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The global pandemic of obesity continues to escalate worldwide and results in severe multisystem metabolic dysfunction in the expanding population of its sufferers. It is associated with the concurrent pathologies of type 2 diabetes, cardiovascular disease, cancer and sleep apnea, which have also increased in prevalence over the past decade. Obesity can be mapped in social networks and is recognised as a fundamental element of the metabolic syndrome contributing to the global burden of diabesity and oncobesity. Its impact on global health has resulted in a massive burden on healthcare services and is among the most prominent contributors to mounting healthcare costs. Despite its pathological impact, the non-surgical management of obesity through behavioural, lifestyle and pharmacotherapies has not offered dependable benefits in severely obese patients. Bariatric surgery has demonstrated consistent weight loss in morbidly obese subjects and is increasingly performed worldwide to treat morbid obesity. Furthermore, these operations may produce beneficial metabolic effects especially with respect to improvement in type 2 diabetes and the metabolic syndrome. Understanding surgical weight loss mechanisms and metabolic modulation is required to enhance patient benefits and operative outcomes. A surgical model of Roux-en-Y gastric bypass (RYGB) was developed as an experimental platform to investigate the metabolic effects of bariatric surgery. The model was studied through a systems biology approach to characterize systemic and gastro-intestinal surgical metabolic modulation. Analysis of postoperative faecal samples from this rodent model revealed a powerful shift in gut microbial ecology and also highlighted the role of RYGB surgery in regulating the cross-talk between the gut microbiome and its mammalian host. Similar metabolic changes were also identified in human subjects undergoing bariatric surgery. Analysis of plasma and cardiac tissue revealed shifts in metabolic activity, reflected by enhanced cardiac energy metabolism. Overall, the results of this work identify some of the potential mechanisms behind bariatric surgical weight loss and systemic metabolic enhancement. This study not only supports the term metabolic surgery but also identifies the global multi-systemic benefits of bariatric surgical procedures. As such, the findings presented in this thesis may in future contribute to the enhancement of current bariatric procedures and the development of the next-generation of innovative metabolic therapies.

Modern training methods for surgery have undergone a paradigm shift in recent decades and encompasses many challenges including surgeon-specific outcome reporting, reduced staffing levels, risks of legal recourse and increased financial pressures. Validated assessment tools are not routinely utilised in surgical practice. The measure of performance changes from objective assessment in trainees to evaluation of generic clinical outcomes and local processes for experts. Research in the field of evaluating the relationship between performance assessment and clinical outcomes in general surgery is limited. Studies conducted to date are of a high variability and include relatively small numbers. Despite this, there exists a relationship between performance assessment scores and clinical outcomes using the measures of procedure duration, complication rate and length of stay. The views held by all key stakeholders including trainees, trainers and the public were examined. Novel methods of training are not being uniformly utilised. The value of simulation training is unclear due to a lack of objective evidence; however, the public believe that this is mandatory prior to a patient encounter. There also exists a desire for regular performance assessment as a quality assurance of surgical practice. An evaluation of the relationship between performance assessments, in both technical and non-technical domains, and clinical outcomes was conducted whilst controlling for various clinical and expertise-based variables. No clear relationship with clinical outcomes was found although there was a trend towards significance with composite scoring. Unit-based scores also demonstrated similar variability. Trends were observed in temporal analysis, but these were not statistically significant. Motivational factors also have an impact upon clinical performance and further research is required to evaluate the degree of impact. This thesis has highlighted key areas where more research is needed to formally identify how to assess performance amongst surgeons in a method that has an evidence-based clinical impact.

Noncommunicable diseases (NCDs) are the main cause of death and disability worldwide. They are responsible for more than 70% of all global mortality. Furthermore, being among the biggest generators of health care expenditure, they pose important economic sustainability challenges to health care systems worldwide. After a slow start, the international community has come to prioritise these conditions, as evidenced by high-level meetings on NCDs at the UN General Assembly. In 2015, 193 countries committed to reducing premature deaths from NCDs by a third by 2030, as part of the Sustainable Development Goals. WHO Member States have also endorsed a menu of cost-effective NCDs best buy policy options that can be used to tackle the NCD pandemic. However, many governments have been grappling with this challenge and looking for effective policy-based solutions, particularly in the area of promoting healthy eating. In Europe, NCDs are responsible for approximately 80% of all health care spending. Nevertheless, 80% of such NCDs are preventable if their behavioural risk factors are properly addressed. This was why countries in the WHO European Region have implemented a wide range of mandatory and voluntary policies to promote healthy lifestyles, including a growing number of interpretative nutrition labelling schemes, targeted food and beverage taxes, comprehensive reformulation strategies, and restrictions on the marketing of unhealthy foods. Recently, the Portuguese example has been repeatedly used by the WHO as a good role model for other countries to follow in this area. The aim of this thesis was to assess whether Portugal is a strong implementer of the WHO's recommended policies for tackling NCDs and whether the strategy used for the implementation of the healthy nutrition policies was therefore successful. In this thesis, five of the most challenging policies to implement were individually analysed and characterised using different health impact and effectiveness assessment methods. Furthermore, all the policy areas were critically assessed regarding their implementation challenges and determinants. Among the biggest scientific innovations resulting from this thesis research development is the usage of real food consumption data from Portuguese Population cohorts in order to model the impact of both mandatory and voluntary policies. Furthermore, this thesis presents research using total SSBs consumption data at the national level for the first time in this research area. Also, the ability to model the impact of a SSBs tax on obesity incidence is one of the biggest scientific break throughs of the hereby-presented research. The outcomes of the strategy developed by Portugal in order to address its unhealthy eating habits provide an opportunity for refining the reason why some countries score better than others at implementing the WHO's NCD policies. Furthermore, the lessons learned from this case study may contribute to the improvement of change management as a way to push for high health impact implementation of NCD policies.

