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1.
PLoS One ; 15(1): e0227471, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978127

RESUMO

BACKGROUND: Delirium is a common and serious acute neuropsychiatric syndrome which is often missed in routine clinical care. Inattention is the core cognitive feature. Diagnostic test accuracy (including cut-points) of a smartphone Delirium App (DelApp) for assessing attention deficits was assessed in older hospital inpatients. METHODS: This was a case-control study of hospitalised patients aged ≥65 years with delirium (with or without pre-existing cognitive impairment), who were compared to patients with dementia without delirium, and patients without cognitive impairment. Reference standard delirium assessment, which included a neuropsychological test battery, was based on Diagnostic and Statistical Manual of Mental Disorders-5 criteria. A separate blinded assessor administered the DelApp arousal assessment (score 0-4) and attention task (0-6) yielding an overall score of 0 to 10 (lower scores indicate poorer performance). Analyses included receiver operating characteristic curves and sensitivity and specificity. Optimal cut-points for delirium detection were determined using Youden's index. RESULTS: A total of 187 patients were recruited, mean age 83.8 (range 67-98) years, 152 (81%) women; n = 61 with delirium; n = 61 with dementia without delirium; and n = 65 without cognitive impairment. Patients with delirium performed poorly on the DelApp (median score = 4/10; inter-quartile range 3.0, 5.5) compared to patients with dementia (9.0; 5.5, 10.0) and those without cognitive impairment (10.0; 10.0, 10.0). Area under the curve for detecting delirium was 0.89 (95% Confidence Interval 0.84, 0.94). At an optimal cut-point of ≤8, sensitivity was 91.7% (84.7%, 98.7%) and specificity 74.2% (66.5%, 81.9%) for discriminating delirium from the other groups. Specificity was 68.3% (56.6%, 80.1%) for discriminating delirium from dementia (cut-point ≤6). CONCLUSION: Patients with delirium (with or without pre-existing cognitive impairment) perform poorly on the DelApp compared to patients with dementia and those without cognitive impairment. A cut-point of ≤8/10 is suggested as having optimal sensitivity and specificity. The DelApp is a promising tool for assessment of attention deficits associated with delirium in older hospitalised adults, many of whom have prior cognitive impairment, and should be further validated in representative patient cohorts.

2.
Lancet Neurol ; 19(3): 214-225, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31981516

RESUMO

BACKGROUND: Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. METHODS: We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259. FINDINGS: Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI -0·4 to 0·5; p=0·99]; fluoxetine vs placebo -0·1% [-0·5 to 0·3; p=0·86]; riluzole vs placebo -0·1% [-0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes. INTERPRETATION: The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine. FUNDING: Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.

3.
Arch Dis Child ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937568

RESUMO

OBJECTIVE: To examine temporal trends in incidence of Rolandic epilepsy (RE), prevalence of comorbidities and antiepileptic drug (AED) prescribing patterns. DESIGN: Retrospective cohort study. SETTING: The UK. PATIENTS: Children aged 0-16 years born 1994-2012 were followed from birth until September 2017, transfer to another general practitioner practice or death or practice withdrawal from The Health Improvement Network (THIN), whichever occurred first. MAIN OUTCOME MEASURES: Incidence of RE, prevalence of comorbidity and AED prescribing patterns. Read codes for comorbidities and AEDs were adapted from other UK population-based epilepsy studies. RESULTS: There were 379 children with first RE event recorded between 2000 and 2014 from active THIN practices with available mid-year population counts. Crude annual incidence across all years was 5.31/100 000 (95% CI 4.81 to 5.88). There was no significant time trend in adjusted incidence rate ratios (aIRR) (0.99/year, 95% CI 0.96 to 1.02). Males had higher aIRR (1.48, 95% CI 1.20 to 1.82) as did children aged 6-8 and 9-11 years compared with 4-5 years (aIRR 2.43, 95% CI 1.73 to 3.40; aIRR 2.77, 95% CI 1.97 to 3.90, respectively). There was recorded comorbidity in 12% with 6% with a recorded diagnosis of pervasive developmental disorder. Half of children with RE had a record of being prescribed AEDs. CONCLUSIONS: UK incidence of RE has remained stable with crude incidence of 5/100 000/year. Carers and clinicians need to be aware that comorbidities may exist, particularly pervasive developmental disorders. Carbamazepine is consistently the most commonly prescribed AED for RE in the UK.

