Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is characterised by neurovascular degeneration as a result of chronic hyperglycaemia. Proliferative diabetic retinopathy (PDR) is the most serious complication of DR and can lead to total (central and peripheral) visual loss. PDR is characterised by the presence of abnormal new blood vessels, so-called "new vessels," at the optic disc (NVD) or elsewhere in the retina (NVE). PDR can progress to high-risk characteristics (HRC) PDR (HRC-PDR), which is defined by the presence of NVD more than one-fourth to one-third disc area in size plus vitreous haemorrhage or pre-retinal haemorrhage, or vitreous haemorrhage or pre-retinal haemorrhage obscuring more than one disc area. In severe cases, fibrovascular membranes grow over the retinal surface and tractional retinal detachment with sight loss can occur, despite treatment. Although most, if not all, individuals with diabetes will develop DR if they live long enough, only some progress to the sight-threatening PDR stage.  OBJECTIVES: To determine risk factors for the development of PDR and HRC-PDR in people with diabetes and DR. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 5), Ovid MEDLINE, and Ovid Embase. The date of the search was 27 May 2022. Additionally, the search was supplemented by screening reference lists of eligible articles. There were no restrictions to language or year of publication.  SELECTION CRITERIA: We included prospective or retrospective cohort studies and case-control longitudinal studies evaluating prognostic factors for the development and progression of PDR, in people who have not had previous treatment for DR. The target population consisted of adults (≥18 years of age) of any gender, sexual orientation, ethnicity, socioeconomic status, and geographical location, with non-proliferative diabetic retinopathy (NPDR) or PDR with less than HRC-PDR, diagnosed as per standard clinical practice. Two review authors independently screened titles and abstracts, and full-text articles, to determine eligibility; discrepancies were resolved through discussion. We considered prognostic factors measured at baseline and any other time points during the study and in any clinical setting. Outcomes were evaluated at three and eight years (± two years) or lifelong.  DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from included studies using a data extraction form that we developed and piloted prior to the data collection stage. We resolved any discrepancies through discussion. We used the Quality in Prognosis Studies (QUIPS) tool to assess risk of bias. We conducted meta-analyses in clinically relevant groups using a random-effects approach. We reported hazard ratios (HR), odds ratios (OR), and risk ratios (RR) separately for each available prognostic factor and outcome, stratified by different time points. Where possible, we meta-analysed adjusted prognostic factors. We evaluated the certainty of the evidence with an adapted version of the GRADE framework.   MAIN RESULTS: We screened 6391 records. From these, we identified 59 studies (87 articles) as eligible for inclusion. Thirty-five were prospective cohort studies, 22 were retrospective studies, 18 of which were cohort and six were based on data from electronic registers, and two were retrospective case-control studies. Twenty-three studies evaluated participants with type 1 diabetes (T1D), 19 with type 2 diabetes (T2D), and 17 included mixed populations (T1D and T2D). Studies on T1D included between 39 and 3250 participants at baseline, followed up for one to 45 years. Studies on T2D included between 100 and 71,817 participants at baseline, followed up for one to 20 years. The studies on mixed populations of T1D and T2D ranged from 76 to 32,553 participants at baseline, followed up for four to 25 years.  We found evidence indicating that higher glycated haemoglobin (haemoglobin A1c (HbA1c)) levels (adjusted OR ranged from 1.11 (95% confidence interval (CI) 0.93 to 1.32) to 2.10 (95% CI 1.64 to 2.69) and more advanced stages of retinopathy (adjusted OR ranged from 1.38 (95% CI 1.29 to 1.48) to 12.40 (95% CI 5.31 to 28.98) are independent risk factors for the development of PDR in people with T1D and T2D. We rated the evidence for these factors as of moderate certainty because of moderate to high risk of bias in the studies.  There was also some evidence suggesting several markers for renal disease (for example, nephropathy (adjusted OR ranged from 1.58 (95% CI not reported) to 2.68 (2.09 to 3.42), and creatinine (adjusted meta-analysis HR 1.61 (95% CI 0.77 to 3.36)), and, in people with T1D, age at diagnosis of diabetes (< 12 years of age) (standardised regression estimate 1.62, 95% CI 1.06 to 2.48), increased triglyceride levels (adjusted RR 1.55, 95% CI 1.06 to 1.95), and larger retinal venular diameters (RR 4.28, 95% CI 1.50 to 12.19) may increase the risk of progression to PDR. The certainty of evidence for these factors, however, was low to very low, due to risk of bias in the included studies, inconsistency (lack of studies preventing the grading of consistency or variable outcomes), and imprecision (wide CIs). There was no substantial and consistent evidence to support duration of diabetes, systolic or diastolic blood pressure, total cholesterol, low- (LDL) and high- (HDL) density lipoproteins, gender, ethnicity, body mass index (BMI), socioeconomic status, or tobacco and alcohol consumption as being associated with incidence of PDR. There was insufficient evidence to evaluate prognostic factors associated with progression of PDR to HRC-PDR.  AUTHORS' CONCLUSIONS: Increased HbA1c is likely to be associated with progression to PDR; therefore, maintaining adequate glucose control throughout life, irrespective of stage of DR severity, may help to prevent progression to PDR and risk of its sight-threatening complications. Renal impairment in people with T1D or T2D, as well as younger age at diagnosis of diabetes mellitus (DM), increased triglyceride levels, and increased retinal venular diameters in people with T1D may also be associated with increased risk of progression to PDR. Given that more advanced DR severity is associated with higher risk of progression to PDR, the earlier the disease is identified, and the above systemic risk factors are controlled, the greater the chance of reducing the risk of PDR and saving sight.

