The impact of intestinal microbiota imbalance on the development of obesity / O impacto do desequilíbrio da microbiota intestinal no desenvolvimento da obesidade

Objective: review current databases to identify the impacts of intestinal dysbiosis on obesity, as well as serve as a pillar for carrying out preventive, diagnostic and therapeutic measures. Methodology: this is an integrative review carried out from the collection of data obtained from the SciELO, PubMed, VHL, and LILACS platforms using the descriptors "dysbiosis", "obesity" and "gastrointestinal microbiome"; Inclusion criteria were: articles published in the last five years (from 2017 to 2022), original articles, meta-analyses, and observational studies (clinical trials and cohort study) and written in Portuguese, English, or Spanish. Results: Western diet and use of sweeteners cause anthropometric changes, blood pressure, glucose intolerance, among others, in addition to leading to the prevalence of deleterious bacteria in the body, culminating in obesity and diabetes mellitus; on the other hand, a diet rich in fiber and administration of probiotics can generate beneficial changes in the diversity of the intestinal flora, in addition to combating the inflammatory state generated by obesity (AU).

Objetivo: revisar as bases de dados atuais para identificar os impactos da disbiose intestinal na obesidade, bem como servir de pilar para realização de medidas preventivas, diagnósticas e terapêuticas. Metodologia: trata-se de revisão integrativa realizada a partir de coleta de dados obtidos nas plataformas SciELO, PuBMed, BVS e LILACS usando os descritores "dysbiosis", "obesity" and "gastrointestinal microbiome"; os critérios de inclusão foram: artigos publicados nos últimos cinco anos (de 2017 a 2022), artigos originais, metanálises e estudos observacionais (ensaios clínicos e estudo de coorte) e escritos em português, inglês ou espanhol. Resultados: dieta ocidental e uso de adoçante provocam alterações antropométricas, de pressão arterial, intolerância à glicose, entre outras, além de levar à prevalência de bactérias deletérias ao organismo, culminando em obesidade e diabetes mellitus; em contrapartida, dieta rica em fibras e administração de probióticos podem gerar mudanças benéficas na diversidade da flora intestinal, ademais combatem o estado inflamatório gerado pela obesidade (AU).

Prognostic tools for identification of high risk in people with Crohn's disease: systematic review and cost-effectiveness study.

BACKGROUND: Crohn's disease is a lifelong condition that can affect any segment of the gastrointestinal tract. Some people with Crohn's disease may be at higher risk of following a severe course of disease than others and being able to identify the level of risk a patient has could lead to personalised management. OBJECTIVE: To assess the prognostic test accuracy, clinical impact and cost-effectiveness of two tools for the stratification of people with a diagnosis of Crohn's disease by risk of following a severe course of disease. DATA SOURCES: The data sources MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials were searched to inform the systematic reviews on prognostic accuracy, clinical impact of the prognostic tools, and economic evaluations. Additional data sources to inform the review of economic evaluations were NHS Economic Evaluation Database, Database of Abstracts of Reviews of Effects and the Health Technology Assessment Database. REVIEW METHODS: Systematic reviews of electronic databases were carried out from inception to June 2019 for studies assessing the prognostic accuracy and clinical impact of the IBDX® (Crohn's disease Prognosis Test; Glycominds Ltd, Lod, Israel) biomarker stratification tool and the PredictSURE-IBD™ (PredictImmune Ltd, Cambridge, UK) tool. Systematic reviews of studies reporting on the cost-effectiveness of treatments for Crohn's disease were run from inception to July 2019. Two reviewers independently agreed on studies for inclusion, assessed the quality of included studies and validated the data extracted from studies. Clinical and methodological heterogeneity across studies precluded the synthesis of data for prognostic accuracy. A de novo economic model was developed to compare the costs and consequences of two treatment approaches - the 'top-down' and 'step-up' strategies, with step-up considered standard care - in people at high risk of following a severe course of Crohn's disease. The model comprised a decision tree and a Markov cohort model. RESULTS: Sixteen publications, including eight original studies (n = 1478), were deemed relevant to the review of prognostic accuracy. Documents supplied by the companies marketing the prognostic tools were also reviewed. No study meeting the eligibility criteria reported on the sensitivity or specificity of the IBDX biomarker stratification tool, whereas one study provided estimates of sensitivity, specificity and negative predictive value for the PredictSURE-IBD tool. All identified studies were observational and were considered to provide weak evidence on the effectiveness of the tools. Owing to the paucity of data on the two tools, in the base-case analysis the accuracy of PredictSURE-IBD was assumed to be 100%. Accuracy of IBDX was assumed to be 100% in a scenario analysis, with the cost of the tests being the only difference between the analyses. The incremental analysis of cost-effectiveness demonstrated that top-down (via the use of PredictSURE-IBD in the model) is more expensive and generates fewer quality-adjusted life-years than step-up (via the standard care arm of the model). LIMITATIONS: Despite extensive systematic searches of the literature, no robust evidence was identified of the prognostic accuracy of the biomarker stratification tools IBDX and PredictSURE-IBD. CONCLUSIONS: Although the model indicates that standard care dominates the tests, the lack of evidence of prognostic accuracy of the two tests and the uncertainty around the benefits of the top-down and step-up treatment approaches mean that the results should be interpreted as indicative rather than definitive. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019138737. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 23. See the NIHR Journals Library website for further project information.

