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BACKGROUND: In the United Kingdom (UK), cancer screening invitations are based on general practice (GP) registrations. We hypothesize that GP electronic medical records (EMR) can be utilised to calculate a lung cancer risk score with good accuracy/clinical utility. METHODS: The development cohort was Secure Anonymised Information Linkage-SAIL (2.3 million GP EMR) and the validation cohort was UK Biobank-UKB (N = 211,597 with GP-EMR availability). Fast backward method was applied for variable selection and area under the curve (AUC) evaluated discrimination. RESULTS: Age 55-75 were included (SAIL: N = 574,196; UKB: N = 137,918). Six-year lung cancer incidence was 1.1% (6430) in SAIL and 0.48% (656) in UKB. The final model included 17/56 variables in SAIL for the EMR-derived score: age, sex, socioeconomic status, smoking status, family history, body mass index (BMI), BMI:smoking interaction, alcohol misuse, chronic obstructive pulmonary disease, coronary heart disease, dementia, hypertension, painful condition, stroke, peripheral vascular disease and history of previous cancer and previous pneumonia. The GP-EMR-derived score had AUC of 80.4% in SAIL and 74.4% in UKB and outperformed ever-smoked criteria (currently the first step in UK lung cancer screening pilots). DISCUSSION: A GP-EMR-derived score may have a role in UK lung cancer screening by accurately targeting high-risk individuals without requiring patient contact.
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Medicina General , Neoplasias Pulmonares , Humanos , Persona de Mediana Edad , Anciano , Registros Electrónicos de Salud , Detección Precoz del Cáncer , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Factores de Riesgo , Medición de RiesgoRESUMEN
BACKGROUND: Systemic corticosteroids have been widely used for treating patients with severe acute respiratory distress syndrome. Inhaled corticosteroids may have a protective effect for treating acute coronavirus disease 2019 (COVID-19); however, little is known about the potential effect of intranasal corticosteroids (INCS) on COVID-19 outcomes and severity. OBJECTIVE: To assess the impact of prior long-term INCS exposure on COVID-19 mortality among patients with chronic respiratory disease and in the general population. METHODS: A retrospective cohort study was conducted. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between INCS exposure and all-cause and COVID-19 mortality, adjusted by age, sex, deprivation, exacerbations in the last year, and comorbidities. RESULTS: Exposure to INCS did not have a significant association with COVID-19 mortality among the general population or cohorts with chronic obstructive pulmonary disease or asthma, with HRs of 0.8 (95% CI, 0.6-1.0, P = .06), 0.6 (95% CI, 0.3-1.1, P = .1), and 0.9 (95% CI, 0.2-3.9, P = .9), respectively. Exposure to INCS was, however, significantly associated with reduction in all-cause mortality in all groups, which was 40% lower (HR, 0.6 [95% CI, 0.5-0.6, P < .001]) among the general population, 30% lower (HR, 0.7; 95% CI, 0.6-0.8, P < .001) among patients with chronic obstructive pulmonary disease, and 50% lower (HR, 0.5; 95% CI, 0.3-0.7, P = .003) among patients with asthma. CONCLUSION: The role of INCS in COVID-19 is still unclear, but exposure to INCS does not adversely affect COVID-19 mortality. Further studies are needed to explore the association between their use and inflammatory activation, viral load, angiotensin-converting enzyme 2 gene expression, and outcomes, exploring different types and doses of INCS.