ANTECEDENTES: La retinopatía diabética (RD) se caracteriza por la degeneración neurovascular como consecuencia de la hiperglucemia crónica. La retinopatía diabética proliferativa (RDP) es la complicación más grave de la RD y puede provocar una pérdida total (central y periférica) de la visión. La RDP se caracteriza por la presencia de vasos sanguíneos de neoformación anormales, neovascularización, en la papila óptica (NVP) o en cualquier otra parte de la retina (NVE). La RDP puede evolucionar a una RDP con características de alto riesgo (RDP­CAR), que se define por la presencia de NVP de más de un cuarto a un tercio del área discal más hemorragia vítrea o prerretiniana, o hemorragia vítrea o prerretiniana que oscurece más de un área papilar. En los casos graves, crecen membranas fibrovasculares sobre la superficie retiniana y se puede producir un desprendimiento de retina por tracción con pérdida de la visión, a pesar del tratamiento. Aunque la mayoría de las personas con diabetes, si no todas, desarrollarán RD si viven lo suficiente, solo algunas llegan a la fase de RDP, que pone en peligro la vista. OBJETIVOS: Determinar los factores de riesgo de aparición de la RDP y RDP­CAR en personas con diabetes y RD. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials, CENTRAL; que contiene el Registro de ensayos del Grupo Cochrane de Salud ocular y de la visión [Cochrane Eyes and Vision]; 2022, número 5), Ovid MEDLINE y Ovid Embase. La fecha de búsqueda fue el 27 de mayo de 2022. Además, la búsqueda se complementó con el cribado de las listas de referencias de los artículos elegibles. No hubo restricciones en cuanto al idioma ni al año de publicación. CRITERIOS DE SELECCIÓN: Se incluyeron estudios de cohortes prospectivos o retrospectivos y estudios longitudinales de casos y controles que evaluaran los factores pronósticos para la aparición y la progresión de la RDP, en personas que no habían recibido tratamiento previo para la RD. La población de interés estaba formada por adultos (≥18 años de edad) de cualquier sexo, orientación sexual, etnia, nivel socioeconómico y ubicación geográfica, con retinopatía diabética no proliferativa (RDNP) o RDP sin llegar a RDP­CAR, diagnosticada según la práctica clínica habitual. Dos autores de la revisión examinaron de forma independiente los títulos y resúmenes, así como los artículos completos, para determinar la elegibilidad; las discrepancias se resolvieron mediante debate. Se tuvieron en cuenta los factores pronósticos medidos al inicio del estudio y en cualquier otro punto temporal durante el estudio y en cualquier contexto clínico. Los desenlaces se evaluaron a los tres y ocho años (± dos años) o de por vida. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión extrajeron de forma independiente los datos de los estudios incluidos mediante un formulario de extracción de datos que se desarrolló y evaluó antes de la etapa de obtención de datos. Las discrepancias se resolvieron mediante debate. Para evaluar el riesgo de sesgo se utilizó la herramienta Quality in Prognosis Studies (QUIPS). Se realizaron metanálisis en grupos clínicamente relevantes utilizando un enfoque de efectos aleatorios. Se proporcionaron los cociente de riesgos instantáneos (CRI), los odds ratios (OR) y las razones de riesgos (RR) por separado para cada factor pronóstico y desenlace disponibles, estratificados por diferentes puntos temporales. Cuando fue posible, se realizó un metanálisis de los factores pronósticos ajustados. La certeza de la evidencia se evaluó con una versión adaptada del método GRADE. RESULTADOS PRINCIPALES: Se han examinado 6391 registros. A partir de estos se identificaron 59 estudios (87 artículos) elegibles para inclusión. Treinta y cinco fueron estudios de cohortes prospectivos, 22 fueron estudios retrospectivos, 18 de los cuales fueron de cohortes y 6 se basaron en datos de registros electrónicos, y 2 fueron estudios retrospectivos de casos y controles. Veintitrés estudios evaluaron a participantes con diabetes tipo 1 (DT1), 19 con diabetes tipo 2 (DT2) y 17 incluyeron poblaciones mixtas (DT1 y DT2). Los estudios sobre la DT1 incluyeron entre 39 y 3250 participantes al inicio del estudio, con un seguimiento de 1 a 45 años. Los estudios sobre la DT2 incluyeron entre 100 y 71 817 participantes al inicio del estudio, con un seguimiento de 1 a 20 años. Los estudios sobre poblaciones mixtas de DT1 y DT2 variaron entre 76 y 32 553 participantes al inicio del estudio, con un seguimiento de 4 a 25 años. Se encontró evidencia que indicó que los niveles más altos de hemoglobina glucosilada (hemoglobina A1c [HbA1c]) (OR ajustado que varió de 1,11 [intervalo de confianza (IC) del 95%: 0,93 a 1,32] a 2,10 [IC del 95%: 1,64 a 2,69]) y los estadios más avanzados de retinopatía (OR ajustado que varió entre 1,38 [IC del 95%: 1,29 a 1,48] y 12,40 [IC del 95%: 5,31 a 28,98]) son factores de riesgo independientes para el desarrollo de RDP en personas con DT1 y DT2. La evidencia para estos factores se consideró de certeza moderada debido al riesgo moderado a alto de sesgo en los estudios. También hubo alguna evidencia que indicó varios marcadores de enfermedad renal (por ejemplo, nefropatía [OR ajustado que varió entre 1,58 (IC del 95% no proporcionado) y 2,68 (2,09 a 3,42)] y creatinina [metanálisis ajustado CRI 1,61 (IC del 95%: 0,77 a 3.36)]), y, en las personas con DT1, la edad en el momento del diagnóstico de la diabetes (< 12 años) (estimación de la regresión estandarizada 1,62; IC del 95%: 1,06 a 2,48), el aumento de los niveles de triglicéridos (RR ajustado 1,55; IC del 95%: 1,06 a 1,95) y los diámetros venulares retinianos mayores (RR 4,28; IC del 95%: 1,50 a 12,19) podrían aumentar el riesgo de progresión a RDP. Sin embargo, la certeza de la evidencia para estos factores fue de baja a muy baja, debido al riesgo de sesgo en los estudios incluidos, la inconsistencia (falta de estudios que impide la calificación de consistencia o desenlaces variables) y la imprecisión (IC amplios). No hubo evidencia importante ni consistente que apoyara que la duración de la diabetes, la presión arterial sistólica o diastólica, el colesterol total, las lipoproteínas de baja (LDL) y alta (HDL) densidad, el sexo, el origen étnico, el índice de masa corporal (IMC), el nivel socioeconómico o el consumo de tabaco y alcohol estuvieran asociados con la incidencia de RDP. No hubo evidencia suficiente para evaluar los factores pronósticos asociados con la progresión de la RDP a RDP­CAR. CONCLUSIONES DE LOS AUTORES: Es probable que el aumento de la HbA1c se asocie con la progresión a la RDP; por lo tanto, mantener un control adecuado de la glucosa durante toda la vida, independientemente del estadio de gravedad de la RD, podría ayudar a prevenir la progresión a la RDP y el riesgo de sus complicaciones que ponen en peligro la vista. La insuficiencia renal en personas con DT1 o DT2, así como una menor edad en el momento del diagnóstico de la diabetes mellitus (DM), el aumento de los niveles de triglicéridos y el aumento de los diámetros venulares retinianos en personas con DT1 también se podrían asociar con un mayor riesgo de progresión a RDP. Dado que la gravedad más avanzada de la RD se asocia con un mayor riesgo de progresión a RDP, cuanto antes se identifique la enfermedad y se controlen los factores de riesgo sistémicos mencionados, mayores serán las posibilidades de reducir el riesgo de RDP y conservar la vista.

