candidates (BSC) are a highly vulnerable group for mental health impairments. According to the theoretical model of weight stigma, weight-related experienced stigmatization (ES) negatively influences mental health through weight bias internalization (WBI). This study tested this model among BSC and investigated whether this association depends on a negative body image in terms of weight and shape concern as a potential moderator. As part of a German multicenter study, ES, WBI, weight and shape concern, and depressive symptoms were assessed via self-report questionnaires among n = 854 BSC. Simple and moderated mediation analyses were applied to analyze whether WBI influences the relationship between ES and depressive symptoms, and whether this influence depends on weight and shape concern. WBI significantly mediated the relationship between ES and depressive symptoms by partially reducing the association of ES with depressive symptoms. Weight and shape concern emerged as significant moderators in the overall model and specifically for associations between WBI and depressive symptoms. The results suggest that the association between ES and depressive symptoms among BSC is stronger in those with high WBI. This association is strengthened by weight and shape concern, especially at low and mean levels. Studies evaluating longitudinal associations between weight-related stigmatization and mental health are indicated, as well as intervention studies targeting WBI in order to reduce adverse effects of ES on mental health in BSC.

The Role of Phosphatidylethanolamine N-Methyltransferase (PEMT) and Its Waist-Hip-Ratio-Associated Locus rs4646404 in Obesity-Related Metabolic Traits and Liver Disease.

In previous genome-wide association studies (GWAS), genetic loci associated with obesity and impaired fat distribution (FD) have been identified. In the present study, we elucidated the role of the PEMT gene, including the waist-hip-ratio-associated single nucleotide polymorphism rs4646404, and its influence on obesity-related metabolic traits. DNA from 2926 metabolically well-characterized subjects was used for genotyping. PEMT expression was analyzed in paired visceral (vis) and subcutaneous (sc) adipose tissue (AT) from a subset of 574 individuals. Additionally, PEMT expression was examined in vis, sc AT and liver tissue in a separate cohort of 64 patients with morbid obesity and liver disease. An in vitro Pemt knockdown was conducted in murine epididymal and inguinal adipocytes. Our findings highlight tissue-specific variations in PEMT mRNA expression across the three studied tissues. Specifically, vis PEMT mRNA levels correlated significantly with T2D and were implicated in the progression of non-alcoholic steatohepatitis (NASH), in contrast to liver tissue, where no significant associations were found. Moreover, sc PEMT expression showed significant correlations with several anthropometric- and metabolic-related parameters. The rs4646404 was associated with vis AT PEMT expression and also with diabetes-related traits. Our in vitro experiments supported the influence of PEMT on adipogenesis, emphasizing its role in AT biology. In summary, our data suggest that PEMT plays a role in regulating FD and has implications in metabolic diseases.

Barrett`s Esophagus in Bariatric Surgery: Regression or Progression?

INTRODUCTION: Morbid obesity is well known as a risk factor for gastroesophageal reflux disease (GERD) and its related disorders such as Barrett's esophagus (BE). This study aimed to evaluate the development of BE in patients who underwent bariatric surgery. MATERIALS AND METHODS: Using a single-center prospectively established database of obese patients who underwent bariatric surgery from 01/2012 to 12/2019, we retrospectively compared the preoperative endoscopic findings of BE to those after 1-2 years and 3-5 years following bariatric surgery. The change of BE was detected endoscopically according to Prague classification and histologically according to the British guidelines of detecting columnar epithelium on the distal esophagus. RESULTS: Among 914 obese patients who underwent bariatric surgery and received a preoperative esophagogastroduodenoscopy (EGD), we found 119 patients (13%) with BE. A follow-up EGD was performed in 74 of the BE patients (62.2%). A total of 37 (50%) patients underwent a follow-up EGD after 1-2 years and 45 (60.8%) patients underwent it after 3-5 years. Among many clinical parameters, the surgical procedure was the only significant factor for the change of BE after bariatric surgery (p < 0.05). A regression of BE was found in 19 patients (n = 54, 35%) after laparoscopic Roux-en-Y- gastric bypass (LRYGB). Furthermore, a progression of BE was detected in six patients (n = 20, 30%) after laparoscopic sleeve gastrectomy (LSG). CONCLUSION: RYGB should be considered in obese patients with BE. Detecting BE prior to bariatric surgery may have an impact on decision-making regarding the suitable surgical bariatric procedure.

