Towards precision medicine in bariatric surgery prescription

Obesity is a complex, multifactorial and chronic disease. Bariatric surgery is a safe and effective treatment intervention for obesity and obesity-related diseases. However, weight loss after surgery can be highly heterogeneous and is not entirely predictable, particularly in the long-term after intervention. In this review, we present and discuss the available data on patient-related and procedure-related factors that were previously appointed as putative predictors of bariatric surgery outcomes. In addition, we present a critical appraisal of the available evidence on which factors could be taken into account when recommending and deciding which bariatric procedure to perform. Several patient-related features were identified as having a potential impact on weight loss after bariatric surgery, including age, gender, anthropometrics, obesity co-morbidities, eating behavior, genetic background, circulating biomarkers (microRNAs, metabolites and hormones), psychological and socioeconomic factors. However, none of these factors are sufficiently robust to be used as predictive factors. Overall, there is no doubt that before we long for precision medicine, there is the unmet need for a better understanding of the socio-biological drivers of weight gain, weight loss failure and weight-regain after bariatric interventions. Machine learning models targeting preoperative factors and effectiveness measurements of specific bariatric surgery interventions, would enable a more precise identification of the causal links between determinants of weight gain and weight loss. Artificial intelligence algorithms to be used in clinical practice to predict the response to bariatric surgery interventions could then be created, which would ultimately allow to move forward into precision medicine in bariatric surgery prescription

Apoptosis regulation in adrenocortical carcinoma

Apoptosis evading is a hallmark of cancer. Tumor cells are characterized by having an impaired apoptosis signaling, a fact that deregulates the balance between cell death and survival, leading to tumor development, invasion and resistance to treatment. In general, patients with adrenocortical carcinomas (ACC) have an extremely bad prognosis, which is related to disease progression and significant resistance to treatments. In this report, we performed an integrative review about the disruption of apoptosis in ACC that may underlie the characteristic poor prognosis in these patients. Although the apoptosis has been scarcely studied in ACC, the majority of the deregulation phenomena already described are anti-apoptotic. Most importantly, in a near future, targeting apoptosis modulation in ACC patients may become a promising therapeutic.The work was supported by the Foundation for Science and Technology (FCT) (PTDC/MEC-ONC/31384/2017). Unit for Multidisciplinary Research in Biomedicine (UMIB) is funded by grants from FCT (UID/Multi/00215/2013)

Angiogenesis in the Normal Adrenal Fetal Cortex and Adrenocortical Tumors

Simple Summary Pharmacological angiogenesis modulation was robustly demonstrated to be a powerful clinical resource in oncotherapy. Adrenocortical carcinomas (ACC) often have a poor prognosis for which therapeutic options are limited. Understanding the mechanisms that regulate adrenocortical angiogenesis both under physiological conditions and in ACC could provide important clues on how these processes could be modulated for clinical purposes. This report summarizes the current knowledge on adrenal cortex angiogenesis regulation in physiological conditions and ACC. Embryonic adrenal angiogenesis is regulated by VEGF and Ang-Tie signaling pathways. VEGF angiogenic pathway was initially considered a promising therapeutic target for improving ACC prognosis. However, every single VEGF pathway-targeting clinical trial in ACC so far conducted yielded disappointing results. In contrast, the potential of Ang-Tie pathway-targeting in ACC is yet to be explored. Therefore, further investigation on the role and efficacy of modulating both Ang-Tie and VEGF pathways in ACC is still an unmet need. Angiogenesis plays an important role in several physiological and pathological processes. Pharmacological angiogenesis modulation has been robustly demonstrated to achieve clinical benefits in several cancers. Adrenocortical carcinomas (ACC) are rare tumors that often have a poor prognosis. In addition, therapeutic options for ACC are limited. Understanding the mechanisms that regulate adrenocortical angiogenesis along the embryonic development and in ACC could provide important clues on how these processes could be pharmacologically modulated for ACC treatment. In this report, we performed an integrative review on adrenal cortex angiogenesis regulation in physiological conditions and ACC. During embryonic development, adrenal angiogenesis is regulated by both VEGF and Ang-Tie signaling pathways. In ACC, early research efforts were focused on VEGF signaling and this pathway was identified as a good prognostic factor and thus a promising therapeutic target. However, every clinical trial so far conducted in ACC using VEGF pathway- targeting drugs, alone or in combination, yielded disappointing results. In contrast, although the Ang-Tie pathway has been pointed out as an important regulator of fetal adrenocortical angiogenesis, its role is yet to be explored in ACC. In the future, further research on the role and efficacy of modulating both Ang-Tie and VEGF pathways in ACC is needed

