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Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10-8); rs79942605 (OR = 2.17, P = 2.81×10-8) and rs208908 (OR = 0.70, P = 4.54×10-8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.
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Estudo de Associação Genômica Ampla , Neoplasias Pulmonares , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Pulmão , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
AIM: To assess the association of country-level obesity prevalence with COVID-19 case and mortality rates, to evaluate the impact of obesity prevalence on worldwide variation. METHODS: Data on COVID-19 prevalence and mortality, country-specific governmental actions, socioeconomic, demographic, and healthcare capacity factors were extracted from publicly available sources. Multivariable negative binomial regression was used to assess the independent association of obesity with COVID-19 case and mortality rates. RESULTS: Across 168 countries for which data were available, higher obesity prevalence was associated with increased COVID-19 mortality and prevalence rates. For every 1% increase in obesity prevalence, the mortality rate was increased by 8.3% (incidence rate ratio [IRR] 1.083, 95% confidence interval [CI] 1.048-1.119; P < 0.001) and the case rate was higher by 6.6% (IRR 1.066, 95% CI 1.035-1.099; P < 0.001). Additionally, higher median population age, greater female ratio, higher Human Development Index (HDI), lower population density, and lower hospital bed availability were all significantly associated with higher COVID-19 mortality rate. In addition, stricter governmental actions, higher HDI and lower mean annual temperature were significantly associated with higher COVID-19 case rate. CONCLUSION: These findings demonstrate that obesity prevalence is a significant and potentially modifiable risk factor of increased COVID-19 national caseload and mortality. Future research to study whether weight loss improves COVID-19 outcomes is urgently required.
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COVID-19 , Feminino , Humanos , Incidência , Obesidade/complicações , Obesidade/epidemiologia , Densidade Demográfica , SARS-CoV-2RESUMO
BACKGROUND: A substantial number of melanoma patients develop local or metastatic recurrence, and early detection of these is vital to maximise benefit from new therapies such as inhibitors of BRAF and MEK, or immune checkpoints. This study explored the use of novel DNA copy-number profiles in circulating cell-free DNA (cfDNA) as a potential biomarker of active disease and survival. PATIENTS AND METHODS: Melanoma patients were recruited from oncology and dermatology clinics in Sheffield, UK, and cfDNA was isolated from stored blood plasma. Using low-coverage whole-genome sequencing, we created copy-number profiles from cfDNA from 83 melanoma patients, 44 of whom had active disease. We used scoring algorithms to summarize copy-number aberrations and investigated their utility in multivariable logistic and Cox regression analyses. RESULTS: The copy-number aberration score (CNAS) was a good discriminator of active disease (odds ratio, 3.1; 95% CI, 1.5-6.2; P = 0.002), and CNAS above or below the 75th percentile remained a significant discriminator in multivariable analysis for active disease (P = 0.019, with area under ROC curve of 0.90). Additionally, mortality was higher in those with CNASs above the 75th percentile than in those with lower scores (HR, 3.4; 95% CI, 1.5-7.9; P = 0.005), adjusting for stage of disease, disease status (active or resected), BRAF status, and cfDNA concentration. CONCLUSIONS: This study demonstrates the potential of a de novo approach utilizing copy-number profiling of cfDNA as a biomarker of active disease and survival in melanoma. Longitudinal analysis of copy-number profiles as an early marker of relapsed disease is warranted.
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Ácidos Nucleicos Livres/sangue , Variações do Número de Cópias de DNA , Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Estudos de Viabilidade , Humanos , Melanoma/genética , Melanoma/cirurgia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/cirurgia , Análise de SobrevidaRESUMO
Hyperpolarised 3He ventilation-MRI, anatomical lung MRI, lung clearance index (LCI), low-dose CT and spirometry were performed on 19 children (6-16â years) with clinically stable mild cystic fibrosis (CF) (FEV1>-1.96), and 10 controls. All controls had normal spirometry, MRI and LCI. Ventilation-MRI was the most sensitive method of detecting abnormalities, present in 89% of patients with CF, compared with CT abnormalities in 68%, LCI 47% and conventional MRI 22%. Ventilation defects were present in the absence of CT abnormalities and in patients with normal physiology, including LCI. Ventilation-MRI is thus feasible in young children, highly sensitive and provides additional information about lung structure-function relationships.
