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BACKGROUND: Tonsillectomy is regularly performed in adults with acute tonsillitis, but with scarce evidence. A reduction in tonsillectomies has coincided with an increase in acute adult hospitalisation for tonsillitis complications. We aimed to assess the clinical effectiveness and cost-effectiveness of conservative management versus tonsillectomy in patients with recurrent acute tonsillitis. METHODS: This pragmatic multicentre, open-label, randomised controlled trial was conducted in 27 hospitals in the UK. Participants were adults aged 16 years or older who were newly referred to secondary care otolaryngology clinics with recurrent acute tonsillitis. Patients were randomly assigned (1:1) to receive tonsillectomy or conservative management using random permuted blocks of variable length. Stratification by recruiting centre and baseline symptom severity was assessed using the Tonsil Outcome Inventory-14 score (categories defined as mild 0-35, moderate 36-48, or severe 49-70). Participants in the tonsillectomy group received elective surgery to dissect the palatine tonsils within 8 weeks after random assignment and those in the conservative management group received standard non-surgical care during 24 months. The primary outcome was the number of sore throat days collected during 24 months after random assignment, reported once per week with a text message. The primary analysis was done in the intention-to-treat (ITT) population. This study is registered with the ISRCTN registry, 55284102. FINDINGS: Between May 11, 2015, and April 30, 2018, 4165 participants with recurrent acute tonsillitis were assessed for eligibility and 3712 were excluded. 453 eligible participants were randomly assigned (233 in the immediate tonsillectomy group vs 220 in the conservative management group). 429 (95%) patients were included in the primary ITT analysis (224 vs 205). The median age of participants was 23 years (IQR 19-30), with 355 (78%) females and 97 (21%) males. Most participants were White (407 [90%]). Participants in the immediate tonsillectomy group had fewer days of sore throat during 24 months than those in the conservative management group (median 23 days [IQR 11-46] vs 30 days [14-65]). After adjustment for site and baseline severity, the incident rate ratio of total sore throat days in the immediate tonsillectomy group (n=224) compared with the conservative management group (n=205) was 0·53 (95% CI 0·43 to 0·65; <0·0001). 191 adverse events in 90 (39%) of 231 participants were deemed related to tonsillectomy. The most common adverse event was bleeding (54 events in 44 [19%] participants). No deaths occurred during the study. INTERPRETATION: Compared with conservative management, immediate tonsillectomy is clinically effective and cost-effective in adults with recurrent acute tonsillitis. FUNDING: National Institute for Health Research.
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Faringitis , Trastornos Respiratorios , Tonsilectomía , Tonsilitis , Masculino , Femenino , Humanos , Adulto , Adulto Joven , Tonsilectomía/efectos adversos , Tratamiento Conservador , Tonsilitis/cirugía , Tonsilitis/complicaciones , Faringitis/etiología , Dolor/etiología , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Emergency abdominal surgery is associated with significant postoperative morbidity and mortality. The delivery of standardized pathways in this setting may have the potential to transform clinical care and improve patient outcomes. METHODS: The OVID SP versions of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched between January 1950 and October 2022. All randomized and non-randomized cohort studies comparing protocolized care streams with standard care protocols in adult patients (>18 years old) undergoing major emergency abdominal surgery with 30-day follow-up data were included. Studies were excluded if they reported on standardized care protocols in the trauma or elective setting. Outcomes assessed included length of stay, 30-day postoperative morbidity, 30-day postoperative mortality and 30-day readmission and reoperations rates. Risk of bias was assessed using ROBINS-I for non-randomized studies and RoB-2 for randomized controlled trials. Meta-analysis was performed using random effects modelling. RESULTS: Seventeen studies including 20 927 patients were identified, with 12 359 patients undergoing protocolized care pathways and 8568 patients undergoing standard care pathways. Thirteen unique protocolized pathways were identified, with a median of eight components (range 6-15), with compliance of 24-100%. Protocolized care pathways were associated with a shorter hospital stay compared to standard care pathways (mean difference -2.47, 95% c.i. -4.01 to -0.93, P = 0.002). Protocolized care pathways had no impact on postoperative mortality (OR 0.87, 95% c.i. 0.41 to 1.87, P = 0.72). A reduction in specific postoperative complications was observed, including postoperative pneumonia (OR 0.42 95% c.i. 0.24 to 0.73, P = 0.002) and surgical site infection (OR 0.34, 95% c.i. 0.21 to 0.55, P < 0.001). DISCUSSION: Protocolized care pathways in the emergency setting currently lack standardization, with variable components and low compliance; however, despite this they are associated with short-term clinical benefits.