The incidence and prevalence of Obesity and T2DM is increasing at an alarming rate and now poses a global threat to mankind. Bariatric surgery is now an established strategy for combating both these conditions but recent years have also seen the emergence of endoscopic treatments designed to mimic the effects of surgery. These devices have the added advantage of being minimally invasive and easily reversible. The Endobarrier (EB) is an endoluminal duodenal-jejunal bypass liner (DJBL) licensed for up to 12 months of treatment in patients with type 2 diabetes who are obese. In this thesis I explored the feasibility and safety of this device as an effective method of weight loss and glycaemic control in the setting of nationally funded multicenter randomised control trial. This clinical trial compared the device implanted for 1 year versus standard medical therapy (control) in a cohort of 170 obese patients with type 2 diabetes. Body weight decreased by 10.8±5.3kg in the EB group and 12.1±7.8kg at 6 and 12 months respectively. In comparison the control group lost 6.3±5.5kg at 6 months and 6.2±6.4kg at 12 months (P=<0.001). Significant improvements in fasting insulin levels, total cholesterol and liver biochemistry were also seen between both patient cohorts. Plasma, urine and stool from participants were also analysed using nuclear magnetic resonance to identify key metabolic perturbations between both patient cohorts. The metabolite trimethylamine N-oxide (TMAO) which is associated with the development of diabetes was found to reduce in the plasma of Endobarrier patients. Microbial derived metabolites phenylacetylglycine and 3-indoxylsulfate were found in increasing amounts in the urine whilst a reduction in tricarboxylic acid cycle intermediates fumarate and malate were seen in the stool. The results of this study help in defining the current role of the DJBL in the treatment algorithm of patients with diabetes and obesity but also identifies some of the devices similarities to gastric bypass surgery. Crucially this research provides a possible insight into the mechanisms of how this device may elicit its effect which may include altering the gut microbiome, reducing levels of TMAO and increasing anaerobic energy metabolism.

The rising obesity pandemic and the concomitant rise in its co-morbidities are leading causes of global morbidity and mortality. Bariatric surgery is a form of gastrointestinal surgery that leads to sustained weight loss, diabetes resolution, reduction in cancer risk and other improvements in health. MicroRNAs are a family of small, endogenous, non-coding RNAs that regulate gene expression at the post-transcriptional level. MicroRNAs control expression of over half the human transcriptome and are involved in processes fundamental to both normal physiology and disease, including obesity and diabetes. This study hypothesizes that microRNAs are biomarkers for health improvements following bariatric surgery. Using quantitative PCR, a microRNA baseline was established in the serum and urine of an obese human population and increases in three anti-fibrotic microRNAs were found in urine following bariatric surgery. Circulating microRNA profiles were characterised in Roux-en-Y gastric bypass patients preoperatively and at 5 timepoints postoperatively. Roux-en-Y gastric bypass significantly altered circulating microRNA profiles in a time dependent manner. Relative to preoperative levels, of the 159 circulating microRNAs assayed 2 were significantly deregulated 1 month postoperatively, 5 were deregulated at 3 months, 10 at 6 months, 28 at 9 months and 31 at 12 months. Target prediction and pathway analysis revealed that these differentiated microRNAs regulate biological pathways that are involved in obesity and that microRNAs may contribute to the development of the beneficial post-bariatric phenotype. Both circulating and urinary post-bariatric microRNA levels correlated with measured clinical biomarkers such as BMI and blood glucose. These results indicate that bariatric operations fundamentally alter microRNA expression both in urine and in circulation and suggest that microRNAs represent not only potentially novel biomarkers for improvements in health following surgery, but are possible biological effectors that contribute to the mechanisms behind bariatric surgery. MicroRNA expression profiles could potentially be used to monitor operative outcomes and understanding the role of these differentially expressed microRNAs could shed light behind the mechanism by which bariatric surgery improves health.