Neutrophil-endothelial interactions in ischaemia-reperfusion injury

Ischaemia is a common clinical event leading to both local and remote tissue injury. Evidence suggests that the injury results mainly from subsequent reperfusion which causes activated neutrophils to migrate into the reperfused tissue and sequester in the lungs, inducing permeability and oedema. This thesis examines the mechanisms by which neutrophils are recruited into reperfused tissue and accumulate in the lungs, and the means by which they then induce injury. Rabbits or rats were subjected to 3 or 4 hours of bilateral hindlimb tourniquet ischaemia. When the tourniquets were released there was peripheral neutropenia, due to the microvascular adhesion of neutrophils. A chemotactic factor was generated in plasma which was identified as leukotriene (LT) B4. The plasma was capable of inducing neutrophil diapedesis which, like the neutropenia, was dependent upon the CD 18 complex of neutrophil adhesive glycoproteins. The mechanism of both the neutropenia and the diapedesis was probably a change in the conformation of existing cell surface CD 18, because there was no increase in its quantitative cell surface expression. Following reperfusion, neutrophils were sequestered locally in skeletal muscle and also in the lungs, where they induced permeability and oedema. Moreover, LTB4 was also generated in bronchoalveolar lavage fluid. Neutrophils induced lung injury via a CD 18-dependent mechanism involving elastase and reactive oxygen metabolites. Since the time course of sequestration of neutrophils in the lungs suggested that endothelium was activated directly by tumour necrosis factor-α (TNF), evidence for involvement of this cytokine was sought. TNF was identified in plasma in some, but not all, ischaemic and reperfused rats. Use of polyclonal anti-TNF anti-serum reduced the lung injury. Infusion of TNF induces a similar lung injury, and this suggests a mechanism whereby the lung is a target for reperfusion injury following hindlimb ischaemia

Weight loss surgery for non-morbidly obese populations with type 2 diabetes: is this an acceptable option for patients?

Aim To explore the views of non-morbidly obese people (BMI 30-40 kg/m2) with type 2 diabetes regarding: (a) the acceptability of bariatric surgery (BS) as a treatment for type 2 diabetes, and (b) willingness to participate in randomised controlled trials comparing BS versus non-surgical intervention. BACKGROUND: Despite weight management being a key therapeutic goal in type 2 diabetes, achieving and sustaining weight loss is problematic. BS is an effective treatment for people with morbid obesity and type 2 diabetes; it is less certain whether non-morbidly obese patients (BMI 30-39.9 kg/m2) with type 2 diabetes benefit from this treatment and whether this approach would be cost-effective. Before evaluating this issue by randomised trials, it is important to understand whether BS and such research are acceptable to this population. METHODS: Non-morbidly obese people with type 2 diabetes were purposively sampled from primary care and invited to participate in semi-structured interviews. Interviews explored participants' thoughts surrounding their diabetes and weight, the acceptability of BS and the willingness to participate in BS research. Data were analysed using Framework Analysi

The use of adjustable gastric bands for management of severe and complex obesity

BACKGROUND: Obesity levels in the UK have reached a sustained high and ∼4% of the population would be candidates for bariatric surgery based upon current UK NICE guidelines, which has important implications for Clinical Commissioning Groups. SOURCES OF DATA: Summary data from Cochrane systematic reviews, randomized controlled trials (RCTs) and cohort studies. AREAS OF AGREEMENT: Currently, the only treatment that offers significant and durable weight loss for those with severe and complex obesity is surgery. Three operations account for 95% of all bariatric surgery in the UK, but the NHS offers surgery to only a small fraction of those who could benefit. Laparoscopic adjustable gastric banding (gastric banding) has potentially the lowest risk and up-front costs of the three procedures. AREAS OF CONTROVERSY: Reliable Level 1 evidence of the relative effectiveness of the operations is lacking. GROWING POINTS: As a point intervention, weight loss surgery together with the chronic disease management strategy for obesity can prevent significant future disease and mortality, and the NHS should embrace both. AREAS TIMELY FOR DEVELOPING RESEARCH: Better RCT evidence is needed including clinical effectiveness and economic analysis to answer the important question ‘which is the best of the three operations most frequently performed?’ This review considers the current evidence for gastric banding for the treatment of severe and complex obesity

Why the NHS should do more bariatric surgery; how much should we do?