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Tratamiento de Urgencia , Complicaciones Posoperatorias , Humanos , Abdomen/cirugía , Protocolos Clínicos , Vías Clínicas , Tiempo de Internación , Readmisión del Paciente/estadística & datos numéricos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Tratamiento de Urgencia/efectos adversosRESUMEN
BACKGROUND: The contribution of the statistician to the design and analysis of a clinical trial is acknowledged as essential. Ability to reconstruct the statistical contribution to a trial requires rigorous and transparent documentation as evidenced by the reproducibility of results. The process of validating statistical programmes is a key requirement. While guidance relating to software development and life cycle methodologies details steps for validation by information systems developers, there is no guidance applicable to programmes written by statisticians. We aimed to develop a risk-based approach to the validation of statistical programming that would support scientific integrity and efficient resource use within clinical trials units. METHODS: The project was embedded within the Information Systems Operational Group and the Statistics Operational Group of the UK Clinical Research Collaboration Registered Clinical Trials Unit network. Members were asked to share materials relevant to validation of statistical programming. A review of the published literature, regulatory guidance and knowledge of relevant working groups was undertaken. Surveys targeting the Information Systems Operational Group and Statistics Operational Group were developed to determine current practices across the Registered Clinical Trials Unit network. A risk-based approach was drafted and used as a basis for a workshop with representation from statisticians, information systems developers and quality assurance managers (n = 15). The approach was subsequently modified and presented at a second, larger scale workshop (n = 47) to gain a wider perspective, with discussion of content and implications for delivery. The approach was revised based on the discussions and suggestions made. The workshop was attended by a member of the Medicines for Healthcare products Regulatory Agency Inspectorate who also provided comments on the revised draft. RESULTS: Types of statistical programming were identified and categorised into six areas: generation of randomisation lists; programmes to explore/understand the data; data cleaning, including complex checks; derivations including data transformations; data monitoring; or interim and final analysis. The risk-based approach considers each category of statistical programme against the impact of an error and its likelihood, whether the programming can be fully prespecified, the need for repeated use and the need for reproducibility. Approaches to the validation of programming within each category are proposed. CONCLUSION: We have developed a risk-based approach to the validation of statistical programming. It endeavours to facilitate the implementation of targeted quality assurance measures while making efficient use of limited resources.
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Ensayos Clínicos como Asunto , Humanos , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Cervical radiculopathy occurs when a nerve root is compressed in the spine, if symptoms fail to resolve after 6 weeks surgery may be indicated. Anterior Cervical Discectomy (ACD) is the commonest procedure, Posterior Cervical Foraminotomy (PCF) is an alternative that avoids the risk of damage to anterior neck structures. This prospective, Phase III, UK multicentre, open, individually randomised controlled trial was performed to determine whether PCF is superior to ACD in terms of improving clinical outcome as measured by the Neck Disability Index (NDI) 52 weeks post-surgery. METHOD: Following consent to participate and collection of baseline data, subjects with cervical brachialgia were randomised to ACD or PCF in a 1:1 ratio on the day of surgery. Clinical outcomes were assessed on day 1 and patient reported outcomes on day 1 and weeks 6, 12, 26, 39 and 52 post-operation. A total of 252 participants were planned to be randomised. Statistical analysis was limited to descriptive statistics. Health economic outcomes were also described. RESULTS: The trial was closed early (n = 23). Compared to baseline, the median (interquartile range (IQR)) NDI score at 52 weeks reduced from 44.0 (36.0, 62.0) to 25.3 (20.0, 42.0) in the PCF group and increased from 35.6 (34.0, 44.0) to 45.0 (20.0, 57.0) in the ACD group. ACD may be associated with more swallowing, voice and other complications and was more expensive; neck and arm pain scores were similar. CONCLUSIONS: The trial was closed early, therefore no definitive conclusions on clinical or cost-effectiveness could be made.