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Asma , COVID-19 , Enfermedad Pulmonar Obstructiva Crónica , Humanos , COVID-19/complicaciones , Estudios Retrospectivos , Asma/tratamiento farmacológico , Asma/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Esteroides/uso terapéuticoRESUMEN
The EarlyCDT-Lung test is a high-specificity blood-based autoantibody biomarker that could contribute to predicting lung cancer risk. We report on the results of a phase IV biomarker evaluation of whether using the EarlyCDT-Lung test and any subsequent computed tomography (CT) scanning to identify those at high risk of lung cancer reduces the incidence of patients with stage III/IV/unspecified lung cancer at diagnosis compared with the standard clinical practice at the time the study began.The Early Diagnosis of Lung Cancer Scotland (ECLS) trial was a randomised controlled trial of 12â208 participants at risk of developing lung cancer in Scotland in the UK. The intervention arm received the EarlyCDT-Lung test and, if test-positive, low-dose CT scanning 6-monthly for up to 2â years. EarlyCDT-Lung test-negative and control arm participants received standard clinical care. Outcomes were assessed at 2â years post-randomisation using validated data on cancer occurrence, cancer staging, mortality and comorbidities.At 2â years, 127 lung cancers were detected in the study population (1.0%). In the intervention arm, 33 out of 56 (58.9%) lung cancers were diagnosed at stage III/IV compared with 52 out of 71 (73.2%) in the control arm. The hazard ratio for stage III/IV presentation was 0.64 (95% CI 0.41-0.99). There were nonsignificant differences in lung cancer and all-cause mortality after 2â years.ECLS compared EarlyCDT-Lung plus CT screening to standard clinical care (symptomatic presentation) and was not designed to assess the incremental contribution of the EarlyCDT-Lung test. The observation of a stage shift towards earlier-stage lung cancer diagnosis merits further investigations to evaluate whether the EarlyCDT-Lung test adds anything to the emerging standard of low-dose CT.
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Detección Precoz del Cáncer , Neoplasias Pulmonares , Pruebas Hematológicas , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Estadificación de Neoplasias , Escocia/epidemiologíaRESUMEN
BACKGROUND: There is an urgent need for epidemiological research in primary care to develop risk assessment processes for patients presenting with COVID-19, but lack of a standardised approach to data collection is a significant barrier to implementation. AIM: To collate a list of relevant symptoms, assessment items, demographics, and lifestyle and health conditions associated with COVID-19, and match these data items with corresponding SNOMED CT clinical terms to support the development and implementation of consultation templates. DESIGN & SETTING: Published and preprint literature for systematic reviews, meta-analyses, and clinical guidelines describing the symptoms, assessment items, demographics, and/or lifestyle and health conditions associated with COVID-19 and its complications were reviewed. Corresponding clinical concepts from SNOMED CT, a widely used structured clinical vocabulary for electronic primary care health records, were identified. METHOD: Guidelines and published and unpublished reviews (N = 61) were utilised to collate a list of relevant data items for COVID-19 consultations. The NHS Digital SNOMED CT Browser was used to identify concept and descriptive identifiers. Key implementation challenges were conceptualised through a Normalisation Process Theory (NPT) lens. RESULTS: In total, 32 symptoms, eight demographic and lifestyle features, 25 health conditions, and 20 assessment items relevant to COVID-19 were identified, with proposed corresponding SNOMED CT concepts. These data items can be adapted into a consultation template for COVID-19. Key implementation challenges include: 1) engaging with key stakeholders to achieve 'buy in'; and 2) ensuring any template is usable within practice settings. CONCLUSION: Consultation templates for COVID-19 are needed to standardise data collection, facilitate research and learning, and potentially improve quality of care for COVID-19.
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RATIONALE, AIMS, AND OBJECTIVES: High response rates to research questionnaires can help to ensure results are more representative of the population studied and provide increased statistical power, on which the study may have been predicated. Improving speed and quality of response can reduce costs. METHOD: We conducted a randomized study within a trial (SWAT) to assess questionnaire response rates, reminders sent, and data completeness with unconditional compared with conditional monetary incentives. Eligible individuals were mailed a series of psychological questionnaires as a follow-up to a baseline host trial questionnaire. Half received a £5 gift voucher with questionnaires (unconditional), and half were promised the voucher after returning questionnaires (conditional). RESULTS: Of 1079 individuals, response rates to the first follow-up questionnaire were 94.2% and 91.7% in the unconditional and conditional monetary incentive groups, respectively (OR 1.78; 95% CI, 0.85-3.72). There were significantly greater odds of returning repeat questionnaires in the unconditional group at 6 months (OR 2.97; 95% CI, 1.01-8.71; .047) but not at 12 months (OR 1.12; 95% CI, 0.44-2.85). Incentive condition had no impact at any time point on the proportion of sent questionnaires that needed reminders. Odds of incomplete questionnaires were significantly greater at 3 months in the unconditional compared with the conditional incentive group (OR 2.45; 95% CI, 1.32-4.55; .004). CONCLUSIONS: Unconditional monetary incentives can produce a transitory greater likelihood of mailed questionnaire response in a clinical trial participant group, consistent with the direction of effect in other settings. However, this could have been a chance finding. The use of multiple strategies to promote response may have created a ceiling effect. This strategy has potential to reduce administrative and postage costs, weighed against the cost of incentives used, but could risk compromising the completeness of data.