4.
Circulation ; 141(3): 161-171, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31587565

RESUMO

BACKGROUND: The introduction of more sensitive cardiac troponin assays has led to increased recognition of myocardial injury in acute illnesses other than acute coronary syndrome. The Universal Definition of Myocardial Infarction recommends high-sensitivity cardiac troponin testing and classification of patients with myocardial injury based on pathogenesis, but the clinical implications of implementing this guideline are not well understood. METHODS: In a stepped-wedge cluster randomized, controlled trial, we implemented a high-sensitivity cardiac troponin assay and the recommendations of the Universal Definition in 48 282 consecutive patients with suspected acute coronary syndrome. In a prespecified secondary analysis, we compared the primary outcome of myocardial infarction or cardiovascular death and secondary outcome of noncardiovascular death at 1 year across diagnostic categories. RESULTS: Implementation increased the diagnosis of type 1 myocardial infarction by 11% (510/4471), type 2 myocardial infarction by 22% (205/916), and acute and chronic myocardial injury by 36% (443/1233) and 43% (389/898), respectively. Compared with those without myocardial injury, the rate of the primary outcome was highest in those with type 1 myocardial infarction (cause-specific hazard ratio [HR] 5.64 [95% CI, 5.12-6.22]), but was similar across diagnostic categories, whereas noncardiovascular deaths were highest in those with acute myocardial injury (cause specific HR 2.65 [95% CI, 2.33-3.01]). Despite modest increases in antiplatelet therapy and coronary revascularization after implementation in patients with type 1 myocardial infarction, the primary outcome was unchanged (cause specific HR 1.00 [95% CI, 0.82-1.21]). Increased recognition of type 2 myocardial infarction and myocardial injury did not lead to changes in investigation, treatment or outcomes. CONCLUSIONS: Implementation of high-sensitivity cardiac troponin assays and the recommendations of the Universal Definition of Myocardial Infarction identified patients at high-risk of cardiovascular and noncardiovascular events but was not associated with consistent increases in treatment or improved outcomes. Trials of secondary prevention are urgently required to determine whether this risk is modifiable in patients without type 1 myocardial infarction. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01852123.

5.
J Biopharm Stat ; 30(2): 364-376, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31887069

RESUMO

In clinical trials, surrogate outcomes are early measures of treatment effect that are used to predict treatment effect on a later primary outcome of interest: the primary outcome therefore does not need to be observed and trials can be shortened. Evaluating surrogates is a complex area as a given treatment can act through multiple pathways, some of which may circumvent the surrogate. One of the best established and practically sound approaches to surrogacy evaluation is based on information theory. We have extended this approach to the case of ordinal outcomes, which are used as primary outcomes in many medical areas. This extension provides researchers with the means of evaluating surrogates in this setting, which expands the usefulness of the information theory approach while also demonstrating its versatility.