Newly diagnosed Crohn's disease, and hepatocellular and renal cell carcinoma in a bariatric surgery patient-dealing with the complexity of obesity-associated diseases: a case report and review of the literature.

BACKGROUND: Bariatric surgery candidates commonly suffer from conditions that constitute the metabolic syndrome. But they also have a higher risk for autoimmune and malignant diseases. Obesity-associated comorbidities aside from the metabolic syndrome are often given insufficient attention in the clinical routine, including preoperative work-ups for bariatric surgery. CASE PRESENTATION: We retrospectively report the case of a 65 years old Caucasian patient who was diagnosed with Crohn's disease prior to, a hepatocellular carcinoma during, and a renal cell carcinoma post bariatric surgery. The relevance of these diseases for decision making in bariatric procedures and current recommendations for preoperative bariatric work-ups are discussed. In our case, the diagnosis of Crohn's disease led to the performance of a sleeve gastrectomy instead of a Roux-en-Y gastric bypass and a previously unknown hepatocellular carcinoma was simultaneously removed by hepatic wedge resection. CONCLUSIONS: Preoperative endoscopy and imaging techniques can be valuable since surprising pre- and intraoperative findings can force the bariatric surgeon to change the initially planned operative strategy. But the diagnostic accuracy of abdominal ultrasound may be limited in bariatric surgery patients. With the expansion of bariatric surgery, the complexity of bariatric surgery patients is also likely to increase. However, with the appropriate awareness and strategies, bariatric surgery can be safely executed and even contribute to the treatment of severe comorbidities that exceed the metabolic spectrum.

Impact of Surgical Postponements due to Covid-19 on Weight and Metabolic Parameters in Bariatric Surgery in Germany: Monocentric Experiences and Considerations in a National Context.

BACKGROUND: Due to Covid-19, elective medical procedures were partly postponed to reduce the burden on the medical system. The impact of these effects in bariatric surgery and their individual consequences remain unknown. MATERIALS/METHODS: In a retrospective monocentric analysis, all bariatric patients at our centre between 01/2020 and 12/2021 were investigated. All patients with postponed surgery due to pandemic were analysed regarding weight change and metabolic parameters. In addition, we performed a nationwide cohort study of all bariatric patients in 2020 using billing data provided by the Federal Statistical Office. Population adjusted procedure rates of 2020 were compared to 2018/2019. RESULTS: Seventy-four patients (42.5%) out of 174 scheduled for bariatric surgery were postponed due to pandemic-related limitations, and 47 (63.5%) patients waited longer than 3 months. Mean postponement was 147.7 days. Apart from outliers (6.8% of all patients), mean weight (+0.9 kg) and body mass index (+0.3 kg/m2) remained stable. HbA1c increased significantly in patients with a postponement longer than 6 months (p = 0.024) and in diabetic patients (+0.18% vs -0.11 in non-diabetic, p = 0.042). In the Germany-wide cohort, the overall reduction of bariatric procedures in the first lockdown (04-06/2020) was -13.4% (p = 0.589). In the second lockdown (10-12/2020), there was no nationwide detectable reduction (+3.5%, p = 0.843) but inter-state differences. There was a catch-up in the interim months (+24.9%, p = 0.002). CONCLUSION: For future lockdowns or other healthcare bottleneck circumstances, the impact of postponement in bariatric patients has to be addressed and prioritization of vulnerable patients (e.g. diabetics) should be considered.

Patient-Related Predictors for Seeking and Receiving Obesity Surgery.