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Motivación , Servicios Postales , Humanos , Proyectos de Investigación , Encuestas y CuestionariosRESUMEN
In an OECD Test Guideline 416 multigenerational study, groups of 24 male and 24 female Sprague-Dawley rats were administered sodium molybdate dihydrate at 0, 5, 17, or 40 mg molybdenum (Mo)/kg bw/day in the drinking water or 40 mg Mo/kg bw/day in the diet over two generations to assess reproductive toxicity. No adverse effect on reproductive function was observed at any dose level in either generation as indicated by no significant dose-related effect on estrus cycles, sperm parameters, mating, fertility, gestation, litter size, pup survival, growth or postnatal development. Systemic toxicity, including decreased body weight, food consumption (males only) and water consumption, was observed among both sexes given 40 mg Mo/kg bw/day in the diet. Serum levels of Mo and copper were increased in a dose-related manner. The No Observed Adverse Effect Levels (NOAEL) are 17 mg Mo/kg bw/day for systemic toxicity and 40 mg Mo/kg bw/day for reproductive toxicity.
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Molibdeno/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Dieta , Agua Potable , Ingestión de Alimentos/efectos de los fármacos , Femenino , Masculino , Molibdeno/sangre , Molibdeno/farmacocinética , Molibdeno/orina , Nivel sin Efectos Adversos Observados , Embarazo , Ratas Sprague-Dawley , Fenómenos Fisiológicos Reproductivos/efectos de los fármacosRESUMEN
BACKGROUND: The promotion of smoking cessation within lung cancer screening could lead to benefits for smoking-related disease and improve cost-effectiveness of screening. Little is known about how smokers respond to lung cancer screening and how this impacts smoking behaviour. We aimed to understand how lung cancer screening influences individual motivations about smoking, including in those who have stopped smoking since screening. METHODS: Thirty one long-term smokers aged 51-74 took part in semi-structured interviews about smoking. They had been screened with the EarlyCDT-Lung Test (13 positive result; 18 negative) as part of the Early Cancer Detection Test Lung Cancer Scotland Study. They were purposively sampled for interview based on their self-reported post-screening smoking behaviour. Eleven participants had stopped smoking since screening. Verbatim interview transcripts were analysed using thematic analysis. RESULTS: Two key overarching themes were interpretations of screening test results and emotional responses to those interpretations. Participants' understanding of the risk implied by their test result was often inaccurate, for example a negative result interpreted as an 'all-clear' from lung cancer and a positive result as meaning lung cancer would definitely develop. Those interpretations led to emotional responses (fear, shock, worry, relief, indifference) influencing motivations about smoking. Other themes included a wake-up call causing changes in perceived risk of smoking-related disease, a feeling that now is the time to stop smoking and family influences. There was no clear pattern in smoking motivations in those who received positive or negative test results. Of those who had stopped smoking, some cited screening experiences as the sole motivation, some cited screening along with other coinciding factors, and others cited non-screening reasons. Cues to change were experienced at different stages of the screening process. Some participants indicated they underwent screening to try and stop smoking, while others expressed little or no desire to stop. CONCLUSIONS: We observed complex and individualised motivations about smoking following lung cancer screening. To be most effective, smoking cessation support in this context should explore understanding of screening test results and may need to be highly tailored to individual emotional responses to screening.