Visual cycle modulators versus placebo or observation for the prevention and treatment of geographic atrophy due to age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is a highly prevalent condition in an ever-increasing elderly population. Although insidious in the early stages, advanced AMD (neovascular and atrophic forms) can cause significant visual disability and economic burden on health systems worldwide. The most common form, geographic atrophy, has no effective treatment to date, whereas neovascular AMD can be treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Geographic atrophy has a slow disease progression and patients tend to have preserved central vision until the final stages. This tendency, coupled with the use of modern imaging modalities, provides a large window of opportunity to intervene with validated methods to assess treatment efficacy. As geographic atrophy is an increasingly common condition with no effective intervention, many treatments are under investigation, one of which is visual cycle modulators. These medications have been shown to reduce lipofuscin accumulation in pre-clinical studies that have led to several clinical trials, reviewed herein. OBJECTIVES: To assess the efficacy and safety of visual cycle modulators for the prevention and treatment of geographic atrophy secondary to AMD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); MEDLINE Ovid; Embase Ovid; Web of Science Core Collection; Scopus; Association for Research in Vision and Ophthalmology (ARVO) website; ClinicalTrials.gov and the WHO ICTRP to 11 January 2020 with no language restrictions. We also searched using the reference lists of reviews and existing studies and the Cited Reference Search function in Web of Science to identify further relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised clinical studies (if available) that compared visual cycle modulators to placebo or no treatment (observation) in people diagnosed with AMD (early, intermediate or geographic atrophy). DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias in the included studies and extracted data. Both authors entered data into RevMan 5. We resolved discrepancies through discussion. We graded the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included three RCTs from the USA; one of these had clinical sites in Germany. Two studies compared emixustat to placebo while the other compared fenretinide to placebo. All assigned one study eye per participant and, combined, have a total of 821 participants with a majority white ethnicity (97.6%). All participants were diagnosed with geographic atrophy due to AMD based on validated imaging modalities. All three studies have high risk of attrition bias mainly due to ocular adverse effects of emixustat and fenretinide. We considered only one study to be adequately conducted and reported with high risk of bias in only one domain (attrition bias). We considered the other two studies to be poorly reported and to have high risk of attrition bias and reporting bias. People with geographic atrophy treated with emixustat may not experience a clinically important change in best-corrected visual acuity (BCVA) between baseline and 24 months compared to people treated with placebo (mean difference (MD) 1.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (CI) -2.34 to 6.14, low-certainty evidence). Emixustat may also result in little or no difference in loss of 15 ETDRS letters or more of BCVA compared with placebo at 24 months (16.4% versus 18%) (risk ratio (RR) 0.91, 95% CI 0.59 to 1.4, low-certainty evidence). In terms of disease progression, emixustat may result in little or no difference in the annual growth rate of geographic atrophy compared with placebo (mean difference MD 0.09 mm2/year (95% CI -0.26 to 0.44, low-certainty evidence). All three studies reported adverse events of both drugs (emixustat: moderate-certainty evidence; fenretinide: low-certainty evidence). The main adverse events were ocular in nature and associated with the mechanism of action of the drugs. Delayed dark adaptation (emixustat: 54.5%; fenretinide: 39.3%) and chromatopsia (emixustat: 22.6%; fenretinide: 25.2%) were the most common adverse events reported, and were the most prevalent reasons for study dropout in emixustat trials. These effects were dose-dependent and resolved after drug cessation. No specific systemic adverse events were considered related to emixustat; only pruritus and rash were considered to be due to fenretinide. One emixustat study reported six deaths, none deemed related to the drug. None of the included RCTs reported the other pre-specified outcomes, including proportion of participants losing 10 letters or more, and mean change in macular sensitivity. We planned to investigate progression to advanced AMD (geographic atrophy or neovascular AMD) in prevention studies, including participants with early or intermediate AMD, but we identified no such studies. Two of the included studies reported an additional outcome - incidence of choroidal neovascularisation (CNV) - that was not in our published protocol. CNV onset may be reduced in those treated with emixustat but the evidence was uncertain (risk ratio (RR) 0.67, 95% CI 0.27 to 1.65, low-certainty evidence), or fenretinide (RR 0.5, 95% CI 0.26 to 0.98, low-certainty evidence) compared to placebo. A dose-dependent relationship was observed with emixustat. AUTHORS' CONCLUSIONS: There is limited evidence to support the use of visual cycle modulators (emixustat and fenretinide) for the treatment of established geographic atrophy due to AMD. The possible reduction in the incidence of CNV observed with fenretinide, and to a lesser extent, emixustat, requires formal assessment in focused studies.

Correction: Interventions for treating children and adolescents with overweight and obesity: an overview of Cochrane reviews.

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Autograft or allograft for reconstruction of anterior cruciate ligament: a health economics perspective.

PURPOSE: To assess the clinical and cost-effectiveness of allografts versus autografts in the reconstruction of anterior cruciate ligaments. METHODS: Systematic review of comparative clinical effectiveness and cost-effectiveness analysis. RESULTS: Both autograft and allograft reconstruction are highly effective. Recent studies show little difference in failure rates between autografts and allografts (about 6% and 7%, respectively). In cost-effectiveness analysis, the price differential is the main factor, making autografts the first choice. However, there will be situations, particularly in revision ACL reconstruction, where an allograft may be preferred, or may be the only reasonable option available. CONCLUSION: In ACL reconstruction, clinical results with autografts are as good as or slightly better than with allografts. Allografts cost more, indicating that autografts are more cost-effective and should usually be first choice. LEVEL OF EVIDENCE: II.

The cost-effectiveness of osteochondral allograft transplantation in the knee.

PURPOSE: Osteochondral allografts (OCA) consist of a layer of hyaline cartilage and a layer of underlying bone. They are used to repair combined defects of articular cartilage and bone. Such defects often occur in people far too young to have knee arthroplasty, for whom the main alternative to OCA is conservative symptomatic care, which will not prevent development of osteoarthritis. The aim of this report was to assess the cost-effectiveness of osteochondral allograft transplantation in the knee. METHODS: Systematic review of evidence on clinical effectiveness and economic modelling. RESULTS: The evidence on osteochondral allograft transplantation comes from observational studies, but often based on good quality prospective registries of all patients having such surgery. Without controlled trials, it was necessary to use historical cohorts to assess the effect of osteochondral grafts. There is good evidence that OCA are clinically effective with a high graft survival rate over 20 years. If an OCA graft fails, there is some evidence that revision with a second OCA is also effective, though less so than primary OCA. Economic modelling showed that osteochondral allograft transplantation was highly cost-effective, with costs per quality adjusted life year much lower than many other treatments considered cost effective. CONCLUSIONS: Osteochondral allograft transplantation appears highly cost-effective though the cost per quality adjusted life year varies according to the widely varying costs of allografts. Based on one small study, revision OCA also appears very cost-effective, but more evidence is needed. LEVEL OF EVIDENCE: II.

Allografts in reconstruction of the posterior cruciate ligament: a health economics perspective.

PURPOSE: To review the relative cost-effectiveness of allografts and autografts in reconstruction of the posterior cruciate ligament. METHODS: Systematic review and cost-effectiveness analysis. RESULTS: The available evidence does not show any significant difference in clinical effectiveness between autografts and allografts. Given that, only a cost analysis is provided, which shows that allografts are more costly. CONCLUSION: Given the lack of any benefit of allografts over autografts, autografts should be preferred on cost grounds, if available. However, there may be situations where an allograft is indicated, for example, in multiple ligament reconstructions. LEVEL OF EVIDENCE: IV.

Meniscal allograft transplantation after meniscectomy: clinical effectiveness and cost-effectiveness.

PURPOSE: To assess the clinical effectiveness and cost-effectiveness of meniscal allograft transplantation (MAT) after meniscal injury and subsequent meniscectomy. METHODS: Systematic review of clinical effectiveness and cost-effectiveness analysis. RESULTS: There is considerable evidence from observational studies, of improvement in symptoms after meniscal allograft transplantation, but we found only one small pilot trial with a randomised comparison with a control group that received non-surgical care. MAT has not yet been proven to be chondroprotective. Cost-effectiveness analysis is not possible due to a lack of data on the effectiveness of MAT compared to non-surgical care. CONCLUSION: The benefits of MAT include symptomatic relief and restoration of at least some previous activities, which will be reflected in utility values and hence in quality-adjusted life years, and in the longer term, prevention or delay of osteoarthritis, and avoidance or postponement of some knee replacements, with resulting savings. It is likely to be cost-effective, but this cannot be proven on the basis of present evidence. LEVEL OF EVIDENCE: IV.

Choice of Methodology Impacts Outcome in Indirect Comparisons of Drugs for Idiopathic Pulmonary Fibrosis.