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Foraminotomía , Radiculopatía , Fusión Vertebral , Humanos , Foraminotomía/métodos , Resultado del Tratamiento , Análisis Costo-Beneficio , Estudios Prospectivos , Vértebras Cervicales/cirugía , Fusión Vertebral/métodos , Discectomía/efectos adversos , Discectomía/métodos , Radiculopatía/cirugíaRESUMEN
BACKGROUND: Cervical foraminal stenosis on MRI may be assessed using the Kim, modified Kim or Siller methods. This study aimed to investigate which morphological features of cervical foraminal stenosis in patients with cervical radiculopathy correlated best with pre-operative and post-operative surgical outcome following Anterior Cervical Discectomy (ACD) or a Posterior Cervical Foraminotomy (PCF). METHODS: Pre-operative MRIs of adults with cervical radiculopathy were assessed by six raters. The following measurements were made; uncompressed nerve root diameter, maximal compressed nerve root diameter, anterior & posterior compression, length of the neuroforaminal canal where the diameter was less than the uncompressed nerve root diameter and the distance of maximum compression from the apex of the ligamentum flavum. The Kim, modified Kim and Siller grades were calculated. Neck Disability Index (NDI) was measured pre-operatively and six weeks post-operatively. The radiological measurements and grades were compared to the pre-operative and change in NDI. RESULTS: Mean NDI was higher in female (58.2) than male patients (45.6) p = 0.05. No other baseline, operative or radiological factors where significantly associated with the pre-operative NDI. The mean [±SD] post-operative NDI was 14.3 [±22.5]. This represents a change of 37.8 (p < 0.001). The pre-operative NDI correlated strongly with the post-operative NDI but no other patient, operation or radiological factors correlated significantly. Neither pre-operative NDI or change in NDI was statistically different in those treated with ACD and those treated with PCF. CONCLUSION: There was no association between pre-operative NDI and any of the radiological measurements or radiological grades. Furthermore, whilst surgery significantly improved NDI, for those patients with anterior compression, there was no difference in outcome between those treated with an ACD and those treated with a PCF. Current axial MRIs do not adequately assess the cervical nerve root foramina or predict surgical approach, 3D isotropic acquisition and DTI should be explored.
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BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is characterized by blunting of the positive relationship between heart rate and left ventricular (LV) contractility known as the force-frequency relationship (FFR). We have previously described that tailoring the rate-response programming of cardiac implantable electronic devices in patients with HFrEF on the basis of individual noninvasive FFR data acutely improves exercise capacity. We aimed to examine whether using FFR data to tailor heart rate response in patients with HFrEF with cardiac implantable electronic devices favorably influences exercise capacity and LV function 6 months later. METHODS: We conducted a single-center, double-blind, randomized, parallel-group trial in patients with stable symptomatic HFrEF taking optimal guideline-directed medical therapy and with a cardiac implantable electronic device (cardiac resynchronization therapy or implantable cardioverter-defibrillator). Participants were randomized on a 1:1 basis between tailored rate-response programming on the basis of individual FFR data and conventional age-guided rate-response programming. The primary outcome measure was change in walk time on a treadmill walk test. Secondary outcomes included changes in LV systolic function, peak oxygen consumption, and quality of life. RESULTS: We randomized 83 patients with a mean±SD age 74.6±8.7 years and LV ejection fraction 35.2±10.5. Mean change in exercise time at 6 months was 75.4 (95% CI, 23.4 to 127.5) seconds for FFR-guided rate-adaptive pacing and 3.1 (95% CI, -44.1 to 50.3) seconds for conventional settings (analysis of covariance; P=0.044 between groups) despite lower peak mean±SD heart rates (98.6±19.4 versus 112.0±20.3 beats per minute). FFR-guided heart rate settings had no adverse effect on LV structure or function, whereas conventional settings were associated with a reduction in LV ejection fraction. CONCLUSIONS: In this phase II study, FFR-guided rate-response programming determined using a reproducible, noninvasive method appears to improve exercise time and limit changes to LV function in people with HFrEF and cardiac implantable electronic devices. Work is ongoing to confirm our findings in a multicenter setting and on longer-term clinical outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02964650.