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Motivación , Fumadores/psicología , Cese del Hábito de Fumar/psicología , Prevención del Hábito de Fumar , Fumar/psicología , Anciano , Detección Precoz del Cáncer/estadística & datos numéricos , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Persona de Mediana Edad , Investigación Cualitativa , Escocia , Fumadores/estadística & datos numéricosRESUMEN
INTRODUCTION: Cost-related non-adherence to medicines is common in low-income, middle-income and high-income countries such as Canada. Medicine non-adherence is associated with poor health outcomes and increased mortality. This randomised trial will test the impact of a carefully selected list of essential medicines at no charge (compared with usual medicine access) in primary care patients reporting cost-related non-adherence. METHODS AND ANALYSIS: This is an open-label, parallel two-arm, superiority, individually randomised controlled trial conducted in three primary care sites (one urban, two rural) in Ontario, Canada, that was codesigned by a community guidance panel. Adult patients (≥18 years) who report cost-related non-adherence to medicines are eligible to participate in the study. Participants will be randomised to receive free and convenient access to a carefully selected list of 125 essential medicines (based on the WHO's Model List of Essential Medicines) or usual means of medicine access. Care for patients in both groups will otherwise be unchanged. The primary outcome of this trial is adherence to appropriately prescribed medicines. Secondary outcomes include medicine adherence, appropriate prescribing, blood pressure, haemoglobin A1c, low-density lipoprotein cholesterol, patient-oriented outcomes and healthcare costs. All participants will be followed for at least 12 months. ETHICS AND DISSEMINATION: Ethics approval was obtained in all three participating sites. Results of the main trial and secondary outcomes will be submitted for publication in a peer-reviewed journal and discussed with members of the public and decision makers. TRIAL REGISTRATION NUMBER: NCT02744963.
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Medicamentos Esenciales/economía , Cumplimiento de la Medicación/estadística & datos numéricos , Atención Primaria de Salud/economía , Adolescente , Adulto , Anciano , Costos de los Medicamentos , Femenino , Costos de la Atención en Salud , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Ontario , Calidad de Vida , Proyectos de Investigación , Autoinforme , Adulto JovenRESUMEN
OBJECTIVES: PRagmatic Explanatory Continuum Indicator Summary (PRECIS)-2 is a tool that could improve design insight for trialists. Our aim was to validate the PRECIS-2 tool, unlike its predecessor, testing the discriminant validity and interrater reliability. STUDY DESIGN AND SETTING: Over 80 international trialists, methodologists, clinicians, and policymakers created PRECIS-2 helping to ensure face validity and content validity. The interrater reliability of PRECIS-2 was measured using 19 experienced trialists who used PRECIS-2 to score a diverse sample of 15 randomized controlled trial protocols. Discriminant validity was tested with two raters to independently determine if the trial protocols were more pragmatic or more explanatory, with scores from the 19 raters for the 15 trials as predictors of pragmatism. RESULTS: Interrater reliability was generally good, with seven of nine domains having an intraclass correlation coefficient over 0.65. Flexibility (adherence) and recruitment had wide confidence intervals, but raters found these difficult to rate and wanted more information. Each of the nine PRECIS-2 domains could be used to differentiate between trials taking more pragmatic or more explanatory approaches with better than chance discrimination for all domains. CONCLUSION: We have assessed the validity and reliability of PRECIS-2. An elaboration study and web site provide guidance to help future users of the tool which is continuing to be tested by trial teams, systematic reviewers, and funders.
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Proyectos de Investigación/normas , Humanos , Variaciones Dependientes del Observador , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Reproducibilidad de los ResultadosRESUMEN
PURPOSE: Recruitment to trials is often difficult. Many trials fail to meet recruitment targets resulting in underpowered studies which waste resources and the time of those who participated. While there is evidence that many people are willing to take part in research, particularly if it involves a condition from which they suffer, researchers are unable to easily contact such people often relying on busy clinicians to identify them. Many clinicians perceive themselves as too busy to take part in research activities. The Scottish Health Research Register SHARE adopts an approach which asks the public to consent to their data held in National Health Service databases to be used to determine their suitability for research projects. Additionally, participants can consent for spare blood, left after routine venepuncture to be automatically identified in the laboratory and stored for future research studies. PARTICIPANTS: Anyone over the age of 16â years in Scotland can participate. Participants are approached through a range of methods including directly at outpatient clinics and general practitioners practices, leaflets with hospital letters and personal email from employers. FINDINGS TO DATE: SHARE has recruited around 130â 000 people. SHARE has demonstrated that it can quickly and efficiently recruit to studies, over 20 until now. In addition, it can be used to administer questionnaire studies by email and recruit to patient and public involvement groups. FUTURE PLANS: SHARE continues to steadily recruit with the ambition of eventually achieving 1â 000â 000 people in Scotland. We are steadily increasing the number of data sets we use for identifying participants. We are adding a mobile app which will facilitate dissemination about research and allow the collection of physiological and activity data if desired. We anticipate that SHARE will soon become the main source of health research recruitment in Scotland.