Background and Objectives: Idiopathic pulmonary fibrosis (IPF) is a chronic condition leading to lung damage and deterioration in lung function. Following the availability of two new drugs, nintedanib and pirfenidone, a number of network meta-analyses (NMAs) of randomised controlled trials have been published which have conducted indirect comparisons on the two drugs. Differing recommendations from these studies are potentially confusing to clinicians and decision-makers. We aimed to systematically review published NMAs of IPF treatments, to compare their findings and summarise key recommendations. Materials and Methods: We systematically reviewed (PROSPERO: CRD42017072876) six eligible NMAs and investigated the differences in their findings with respect to key endpoints. We focused on differences in head-to-head comparisons between nintedanib and pirfenidone. Results: The NMAs were broadly consistent, with most differences being explained by model choice, endpoint definitions, inclusion of different studies, different follow-up durations, and access to unpublished data. A substantive difference remained, however, in the change from baseline forced vital capacity (FVC). One NMA favoured nintedanib, another found no statistical difference, whilst others did not conduct the analysis. These differences can be attributed to the choice of methodology, the use of the standardised mean difference (SMD) scale, and population heterogeneity. Conclusions: NMA methods facilitated the comparison of nintedanib and pirfenidone in the absence of a head-to-head trial. However, further work is needed to determine whether the trial populations are homogeneous and whether the SMD is appropriate in this population. Differences in patient characteristics may obscure the difference in treatment effects. To assist decision-makers, an exploration of efficacy in real-world populations may be prudent.

Interventions for treating children and adolescents with overweight and obesity: an overview of Cochrane reviews.

Children and adolescents with overweight and obesity are a global health concern. This is an integrative overview of six Cochrane systematic reviews, providing an up-to-date synthesis of the evidence examining interventions for the treatment of children and adolescents with overweight or obesity. The data extraction and quality assessments for each review were conducted by one author and checked by a second. The six high quality reviews provide evidence on the effectiveness of behaviour changing interventions conducted in children <6 years (7 trials), 6-11 years (70 trials), adolescents 12-17 years (44 trials) and interventions that target only parents of children aged 5-11 years (20 trials); in addition to interventions examining surgery (1 trial) and drugs (21 trials). Most of the evidence was derived from high-income countries and published in the last two decades. Collectively, the evidence suggests that multi-component behaviour changing interventions may be beneficial in achieving small reductions in body weight status in children of all ages, with low adverse event occurrence were reported. More research is required to understand which specific intervention components are most effective and in whom, and how best to maintain intervention effects. Evidence from surgical and drug interventions was too limited to make inferences about use and safety, and adverse events were a serious consideration.

Low glycaemic index diets for the prevention of cardiovascular disease.

BACKGROUND: The glycaemic index (GI) is a physiological measure of the ability of a carbohydrate to affect blood glucose. Interest is growing in this area for the clinical management of people at risk of, or with, established cardiovascular disease. There is a need to review the current evidence from randomised controlled trials (RCTs) in this area. This is an update of the original review published in 2008. OBJECTIVES: To assess the effect of the dietary GI on total mortality, cardiovascular events, and cardiovascular risk factors (blood lipids, blood pressure) in healthy people or people who have established cardiovascular disease or related risk factors, using all eligible randomised controlled trials. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and CINAHL in July 2016. We also checked reference lists of relevant articles. No language restrictions were applied. SELECTION CRITERIA: We selected RCTs that assessed the effects of low GI diets compared to diets with a similar composition but a higher GI on cardiovascular disease and related risk factors. Minimum trial duration was 12 weeks. Participants included were healthy adults or those at increased risk of cardiovascular disease, or previously diagnosed with cardiovascular disease. Studies in people with diabetes mellitus were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened and selected studies. Two review authors independently assessed risk of bias, evaluated the overall quality of the evidence using GRADE, and extracted data following the Cochrane Handbook for Systematic Reviews of Interventions. We contacted trial authors for additional information. Analyses were checked by a second reviewer. Continuous outcomes were synthesized using mean differences and adverse events were synthesized narratively. MAIN RESULTS: Twenty-one RCTs were included, with a total of 2538 participants randomised to low GI intervention (1288) or high GI (1250). All 21 included studies reported the effect of low GI diets on risk factors for cardiovascular disease, including blood lipids and blood pressure.Twenty RCTs (18 of which were newly included in this version of the review) included primary prevention populations (healthy individuals or those at high risk of CVD, with mean age range from 19 to 69 years) and one RCT was in those diagnosed with pre-existing CVD (a secondary prevention population, with mean age 26.9 years). Most of the studies did not have an intervention duration of longer than six months. Difference in GI intake between comparison groups varied widely from 0.6 to 42.None of the included studies reported the effect of low GI dietary intake on cardiovascular mortality and cardiovascular events such as fatal and nonfatal myocardial infarction, unstable angina, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, and stroke. The unclear risk of bias of most of the included studies makes overall interpretation of the data difficult. Only two of the included studies (38 participants) reported on adverse effects and did not observe any harms (low-quality evidence). AUTHORS' CONCLUSIONS: There is currently no evidence available regarding the effect of low GI diets on cardiovascular disease events. Moreover, there is currently no convincing evidence that low GI diets have a clear beneficial effect on blood lipids or blood pressure parameters.

Whole grain cereals for the primary or secondary prevention of cardiovascular disease.

BACKGROUND: There is evidence from observational studies that whole grains can have a beneficial effect on risk for cardiovascular disease (CVD). Earlier versions of this review found mainly short-term intervention studies. There are now longer-term randomised controlled trials (RCTs) available. This is an update and expansion of the original review conducted in 2007. OBJECTIVES: The aim of this systematic review was to assess the effect of whole grain foods or diets on total mortality, cardiovascular events, and cardiovascular risk factors (blood lipids, blood pressure) in healthy people or people who have established cardiovascular disease or related risk factors, using all eligible RCTs. SEARCH METHODS: We searched CENTRAL (Issue 8, 2016) in the Cochrane Library, MEDLINE (1946 to 31 August 2016), Embase (1980 to week 35 2016), and CINAHL Plus (1937 to 31 August 2016) on 31 August 2016. We also searched ClinicalTrials.gov on 5 July 2017 and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) on 6 July 2017. We checked reference lists of relevant articles and applied no language restrictions. SELECTION CRITERIA: We selected RCTs assessing the effects of whole grain foods or diets containing whole grains compared to foods or diets with a similar composition, over a minimum of 12 weeks, on cardiovascular disease and related risk factors. Eligible for inclusion were healthy adults, those at increased risk of CVD, or those previously diagnosed with CVD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies. Data were extracted and quality-checked by one review author and checked by a second review author. A second review author checked the analyses. We assessed treatment effect using mean difference in a fixed-effect model and heterogeneity using the I2 statistic and the Chi2 test of heterogeneity. We assessed the overall quality of evidence using GRADE with GRADEpro software. MAIN RESULTS: We included nine RCTs randomising a total of 1414 participants (age range 24 to 70; mean age 45 to 59, where reported) to whole grain versus lower whole grain or refined grain control groups. We found no studies that reported the effect of whole grain diets on total cardiovascular mortality or cardiovascular events (total myocardial infarction, unstable angina, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, total stroke). All included studies reported the effect of whole grain diets on risk factors for cardiovascular disease including blood lipids and blood pressure. All studies were in primary prevention populations and had an unclear or high risk of bias, and no studies had an intervention duration greater than 16 weeks.Overall, we found no difference between whole grain and control groups for total cholesterol (mean difference 0.07, 95% confidence interval -0.07 to 0.21; 6 studies (7 comparisons); 722 participants; low-quality evidence).Using GRADE, we assessed the overall quality of the available evidence on cholesterol as low. Four studies were funded by independent national and government funding bodies, while the remaining studies reported funding or partial funding by organisations with commercial interests in cereals. AUTHORS' CONCLUSIONS: There is insufficient evidence from RCTs of an effect of whole grain diets on cardiovascular outcomes or on major CVD risk factors such as blood lipids and blood pressure. Trials were at unclear or high risk of bias with small sample sizes and relatively short-term interventions, and the overall quality of the evidence was low. There is a need for well-designed, adequately powered RCTs with longer durations assessing cardiovascular events as well as cardiovascular risk factors.