Crohn's disease is a condition in which parts of the digestive system become inflamed (swollen). People of any age can develop Crohn's disease. It is a lifelong condition for which there is no cure. In the UK, Crohn's disease affects about 1 in every 650 people. Any part of the digestive system can be affected, and the severity of the disease can vary from person to person. Symptoms come and go, and there can be times when there are no symptoms at all. Common symptoms of Crohn's disease are diarrhoea, stomach-ache and blood in faeces. Treatment is given to reduce or control symptoms and to try to stop inflammation from coming back. Some people with Crohn's disease are more likely than others to have more relapses and to develop complications of Crohn's disease that might require surgery. This project looked at how well two tools worked at identifying people with Crohn's disease who might develop complications or need surgery. Identifying those who have a higher chance of experiencing complications of Crohn's disease could help them and their doctor to choose their treatment, with the goal of reducing the number of relapses and the risk of surgery in the longer term. In addition, the review assessed whether or not the tools offered value for money. We found limited evidence of how well the tools worked in identifying people who were more likely to develop complications of Crohn's disease. The lack of evidence on the tools meant that the cost-effectiveness analysis could only assess the value for money of the treatment that is given in clinical practice at this time or of more intensive treatments for people who are more likely to develop complications. The analysis found that current standard care offers more value for money than intensive treatments for people with a higher chance of developing complications of Crohn's disease.

Dinutuximab Beta for Treating Neuroblastoma: An Evidence Review Group and Decision Support Unit Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (EUSA Pharma) of dinutuximab beta (Qarziba®) to submit evidence of its clinical and cost effectiveness for treating neuroblastoma. The BMJ Technology Assessment Group (BMJ-TAG) was commissioned to act as the Evidence Review Group (ERG), reviewing the submission from the company. The Decision Support Unit (DSU) was commissioned to review additional evidence submitted by the company and to undertake further analyses. This article presents the critical review of the company's submissions by the ERG and DSU, further analyses undertaken by the DSU, and the outcome of the NICE guidance. The clinical effectiveness for dinutuximab beta was derived from a phase III randomised controlled trial (RCT) that assessed the safety and efficacy of the addition of interleukin (IL)-2 to dinutuximab beta plus isotretinoin. This trial did not inform the relative effectiveness of dinutuximab beta versus isotretinoin alone, which was established practice in the UK for maintenance treatment. In the absence of direct evidence, the company initially conducted a naïve indirect treatment comparison against a historical control, and later performed a matching-adjusted indirect comparison (MAIC) against the isotretinoin arm of an RCT comparing dinutuximab alpha and isotretinoin. The company submitted a partitioned survival analysis model that calculated the incremental cost effectiveness of dinutuximab beta versus isotretinoin. The company's original incremental cost-effectiveness ratio (ICER) was £22,338 per quality-adjusted life-year (QALY) gained. However, the ERG were concerned that the company's ICER was not suitable for decision making, and thus carried out initial exploratory analysis as a first step to overcome the naïve estimation of treatment effectiveness in the model. The ERG's analysis estimated an ICER of £111,858 per QALY gained. In their revised analysis incorporating the MAIC and other changes as requested by the appraisal committee, the company's ICER was £24,661 per QALY gained. When the DSU incorporated longer-term isotretinoin data and made corrections to the model, the ICER increased to between £62,886 and £87,164 per QALY gained depending on the choice of survival model. A confidential Patient Access Scheme (PAS) decreased the ICERs. The ICERs with the PAS were over £40,000 per QALY gained, but the NICE committee additionally considered the patient population and its size, the disease severity, the potential for significant survival benefit and uncaptured health benefits, and recommended dinutuximab beta as a treatment option, subject to the company providing the agreed discount in the PAS.