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Investigación Biomédica , Selección de Paciente , Sistema de Registros , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bancos de Sangre , Conjuntos de Datos como Asunto , Registros Electrónicos de Salud , Femenino , Financiación Gubernamental , Humanos , Consentimiento Informado , Masculino , Registro Médico Coordinado , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Sistema de Registros/ética , Escocia , Adulto JovenRESUMEN
AIMS: Unrecognized myocardial infarctions (UMIs) have been described in 19-30% of the general population using late gadolinium enhancement (LGE) on cardiac magnetic resonance. However, these studies have focused on an unselected cohort including those with known cardiovascular disease (CVD). The aim of the current study was to ascertain the prevalence of UMIs in a non-high-risk population using magnetic resonance imaging (MRI). METHODS AND RESULTS: A total of 5000 volunteers aged >40 years with no history of CVD and a 10-year risk of CVD of <20%, as assessed by the ATP-III risk score, were recruited to the Tayside Screening for Cardiac Events study. Those with a B-type natriuretic peptide (BNP) level greater than their gender-specific median were invited for a whole-body MR angiogram and cardiac MR including LGE assessment. LGE was classed as absent, UMI, or non-specific. A total of 1529 volunteers completed the imaging study; of these, 53 (3.6%) were excluded because of either missing data or inadequate LGE image quality. Ten of the remaining 1476 (0.67%) displayed LGE. Of these, three (0.2%) were consistent with UMI, whereas seven were non-specific occurring in the mid-myocardium (n = 4), epicardium (n = 1), or right ventricular insertion points (n = 2). Those with UMI had a significantly higher BNP [median 116 (range 31-133) vs. 22.6 (5-175) pg/mL, P = 0.015], lower ejection fraction [54.6 (36-62) vs. 68.9 (38-89)%, P = 0.007], and larger end-systolic volume [36.3 (27-61) vs. 21.7 (5-65) mL/m2, P = 0.014]. Those with non-specific LGE had lower diastolic blood pressure [68 (54-70) vs. 72 (46-98) mmHg, P = 0.013] but no differences in their cardiac function. CONCLUSION: Despite previous reports describing high prevalence of UMI in older populations, in a predominantly middle-aged cohort, those who are of intermediate or low cardiovascular risk have a very low risk of having an unrecognized myocardial infarct.
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Enfermedades Asintomáticas/epidemiología , Aterosclerosis/diagnóstico por imagen , Gadolinio , Imagen por Resonancia Cinemagnética/métodos , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Aterosclerosis/epidemiología , Aterosclerosis/fisiopatología , Estudios de Cohortes , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/patología , Prevalencia , Pronóstico , Intensificación de Imagen Radiográfica , Medición de Riesgo , Factores SexualesRESUMEN
BACKGROUND: The conduct of clinical trials is increasingly challenging due to greater complexity and governance requirements as well as difficulties with recruitment and retention. Electronic Health Records for Clinical Research (EHR4CR) aims at improving the conduct of trials by using existing routinely collected data, but little is known about stakeholder views on data availability, information governance, and acceptable working practices. METHODS: Senior figures in healthcare organisations across Europe were provided with a description of the project and structured interviews were subsequently conducted to elicit their views. RESULTS: 37 structured interviewees in Germany, UK, Switzerland, and France indicated strong support for the proposed EHR4CR platform. All interviewees reported that using the platform for assessing feasibility would enhance the conduct of clinical trials and the majority also felt it would reduce workloads. Interviewees felt the platform could enhance trial recruitment and adverse event reporting but also felt it could raise either ethical or information governance concerns in their country. CONCLUSIONS: There was clear support for EHR4CR and a belief that it could reduce workloads and improve the conduct and quality of trials. However data security, privacy, and information governance issues would need to be carefully managed in the development of the platform.