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Dispositivos de Terapia de Resincronización Cardíaca , Terapia de Resincronización Cardíaca , Desfibriladores Implantables , Cardioversión Eléctrica/instrumentación , Tolerancia al Ejercicio , Insuficiencia Cardíaca/terapia , Frecuencia Cardíaca , Volumen Sistólico , Función Ventricular Izquierda , Anciano , Anciano de 80 o más Años , Terapia de Resincronización Cardíaca/efectos adversos , Método Doble Ciego , Cardioversión Eléctrica/efectos adversos , Inglaterra , Femenino , Estado Funcional , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Recuperación de la Función , Factores de Tiempo , Resultado del Tratamiento , Prueba de PasoRESUMEN
The study design of this paper is systematic review. The purpose of this review is to evaluate the existing radiological grading systems that are used to assess cervical foraminal stenosis. The importance of imaging the cervical spine using CT or MRI in evaluating cervical foraminal stenosis is widely accepted; however, there is no consensus for standardized methodology to assess the compression of the cervical nerve roots. A systematic search of Ovid Medline databases, Embase 1947 to present, Cinahl, Web of Science, Cochrane Library, ISRCTN and WHO international clinical trials was performed for reports of cervical foraminal stenosis published before 01 February 2020. In collaboration with the University of Leeds, a search strategy was developed. A total of 6952 articles were identified with 59 included. Most of the reports involved multiple imaging modalities with standard axial and sagittal imaging used most. The grading themes that came from this systematic review show that the most mature for cervical foraminal stenosis is described by (Kim et al. Korean J Radiol 16:1294, 2015) and (Park et al. Br J Radiol 86:20120515, 2013). Imaging of the cervical nerve root canals is mostly performed using MRI and is reported using subjective terminology. The Park, Kim and Modified Kim systems for classifying the degree of stenosis of the nerve root canal have been described. Clinical application of these scoring systems is limited by their reliance on nonstandard imaging (Park), limited validation against clinical symptoms and surgical outcome data. Oblique fine cut images derived from three dimensional MRI datasets may yield more consistency, better clinical correlation, enhanced surgical decision-making and outcomes.
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Radiculopatía , Estenosis Espinal , Vértebras Cervicales/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Radiculopatía/diagnóstico por imagen , Radiografía , Raíces Nerviosas Espinales , Estenosis Espinal/diagnóstico por imagenRESUMEN
Importance: Thyroid hormones play a key role in modulating myocardial contractility. Subclinical hypothyroidism in patients with acute myocardial infarction is associated with poor prognosis. Objective: To evaluate the effect of levothyroxine treatment on left ventricular function in patients with acute myocardial infarction and subclinical hypothyroidism. Design, Setting, and Participants: A double-blind, randomized clinical trial conducted in 6 hospitals in the United Kingdom. Patients with acute myocardial infarction including ST-segment elevation and non-ST-segment elevation were recruited between February 2015 and December 2016, with the last participant being followed up in December 2017. Interventions: Levothyroxine treatment (n = 46) commencing at 25 µg titrated to aim for serum thyrotropin levels between 0.4 and 2.5 mU/L or identical placebo (n = 49), both provided in capsule form, once daily for 52 weeks. Main Outcomes and Measures: The primary outcome measure was left ventricular ejection fraction at 52 weeks, assessed by magnetic resonance imaging, adjusted for age, sex, type of acute myocardial infarction, affected coronary artery territory, and baseline left ventricular ejection fraction. Secondary measures were left ventricular volumes, infarct size (assessed in a subgroup [n = 60]), adverse events, and patient-reported outcome measures of health status, health-related quality of life, and depression. Results: Among the 95 participants randomized, the mean (SD) age was 63.5 (9.5) years, 72 (76.6%) were men, and 65 (69.1%) had ST-segment elevation myocardial infarction. The median serum thyrotropin level was 5.7 mU/L (interquartile range, 4.8-7.3 mU/L) and the mean (SD) free thyroxine level was 1.14 (0.16) ng/dL. The primary outcome measurements at 52 weeks were available in 85 patients (89.5%). The mean left ventricular ejection fraction at baseline and at 52 weeks was 51.3% and 53.8%, respectively, in the levothyroxine group compared with 54.0% and 56.1%, respectively, in the placebo group (adjusted difference in groups, 0.76% [95% CI, -0.93% to 2.46%]; P = .37). None of the 6 secondary outcomes showed a significant difference between the levothyroxine and placebo treatment groups. There were 15 (33.3%) and 18 (36.7%) cardiovascular adverse events in the levothyroxine and placebo groups, respectively. Conclusions and Relevance: In this preliminary study involving patients with subclinical hypothyroidism and acute myocardial infarction, treatment with levothyroxine, compared with placebo, did not significantly improve left ventricular ejection fraction after 52 weeks. These findings do not support treatment of subclinical hypothyroidism in patients with acute myocardial infarction. Trial Registration: isrctn.org Identifier: http://www.isrctn.com/ISRCTN52505169.