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Fibrose Cística/diagnóstico , Diagnóstico Precoce , Pulmão/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Respiração Artificial/métodos , Adolescente , Criança , Fibrose Cística/fisiopatologia , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Pulmão/diagnóstico por imagem , Masculino , Espirometria/métodos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types. METHODS: The original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded. RESULTS: The search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods). CONCLUSION: We have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection.
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Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/sangue , Detecção Precoce de Câncer/métodos , Neoplasias/diagnóstico , Humanos , Mutação , Neoplasias/sangueRESUMO
The paper by Body et al is concerned with the evaluation of decision aids, which can be used to identify potential acute coronary syndromes (ACS) in the ED. The authors previously developed the Manchester Acute Coronary Syndromes model (MACS) decision aid, which uses several clinical variables and two biomarkers to 'rule in' and 'rule out' ACS. However, one of the two biomarkers (heart-type fatty acid bindingprotein, H-FABP) is not widely used so a revised decision aid has been developed (Troponin-only Manchester Acute Coronary Syndromes, T-MACS), which include a single biomarker hs-cTnT. In this issue, the authors show how they derive a revised decision aid and describe its performance in a number of independent diagnostic cohort studies. Decision aids (as well as other types of 'diagnostic tests') are often evaluated in terms of diagnostic testing parameters such as the area under the receiver operating characteristic (ROC) curve, sensitivity and specificity. In this article, we explain how the ROC analysis is conducted and why it is an essential step towards developing a test with the desirable levels of sensitivity and specificity.
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Técnicas de Apoio para a Decisão , Curva ROC , Sensibilidade e Especificidade , Interpretação Estatística de Dados , Serviço Hospitalar de Emergência/organização & administração , HumanosRESUMO
Molecular profiling using low coverage whole genome sequencing of cell free DNA (cfDNA) represents a non-targeted approach to identify multiple somatic copy number alterations (SCNA) across different lung cancer subtypes. We aim to establish that SCNA can be detected in cfDNA of lung cancer cases.Standard protocols were followed to process matched cfDNA, formalin-fixed paraffin embedded (FFPE) tumour and lymphocyte DNA. Copy number profiles for cfDNA or FFPE DNA were normalised to profiles from matched lymphocyte DNA with the software CNAnorm. Technical sensitivity was determined by spiking different proportions of FFPE tumour DNA into cfDNA from controls.The median genome coverage was 0.26X (range 0.05X-0.97X). For two advanced stage cases there was a positive correlation between copy number ratio profiles of matched cfDNA and FFPE DNA (r = 0.62, p < 0.0001 and r = 0.75, p < 0.0001). There was no correlation for four advanced and two early stage cases. There were low magnitude copy number aberrations detected in high-risk controls (N = 5). We detected spiked FFPE DNA derived SCNAs with a tumour fraction as low as 10 % of cfDNA.Our preliminary results demonstrate non-invasive detection of tumour-derived copy number alterations in advanced lung cancer cases with low coverage whole genome sequencing. Clinical characteristics and treatment may influence whether SCNA are detected in cfDNA.
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Variações do Número de Cópias de DNA , DNA de Neoplasias/genética , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , DNA de Neoplasias/sangue , Formaldeído , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Inclusão em Parafina , Fatores de Risco , Sensibilidade e Especificidade , Fixação de TecidosRESUMO
OBJECTIVES: Up to 20% of coronary angiograms reveal normal arteries. How long they stay normal is poorly understood. This study investigated the fate of normal coronary arteries and determined the rate of development of coronary artery disease. METHODS: We interrogated the angiographic archive of the South Yorkshire Cardiothoracic Centre between 2004 and 2013 to identify patients with truly normal coronary arteries who underwent repeat coronary angiography more than 1 year later. Follow up angiograms were scored for the severity and extent of CAD (graded per segment as 0%, 1-50%, >50%). Risk factors for the development of coronary artery disease were documented. Univariate predictors of disease development were identified and entered into a logistic regression model to identify independent predictors. RESULTS: Out of over 25,000 angiographic procedures in the archives we found 6068 patients reported to have normal coronary arteries. Of these, 162 patients had also undergone subsequent repeat coronary angiography. Of these, 97 had truly normal (smooth) coronary arteries at baseline and had undergone repeat angiography >1 year later. At a median 51 months, 87 continued to have normal arteries, and all the remaining 10 had mild disease only (average 37% stenosis in an average 1.2 segments). No patients developed any significant (>50% stenosis) disease. Advanced age, time between angiograms, and smoking status were identified as independent predictors of development of CAD. CONCLUSIONS: Truly normal coronary arteries do not progress to significant disease within a time frame of 4 years. Repeat coronary angiography within that period is probably not indicated.