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Ensayos Clínicos como Asunto/métodos , Registros Electrónicos de Salud/estadística & datos numéricos , Personal de Salud/estadística & datos numéricos , Sistemas de Registro de Reacción Adversa a Medicamentos , Europa (Continente) , Estudios de Factibilidad , Humanos , Selección de PacienteRESUMEN
Molybdenum is an essential nutrient for humans and animals and is a constituent of several important oxidase enzymes. It is normally absorbed from the diet and to a lesser extent from drinking water and the typical human intake is around 2µg/kg bodyweight per day. No developmental toxicity studies to contemporary standards have been published and regulatory decisions have been based primarily on older studies where the nature of the test material, or the actual dose levels consumed is uncertain. In the current study the developmental toxicity of sodium molybdate dihydrate as a representative of a broad class of soluble molybdenum(VI) compounds, was given in the diet to Sprague Dawley rats in accordance with OECD Test Guideline 414. Dose levels of 0, 3, 10, 20 and 40mgMo/kgbw/day were administered from GD6 to GD20. No adverse effects were observed at any dose level on the dams, or on embryofetal survival, fetal bodyweight, or development, with no increase in malformations or variations. Significant increases in serum and tissue copper levels were observed but no toxicity related to these was observed. The NOAEL observed in this study was 40mgMo/kgbw/day, the highest dose tested.
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Suplementos Dietéticos/toxicidad , Desarrollo Fetal/efectos de los fármacos , Molibdeno/toxicidad , Anomalías Inducidas por Medicamentos/etiología , Animales , Relación Dosis-Respuesta a Droga , Femenino , Peso Fetal/efectos de los fármacos , Embarazo/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To derive and validate a clinical prediction model to estimate the risk of liver disease diagnosis following liver function tests (LFTs) and to convert the model to a simplified scoring tool for use in primary care. DESIGN: Population-based observational cohort study of patients in Tayside Scotland identified as having their LFTs performed in primary care and followed for 2â years. Biochemistry data were linked to secondary care, prescriptions and mortality data to ascertain baseline characteristics of the derivation cohort. A separate validation cohort was obtained from 19 general practices across the rest of Scotland to externally validate the final model. SETTING: Primary care, Tayside, Scotland. PARTICIPANTS: Derivation cohort: LFT results from 310â 511 patients. After exclusions (including: patients under 16â years, patients having initial LFTs measured in secondary care, bilirubin >35â µmol/L, liver complications within 6â weeks and history of a liver condition), the derivation cohort contained 95â 977 patients with no clinically apparent liver condition. Validation cohort: after exclusions, this cohort contained 11â 653 patients. PRIMARY AND SECONDARY OUTCOME MEASURES: Diagnosis of a liver condition within 2â years. RESULTS: From the derivation cohort (n=95â 977), 481 (0.5%) were diagnosed with a liver disease. The model showed good discrimination (C-statistic=0.78). Given the low prevalence of liver disease, the negative predictive values were high. Positive predictive values were low but rose to 20-30% for high-risk patients. CONCLUSIONS: This study successfully developed and validated a clinical prediction model and subsequent scoring tool, the Algorithm for Liver Function Investigations (ALFI), which can predict liver disease risk in patients with no clinically obvious liver disease who had their initial LFTs taken in primary care. ALFI can help general practitioners focus referral on a small subset of patients with higher predicted risk while continuing to address modifiable liver disease risk factors in those at lower risk.