Axitinib, cabozantinib, everolimus, nivolumab, sunitinib and best supportive care in previously treated renal cell carcinoma: a systematic review and economic evaluation.

BACKGROUND: Several therapies have recently been approved for use in the NHS for pretreated advanced or metastatic renal cell carcinoma (amRCC), but there is a lack of comparative evidence to guide decisions between them. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of axitinib (Inlyta®, Pfizer Inc., NY, USA), cabozantinib (Cabometyx®, Ipsen, Slough, UK), everolimus (Afinitor®, Novartis, Basel, Switzerland), nivolumab (Opdivo®, Bristol-Myers Squibb, NY, USA), sunitinib (Sutent®, Pfizer, Inc., NY, USA) and best supportive care (BSC) for people with amRCC who were previously treated with vascular endothelial growth factor (VEGF)-targeted therapy. DATA SOURCES: A systematic review and mixed-treatment comparison (MTC) of randomised controlled trials (RCTs) and non-RCTs. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were objective response rates (ORRs), adverse events (AEs) and health-related quality of life (HRQoL). MEDLINE, EMBASE and The Cochrane Library were searched from inception to January and June 2016 for RCTs and non-RCTs, respectively. Two reviewers abstracted data and performed critical appraisals. REVIEW METHODS: A fixed-effects MTC was conducted for OS, PFS [hazard ratios (HRs)] and ORR (odds ratios), and all were presented with 95% credible intervals (CrIs). The RCT data formed the primary analyses, with non-RCTs and studies rated as being at a high risk of bias included in sensitivity analyses (SAs). HRQoL and AE data were summarised narratively. A partitioned survival model with health states for pre progression, post progression and death was developed to perform a cost-utility analysis. Survival curves were fitted to the PFS and OS results from the MTC. A systematic review of HRQoL was undertaken to identify sources of health state utility values. RESULTS: Four RCTs (n = 2618) and eight non-RCTs (n = 1526) were included. The results show that cabozantinib has longer PFS than everolimus (HR 0.51, 95% CrI 0.41 to 0.63) and both treatments are better than BSC. Both cabozantinib (HR 0.66, 95% CrI 0.53 to 0.82) and nivolumab (HR 0.73, 95% CrI 0.60 to 0.89) have longer OS than everolimus. SAs were consistent with the primary analyses. The economic analysis, using drug list prices, shows that everolimus may be more cost-effective than BSC with an incremental cost-effectiveness ratio (ICER) of £45,000 per quality-adjusted life-year (QALY), as it is likely to be considered an end-of-life treatment. Cabozantinib has an ICER of £126,000 per QALY compared with everolimus and is unlikely to be cost-effective. Nivolumab was dominated by cabozantinib (i.e. more costly and less effective) and axitinib was dominated by everolimus. LIMITATIONS: Treatment comparisons were limited by the small number of RCTs. However, the key limitation of the analysis is the absence of the drug prices paid by the NHS, which was a limitation that could not be avoided owing to the confidentiality of discounts given to the NHS. CONCLUSIONS: The RCT evidence suggests that cabozantinib is likely to be the most effective for PFS and OS, closely followed by nivolumab. All treatments appear to delay disease progression and prolong survival compared with BSC, although the results are heterogeneous. The economic analysis shows that at list price everolimus could be recommended as the other drugs are much more expensive with insufficient incremental benefit. The applicability of these findings to the NHS is somewhat limited because existing confidential patient access schemes could not be used in the analysis. Future work using the discounted prices at which these drugs are provided to the NHS would better inform estimates of their relative cost-effectiveness. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016042384. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The use of fibrin sealant during non-emergency surgery: a systematic review of evidence of benefits and harms.