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Hipotiroidismo/complicaciones , Infarto del Miocardio sin Elevación del ST/complicaciones , Infarto del Miocardio con Elevación del ST/complicaciones , Volumen Sistólico/efectos de los fármacos , Tiroxina/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Depresión , Método Doble Ciego , Femenino , Estado de Salud , Humanos , Hipotiroidismo/sangre , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/fisiopatología , Masculino , Persona de Mediana Edad , Infarto del Miocardio sin Elevación del ST/patología , Infarto del Miocardio sin Elevación del ST/fisiopatología , Medición de Resultados Informados por el Paciente , Calidad de Vida , Infarto del Miocardio con Elevación del ST/patología , Infarto del Miocardio con Elevación del ST/fisiopatología , Tamaño de la Muestra , Tirotropina/sangre , Tiroxina/efectos adversos , Factores de Tiempo , Reino UnidoRESUMEN
BACKGROUND: Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer. METHODS: This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13. FINDINGS: Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37-60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6-59·1) in the capecitabine group compared with 36·4 months (29·7-44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55-0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0·75, 95% CI 0·58-0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6-35·9) in the capecitabine group and 17·5 months (12·0-23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8-46·3) in the capecitabine group and 17·4 months (12·0-23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related. INTERPRETATION: Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting. FUNDING: Cancer Research UK and Roche.
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Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias del Sistema Biliar/terapia , Procedimientos Quirúrgicos del Sistema Biliar , Capecitabina/administración & dosificación , Espera Vigilante , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Neoplasias del Sistema Biliar/mortalidad , Neoplasias del Sistema Biliar/patología , Procedimientos Quirúrgicos del Sistema Biliar/efectos adversos , Procedimientos Quirúrgicos del Sistema Biliar/mortalidad , Capecitabina/efectos adversos , Quimioterapia Adyuvante , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Supervivencia sin Progresión , Factores de Tiempo , Reino UnidoRESUMEN
Patient reporting suggests that the physical and psychological effects of autoimmune hepatitis (AIH) can be substantial. However, health-related quality of life (HRQOL) in patients with AIH remains incompletely characterized, and health utility remains to be explored. Treatment for AIH often includes the use of corticosteroids, which are agents that can be associated with significant adverse effects. Here we explore the impact of AIH and its treatments on patient-reported HRQOL and health utility in a large cohort of prevalent cases from the United Kingdom Autoimmune Hepatitis (UK-AIH) national study. Data were collected from 990 adult participants with a clinical diagnosis of AIH using validated HRQOL tools including the European Quality-of-Life 5-Dimension 5-Level (EQ-5D-5L) and clinical data forms. The EQ-5D-5L dimension scores were compared with UK population norms and with a disease control cohort with primary biliary cholangitis (PBC). Within the AIH cohort, regression analysis was used to explore associations between HRQOL and demographic and clinical variables with a particular focus on the impact of AIH therapies including corticosteroid use. HRQOL, measured by the EQ-5D-5L utility index, is shown to be significantly impaired in our cohort of AIH patients compared with population norms. Within the AIH cohort, corticosteroid use was found to be significantly associated with impaired HRQOL, even when controlling for biochemical disease activity status. CONCLUSION: Our data show evidence of HRQOL impairment in a large cohort of AIH patients compared with the general population. Furthermore, corticosteroid use is strongly associated with decreased HRQOL, independent of remission status. This highlights the need for better corticosteroid-free therapy approaches and it emphasizes the need for future novel therapeutic trials in AIH. (Hepatology 2018; 00:000-000).