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Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Procedimentos Desnecessários , Idoso , Distribuição de Qui-Quadrado , Doença da Artéria Coronariana/etiologia , Estenose Coronária/etiologia , Progressão da Doença , Inglaterra , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Valor Preditivo dos Testes , Sistemas de Informação em Radiologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de TempoRESUMO
Clinical trials are the backbone of medical research, and are often the last step in the development of new therapies for use in patients. Prior to human testing, however, preclinical studies using animal subjects are usually performed in order to provide initial data on the safety and effectiveness of prospective treatments. These studies can be costly and time consuming, and may also raise concerns about the ethical treatment of animals when potentially harmful procedures are involved. Adaptive design is a process by which the methods used in a study may be altered while it is being conducted in response to preliminary data or other new information. Adaptive design has been shown to be useful in reducing the time and costs associated with clinical trials, and may provide similar benefits in preclinical animal studies. The purpose of this review is to summarize various aspects of adaptive design and evaluate its potential for use in preclinical research.
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Pesquisa Biomédica/métodos , Ensaios Clínicos como Assunto/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Projetos de Pesquisa , AnimaisRESUMO
INTRODUCTION: Neovascular age-related macular degeneration (nAMD) management is one of the largest single-disease contributors to hospital outpatient appointments. Partial automation of nAMD treatment decisions could reduce demands on clinician time. Established artificial intelligence (AI)-enabled retinal imaging analysis tools, could be applied to this use-case, but are not yet validated for it. A primary qualitative investigation of stakeholder perceptions of such an AI-enabled decision tool is also absent. This multi-methods study aims to establish the safety and efficacy of an AI-enabled decision tool for nAMD treatment decisions and understand where on the clinical pathway it could sit and what factors are likely to influence its implementation. METHODS AND ANALYSIS: Single-centre retrospective imaging and clinical data will be collected from nAMD clinic visits at a National Health Service (NHS) teaching hospital ophthalmology service, including judgements of nAMD disease stability or activity made in real-world consultant-led-care. Dataset size will be set by a power calculation using the first 127 randomly sampled eligible clinic visits. An AI-enabled retinal segmentation tool and a rule-based decision tree will independently analyse imaging data to report nAMD stability or activity for each of these clinic visits. Independently, an external reading centre will receive both clinical and imaging data to generate an enhanced reference standard for each clinic visit. The non-inferiority of the relative negative predictive value of AI-enabled reports on disease activity relative to consultant-led-care judgements will then be tested. In parallel, approximately 40 semi-structured interviews will be conducted with key nAMD service stakeholders, including patients. Transcripts will be coded using a theoretical framework and thematic analysis will follow. ETHICS AND DISSEMINATION: NHS Research Ethics Committee and UK Health Research Authority approvals are in place (21/NW/0138). Informed consent is planned for interview participants only. Written and oral dissemination is planned to public, clinical, academic and commercial stakeholders.