INTRODUCTION: The decision for obesity surgery (OS) is complex and strongly driven by patients' preference. This study aimed to examine patients' preference for OS before and after behavioral weight loss treatment (BWLT), associated patient characteristics, its role in predicting the receipt of OS after BWLT, and potential mediators. METHODS: Data of N = 431 adults with obesity starting a 1-year routine care obesity BWLT were analyzed. Patients were interviewed before (pre-BWLT) and after BWLT (post-BWLT) regarding their preference for OS, and anthropometric, medical, and psychological data were collected. RESULTS: Only a minority of patients (11.6%) had an explicit preference for OS pre-BWLT. Post-BWLT, the number of patients preferring OS significantly increased (27.4%). Patients with a constant or emerging preference for OS showed less favorable anthropometric, psychological, and medical characteristics than patients without or with a vanishing preference for OS. Patients' pre-BWLT preference for OS significantly predicted receiving OS post-BWLT. This association was mediated by higher body mass index pre- and post-BWLT, but not by less percentage total body weight loss (%TBWL) through BWLT. CONCLUSION: Although the preference for OS pre-BWLT predicted the receipt of OS post-BWLT, it was not associated with %TBWL during BWLT. Further prospective studies with multiple assessment time points during BWLT may help understand when and why patients' attitude toward OS changes, and identify possible mediators on the association between the preference and receipt of OS.

[Anastomotic techniques in minimally invasive bariatric surgery]. / Anastomosentechniken in der minimal-invasiven bariatrischen Chirurgie.

BACKGROUND: Recommendations for the use of specific anastomotic techniques are not available in laparoscopic bariatric surgery. Recommendation criteria should consider the rate of insufficiency, bleeding, tendency to stricture or ulceration as well as the impact on weight loss or dumping. OBJECTIVE: This article gives a review of the available evidence on the anastomotic techniques of typical surgical procedures in laparoscopic bariatric surgery. MATERIAL AND METHODS: The current literature was reviewed and is discussed regarding anastomotic techniques for Roux-en­Y gastric bypass (RYGB), one-anastomosis gastric bypass (OAGB), single anastomosis sleeve ileal (SASI) bypass and biliopancreatic diversion with duodenal switch (BPD-DS). RESULTS: Few comparative studies exist, except for the RYGB. In RYGB gastrojejunostomy, a complete manual suture was shown to be equivalent to a mechanical anastomosis. In addition, the linear staple suture showed slight advantages over the circular stapler in terms of wound infections and bleeding. The anastomosis technique of the OAGB and SASI can be performed entirely with a linear stapler or with suture closure of the anterior wall defect. There seems to be an advantage of manual anastomosis in BPD-DS. CONCLUSION: Due to the lack of evidence, no recommendations can be made. Only in RYGB was there an advantage of the linear stapler technique with hand closure of the stapler defect compared to the linear stapler. In principle, prospective, randomized studies should be strived for.

Distinct adaptations of endocrine and cognitive functions may contribute to high variability in long-term weight loss outcome after bariatric surgery.

BACKGROUND: Bariatric surgery has been widely recognized as the most efficient long-term treatment method in severe obesity, yet therapy success shows considerable interindividual variability. Postoperative metabolic adaptations, including improved gut hormone secretion (GLP-1, PYY and ghrelin), and restored executive function may play an explanatory role in weight loss, yet causes for poor success in individual patients remain unknown. This study investigates gut-hormonal and cognitive characteristics in extreme weight loss responders to bariatric surgery. METHODS: Patients (n = 47) with high or low excessive weight loss (EWL) at least 2 years after Roux-en-Y-gastric bypass or sleeve gastrectomy were allocated into good responders (GR, EWL 82.4 ± 11.6%) and poor responders (PR, EWL 24.0 ± SD 12.8%) to study differences in postprandial secretion of GLP-1, PYY, ghrelin and in working memory (WM). RESULTS: Mean BMI was 47.1 ± 6.2 kg/m² in PR (n = 21) and 28.9 ± 3.1 kg/m² in GR (n = 26, p < 0.001). Fasted GLP-1 and PYY were comparable for GR and PR (p > 0.2) and increased strongly after a standardized test meal (300 kcal liquid meal) with a peak at 15 to 30 min. The increase was stronger in GR compared to PR (GLP-1, PYY: Time x Group p < 0.05). Plasma ghrelin levels already differed between groups at fasted state, showing significantly higher levels for GR (p < 0.05). Postprandially, ghrelin secretion was suppressed in both groups, but suppression was higher in GR (Time x Group p < 0.05). GR showed significantly higher WM scores than PR (p < 0.05). Postprandial ghrelin (iAUC), but not GLP-1 or PYY plasma levels, significantly mediated the relationship between EWL and a WM subscore (IS score, CI = 0.07 - 1.68), but not WM main score (MIS score, CI = -0.07 - 1.54), in mediation analyses. CONCLUSION: Excess weight loss success after bariatric surgical procedures is associated with distinct profiles of gut-hormones at fasted and postprandial state, and differences in working memory. Better working memory performance in GR might be mediated by higher postprandial reduction in ghrelin plasma levels. Future studies need to integrate longitudinal data, larger samples and more sensitive cognitive tests.