An instability of higher-dimensional rotating black holes

We present the first example of a linearized gravitational instability of an asymptotically flat vacuum black hole. We study perturbations of a Myers-Perry black hole with equal angular momenta in an odd number of dimensions. We find no evidence of any instability in five or seven dimensions, but in nine dimensions, for sufficiently rapid rotation, we find perturbations that grow exponentially in time. The onset of instability is associated with the appearance of time-independent perturbations which generically break all but one of the rotational symmetries. This is interpreted as evidence for the existence of a new 70-parameter family of black hole solutions with only a single rotational symmetry. We also present results for the Gregory-Laflamme instability of rotating black strings, demonstrating that rotation makes black strings more unstable.Comment: 38 pages, 13 figure

Renal Dysfunction Phenotypes in Patients Undergoing Obesity Surgery

Obesity surgery candidates are at an increased risk of kidney injury, but pre-operative evaluation usually neglects kidney function assessment. This study aimed to identify renal dysfunction in candidates for bariatric surgery. To reduce the sources of bias, subjects with diabetes, prediabetes under metformin treatment, neoplastic or inflammatory diseases were excluded. Patients' (n = 192) average body mass index was 41.7 +/- 5.4 kg/m(2). Among these, 51% (n = 94) had creatinine clearance over 140 mL/min, 22.4% (n = 43) had proteinuria over 150 mg/day and 14.6% (n = 28) albuminuria over 30 mg/day. A creatinine clearance higher than 140 mL/min was associated with higher levels of proteinuria and albuminuria. Univariate analysis identified sex, glycated hemoglobin, uric acid, HDL and VLDL cholesterol as being associated with albuminuria, but not with proteinuria. On multivariate analysis, glycated hemoglobin and creatinine clearance as continuous variables were significantly associated with albuminuria. In summary, in our patient population prediabetes, lipid abnormalities and hyperuricemia were associated with albuminuria, but not with proteinuria, suggesting different disease mechanisms might be implicated. Data suggest that in obesity-associated kidney disease, tubulointerstitial injury precedes glomerulopathy. A significant proportion of obesity surgery candidates present clinically relevant albuminuria and proteinuria along with renal hyperfiltration, suggesting that routine pre-operative assessment of these parameters should be considered

Accuracy of prediction models for long-term type 2 diabetes remission after gastric bypass

AimTo evaluate the accuracy of DiaBetter, DiaRem, Ad-DiaRem and 5y-Ad-DiaRem scores' at predicting T2D remission 10 or more years after surgery.MethodsPatients with obesity and T2D (n = 126) submitted to RYGB with 10 or more years of follow-up. It was a unicentric trial. Pre-operative anthropometric and clinical data was retrieved to calculate DiaRem, DiaBetter, Ad-DiaRem and 5y-Ad-DiaRem scores, while a hospital visit was conducted to assess current diabetes status. The area under the receiver operating characteristic (AUROC) curve was calculated as estimate of the scores' accuracy to predict long-term T2D remission.ResultsAmong the entire cohort (n = 126), 70 subjects (55.6%) achieved and maintained T2D remission 10 or more years after RYGB. The 5y-Ad-DiaRem score was the one that depicted the highest discriminative power (AUROC = 0.838) to predict long-term T2D remission when compared to DiaBetter (AUROC = 0.735), DiaRem (AUROC = 0.721) and Ad-DiaRem (AUROC = 0.720).ConclusionThe score with highest accuracy to predict long-term T2D remission after RYGB surgery was the 5y-Ad-DiaRem. Yet, the available scores accuracy to predict T2D remission in the long term is still suboptimal, highlighting the unmet need for a better scoring system

Power electronics converters for an electric vehicle fast charging station with storage capability