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Inibidores da Angiogênese , Degeneração Macular , Humanos , Inibidores da Angiogênese/uso terapêutico , Procedimentos Clínicos , Medicina Estatal , Inteligência Artificial , Estudos Retrospectivos , Degeneração Macular/tratamento farmacológicoRESUMO
INTRODUCTION: Undiagnosed fatty liver disease is prevalent in the community, due to high rates of harmful alcohol consumption and/or obesity. Fatty liver disease can progress to cirrhosis and its complications. Early identification of liver disease and treatment may prevent progression to cirrhosis. Biomarkers including FIB-4, enhanced liver fibrosis (ELF), PRO-C3 and vibration controlled transient elastography (VCTE) can stage liver fibrosis, but it is not known how well they perform in a primary care population. Moreover, no assessment of long-term prognostic ability of these biomarkers has been conducted in primary care. We aim to evaluate the performance of fibrosis biomarkers in primary care to develop a pathway to detect advanced fibrosis. METHODS AND ANALYSIS: This prospective, observational cohort study will recruit 3000 individuals with fatty liver disease risk factors (obesity, type 2 diabetes or hazardous alcohol consumption) at their primary care 'annual chronic disease review'. Participants will have a 'liver health check'. Two pathways will be evaluated: (1) all have FIB-4, ELF and VCTE performed, and (2) patients have an initial assessment with FIB-4 and ELF, followed by VCTE in only those with increased FIB-4 and/or ELF. Individuals with suspected significant/advanced liver fibrosis (liver stiffness measurement>8 kPa), will be reviewed in secondary care to confirm their fibrosis stage and institute treatment. The performance of FIB-4, ELF, PRO-C3, VCTE and novel biomarkers alone or in combination for advanced fibrosis/cirrhosis will be evaluated. Participants will be followed longitudinally via their electronic health records to assess long-term clinical outcomes. ETHICS AND DISSEMINATION: Ethical approval was obtained from the London-Chelsea Research Ethics Committee (22/PR/0535; 27 June 2022). Recruitment began on 31 October 2022. Outcomes of this study will be published in peer-reviewed journals and presented at scientific meetings. A lay summary of the results will be available for study participants and will be disseminated widely by LIVErNORTH.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Humanos , Estudos Prospectivos , Atenção Secundária à Saúde , Complemento C3 , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Cirrose Hepática/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Biomarcadores , Obesidade/complicações , Estudos Observacionais como AssuntoRESUMO
INTRODUCTION: Laryngeal cancer disproportionately affects socioeconomically disadvantaged patients. Treatment can render a patient nil by mouth or in need of a permanent tracheostomy. In the past 30 years, survival has remained at best static and at worst it has declined. Currently, there is no method of prognosticating how a patient will respond to treatment.The LARyngeal Cancer coHort (LARCH) aims to establish how survival and quality-of-life outcomes compare between surgery and (chemo)radiotherapy in early and advanced laryngeal cancer and how the presenting features of laryngeal cancer influence oncological, functional and quality-of-life outcome. METHODS AND ANALYSIS: This study is the first enhanced laryngeal cancer disease cohort. In the initial phase, we aim to deliver a prospective cohort study of 150 patients in 8 centres over a 3-year period.Patient, tumour, quality-of-life and laryngeal functional data will be collected from patients with squamous cell carcinoma of the larynx at baseline, 6, 12 and 24 months. Multiple logistic regression analyses will be used to quantify locoregional control and identify factors associated with control overall and by treatment modality and identify factors associated with quality of life overall and by treatment modality. ETHICS AND DISSEMINATION: Most interventions take place as part of routine care, with LARCH providing a mechanism for recording this data centrally. When successfully recruiting in the North of England, we plan to roll out LARCH nationwide; in the future, LARCH can be used as a trial platform in the disease. The results will be submitted for publication in high-impact international peer-reviewed journals and presented to scientific meetings. Access to the anonymised LARCH dataset by other researchers will be publicised and promoted. TRIAL REGISTRATION NUMBER: ISRCTN27819867.
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Larix , Neoplasias Laríngeas , Humanos , Neoplasias Laríngeas/terapia , Estudos Prospectivos , Medicina de Precisão , Qualidade de VidaRESUMO
INTRODUCTION: Maternal obesity increases the risk of multiple maternal and infant pregnancy complications, such as gestational diabetes and pre-eclampsia. Current UK guidelines use body mass index (BMI) to identify which women require additional care due to increased risk of complications. However, BMI may not accurately predict which women will develop complications during pregnancy as it does not determine amount and distribution of adipose tissue. Some adiposity measures (eg, waist circumference, ultrasound measures of abdominal visceral fat) can better identify where body fat is stored, which may be useful in predicting those women who need additional care. METHODS AND ANALYSIS: This prospective cohort study (SHAPES, Study of How Adiposity in Pregnancy has an Effect on outcomeS) aims to evaluate the prognostic performance of adiposity measures (either alone or in combination with other adiposity, sociodemographic or clinical measures) to estimate risk of adverse pregnancy outcomes. Pregnant women (n=1400) will be recruited at their first trimester ultrasound scan (11+2-14+1 weeks') at Newcastle upon Tyne National Health Service Foundation Trust, UK. Early pregnancy adiposity measures and clinical and sociodemographic data will be collected. Routine data on maternal and infant pregnancy outcomes will be collected from routine hospital records. Regression methods will be used to compare the different adiposity measures with BMI in terms of their ability to predict pregnancy complications. If no individual measure performs better than BMI, multivariable models will be developed and evaluated to identify the most parsimonious model. The apparent performance of the developed model will be summarised using calibration, discrimination and internal validation analyses. ETHICS AND DISSEMINATION: Ethical favourable opinion has been obtained from the North East: Newcastle & North Tyneside 1 Research Ethics Committee (REC reference: 22/NE/0035). All participants provide informed consent to take part in SHAPES. Planned dissemination includes peer-reviewed publications and additional dissemination appropriate to target audiences, including policy briefs for policymakers, media/social-media coverage for public and conferences for research TRIAL REGISTRATION NUMBER: ISRCTN82185177.