[Current evidence on loop length in intestinal bypass procedures]. / Aktuelle Evidenz zur Schlingenlänge bei intestinalen Bypassverfahren.

BACKGROUND: Intestinal bypass procedures are well recognized for their long-term weight reduction and control of metabolic comorbidities. The selection of the length of the small bowel loop has a significant influence on the positive and also negative effects of the chosen procedure but national and international standardization are missing. OBJECTIVE: The aim of this article is to give an overview of the current evidence on the various intestinal bypass procedures and the influence of the chosen small bowel loop length on the desired and adverse postoperative outcomes. The IFSO 2019 consensus recommendations on the standardization of bariatric surgery and metabolic procedures form the basis of these considerations. MATERIAL AND METHODS: The current literature was searched for comparative studies addressing the question of different small bowel loop lengths in a Roux-en­Y gastric bypass, one anastomosis gastric bypass, single anastomosis duodenoileal bypass with sleeve gastrectomy and biliopancreatic diversion (with duodenal switch). RESULTS: Due to the heterogeneity of currently available studies and interindividual differences in total small bowel lengths in humans, it is difficult to give definitive recommendations for the choice of small bowel loop lengths. The longer the biliopancreatic loop (BPL) or the shorter the common channel (CC), the higher is the risk of (severe) malnutrition. To prevent malnutrition, the BPL should not be longer than 200 cm and the CC should have a length of at least 200 cm. CONCLUSION: The intestinal bypass procedures recommended in the German S3 guidelines are safe and show good long-term outcomes. As part of the postbariatric follow-up, the nutritional status of patients following an intestinal bypass has to be followed-up on the long term in order to avoid malnutrition preferably prior to a clinical manifestation.

Anthropometric estimators of abdominal fat volume in adults with overweight and obesity.

BACKGROUND/OBJECTIVES: To evaluate anthropometric measures for the prediction of whole-abdominal adipose tissue volumes VXAT (subcutaneous VSAT, visceral VVAT and total VTAT) in patients with obesity. SUBJECTS/METHODS: A total of 181 patients (108 women) with overweight or obesity were analyzed retrospectively. MRI data (1.5 T) were available from independent clinical trials at a single institution (Integrated Research and Treatment Center of Obesity, University of Leipzig). A custom-made software was used for automated tissue segmentation. Anthropometric parameters (AP) were circumferences of the waist (WC) and hip (HC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and the (hypothetical) hip-to-height ratio (HHtR). Agreement was evaluated by standard deviations sd% of percent differences between estimated volumes (using results of linear AP-VXAT regression) and measured ones as well as Pearson's correlation coefficient r. RESULTS: For SAT volume estimation, the smallest sd% for all patients was seen for HC (25.1%) closely followed by HHtR (25.2%). Sex-specific results for females (17.5% for BMI and 17.2% for HC) and males (20.7% for WC) agreed better. VAT volumes could not be estimated reliably by any of the anthropometric measures considered here. TAT volumes in a mixed population could be best estimated by BMI closely followed by WC (roughly 17.5%). A sex-specific consideration reduced the deviations to around 16% for females (BMI and WC) and below 14% for males (WC). CONCLUSIONS: We suggest the use of sex-specific parameters-BMI or HC for females and WC for males-for the estimation of abdominal SAT and TAT volumes in patients with overweight or obesity.