Diet, physical activity and behavioural interventions for the treatment of overweight or obese adolescents aged 12 to 17 years.

BACKGROUND: Adolescent overweight and obesity has increased globally, and can be associated with short- and long-term health consequences. Modifying known dietary and behavioural risk factors through behaviour changing interventions (BCI) may help to reduce childhood overweight and obesity. This is an update of a review published in 2009. OBJECTIVES: To assess the effects of diet, physical activity and behavioural interventions for the treatment of overweight or obese adolescents aged 12 to 17 years. SEARCH METHODS: We performed a systematic literature search in: CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, and the trial registers ClinicalTrials.gov and ICTRP Search Portal. We checked references of identified studies and systematic reviews. There were no language restrictions. The date of the last search was July 2016 for all databases. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of diet, physical activity and behavioural interventions for treating overweight or obesity in adolescents aged 12 to 17 years. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias, evaluated the overall quality of the evidence using the GRADE instrument and extracted data following the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We contacted trial authors for additional information. MAIN RESULTS: We included 44 completed RCTs (4781 participants) and 50 ongoing studies. The number of participants in each trial varied (10 to 521) as did the length of follow-up (6 to 24 months). Participants ages ranged from 12 to 17.5 years in all trials that reported mean age at baseline. Most of the trials used a multidisciplinary intervention with a combination of diet, physical activity and behavioural components. The content and duration of the intervention, its delivery and the comparators varied across trials. The studies contributing most information to outcomes of weight and body mass index (BMI) were from studies at a low risk of bias, but studies with a high risk of bias provided data on adverse events and quality of life.The mean difference (MD) of the change in BMI at the longest follow-up period in favour of BCI was -1.18 kg/m2 (95% confidence interval (CI) -1.67 to -0.69); 2774 participants; 28 trials; low quality evidence. BCI lowered the change in BMI z score by -0.13 units (95% CI -0.21 to -0.05); 2399 participants; 20 trials; low quality evidence. BCI lowered body weight by -3.67 kg (95% CI -5.21 to -2.13); 1993 participants; 20 trials; moderate quality evidence. The effect on weight measures persisted in trials with 18 to 24 months' follow-up for both BMI (MD -1.49 kg/m2 (95% CI -2.56 to -0.41); 760 participants; 6 trials and BMI z score MD -0.34 (95% CI -0.66 to -0.02); 602 participants; 5 trials).There were subgroup differences showing larger effects for both BMI and BMI z score in studies comparing interventions with no intervention/wait list control or usual care, compared with those testing concomitant interventions delivered to both the intervention and control group. There were no subgroup differences between interventions with and without parental involvement or by intervention type or setting (health care, community, school) or mode of delivery (individual versus group).The rate of adverse events in intervention and control groups was unclear with only five trials reporting harms, and of these, details were provided in only one (low quality evidence). None of the included studies reported on all-cause mortality, morbidity or socioeconomic effects.BCIs at the longest follow-up moderately improved adolescent's health-related quality of life (standardised mean difference 0.44 ((95% CI 0.09 to 0.79); P = 0.01; 972 participants; 7 trials; 8 comparisons; low quality of evidence) but not self-esteem.Trials were inconsistent in how they measured dietary intake, dietary behaviours, physical activity and behaviour. AUTHORS' CONCLUSIONS: We found low quality evidence that multidisciplinary interventions involving a combination of diet, physical activity and behavioural components reduce measures of BMI and moderate quality evidence that they reduce weight in overweight or obese adolescents, mainly when compared with no treatment or waiting list controls. Inconsistent results, risk of bias or indirectness of outcome measures used mean that the evidence should be interpreted with caution. We have identified a large number of ongoing trials (50) which we will include in future updates of this review.

Dietary fibre for the primary prevention of cardiovascular disease.

BACKGROUND: The prevention of cardiovascular disease (CVD) is a key public health priority. A number of dietary factors have been associated with modifying CVD risk factors. One such factor is dietary fibre which may have a beneficial association with CVD risk factors. There is a need to review the current evidence from randomised controlled trials (RCTs) in this area. OBJECTIVES: The primary objective of this systematic review was to determine the effectiveness of dietary fibre for the primary prevention of CVD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, Ovid MEDLINE (1946 to January 2015), Ovid EMBASE (1947 to January 2015) and Science Citation Index Expanded (1970 to January 2015) as well as two clinical trial registers in January 2015. We also checked reference lists of relevant articles. No language restrictions were applied. SELECTION CRITERIA: We selected RCTs that assessed the effects of dietary fibre compared with no intervention or a minimal intervention on CVD and related risk factors. Participants included adults who are at risk of CVD or those from the general population. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, extracted data and assessed risk of bias; a third author checked any differences. A different author checked analyses. MAIN RESULTS: We included 23 RCTs (1513 participants randomised) examining the effect of dietary fibre. The risk of bias was unclear for most studies and studies had small sample sizes. Few studies had an intervention duration of longer than 12 weeks. There was a wide variety of fibre sources used, with little similarity between groups in the choice of intervention.None of the studies reported on mortality (total or cardiovascular) or cardiovascular events. Results on lipids suggest there is a significant beneficial effect of increased fibre on total cholesterol levels (17 trials (20 comparisons), 1067 participants randomised, mean difference -0.23 mmol/L, 95% CI -0.40 to -0.06), and LDL cholesterol levels (mean difference -0.14 mmol/L, 95% CI -0.22 to -0.06) but not on triglyceride levels (mean difference 0.00 mmol/L, 95% CI -0.04 to 0.05), and there was a very small but statistically significant decrease rather than increase in HDL levels with increased fibre intake (mean difference -0.03 mmol/L, 95% CI -0.06 to -0.01). Fewer studies (10 trials, 661 participants randomised) reported blood pressure outcomes where there is a significant effect of increased fibre consumption on diastolic blood pressure (mean difference -1.77 mmHg, 95% CI -2.61 to -0.92) whilst there is a reduction in systolic blood pressure with fibre but this does not reach statistical significance (mean difference -1.92 mmHg, 95% CI -4.02 to 0.19). There did not appear to be any subgroup effects by the nature of the type of intervention (fibre supplements or provision of foods/advice to increase fibre consumption) or the type of fibre (soluble/insoluble) although the number of studies contributing to each subgroup were small. All analyses need to be viewed with caution given the risks of bias observed for total cholesterol and the statistical heterogeneity observed for systolic blood pressure. Adverse events, where reported, appeared to mostly reflect mild to moderate gastrointestinal side-effects and these were generally reported more in the fibre intervention groups than the control groups. AUTHORS' CONCLUSIONS: Studies were short term and therefore did not report on our primary outcomes, CVD clinical events. The pooled analyses for CVD risk factors suggest reductions in total cholesterol and LDL cholesterol with increased fibre intake, and reductions in diastolic blood pressure. There were no obvious effects of subgroup analyses by type of intervention or fibre type but the number of studies included in each of these analyses were small. Risk of bias was unclear in the majority of studies and high for some quality domains so results need to be interpreted cautiously. There is a need for longer term, well-conducted RCTs to determine the effects of fibre type (soluble versus insoluble) and administration (supplements versus foods) on CVD events and risk factors for the primary prevention of CVD.