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Adiposidade , Obesidade Materna , Gravidez , Lactente , Feminino , Humanos , Estudos Prospectivos , Medicina Estatal , ObesidadeRESUMO
Background: The place of tonsillectomy in the management of sore throat in adults remains uncertain. Objectives: To establish the clinical effectiveness and cost-effectiveness of tonsillectomy, compared with conservative management, for tonsillitis in adults, and to evaluate the impact of alternative sore throat patient pathways. Design: This was a multicentre, randomised controlled trial comparing tonsillectomy with conservative management. The trial included a qualitative process evaluation and an economic evaluation. Setting: The study took place at 27 NHS secondary care hospitals in Great Britain. Participants: A total of 453 eligible participants with recurrent sore throats were recruited to the main trial. Interventions: Patients were randomised on a 1 : 1 basis between tonsil dissection and conservative management (i.e. deferred surgery) using a variable block-stratified design, stratified by (1) centre and (2) severity. Main outcome measures: The primary outcome measure was the total number of sore throat days over 24 months following randomisation. The secondary outcome measures were the number of sore throat episodes and five characteristics from Sore Throat Alert Return, describing severity of the sore throat, use of medications, time away from usual activities and the Short Form questionnaire-12 items. Additional secondary outcomes were the Tonsil Outcome Inventory-14 total and subscales and Short Form questionnaire-12 items 6 monthly. Evaluation of the impact of alternative sore throat patient pathways by observation and statistical modelling of outcomes against baseline severity, as assessed by Tonsil Outcome Inventory-14 score at recruitment. The incremental cost per sore throat day avoided, the incremental cost per quality-adjusted life-year gained based on responses to the Short Form questionnaire-12 items and the incremental net benefit based on costs and responses to a contingent valuation exercise. A qualitative process evaluation examined acceptability of trial processes and ramdomised arms. Results: There was a median of 27 (interquartile range 12-52) sore throats over the 24-month follow-up. A smaller number of sore throats was reported in the tonsillectomy arm [median 23 (interquartile range 11-46)] than in the conservative management arm [median 30 (interquartile range 14-65)]. On an intention-to-treat basis, there were fewer sore throats in the tonsillectomy arm (incident rate ratio 0.53, 95% confidence interval 0.43 to 0.65). Sensitivity analyses confirmed this, as did the secondary outcomes. There were 52 episodes of post-operative haemorrhage reported in 231 participants undergoing tonsillectomy (22.5%). There were 47 re-admissions following tonsillectomy (20.3%), 35 relating to haemorrhage. On average, tonsillectomy was more costly and more effective in terms of both sore throat days avoided and quality-adjusted life-years gained. Tonsillectomy had a 100% probability of being considered cost-effective if the threshold for an additional quality-adjusted life year was £20,000. Tonsillectomy had a 69% probability of having a higher net benefit than conservative management. Trial processes were deemed to be acceptable. Patients who received surgery were unanimous in reporting to be happy to have received it. Limitations: The decliners who provided data tended to have higher Tonsillectomy Outcome Inventory-14 scores than those willing to be randomised implying that patients with a higher burden of tonsillitis symptoms may have declined entry into the trial. Conclusions: The tonsillectomy arm had fewer sore throat days over 24 months than the conservative management arm, and had a high probability of being considered cost-effective over the ranges considered. Further work should focus on when tonsillectomy should be offered. National Trial of Tonsillectomy IN Adults has assessed the effectiveness of tonsillectomy when offered for the current UK threshold of disease burden. Further research is required to define the minimum disease burden at which tonsillectomy becomes clinically effective and cost-effective. Trial registration: This trial is registered as ISRCTN55284102. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/146/06) and is published in full in Health Technology Assessment; Vol. 27, No. 31. See the NIHR Funding and Awards website for further award information.