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Corticoesteroides/uso terapéutico , Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/psicología , Calidad de Vida , Adulto , Anciano , Estudios Transversales , Femenino , Hepatitis Autoinmune/diagnóstico , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Valores de Referencia , Análisis de Regresión , Medición de Riesgo , Perfil de Impacto de Enfermedad , Resultado del Tratamiento , Reino Unido , Adulto JovenRESUMEN
BACKGROUND: Clinicians have recognised the role of narrow band imaging (NBI) in the management of head and neck cancer in several studies. However, a recent systematic review was unable to pool the data on diagnostic efficacy in this setting owing to the heterogeneity in the published data. METHODS: Secondary analysis of data, utilising Bayes' theorem, from meta-analyses and randomised trials. RESULTS: In patients with a histological diagnosis of mild dysplasia who show no abnormalities on NBI, the post-test probability of malignancy is estimated to be 2.3%, compared to 10.3% with conventional white light imaging (WLI). For severe dysplasia, similar post-test probabilities after NBI and WLI are estimated to be 8.0% and 29.7%, respectively. Post-test probabilities in this setting indicate the chance of missing malignancy following a negative NBI or WLI in patients who undergo no further intervention. This study also provides a nomogram designed for use in this setting. CONCLUSIONS: This study identifies the evidence base for use of NBI in the follow-up for laryngeal dysplasia.
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Enfermedades de la Laringe/diagnóstico , Laringe/diagnóstico por imagen , Imagen de Banda Estrecha/métodos , Estudios de Seguimiento , Humanos , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis. METHODS: This multicentre, double-blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1·8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119. FINDINGS: Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4·3 [95% CI 1·0-17·7]; p=0·019). Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1-1·0]; p=0·04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhoea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]). INTERPRETATION: Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies. FUNDING: Wellcome Trust, National Institute of Health Research, and Novo Nordisk.
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Incretinas/administración & dosificación , Liraglutida/administración & dosificación , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Adolescente , Adulto , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Femenino , Humanos , Incretinas/efectos adversos , Inyecciones Subcutáneas , Liraglutida/efectos adversos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Resultado del Tratamiento , Adulto JovenRESUMEN
Importance: While guidance on statistical principles for clinical trials exists, there is an absence of guidance covering the required content of statistical analysis plans (SAPs) to support transparency and reproducibility. Objective: To develop recommendations for a minimum set of items that should be addressed in SAPs for clinical trials, developed with input from statisticians, previous guideline authors, journal editors, regulators, and funders. Design: Funders and regulators (n = 39) of randomized trials were contacted and the literature was searched to identify existing guidance; a survey of current practice was conducted across the network of UK Clinical Research Collaboration-registered trial units (n = 46, 1 unit had 2 responders) and a Delphi survey (n = 73 invited participants) was conducted to establish consensus on SAPs. The Delphi survey was sent to statisticians in trial units who completed the survey of current practice (n = 46), CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guideline authors (n = 16), pharmaceutical industry statisticians (n = 3), journal editors (n = 9), and regulators (n = 2) (3 participants were included in 2 groups each), culminating in a consensus meeting attended by experts (N = 12) with representatives from each group. The guidance subsequently underwent critical review by statisticians from the surveyed trial units and members of the expert panel of the consensus meeting (N = 51), followed by piloting of the guidance document in the SAPs of 5 trials. Findings: No existing guidance was identified. The registered trials unit survey (46 responses) highlighted diversity in current practice and confirmed support for developing guidance. The Delphi survey (54 of 73, 74% participants completing both rounds) reached consensus on 42% (n = 46) of 110 items. The expert panel (N = 12) agreed that 63 items should be included in the guidance, with an additional 17 items identified as important but may be referenced elsewhere. Following critical review and piloting, some overlapping items were combined, leaving 55 items. Conclusions and Relevance: Recommendations are provided for a minimum set of items that should be addressed and included in SAPs for clinical trials. Trial registration, protocols, and statistical analysis plans are critically important in ensuring appropriate reporting of clinical trials.