Diet, physical activity, and behavioural interventions for the treatment of overweight or obesity in preschool children up to the age of 6 years.

BACKGROUND: Child overweight and obesity has increased globally, and can be associated with short- and long-term health consequences. OBJECTIVES: To assess the effects of diet, physical activity, and behavioural interventions for the treatment of overweight or obesity in preschool children up to the age of 6 years. SEARCH METHODS: We performed a systematic literature search in the databases Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, and LILACS, as well as in the trial registers ClinicalTrials.gov and ICTRP Search Portal. We also checked references of identified trials and systematic reviews. We applied no language restrictions. The date of the last search was March 2015 for all databases. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of diet, physical activity, and behavioural interventions for treating overweight or obesity in preschool children aged 0 to 6 years. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias, evaluated the overall quality of the evidence using the GRADE instrument, and extracted data following the Cochrane Handbook for Systematic Reviews of Interventions. We contacted trial authors for additional information. MAIN RESULTS: We included 7 RCTs with a total of 923 participants: 529 randomised to an intervention and 394 to a comparator. The number of participants per trial ranged from 18 to 475. Six trials were parallel RCTs, and one was a cluster RCT. Two trials were three-arm trials, each comparing two interventions with a control group. The interventions and comparators in the trials varied. We categorised the comparisons into two groups: multicomponent interventions and dietary interventions. The overall quality of the evidence was low or very low, and six trials had a high risk of bias on individual 'Risk of bias' criteria. The children in the included trials were followed up for between six months and three years.In trials comparing a multicomponent intervention with usual care, enhanced usual care, or information control, we found a greater reduction in body mass index (BMI) z score in the intervention groups at the end of the intervention (6 to 12 months): mean difference (MD) -0.3 units (95% confidence interval (CI) -0.4 to -0.2); P < 0.00001; 210 participants; 4 trials; low-quality evidence, at 12 to 18 months' follow-up: MD -0.4 units (95% CI -0.6 to -0.2); P = 0.0001; 202 participants; 4 trials; low-quality evidence, and at 2 years' follow-up: MD -0.3 units (95% CI -0.4 to -0.1); 96 participants; 1 trial; low-quality evidence.One trial stated that no adverse events were reported; the other trials did not report on adverse events. Three trials reported health-related quality of life and found improvements in some, but not all, aspects. Other outcomes, such as behaviour change and parent-child relationship, were inconsistently measured.One three-arm trial of very low-quality evidence comparing two types of diet with control found that both the dairy-rich diet (BMI z score change MD -0.1 units (95% CI -0.11 to -0.09); P < 0.0001; 59 participants) and energy-restricted diet (BMI z score change MD -0.1 units (95% CI -0.11 to -0.09); P < 0.0001; 57 participants) resulted in greater reduction in BMI than the comparator at the end of the intervention period, but only the dairy-rich diet maintained this at 36 months' follow-up (BMI z score change in MD -0.7 units (95% CI -0.71 to -0.69); P < 0.0001; 52 participants). The energy-restricted diet had a worse BMI outcome than control at this follow-up (BMI z score change MD 0.1 units (95% CI 0.09 to 0.11); P < 0.0001; 47 participants). There was no substantial difference in mean daily energy expenditure between groups. Health-related quality of life, adverse effects, participant views, and parenting were not measured.No trial reported on all-cause mortality, morbidity, or socioeconomic effects.All results should be interpreted cautiously due to their low quality and heterogeneous interventions and comparators. AUTHORS' CONCLUSIONS: Muticomponent interventions appear to be an effective treatment option for overweight or obese preschool children up to the age of 6 years. However, the current evidence is limited, and most trials had a high risk of bias. Most trials did not measure adverse events. We have identified four ongoing trials that we will include in future updates of this review.The role of dietary interventions is more equivocal, with one trial suggesting that dairy interventions may be effective in the longer term, but not energy-restricted diets. This trial also had a high risk of bias.

Parent-only interventions for childhood overweight or obesity in children aged 5 to 11 years.

BACKGROUND: Child and adolescent overweight and obesity have increased globally, and are associated with short- and long-term health consequences. OBJECTIVES: To assess the efficacy of diet, physical activity and behavioural interventions delivered to parents only for the treatment of overweight and obesity in children aged 5 to 11 years. SEARCH METHODS: We performed a systematic literature search of databases including the Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS as well trial registers. We checked references of identified trials and systematic reviews. We applied no language restrictions. The date of the last search was March 2015 for all databases. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of diet, physical activity and behavioural interventions delivered to parents only for treating overweight or obesity in children aged 5 to 11 years. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for risk of bias and evaluated overall study quality using the GRADE instrument. Where necessary, we contacted authors for additional information. MAIN RESULTS: We included 20 RCTs, including 3057 participants. The number of participants ranged per trial between 15 and 645. Follow-up ranged between 24 weeks and two years. Eighteen trials were parallel RCTs and two were cluster RCTs. Twelve RCTs had two comparisons and eight RCTs had three comparisons. The interventions varied widely; the duration, content, delivery and follow-up of the interventions were heterogeneous. The comparators also differed. This review categorised the comparisons into four groups: parent-only versus parent-child, parent-only versus waiting list controls, parent-only versus minimal contact interventions and parent-only versus other parent-only interventions.Trial quality was generally low with a large proportion of trials rated as high risk of bias on individual risk of bias criteria.In trials comparing a parent-only intervention with a parent-child intervention, the body mass index (BMI) z score change showed a mean difference (MD) at the longest follow-up period (10 to 24 months) of -0.04 (95% confidence interval (CI) -0.15 to 0.08); P = 0.56; 267 participants; 3 trials; low quality evidence. In trials comparing a parent-only intervention with a waiting list control, the BMI z score change in favour of the parent-only intervention at the longest follow-up period (10-12 months) had an MD of -0.10 (95% CI -0.19 to -0.01); P = 0.04; 136 participants; 2 trials; low quality evidence. BMI z score change of parent-only interventions when compared with minimal contact control interventions at the longest follow-up period (9 to 12 months) showed an MD of 0.01 (95% CI -0.07 to 0.09); P = 0.81; 165 participants; 1 trial; low quality evidence. There were few similarities between interventions and comparators across the included trials in the parent-only intervention versus other parent-only interventions and we did not pool these data. Generally, these trials did not show substantial differences between their respective parent-only groups on BMI outcomes.Other outcomes such as behavioural measures, parent-child relationships and health-related quality of life were reported inconsistently. Adverse effects of the interventions were generally not reported, two trials stated that there were no serious adverse effects. No trials reported on all-cause mortality, morbidity or socioeconomic effects.All results need to be interpreted cautiously because of their low quality, the heterogeneous interventions and comparators, and the high rates of non-completion. AUTHORS' CONCLUSIONS: Parent-only interventions may be an effective treatment option for overweight or obese children aged 5 to 11 years when compared with waiting list controls. Parent-only interventions had similar effects compared with parent-child interventions and compared with those with minimal contact controls. However, the evidence is at present limited; some of the trials had a high risk of bias with loss to follow-up being a particular issue and there was a lack of evidence for several important outcomes. The systematic review has identified 10 ongoing trials that have a parent-only arm, which will contribute to future updates. These trials will improve the robustness of the analyses by type of comparator, and may permit subgroup analysis by intervention component and the setting. Trial reports should provide adequate details about the interventions to be replicated by others. There is a need to conduct and report cost-effectiveness analyses in future trials in order to establish whether parent-only interventions are more cost-effective than parent-child interventions.

Comparing new treatments for idiopathic pulmonary fibrosis--a network meta-analysis.