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Hepatopatías/diagnóstico , Modelos Estadísticos , Atención Primaria de Salud , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Hepatopatías/epidemiología , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Medición de Riesgo , EscociaRESUMEN
This study investigated the subchronic toxicity of molybdenum (Mo) in Sprague-Dawley rats given sodium molybdate dihydrate in the diet for 90days at dose levels of 0, 5, 17 or 60mgMo/kgbw/day. The study complied with OECD Test Guideline (TG) 408, with additional examination of estrus cycles and sperm count, motility, and morphology from OECD TG 416. The overall no-observed-adverse-effect level was 17mgMo/kgbw/day, based on effects on body weight, body weight gain, food conversion efficiency and renal histopathology (females only) at 60mgMo/kgbw/day. No treatment-related adverse effects on reproductive organ weights or histopathology, estrus cycles or sperm parameters were observed at any dose level. No adverse effects were observed in the high dose animals after the 60-day recovery period, with the exception that male rats did not fully recover from reduced body weight. Serum blood, liver and kidney samples were analyzed for molybdenum, copper, zinc, manganese, iron, cobalt and selenium; high levels of molybdenum and copper were found in the serum, blood, liver and kidneys of rats treated with 60mgMo/kgbw/day. In conclusion, the LOAEL and NOAEL for molybdenum were determined to be 60 and 17mgMo/kgbw/day, respectively.
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Molibdeno/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Cobre/sangre , Cobre/metabolismo , Ciclo Estral/efectos de los fármacos , Femenino , Genitales/anatomía & histología , Genitales/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Hígado/anatomía & histología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Molibdeno/sangre , Molibdeno/farmacocinética , Nivel sin Efectos Adversos Observados , Ratas Sprague-Dawley , Recuento de Espermatozoides , Pruebas de Toxicidad SubcrónicaRESUMEN
BACKGROUND: Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype. OBJECTIVE: We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD. METHODS: A mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD. RESULTS: The matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Matt(ft) mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6684514, [corrected] in the human MATT gene has a small but significant association with AD. CONCLUSION: In mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. A common SNP in MATT has an association with AD in human subjects.
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Dermatitis Atópica/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Animales , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Proteínas Filagrina , Expresión Génica , Humanos , Masculino , Ratones , Mutación , Fenotipo , Mapeo Físico de Cromosoma , Polimorfismo de Nucleótido Simple , Piel/metabolismo , Piel/patologíaRESUMEN
OBJECTIVES: To measure the incidence of Bell's palsy and determine the impact of clinical trial findings on Bell's palsy management in the UK. DESIGN: Interrupted time series regression analysis and incidence measures. SETTING: General practices in the UK contributing to the Clinical Practice Research Datalink (CPRD). PARTICIPANTS: Patients ≥16 years with a diagnosis of Bell's palsy between 2001 and 2012. INTERVENTIONS: (1) Publication of the 2004 Cochrane reviews of clinical trials on corticosteroids and antivirals for Bell's palsy, which made no clear recommendation on their use and (2) publication of the 2007 Scottish Bell's Palsy Study (SBPS), which made a clear recommendation that treatment with prednisolone alone improves chances for complete recovery. MAIN OUTCOME MEASURES: Incidence of Bell's palsy per 100 000 person-years. Changes in the management of Bell's palsy with either prednisolone therapy, antiviral therapy, combination therapy (prednisolone with antiviral therapy) or untreated cases. RESULTS: During the 12-year period, 14 460 cases of Bell's palsy were identified with an overall incidence of 37.7/100 000 person-years. The 2004 Cochrane reviews were associated with immediate falls in prednisolone therapy (-6.3% (-11.0 to -1.6)), rising trends in combination therapy (1.1% per quarter (0.5 to 1.7)) and falling trends for untreated cases (-0.8% per quarter (-1.4 to -0.3)). SBPS was associated with immediate increases in prednisolone therapy (5.1% (0.9 to 9.3)) and rising trends in prednisolone therapy (0.7% per quarter (0.4 to 1.2)); falling trends in combination therapy (-1.7% per quarter (-2.2 to -1.3)); and rising trends for untreated cases (1.2% per quarter (0.8 to 1.6)). Despite improvements, 44% still remain untreated. CONCLUSIONS: SBPS was clearly associated with change in management, but a significant proportion of patients failed to receive effective treatment, which cannot be fully explained. Clarity and uncertainty in clinical trial recommendations may change clinical practice. However, better ways are needed to understand and circumvent barriers in implementing clinical trial findings.