Tonsillectomy is an operation to take out the pair of tonsil glands at the back of the throat. It is an option for adults who suffer from repeated, severe sore throats. Adults who have a tonsillectomy say that they get fewer sore throats afterwards, but it is not clear whether or not they would have got better over time without the operation. There is pressure on doctors to limit the number of tonsillectomies carried out. At the same time, emergency hospital admissions for adults with severe throat infections have been increasing. NAtional Trial of Tonsillectomy IN Adults aimed to find out whether tonsillectomy is an effective and worthwhile treatment for repeated severe sore throats or whether patients would be better off treated without an operation. A total of 453 patients from 27 hospitals in Great Britain took part in the study. Patients were assigned at random to receive either tonsillectomy or conservative management (treatment as needed from their general practitioner). We measured how many sore throats patients had in the next 2 years by sending them text messages every week. We asked about the impact of their sore throats on their quality of life and time off work, and looked at the costs of treatment. We also interviewed 47 patients, general practitioners and hospital staff about their experiences of tonsillectomy and NAtional Trial of Tonsillectomy IN Adults. The typical patient in the tonsillectomy arm had 23 days of sore throat compared with 30 days of sore throat in the conservative management arm. Tonsillectomy resulted in higher quality of life. We looked to see whether or not it was only those with the most severe sore throats who benefited from tonsillectomy, but we found that patients with more or less severe sore throats at the start all did better with tonsillectomy. Patients who had a tonsillectomy were happy to have undertaken this. Our findings suggest a clear benefit of tonsillectomy using modest additional NHS resources for adults with repeated severe sore throats.
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Faringite , Tonsilectomia , Tonsilite , Adulto , Humanos , Análise Custo-Benefício , Tratamento Conservador , Faringite/etiologia , Tonsilite/cirurgia , HemorragiaRESUMO
OBJECTIVES: To assess the cost-effectiveness of LEGO-based therapy compared with usual support. DESIGN: Cost-utility analysis alongside randomised control trial. SETTING: Mainstream primary and secondary schools in the UK. PARTICIPANTS: 248 children and young people (CYP) with autism spectrum disorder (ASD) aged 7-15 years. INTERVENTION: LEGO-based therapy is a group social skills intervention designed specifically for CYP with ASD. Through play, CYP learn to use the skills such as joint attention, sharing, communication and group problem-solving. CYP randomised to the intervention arm received 12 weekly sessions of LEGO-based therapy and usual support, while CYP allocated to control arm received usual support only. MAIN OUTCOME MEASURES: Average costs based on National Health Service (NHS) and personal social services perspective and quality-adjusted life years (QALYs) measured by EQ-5D-Y over time horizon of 1 year were collected during the trial. Incremental cost-effectiveness ratio (ICER) was calculated, and non-parametric bootstrapping was conducted. The uncertainty around the ICER estimates was presented using cost-effectiveness acceptability curve (CEAC). A set of sensitivity analyses were conducted to assess the robustness of the primary findings. RESULTS: After adjustment and bootstrapping, on average, CYP in LEGO-based therapy group incurred less costs (incremental cost was -£251 (95% CI -£752 to £268)) and gained marginal improvement in QALYs (QALYs gained 0.009 (95% CI -0.008 to 0.028)). The CEAC shows that the probability of LEGO-based therapy being cost-effective was 94% at the willingness-to-pay threshold of £20 000 per QALY gained. Results of sensitivity analyses were consistent with the primary outcomes. CONCLUSION: Compared with usual support, LEGO-based therapy produced marginal reduction in costs and improvement in QALYs. Results from both primary and sensitivity analyses suggested that LEGO-based therapy was likely to be cost-effective. TRIAL REGISTRATION NUMBER: ISRCTN64852382.