As the epidemic of severe and complex obesity worsens, availability of the most successful treatment, bariatric surgery, is limited. Less than 1% of those who could benefit get treatment. By contrast, people with other lifestyle health problems such as alcohol related liver disease are treated. We explore the clinical and cost effectiveness of bariatric surgery and examine the barriers to access

Bariatric-metabolic surgery for NHS patients with type 2 diabetes in the United Kingdom National Bariatric Surgery Registry

Aim: Bariatric-metabolic surgery is approved by the National Institute of Health and Care Excellence (NICE) for people with severe obesity and type 2 diabetes (T2DM) (including class 1 obesity after 2014). This study analysed baseline characteristics, disease severity and operations undertaken in people with obesity and T2DM undergoing bariatric-metabolic surgery in the UK National Health Service (NHS) compared to those without T2DM. Methods: Baseline characteristics, trends over time and operations undertaken were analysed for people undergoing primary bariatric-metabolic surgery in the NHS using the National Bariatric Surgical Registry (NBSR) for 11 years from 2009 to 2019. Clinical practice before and after the publication of the NICE guidance (2014) was examined. Multivariate logistic regression was used to determine associations with T2DM status and the procedure undertaken. Results: 14,948/51,715 (28.9%) participants had T2DM, with 10,626 (71.1%) on oral hypoglycaemics, 4322 (28.9%) on insulin/other injectables, and with T2DM diagnosed 10+ years before surgery in 3876 (25.9%). Participants with T2DM, compared to those without T2DM, were associated with older age (p &lt; 0.001), male sex (p &lt; 0.001), poorer functional status (p &lt; 0.001), dyslipidaemia (OR: 3.58 (CI: 3.39–3.79); p &lt; 0.001), hypertension (OR: 2.32 (2.19–2.45); p &lt; 0.001) and liver disease (OR: 1.73 (1.58–1.90); p &lt; 0.001), but no difference in body mass index was noted. Fewer people receiving bariatric-metabolic surgery after 2015 had T2DM (p &lt; 0.001), although a very small percentage increase of those with class I obesity and T2DM was noted. Gastric bypass was the commonest operation overall. T2DM status was associated with selection for gastric bypass compared to sleeve gastrectomy (p &lt; 0.001). Conclusion: NHS bariatric-metabolic surgery is used for people with T2DM much later in the disease process when it is less effective. National guidance on bariatric-metabolic surgery and data from multiple RCTs have had little impact on clinical practice.</p

Roux-en-Y Gastric Bypass Surgery Induces Early Plasma Metabolomic and Lipidomic Alterations in Humans Associated with Diabetes Remission

Roux-en-Y gastric bypass (RYGB) is an effective method to attain sustained weight loss and diabetes remission. We aimed to elucidate early changes in the plasma metabolome and lipidome after RYGB. Plasma samples from 16 insulin-resistant morbidly obese subjects, of whom 14 had diabetes, were subjected to global metabolomics and lipidomics analysis at pre-surgery and 4 and 42 days after RYGB. Metabolites and lipid species were compared between time points and between subjects who were in remission and not in remission from diabetes 2 years after surgery. We found that the variables that were most discriminatory between time points were decanoic acid and octanoic acid, which were elevated 42 days after surgery, and sphingomyelins (18:1/21:0 and 18:1/23:3), which were at their lowest level 42 days after surgery. Insulin levels were lower at 4 and 42 days after surgery compared with pre-surgery levels. At 4 days after surgery, insulin levels correlated positively with metabolites of branched chain and aromatic amino acid metabolism and negatively with triglycerides with long-chain fatty acids. Of the 14 subjects with diabetes prior to surgery, 7 were in remission 2 years after surgery. The subjects in remission displayed higher pre-surgery levels of tricarboxylic acid cycle intermediates and triglycerides with long-chain fatty acids compared with subjects not in remission. Thus, metabolic alterations are induced soon after surgery and subjects with diabetes remission differ in the metabolic profiles at pre- and early post-surgery time points compared to patients not in remission.Peer reviewe

Involving lay and professional stakeholders in the development of a research intervention for the DEPICTED Study