BACKGROUND: Fibrin sealants are used in different types of surgery to prevent the accumulation of post-operative fluid (seroma) or blood (haematoma) or to arrest haemorrhage (bleeding). However, there is uncertainty around the benefits and harms of fibrin sealant use. OBJECTIVES: To systematically review the evidence on the benefits and harms of fibrin sealants in non-emergency surgery in adults. DATA SOURCES: Electronic databases [MEDLINE, EMBASE and The Cochrane Library (including the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment database and the Cochrane Central Register of Controlled Trials)] were searched from inception to May 2015. The websites of regulatory bodies (the Medicines and Healthcare products Regulatory Agency, the European Medicines Agency and the Food and Drug Administration) were also searched to identify evidence of harms. REVIEW METHODS: This review included randomised controlled trials (RCTs) and observational studies using any type of fibrin sealant compared with standard care in non-emergency surgery in adults. The primary outcome was risk of developing seroma and haematoma. Only RCTs were used to inform clinical effectiveness and both RCTs and observational studies were used for the assessment of harms related to the use of fibrin sealant. Two reviewers independently screened all titles and abstracts to identify potentially relevant studies. Data extraction was undertaken by one reviewer and validated by a second. The quality of included studies was assessed independently by two reviewers using the Cochrane Collaboration risk-of-bias tool for RCTs and the Centre for Reviews and Dissemination guidance for adverse events for observational studies. A fixed-effects model was used for meta-analysis. RESULTS: We included 186 RCTs and eight observational studies across 14 surgical specialties and five reports from the regulatory bodies. Most RCTs were judged to be at an unclear risk of bias. Adverse events were inappropriately reported in observational studies. Meta-analysis across non-emergency surgical specialties did not show a statistically significant difference in the risk of seroma for fibrin sealants versus standard care in 32 RCTs analysed [n = 3472, odds ratio (OR) 0.84, 95% confidence interval (CI) 0.68 to 1.04; p = 0.13; I2 = 12.7%], but a statistically significant benefit was found on haematoma development in 24 RCTs (n = 2403, OR 0.62, 95% CI 0.44 to 0.86; p = 0.01; I2 = 0%). Adverse events related to fibrin sealant use were reported in 10 RCTs and eight observational studies across surgical specialties, and 22 RCTs explicitly stated that there were no adverse events. One RCT reported a single death but no other study reported mortality or any serious adverse events. Five regulatory body reports noted death from air emboli associated with fibrin sprays. LIMITATIONS: It was not possible to provide a detailed evaluation of individual RCTs in their specific contexts because of the limited resources that were available for this research. In addition, the number of RCTs that were identified made it impractical to conduct independent data extraction by two reviewers in the time available. CONCLUSIONS: The effectiveness of fibrin sealants does not appear to vary according to surgical procedures with regard to reducing the risk of seroma or haematoma. Surgeons should note the potential risk of gas embolism if spray application of fibrin sealants is used and not to exceed the recommended pressure and spraying distance. Future research should be carried out in surgery specialties for which only limited data were found, including neurological, gynaecological, oral and maxillofacial, urology, colorectal and orthopaedics surgery (for any outcome); breast surgery and upper gastrointestinal (development of haematoma); and cardiothoracic heart or lung surgery (reoperation rates). In addition, studies need to use adequate sample sizes, to blind participants and outcome assessors, and to follow reporting guidelines. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015020710. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

A cost benefit analysis of the Luminex xTAG Gastrointestinal Pathogen Panel for detection of infectious gastroenteritis in hospitalised patients.

OBJECTIVES: Recent advances in the laboratory detection of infectious diarrhoea allow more rapid and sensitive identification of infected patients. Several commercial multiplex molecular panels are now available and may have significant advantages over culture based techniques. Faster and more sensitive testing of hospitalised patients with suspected infectious gastroenteritis could result in significant efficiencies in the utilisation of isolation facilities, however few studies have examined this potential benefit. We studied the potential clinical and cost benefits of a commercially available molecular panel. METHODS: An eight-month parallel diagnostic study was conducted to measure potential economic benefits of testing hospitalised patients with the Luminex xTAG Gastrointestinal Pathogen Panel (GPP) compared with conventional laboratory testing (based on a combination of culture, microscopy and enzyme immunoassay). Laboratory testing costs and patient isolation costs were measured or estimated for 800 patients. RESULTS: Although costing an additional £22,283, use of GPP could enable a reduction in isolation time from 2202 to 1447 days, a saving of £66,765, which more than offsets the additional laboratory testing costs. CONCLUSION: Syndromic testing of patients against a broad panel of organisms using a multiplex molecular panel can both improve detection rates and allow better laboratory workflow practices. Removing patients testing negative using this panel could result in significant patient isolation savings.