BACKGROUND: The treatment landscape for idiopathic pulmonary fibrosis, a devastating lung disease, is changing. To investigate the effectiveness of treatments for idiopathic pulmonary fibrosis we undertook a systematic review, network meta-analysis and indirect comparison. METHODS: We searched MEDLINE, EMBASE and The Cochrane library for relevant studies. Randomised controlled trials of pirfenidone, nintedanib or N-acetylcysteine were eligible. Predefined processes for selecting references, extracting data and assessing study quality were applied. Our network meta-analysis of published data used a fixed effect model. For forced vital capacity measures a standardised mean difference approach was used and converted to odds ratios for interpretation. RESULTS: Of 1076 references, 67 were retrieved and 11 studies included. Studies were of reasonable size, populations were similar, and the overall quality was good. Only two treatments, pirfenidone (odds ratio 0.62, 95% credible interval 0.52, 0.74) and nintedanib (0.41, 95% credible interval 0.34, 0.51) produced a statistically significant slowing in the rate of forced vital capacity decline compared with placebo. In an indirect comparison, results indicate that nintedanib is statistically significantly better than pirfenidone in slowing forced vital capacity decline (odds ratio 0.67, 95% credible interval 0.51, 0.88). Results were stable in scenario analysis and random effects models. Indirect comparisons of mortality were not statistically significant between nintedanib and pirfenidone. CONCLUSIONS: Two treatments show beneficial effects and when compared indirectly nintedanib appears to have superior benefit on forced vital capacity. Limitations to indirect comparisons should be considered when interpreting these results, however, our findings can be useful to inform treatment decisions.

Surgery for weight loss in adults.

BACKGROUND: Bariatric (weight loss) surgery for obesity is considered when other treatments have failed. The effects of the available bariatric procedures compared with medical management and with each other are uncertain. This is an update of a Cochrane review first published in 2003 and most recently updated in 2009. OBJECTIVES: To assess the effects of bariatric surgery for overweight and obesity, including the control of comorbidities. SEARCH METHODS: Studies were obtained from searches of numerous databases, supplemented with searches of reference lists and consultation with experts in obesity research. Date of last search was November 2013. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing surgical interventions with non-surgical management of obesity or overweight or comparing different surgical procedures. DATA COLLECTION AND ANALYSIS: Data were extracted by one review author and checked by a second review author. Two review authors independently assessed risk of bias and evaluated overall study quality utilising the GRADE instrument. MAIN RESULTS: Twenty-two trials with 1798 participants were included; sample sizes ranged from 15 to 250. Most studies followed participants for 12, 24 or 36 months; the longest follow-up was 10 years. The risk of bias across all domains of most trials was uncertain; just one was judged to have adequate allocation concealment.All seven RCTs comparing surgery with non-surgical interventions found benefits of surgery on measures of weight change at one to two years follow-up. Improvements for some aspects of health-related quality of life (QoL) (two RCTs) and diabetes (five RCTs) were also found. The overall quality of the evidence was moderate. Five studies reported data on mortality, no deaths occurred. Serious adverse events (SAEs) were reported in four studies and ranged from 0% to 37% in the surgery groups and 0% to 25% in the no surgery groups. Between 2% and 13% of participants required reoperations in the five studies that reported these data.Three RCTs found that laparoscopic Roux-en-Y gastric bypass (L)(RYGB) achieved significantly greater weight loss and body mass index (BMI) reduction up to five years after surgery compared with laparoscopic adjustable gastric banding (LAGB). Mean end-of-study BMI was lower following LRYGB compared with LAGB: mean difference (MD) -5.2 kg/m² (95% confidence interval (CI) -6.4 to -4.0; P < 0.00001; 265 participants; 3 trials; moderate quality evidence). Evidence for QoL and comorbidities was very low quality. The LRGYB procedure resulted in greater duration of hospitalisation in two RCTs (4/3.1 versus 2/1.5 days) and a greater number of late major complications (26.1% versus 11.6%) in one RCT. In one RCT the LAGB required high rates of reoperation for band removal (9 patients, 40.9%).Open RYGB, LRYGB and laparoscopic sleeve gastrectomy (LSG) led to losses of weight and/or BMI but there was no consistent picture as to which procedure was better or worse in the seven included trials. MD was -0.2 kg/m² (95% CI -1.8 to 1.3); 353 participants; 6 trials; low quality evidence) in favour of LRYGB.  No statistically significant differences in QoL were found (one RCT). Six RCTs reported mortality; one death occurred following LRYGB. SAEs were reported by one RCT and were higher in the LRYGB group (4.5%) than the LSG group (0.9%). Reoperations ranged from 6.7% to 24% in the LRYGB group and 3.3% to 34% in the LSG group. Effects on comorbidities, complications and additional surgical procedures were neutral, except gastro-oesophageal reflux disease improved following LRYGB (one RCT). One RCT of people with a BMI 25 to 35 and type 2 diabetes found laparoscopic mini-gastric bypass resulted in greater weight loss and improvement of diabetes compared with LSG, and had similar levels of complications.Two RCTs found that biliopancreatic diversion with duodenal switch (BDDS) resulted in greater weight loss than RYGB in morbidly obese patients. End-of-study mean BMI loss was greater following BDDS: MD -7.3 kg/m² (95% CI -9.3 to -5.4); P < 0.00001; 107 participants; 2 trials; moderate quality evidence). QoL was similar on most domains. In one study between 82% to 100% of participants with diabetes had a HbA1c of less than 5% three years after surgery. Reoperations were higher in the BDDS group (16.1% to 27.6%) than the LRYGB group (4.3% to 8.3%). One death occurred in the BDDS group.One RCT comparing laparoscopic duodenojejunal bypass with sleeve gastrectomy versus LRYGB found BMI, excess weight loss, and rates of remission of diabetes and hypertension were similar at 12 months follow-up (very low quality evidence). QoL, SAEs and reoperation rates were not reported. No deaths occurred in either group.One RCT comparing laparoscopic isolated sleeve gastrectomy (LISG) versus LAGB found greater improvement in weight-loss outcomes following LISG at three years follow-up (very low quality evidence). QoL, mortality and SAEs were not reported. Reoperations occurred in 20% of the LAGB group and in 10% of the LISG group.One RCT (unpublished) comparing laparoscopic gastric imbrication with LSG found no statistically significant difference in weight loss between groups (very low quality evidence).  QoL and comorbidities were not reported. No deaths occurred. Two participants in the gastric imbrication group required reoperation. AUTHORS' CONCLUSIONS: Surgery results in greater improvement in weight loss outcomes and weight associated comorbidities compared with non-surgical interventions, regardless of the type of procedures used. When compared with each other, certain procedures resulted in greater weight loss and improvements in comorbidities than others. Outcomes were similar between RYGB and sleeve gastrectomy, and both of these procedures had better outcomes than adjustable gastric banding. For people with very high BMI, biliopancreatic diversion with duodenal switch resulted in greater weight loss than RYGB. Duodenojejunal bypass with sleeve gastrectomy and laparoscopic RYGB had similar outcomes, however this is based on one small trial. Isolated sleeve gastrectomy led to better weight-loss outcomes than adjustable gastric banding after three years follow-up. This was based on one trial only.  Weight-related outcomes were similar between laparoscopic gastric imbrication and laparoscopic sleeve gastrectomy in one trial. Across all studies adverse event rates and reoperation rates were generally poorly reported. Most trials followed participants for only one or two years, therefore the long-term effects of surgery remain unclear.