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Transtorno do Espectro Autista , Adolescente , Transtorno do Espectro Autista/terapia , Criança , Análise Custo-Benefício , Humanos , Resolução de Problemas , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Medicina EstatalRESUMO
BACKGROUND: International societies have recommended that levothyroxine should not routinely be prescribed in older individuals for the management of mild subclinical hypothyroidism (SCH). However, it is unknown whether clinicians managing people with SCH are either aware of or adhere to these guidelines. METHODS: A web-based survey of members of several international thyroid associations and general practitioners in North-East England was conducted. Respondents were presented with a vignette of an 80-year-old gentleman with mild persistent SCH experiencing tiredness. Multivariable logistic regression analyses were performed to evaluate predictors of awareness of guidelines and responses to treatment. RESULTS: The survey response rate was 21.9% (565/2,583). Only 7.6% of clinicians were unaware of guidelines regarding management of SCH in older people. Twenty percent of clinicians stated that they would treat the older patient with mild SCH, whereas 13% were unsure. Clinicians from North America were more likely to treat the older person with mild SCH than clinicians from elsewhere (OR 2.24 [1.25-3.98]). Likewise, non-endocrinologists were also more likely than endocrinologists to treat the older person with mild SCH (OR 3.26 [1.45-6.47]). CONCLUSION: The majority of clinicians are aware of guidelines regarding management of SCH in older individuals. However, a considerable proportion of clinicians would still treat an older person with non-specific symptoms and mild SCH. These guidelines need to be disseminated more widely and more research is required to understand barriers to adherence to international recommendations.
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OBJECTIVE: To determine whether the promoter polymorphism tumor necrosis factor (TNF) (-308) is associated with susceptibility to or death from meningococcal sepsis. DESIGN, SETTING, PATIENTS, AND PARTICIPANTS: Association study involving 1321 patients with microbiologically proven invasive meningococcal disease presenting to hospitals throughout United Kingdom during 1998-2001, among whom 134 died. Controls were derived from 1280 northern English blood donors. MEASUREMENTS: DNA from patients and controls was genotyped at TNF (-308). After analysis, DNA was subsequently genotyped at eight other markers in strong linkage disequilibrium with TNF (-308); these markers were IkappaBL (-62), BAT3, LST1, NOTCH4 (+1297), NOTCH4 (+3061), CCHCR1 (+436), CCHCR1 (+2271), and LTalpha. To confirm functional relevance of TNF (-308) in the context of meningococcal disease, TNF secretion by, and TNF messenger RNA expression of macrophages derived from volunteers with known TNF (-308) genotype after exposure to Neisseria meningitidis were measured. MAIN RESULTS: Among cases of meningococcal disease, likelihood of death was shown to be influenced by the age of the affected individual and also with the infecting serogroup, but was not influenced by genotype at TNF (-308) or the other linked markers. However, patients with meningococcal disease, irrespective of whether they died, were more likely to be homozygous for the rare allele at TNF (-308) (odds ratio = 1.93, 95% confidence interval 1.08-3.46), and less likely to be heterozygous for this marker (odds ratio = 0.79, 95% confidence interval 0.64-0.97), compared with the control cohort. There was no association of susceptibility to disease with the other markers studied. Macrophages derived from volunteers homozygous for the rare allele at TNF (-308) expressed higher levels of TNF messenger RNA and secreted higher concentrations of TNF compared with common homozygotes after exposure to N. meningitidis. CONCLUSIONS: Genotype at TNF (-308) modifies cellular TNF secretion in response to N. meningitidis and may influence susceptibility to meningococcal disease, but does not influence the likelihood of death after infection.
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Predisposição Genética para Doença , Infecções Meningocócicas/genética , Infecções Meningocócicas/mortalidade , Polimorfismo Genético , Sepse/genética , Sepse/mortalidade , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Smoking is a well-documented risk for acute ST-segment elevation myocardial infarction (STEMI). The differential effect between sexes has yet to be quantified. OBJECTIVES: The purpose of this study was to differentiate the effect of smoking on increased risk of STEMI between sexes. METHODS: For this retrospective ecological cohort study, all patients at a U.K. tertiary cardiothoracic center who presented between 2009 and 2014 with acute STEMI were combined with population data to generate incidence rates of STEMI. Age-standardized incidence rate ratios (IRRs) using the Poisson distribution were calculated comparing STEMI rates between smokers and nonsmokers stratified by sex and 3 age groups (18 to 49, 50 to 64, and >65 years). RESULTS: A total of 3,343 patients presented over 5,639,328 person-years. Peak STEMI rate for current smokers was in the 70 to 79 years age range for women (235 per 100,000 patient-years) and 50 to 59 years (425 per 100,000 patient-years) in men. Smoking was associated with a significantly greater increase in STEMI rate for women than men (IRR: 6.62; 95% confidence interval [CI]: 5.98 to 7.31, vs. 4.40; 95% CI: 4.15 to 4.67). The greatest increased risk was in women age 18 to 49 (IRR: 13.22; 95% CI: 10.33 to 16.66, vs. 8.60; 95% CI: 7.70 to 9.59 in men). The greatest risk difference was in the age 50 to 64 years group, with IRR of 9.66 (95% CI: 8.30 to 11.18) in women and 4.47 (95% CI: 4.10 to 4.86) in men. CONCLUSIONS: This study quantifies the differential effect of smoking between sexes, with women having a significantly increased risk of STEMI than men. This information encourages continued efforts to prevent smoking uptake and promote cessation.