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Ensayos Clínicos como Asunto/normas , Interpretación Estadística de Datos , Estadística como Asunto/normas , Técnica DelphiRESUMEN
BACKGROUND: Innovations Project (IP) was a new multidisciplinary team based within an inner city, walk-in health centre, North East England (throughout 2011). The aim was to describe the social and mental disorders of the hard to reach young people (HTRYP) from the IP and compare with a matched sample who attended a Community Mental Health Team (CMHT) and follow-up both samples 24 months after discharge. METHODS: A retrospective review of clinical case notes of YP who attended the IP and CMHT. A 24-month (postdischarge) follow-up evaluation of the mental state and social function of the YP in both groups using Health of the Nation Outcome Scales for Child and Adolescent Mental Health (HoNOSCA) and Children's Global Assessment Scale (CGAS). RESULTS: Thirty-six referrals were accepted over a one-year period by the IP, 31 met criteria for the HTRYP, 15 were offered individually tailored therapy. The HTRYP who were more deprived compared to the CMHT matched sample (n = 115), experienced a higher median number of mental disorders (n = 3 compared to CMHT n = 1), higher severity scores and lower levels of social function (HTRYP HoNOSCA mean: 19.1 (95% CI 15.9-22.2) and CMHT mean: 11.2 (95% CI 2.0-23.0) p = <.001, and HTRYP CGAS mean: 51.0 (95% CI 46.0-56.2) and CMHT mean: 58.9 (95% CI 52.9-64.8), p = .05). The HTRYP made significantly greater improvement compared to CMHTYP; (HoNOSCA p = <.001 and CGAS p = <.002) at discharge. A total of 13 HTRYP and 9 CMHT YP attended the follow-up review at 24 months. There was substantial variability in terms of social function between the YP within each sample. CONCLUSIONS: The term 'HTR' describes a state that may be often temporary, as opposed to lifelong. A bespoke service offering a developmental theoretical framework, regular reviews and an individualised care plan, was able to engage and had the potential to reduce morbidity suffered by HTRYP.
RESUMEN
BACKGROUND: Poor cooking skills may be a barrier to healthy eating and a contributor to overweight and obesity. Little population-representative data on adult cooking skills has been published. We explored prevalence and socio-demographic correlates of cooking skills among adult respondents to wave 1 of the UK National Diet and Nutrition Survey (2008-9). METHODS: Socio-demographic variables of interest were sex, age group, occupational socio-economic group and whether or not respondents had the main responsibility for food in their households. Cooking skills were assessed as self-reported confidence in using eight cooking techniques, confidence in cooking ten foods, and ability to prepare four types of dish (convenience foods, a complete meal from ready-made ingredients, a main meal from basic ingredients, and cake or biscuits from basic ingredients). Frequency of preparation of main meals was also reported. RESULTS: Of 509 respondents, almost two-thirds reported cooking a main meal at least five times per week. Around 90 % reported being able to cook convenience foods, a complete meal from ready-made ingredient, and a main dish from basic ingredients without help. Socio-demographic differences in all markers of cooking skills were scattered and inconsistent. Where these were found, women and main food providers were most likely to report confidence with foods, techniques or dishes, and respondents in the youngest age (19-34 years) and lowest socio-economic group least likely. CONCLUSIONS: This is the only exploration of the prevalence and socio-demographic correlates of adult cooking skills using recent and population-representative UK data and adds to the international literature on cooking skills in developed countries. Reported confidence with using most cooking techniques and preparing most foods was high. There were few socio-demographic differences in reported cooking skills. Adult cooking skills interventions are unlikely to have a large population impact, but may have important individual effects if clearly targeted at: men, younger adults, and those in the least affluent social groups.
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Culinaria , Dieta , Conducta Alimentaria , Obesidad , Autoeficacia , Adulto , Anciano , Estudios Transversales , Dieta/normas , Composición Familiar , Comida Rápida , Femenino , Humanos , Masculino , Comidas , Persona de Mediana Edad , Encuestas Nutricionales , Obesidad/etiología , Obesidad/prevención & control , Prevalencia , Encuestas y Cuestionarios , Reino Unido , Adulto JovenRESUMEN
OBJECTIVE: The aim of the knee arthroplasty versus joint distraction (KARDS) randomised trial was to investigate whether knee joint distraction (KJD) is non-inferior to knee arthroplasty, also known as knee replacement (KR). Here we report the findings from qualitative interviews that were part of the planned KARDS process evaluation. DESIGN AND METHODS: Semi-structured qualitative interviews with staff and participants in secondary care. Data were analysed using thematic content analysis. FINDINGS: We were unable to complete the full-planned KARDS process evaluation as recruitment to the trial was closed early but key common themes emerged.Eleven members of staff were interviewed from two KARDS sites (eight initial interviews just after site opening and three follow-up interviews at 12 months). Eleven KARDS participants (six KR and five KJD) were interviewed. One overarching theme emerged: 'An unexpected journey'. This incorporated subthemes including 'an important research question', 'a roller coaster ride', 'lessons learnt', 'managing expectations' and 'a slow recovery'. These encapsulate experiences of both staff and participants. CONCLUSION: The information that we were able to collect highlights that providing adequate and comprehensive information about all aspects of treatment including estimated timelines of recovery are essential in clinical trials of novel interventions. Incorporating a comprehensive rehabilitation package following KJD was a key learning. Process evaluations in these complex trials are essential to determine issues as early as possible so appropriate changes can be made to ensure participants have a smooth journey through the trial experience. TRIAL REGISTRATION NUMBER: ISRCTN14879004.