Sex-Specific Effects of the Genetic Variant rs10487505 Upstream of leptin in the Development of Obesity.

The SNP rs10487505 in the promotor region of the leptin gene was reported to be associated with decreased circulating leptin and increased body mass index (BMI). However, the phenotypic outcomes affected by rs10487505 in the leptin regulatory pathway have not been systematically studied. Therefore, the aim of this study was to elucidate the influence of rs10487505 on leptin mRNA expression and obesity-related parameters. We genotyped rs10487505 in DNA samples from 1665 patients with obesity and lean controls and measured leptin gene expression in paired samples of adipose tissue (AT, N = 310), as well as circulating leptin levels. We confirm the leptin-lowering effect of rs10487505 in women. In contrast to the previously reported data from population-based studies, in this mainly obese cohort, we describe a lower mean BMI in women carrying the C allele of rs10487505. However, no association of rs10487505 with AT leptin mRNA expression was found. Our data suggest that reduced circulating leptin levels are not a result of the direct silencing of leptin mRNA expression. Furthermore, leptin reduction by rs10487505 does not associate with BMI in a linear manner. Instead, the decreasing effect on BMI might be dependent on the severity of obesity.

GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level.

OBJECTIVE: Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett's oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling. DESIGN: We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. RESULTS: The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models. CONCLUSION: Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.

Central Serotonin/Noradrenaline Transporter Availability and Treatment Success in Patients with Obesity.

Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [11C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [11C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m2) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes.

Processing visual ambiguity in fractal patterns: Pareidolia as a sign of creativity.

Creativity is a highly valued and beneficial skill that empirical research typically probes using "divergent thinking" (DT) tasks such as problem solving and novel idea generation. Here, in contrast, we examine the perceptual aspect of creativity by asking whether creative individuals are more likely to perceive recognizable forms in ambiguous stimuli -a phenomenon known as pareidolia. To this end, we designed a visual task in which participants were asked to identify as many recognizable forms as possible in cloud-like fractal images. We found that pareidolic perceptions arise more often and more rapidly in highly creative individuals. Furthermore, high-creatives report pareidolia across a broader range of image contrasts and fractal dimensions than do low creatives. These results extend the established body of work on DT by introducing divergent perception as a complementary manifestation of the creative mind, thus clarifying the perception-creation link while opening new paths for studying creative behavior in humans.

Metabolic Effects of the Waist-To-Hip Ratio Associated Locus GRB14/COBLL1 Are Related to GRB14 Expression in Adipose Tissue.

GRB14/COBLL1 locus has been shown to be associated with body fat distribution (FD), but neither the causal gene nor its role in metabolic diseases has been elucidated. We hypothesize that GRB14/COBLL1 may act as the causal genes for FD-related SNPs (rs10195252 and rs6738627), and that they may be regulated by SNP to effect obesity-related metabolic traits. We genotyped rs10195252 and rs6738627 in 2860 subjects with metabolic phenotypes. In a subgroup of 560 subjects, we analyzed GRB14/COBLL1 gene expression in paired visceral and subcutaneous adipose tissue (AT) samples. Mediation analyses were used to determine the causal relationship between SNPs, AT GRB14/COBLL1 mRNA expression, and obesity-related traits. In vitro gene knockdown of Grb14/Cobll1 was used to test their role in adipogenesis. Both gene expressions in AT are correlated with waist circumference. Visceral GRB14 mRNA expression is associated with FPG and HbA1c. Both SNPs are associated with triglycerides, FPG, and leptin levels. Rs10195252 is associated with HbA1c and seems to be mediated by visceral AT GRB14 mRNA expression. Our data support the role of the GRB14/COBLL1 gene expression in body FD and its locus in metabolic sequelae: in particular, lipid metabolism and glucose homeostasis, which is likely mediated by AT GRB14 transcript levels.