Aim: This paper focuses on stakeholders’ active involvement at key stages of the research as members of a Stakeholder Action Group (SAG), particularly in the context of lay stakeholder involvement. Some challenges that can arise and wider issues (e.g. empowerment, the impact of user involvement) are identified and explored within the literature on service user involvement in health care research, reflecting on the implications for researchers. Background: In the DEPICTED study, lay and professional stakeholders were actively involved in developing a complex research intervention. Lay stakeholders comprised teenage and adult patients with diabetes, parents and patient organization representatives. Professional stakeholders were from a range of disciplines. Methods: Three 1-day research meetings were attended by 13–17 lay stakeholders and 10–11 professional stakeholders (plus researchers). The SAG was responsible for reviewing evidence, advising on developing ideas for the research intervention and guiding plans for evaluation of the intervention in a subsequent trial. Formal evaluations were completed by stakeholders following each SAG meeting. Results: Throughout the first (developmental) stage of this two-stage study, lay and professional stakeholders participated or were actively involved in activities that provided data to inform the research intervention. Lay stakeholders identified the need for and contributed to the design of a patient-held tool, strongly influenced the detailed design and content of the research intervention and outcome questionnaire, thus making a major contribution to the trial design. Conclusion: Stakeholders, including teenagers, can be actively involved in designing a research intervention and impact significantly on study outcomes

Access to publicly funded weight management services in England using routine data from primary and secondary care (2007–2020): An observational cohort study

Background Adults living with overweight/obesity are eligible for publicly funded weight management (WM) programmes according to national guidance. People with the most severe and complex obesity are eligible for bariatric surgery. Primary care plays a key role in identifying overweight/obesity and referring to WM interventions. This study aimed to (1) describe the primary care population in England who (a) are referred for WM interventions and (b) undergo bariatric surgery and (2) determine the patient and GP practice characteristics associated with both. Methods and findings An observational cohort study was undertaken using routinely collected primary care data in England from the Clinical Practice Research Datalink linked with Hospital Episode Statistics. During the study period (January 2007 to June 2020), 1,811,587 adults met the inclusion criteria of a recording of overweight/obesity in primary care, of which 54.62% were female and 20.10% aged 45 to 54. Only 56,783 (3.13%) were referred to WM, and 3,701 (1.09% of those with severe and complex obesity) underwent bariatric surgery. Multivariable Poisson regression examined the associations of demographic, clinical, and regional characteristics on the likelihood of WM referral and bariatric surgery. Higher body mass index (BMI) and practice region had the strongest associations with both outcomes. People with BMI ≥40 kg/m2 were more than 6 times as likely to be referred for WM (10.05% of individuals) than BMI 25.0 to 29.9 kg/m2 (1.34%) (rate ratio (RR) 6.19, 95% confidence interval (CI) [5.99,6.40], p < 0.001). They were more than 5 times as likely to undergo bariatric surgery (3.98%) than BMI 35.0 to 40.0 kg/m2 with a comorbidity (0.53%) (RR 5.52, 95% CI [5.07,6.02], p < 0.001). Patients from practices in the West Midlands were the most likely to have a WM referral (5.40%) (RR 2.17, 95% CI [2.10,2.24], p < 0.001, compared with the North West, 2.89%), and practices from the East of England least likely (1.04%) (RR 0.43, 95% CI [0.41,0.46], p < 0.001, compared with North West). Patients from practices in London were the most likely to undergo bariatric surgery (2.15%), and practices in the North West the least likely (0.68%) (RR 3.29, 95% CI [2.88,3.76], p < 0.001, London compared with North West). Longer duration since diagnosis with severe and complex obesity (e.g., 1.67% of individuals diagnosed in 2007 versus 0.34% in 2015, RR 0.20, 95% CI [0.12,0.32], p < 0.001), and increasing comorbidities (e.g., 2.26% of individuals with 6+ comorbidities versus 1.39% with none (RR 8.79, 95% CI [7.16,10.79], p < 0.001) were also strongly associated with bariatric surgery. The main limitation is the reliance on overweight/obesity being recorded within primary care records to identify the study population. Conclusions Between 2007 and 2020, a very small percentage of the primary care population eligible for WM referral or bariatric surgery according to national guidance received either. Higher BMI and GP practice region had the strongest associations with both. Regional inequalities may reflect differences in commissioning and provision of WM services across the country. Multi-stakeholder qualitative research is ongoing to understand the barriers to accessing WM services and potential solutions. Together with population-wide prevention strategies, improved access to WM interventions is needed to reduce obesity levels