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Artroplastia de Reemplazo de Rodilla , Entrevistas como Asunto , Investigación Cualitativa , Humanos , Artroplastia de Reemplazo de Rodilla/psicología , Artroplastia de Reemplazo de Rodilla/rehabilitación , Femenino , Masculino , Persona de Mediana Edad , Articulación de la Rodilla/cirugía , Anciano , Osteoartritis de la Rodilla/cirugía , Personal de Salud/psicología , Actitud del Personal de SaludRESUMEN
BACKGROUND: Statisticians are fundamental in ensuring clinical research, including clinical trials, are conducted with quality, transparency, reproducibility and integrity. Good Clinical Practice (GCP) is an international quality standard for the conduct of clinical trials research. Statisticians are required to undertake training on GCP but existing training is generic and, crucially, does not cover statistical activities. This results in statisticians undertaking training mostly unrelated to their role and variation in awareness and implementation of relevant regulatory requirements with regards to statistical conduct. The need for role-relevant training is recognised by the UK NHS Health Research Authority and the Medicines and Healthcare products Regulatory Agency (MHRA). METHODS: The Good Statistical Practice (GCP for Statisticians) project was instigated by the UK Clinical Research Collaboration (UKCRC) Registered Clinical Trials Unit (CTU) Statisticians Operational Group and funded by the National Institute for Health and Care Research (NIHR), to develop materials to enable role-specific GCP training tailored to statisticians. Review of current GCP training was undertaken by survey. Development of training materials were based on MHRA GCP. Critical review and piloting was conducted with UKCRC CTU and NIHR researchers with comment from MHRA. Final review was conducted through the UKCRC CTU Statistics group. RESULTS: The survey confirmed the need and desire for the development of dedicated GCP training for statisticians. An accessible, comprehensive, piloted training package was developed tailored to statisticians working in clinical research, particularly the clinical trials arena. The training materials cover legislation and guidance for best practice across all clinical trial processes with statistical involvement, including exercises and real-life scenarios to bridge the gap between theory and practice. Comprehensive feedback was incorporated. The training materials are freely available for national and international adoption. CONCLUSION: All research staff should have training in GCP yet the training undertaken by most academic statisticians does not cover activities related to their role. The Good Statistical Practice (GCP for Statisticians) project has developed and extensively piloted new, role-specific, comprehensive, accessible GCP training tailored to statisticians working in clinical research, particularly the clinical trials arena. This role-specific training will encourage best practice, leading to transparent and reproducible statistical activity, as required by regulatory authorities and funders.
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Ensayos Clínicos como Asunto , Estadística como Asunto , Humanos , Reproducibilidad de los Resultados , Estadística como Asunto/normasRESUMEN
Ensuring diagnostic performance of artificial intelligence (AI) before introduction into clinical practice is essential. Growing numbers of studies using AI for digital pathology have been reported over recent years. The aim of this work is to examine the diagnostic accuracy of AI in digital pathology images for any disease. This systematic review and meta-analysis included diagnostic accuracy studies using any type of AI applied to whole slide images (WSIs) for any disease. The reference standard was diagnosis by histopathological assessment and/or immunohistochemistry. Searches were conducted in PubMed, EMBASE and CENTRAL in June 2022. Risk of bias and concerns of applicability were assessed using the QUADAS-2 tool. Data extraction was conducted by two investigators and meta-analysis was performed using a bivariate random effects model, with additional subgroup analyses also performed. Of 2976 identified studies, 100 were included in the review and 48 in the meta-analysis. Studies were from a range of countries, including over 152,000 whole slide images (WSIs), representing many diseases. These studies reported a mean sensitivity of 96.3% (CI 94.1-97.7) and mean specificity of 93.3% (CI 90.5-95.4). There was heterogeneity in study design and 99% of studies identified for inclusion had at least one area at high or unclear risk of bias or applicability concerns. Details on selection of cases, division of model development and validation data and raw performance data were frequently ambiguous or missing. AI is reported as having high diagnostic accuracy in the reported areas but requires more rigorous evaluation of its performance.