Artificial intelligence software for analysing chest X-ray images to identify suspected lung cancer: an evidence synthesis early value assessment.

Background: Lung cancer is one of the most common types of cancer in the United Kingdom. It is often diagnosed late. The 5-year survival rate for lung cancer is below 10%. Early diagnosis may improve survival. Software that has an artificial intelligence-developed algorithm might be useful in assisting with the identification of suspected lung cancer. Objectives: This review sought to identify evidence on adjunct artificial intelligence software for analysing chest X-rays for suspected lung cancer, and to develop a conceptual cost-effectiveness model to inform discussion of what would be required to develop a fully executable cost-effectiveness model for future economic evaluation. Data sources: The data sources were MEDLINE All, EMBASE, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, Epistemonikos, ACM Digital Library, World Health Organization International Clinical Trials Registry Platform, clinical experts, Tufts Cost-Effectiveness Analysis Registry, company submissions and clinical experts. Searches were conducted from 25 November 2022 to 18 January 2023. Methods: Rapid evidence synthesis methods were employed. Data from companies were scrutinised. The eligibility criteria were (1) primary care populations referred for chest X-ray due to symptoms suggestive of lung cancer or reasons unrelated to lung cancer; (2) study designs that compared radiology specialist assessing chest X-ray with adjunct artificial intelligence software versus radiology specialists alone and (3) outcomes relating to test accuracy, practical implications of using artificial intelligence software and patient-related outcomes. A conceptual decision-analytic model was developed to inform a potential full cost-effectiveness evaluation of adjunct artificial intelligence software for analysing chest X-ray images to identify suspected lung cancer. Results: None of the studies identified in the searches or submitted by the companies met the inclusion criteria of the review. Contextual information from six studies that did not meet the inclusion criteria provided some evidence that sensitivity for lung cancer detection (but not nodule detection) might be higher when chest X-rays are interpreted by radiology specialists in combination with artificial intelligence software than when they are interpreted by radiology specialists alone. No significant differences were observed for specificity, positive predictive value or number of cancers detected. None of the six studies provided evidence on the clinical effectiveness of adjunct artificial intelligence software. The conceptual model highlighted a paucity of input data along the course of the diagnostic pathway and identified key assumptions required for evidence linkage. Limitations: This review employed rapid evidence synthesis methods. This included only one reviewer conducting all elements of the review, and targeted searches that were conducted in English only. No eligible studies were identified. Conclusions: There is currently no evidence applicable to this review on the use of adjunct artificial intelligence software for the detection of suspected lung cancer on chest X-ray in either people referred from primary care with symptoms of lung cancer or people referred from primary care for other reasons. Future work: Future research is required to understand the accuracy of adjunct artificial intelligence software to detect lung nodules and cancers, as well as its impact on clinical decision-making and patient outcomes. Research generating key input parameters for the conceptual model will enable refinement of the model structure, and conversion to a full working model, to analyse the cost-effectiveness of artificial intelligence software for this indication. Study registration: This study is registered as PROSPERO CRD42023384164. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135755) and is published in full in Health Technology Assessment; Vol. 28, No. 50. See the NIHR Funding and Awards website for further award information.

Lung cancer is one of the most common types of cancer in the United Kingdom. Early diagnosis may improve survival, as lung cancer is often diagnosed late. Chest X-rays can be used to identify features of lung cancer. There can be delays in getting X-rays, and sometimes features of lung cancer are not seen on them. Artificial intelligence software may help by finding features of cancer on chest X-rays and highlighting them. A radiologist will look at the X-rays and information from the software. There is a lack of information about how lung cancer diagnosis could change if artificial intelligence software is used and what the costs may be to the National Health Service. This project looked at the use of artificial intelligence software in the detection of lung cancer in people referred from primary care. Software companies were invited to provide evidence. There were no studies that looked at this topic among people from primary care. We summarised the closest evidence we could find instead. All of this had flaws, so we could not tell if the results were accurate or helpful to this review. It was not clear if artificial intelligence helped to find cancers or improve people's health. We made a theoretical model to discuss the best way to assess if artificial intelligence software might be cost-effective in detecting lung cancer and what evidence would be needed to do this in a fully working model. Costs and alternative pricing models provided by five companies were used to calculate the cost of adding artificial intelligence software to review chest X-rays in people referred from their general practitioner, for the first 5 years, based on one National Health Service trust. Future studies are needed to identify the impact of adjunct artificial intelligence on test accuracy, clinical decision-making and patient outcomes (e.g. mortality and morbidity).

Pharmacological and nonpharmacological interventions to improve symptom control, functional exercise capacity and quality of life in interstitial lung disease: an evidence synthesis.

We assessed efficacy and effectiveness of pharmacological and nonpharmacological interventions in improving symptom control, functional exercise capacity and quality of life (QoL) in people living with fibrotic interstitial lung disease (ILD). We summarised evidence from three previous reviews (to June 2014) and conducted an updated search of nine databases and grey literature (2011-2019) (registration: CRD42017065933) for prospective studies of interventions aimed to alleviate symptoms, improve QoL or functional exercise capacity in fibrotic ILD. Data were synthesised through narrative synthesis or meta-analysed as appropriate. Forty-seven studies with 2527 participants were included. From 22 pharmacological studies of 11 different interventions (n=1683), the most tested interventions were bosentan and sildenafil. From 25 nonpharmacological studies, the most tested intervention was for pulmonary rehabilitation/exercise training (PR) (22 studies, n=748). There was an improvement in 6-min walk distance immediately following PR (six studies; n=200, mean difference (MD) (95% CI) 39.9 m (18.2 to 61.5)), but not longer term (3 or 6 months, four studies; n=147, MD 5.3 m (-12.9 to 23.4). Multiple, varied outcome measures were used (e.g. 37 studies assessing dyspnoea used 10 different scales with a lack of reporting of rate of deterioration in outcomes). Evidence gap mapping highlighted the most and least researched symptoms, as dyspnoea and cough, respectively. This evidence synthesis highlights overwhelmingly that the most researched symptom is dyspnoea and the strongest evidence base is for short-term PR. The least researched symptom was cough. Research going forward must focus on prioritising and standardising meaningful outcomes and focussing interventions on neglected symptoms.

Time to full publication of studies of anticancer drugs for breast cancer, and the potential for publication bias.

OBJECTIVES: Nonpublication of results of clinical trials can contribute to inappropriate medical decisions. The primary aim of this systematic review was to investigate publication delays between conference abstracts and full journal publications from randomized controlled trial results of new anticancer agents for breast cancer. The review was restricted to anticancer agents previously, or due to be, appraised in the United Kingdom by the National Institute for Health and Clinical Excellence. A secondary objective was to identify whether there are any apparent biases in the publication and reporting of these trials. METHODS: We searched six electronic databases up to August 2007, including Medline and the Cochrane Library. Two reviewers independently selected studies, extracted and assessed the data. RESULTS: Six anticancer treatments were identified: docetaxel, paclitaxel, trastuzumab, gemcitabine, lapatinib, and bevacizumab. Of eighteen included trials, only four publications from three trials reported the same outcomes in both abstract and full publication. Time delays ranged from 5 to 19 months. Eleven trial abstracts were still without a full publication at the end of our searches, varying from 3 to 38 months since abstract publication. Observational analysis revealed no particular publishing biases. CONCLUSIONS: Whereas delays in publication appear reasonable over a period of months, many were not published in full over a period of years and others would appear to be unlikely to ever be published. Further research should investigate the impact of publication delays on the availability of new drug treatments in clinical practice.