Fast charging stations are a key element for the wide spreading of Electric Vehicles (EVs) by reducing the charging time to a range between 20 to 40 min. However, the integration of fast charging stations causes some adverse impacts on the Power Grid (PG), namely by the huge increase in the peak demand during short periods of time. This paper addresses the design of the power electronics converters for an EV DC fast charging station with local storage capability and easy interface of renewables. In the proposed topology, the energy storage capability is used to smooth the peak power demand, inherent to fast charging systems, and contributes to the stability of the PG. When integrated in a Smart Grid, the proposed topology may even return some of the stored energy back to the power grid, when necessary. The accomplishment of the aforementioned objectives requires a set of different power electronics converters that are described and discussed in this paper.This work has been supported by COMPETE: POCI-01-0145-FEDER-007043 and by FCT within the Project Scope: UID/CEC/00319/2013. This work is financed by the ERDF – COMPETE 2020 Programme, and FCT within project SAICTPAC/0004/2015‐POCI‐01‐0145–FEDER‐016434 and FCT within project PTDC/EEI-EEE/28813/2017. Mr. Luis A. M. Barros is supported by the doctoral scholarship PD/BD/143006/2018 granted by the Portuguese FCT agency. Mr. Tiago Sousa is supported by the doctoral scholarship SFRH/BD/134353/2017 granted by the Portuguese FCT agency

GLP-1 Increases Circulating Leptin Levels in Truncal Vagotomized Rats

GLP-1 is a gastro-intestinal hormone acting within the gut/brain axis for energy balance regulation. We aimed to evaluate the role of the vagus nerve in whole-body energy homeostasis and in mediating GLP-1 effects. For this, rats submitted to truncal vagotomy and sham-operated controls underwent a comprehensive evaluation, including eating behavior, body weight, percentage of white (WAT) and brown adipose tissue (BAT), resting energy expenditure (REE) and acute response to GLP-1. Truncal vagotomized rats had significantly lower food intake, body weight, body weight gain, WAT and BAT, with a higher BAT/WAT ratio, but no significant difference in REE when compared to controls. Vagotomized rats also had significantly higher fasting ghrelin and lower glucose and insulin levels. After GLP-1 administration, vagotomized rats depicted a blunted anorexigenic response and higher plasma leptin levels, as compared to controls. However, in vitro stimulation of VAT explants with GLP-1 resulted in no significant changes in leptin secretion. In conclusion, the vagus nerve influences whole-body energy homeostasis by modifying food intake, body weight and body composition and by mediating the GLP-1 anorectic response. The higher leptin levels in response to acute GLP-1 administration observed after truncal vagotomy suggest the existence of a putative GLP-1-leptin axis that relies on the integrity of gut-brain vagal pathway

Are SADI-S and BPD/DS bariatric procedures identical twins or distant relatives?-A case report

Given the common anatomical features and similar short-term weight loss outcomes, Biliopancreatic Diversion with Duodenal Switch (BPD/DS) and Single-Anastomosis Duodenoileal bypass with Sleeve gastrectomy (SADI-S) are considered identical bariatric procedures, apart from technical complexity being lower for SADI-S. In the absence of prospective randomized trials or long-term comparative studies the rationale for choosing between procedures is hampered. Post-bariatric hormonal profiles could contribute to understand the underlying mechanisms and potentially be used as a decision aid when choosing between procedures. The main aim of this study was to compare the outcomes of BPD/DS and SADI-S, in genetically identical individuals exposed to similar environmental factors. Two identical twin (T) female patients, one submitted to BPD/DS (T_BPD/DS) and another to SADIS-S (T_SADI-S) were followed up to one year after surgery. Before surgery and at 3, 6 and 12 months after surgery, both patients underwent mixed meal tolerance tests (MMTT) to evaluate postprandial glucose, glucagon and GLP-1 response. In addition, 3 months after surgery, glucose dynamics were assessed using a Flash Glucose Monitoring (FGM) system for 14 days. The percentage of total weight loss (%TWL) was higher for T_BPD/DS compared to T_SADI-S (34.03 vs 29.03 %). During MMTT, T_BPD/DS presented lower glucose, glucagon, insulin and C-peptide excursions at all timepoints when compared to SADI-S; along with a greater percentage of time within the low glucose range (55.97 vs 39.93 %) and numerically lower glucose variability indexes on FGM (MAG change:0.51 vs 0.63 mmol/lxh- 1). In patients with the same genetic background, BPD/DS was shown to result in greater weight loss than SADI-S. The differences in glucose and enteropancreatic hormone profiles observed after BPD/DS and SADI-S suggest that different mechanisms underlie weight loss