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Infarto do Miocárdio com Supradesnível do Segmento ST/epidemiologia , Fumar/efeitos adversos , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/etiologia , Fatores Sexuais , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Primary percutaneous coronary intervention (PPCI) is the default treatment for patients with ST elevation myocardial infarction (STEMI) and carries a higher risk of adverse outcomes when compared with elective and urgent PCI. Conventional PCI risk scores tend to be complex and may underestimate the risk associated with PPCI due to under-representation of patients with STEMI in their datasets. This study aimed to develop a simple, practical and contemporary risk model to provide risk stratification in PPCI. METHODS: Demographic, clinical and outcome data were collected for all patients who underwent PPCI between January 2009 and October 2013 at the Northern General Hospital, Sheffield. Multiple regression analysis was used to identify independent predictors of mortality and to construct a risk model. This model was then separately validated on an internal and external dataset. RESULTS: The derivation cohort included 2870 patients with a 30-day mortality of 5.1% (145 patients). Only four variables were required to predict 30-day mortality: age [OR:1.047, 95% CI:1.031-1.063], call-to-balloon (CTB) time [OR:1.829, 95% CI:1.198-2.791], cardiogenic shock [OR:13.886, 95% CI:8.284-23.275] and congestive heart failure [OR:3.169, 95% CI:1.420-7.072]. Internal validation was performed in 693 patients and external validation in 660 patients undergoing PPCI. Our model showed excellent discrimination on ROC-curve analysis (C-Statâ¯=â¯0.87 internal and 0.86, external), and excellent calibration on Hosmer-Lemeshow testing (pâ¯=â¯0.37 internal, 0.55 external). CONCLUSIONS: We have developed a bedside risk model which can predict 30-day mortality after PPCI using only four variables: age, CTB time, congestive heart failure and shock.
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Técnicas de Apoio para a Decisão , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Fatores Etários , Idoso , Bases de Dados Factuais , Inglaterra , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Choque Cardiogênico/mortalidade , Choque Cardiogênico/fisiopatologia , Fatores de Tempo , Tempo para o Tratamento , Resultado do TratamentoRESUMO
INTRODUCTION: Social skills training interventions for children with autism spectrum disorder (ASD) typically focus on a skills deficit model rather than building on existing skills or encouraging the child to seek their own solutions. LEGO-based therapy is a child-oriented intervention to help improve social interactional skills and reduce isolation. The therapy is designed for school-age children with ASD and uses group-based play in a school setting to encourage peer relationships and social learning. Despite the reported potential benefits of LEGO-based therapy in a prior randomised controlled trial (RCT) and its adoption by many schools, the evidence to support its effectiveness on the social and emotional well-being of children with ASD is limited and includes no assessment of cost-effectiveness. METHODS AND ANALYSIS: This multicentre, pragmatic, cluster RCT will randomise 240 participants (aged 7-15 years) with a clinical diagnosis of ASD to receive usual care or LEGO-based therapy with usual care. Cluster randomisation will be conducted on a school level, randomising each school as opposed to each individual child within a school. All prospective participants will be screened for eligibility before assenting to the study (with parents giving informed consent on behalf of their child). All participants will be followed up at 20 and 52 weeks after randomisation to assess for social, emotional and behavioural changes. The primary outcome measure is the social skills subscale of the Social Skills Improvement System completed by a teacher or teaching assistant associated with participating children at the 20-week follow-up time point. ETHICS AND DISSEMINATION: Ethics approval has been obtained via the University of York Research Ethics Committee. The results of the trial will be submitted for publication in a peer-reviewed journal and will be disseminated to participating families, education practitioners and the third sector including voluntary and community organisations. TRIAL REGISTRATION NUMBER: ISRCTN64852382; Pre-results.