6.
J Am Coll Cardiol ; 74(16): 2032-2043, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31623760

RESUMO

BACKGROUND: Major disparities between women and men in the diagnosis, management, and outcomes of acute coronary syndrome are well recognized. OBJECTIVES: The aim of this study was to evaluate the impact of implementing a high-sensitivity cardiac troponin I assay with sex-specific diagnostic thresholds for myocardial infarction in women and men with suspected acute coronary syndrome. METHODS: Consecutive patients with suspected acute coronary syndrome were enrolled in a stepped-wedge, cluster-randomized controlled trial across 10 hospitals. Myocardial injury was defined as high-sensitivity cardiac troponin I concentration >99th centile of 16 ng/l in women and 34 ng/l in men. The primary outcome was recurrent myocardial infarction or cardiovascular death at 1 year. RESULTS: A total of 48,282 patients (47% women) were included. Use of the high-sensitivity cardiac troponin I assay with sex-specific thresholds increased myocardial injury in women by 42% and in men by 6%. Following implementation, women with myocardial injury remained less likely than men to undergo coronary revascularization (15% vs. 34%) and to receive dual antiplatelet (26% vs. 43%), statin (16% vs. 26%), or other preventive therapies (p < 0.001 for all). The primary outcome occurred in 18% (369 of 2,072) and 17% (488 of 2,919) of women with myocardial injury before and after implementation, respectively (adjusted hazard ratio: 1.11; 95% confidence interval: 0.92 to 1.33), compared with 18% (370 of 2,044) and 15% (513 of 3,325) of men (adjusted hazard ratio: 0.85; 95% confidence interval: 0.71 to 1.01). CONCLUSIONS: Use of sex-specific thresholds identified 5 times more additional women than men with myocardial injury. Despite this increase, women received approximately one-half the number of treatments for coronary artery disease as men, and outcomes were not improved. (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome [High-STEACS]; NCT01852123).

7.
Int J Stroke ; : 1747493019871824, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31564241

RESUMO

BACKGROUND: Patients with stroke-associated pneumonia experience poorer outcomes (increased hospital stays, costs, discharge dependency, and risk of death). High-quality, organized oral healthcare may reduce the incidence of stroke-associated pneumonia and improve oral health and quality of life. AIMS: We piloted a pragmatic, stepped-wedge, cluster randomized controlled trial of clinical and cost effectiveness of enhanced versus usual oral healthcare for people in stroke rehabilitation settings. METHODS: Scottish stroke rehabilitation wards were randomly allocated to stepped time-points for conversion from usual to enhanced oral healthcare. All admissions and nursing staff were eligible for inclusion. We piloted the viability of randomization, intervention, data collection, record linkage procedures, our sample size, screening, and recruitment estimates. The stepped-wedge trial design prevented full blinding of outcome assessors and staff. Predetermined criteria for progression included the validity of enhanced oral healthcare intervention (training, oral healthcare protocol, assessment, equipment), data collection, and stroke-associated pneumonia event rate and relationship between stroke-associated pneumonia and plaque. RESULTS: We screened 1548/2613 (59%) admissions to four wards, recruiting n = 325 patients and n = 112 nurses. We observed marked between-site diversity in admissions, recruitment populations, stroke-associated pneumonia events (0% to 21%), training, and resource use. No adverse events were reported. Oral healthcare documentation was poor. We found no evidence of a difference in stroke-associated pneumonia between enhanced versus usual oral healthcare (P = 0.62, odds ratio = 0.61, confidence interval: 0.08 to 4.42). CONCLUSIONS: Our stepped-wedge cluster randomized control trial accommodated between-site diversity. The stroke-associated pneumonia event rate did not meet our predetermined progression criteria. We did not meet our predefined progression criteria including the SAP event rate and consequently were unable to establish whether there is a relationship between SAP and plaque. A wide confidence interval did not exclude the possibility that enhanced oral healthcare may result in a benefit or detrimental effect. TRIAL REGISTRATION: NCT01954212.

8.
BMC Med ; 17(1): 138, 2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31337404

RESUMO

BACKGROUND: Delirium affects > 15% of hospitalised patients but is grossly underdetected, contributing to poor care. The 4 'A's Test (4AT, www.the4AT.com ) is a short delirium assessment tool designed for routine use without special training. The primary objective was to assess the accuracy of the 4AT for delirium detection. The secondary objective was to compare the 4AT with another commonly used delirium assessment tool, the Confusion Assessment Method (CAM). METHODS: This was a prospective diagnostic test accuracy study set in emergency departments or acute medical wards involving acute medical patients aged ≥ 70. All those without acutely life-threatening illness or coma were eligible. Patients underwent (1) reference standard delirium assessment based on DSM-IV criteria and (2) were randomised to either the index test (4AT, scores 0-12; prespecified score of > 3 considered positive) or the comparator (CAM; scored positive or negative), in a random order, using computer-generated pseudo-random numbers, stratified by study site, with block allocation. Reference standard and 4AT or CAM assessments were performed by pairs of independent raters blinded to the results of the other assessment. RESULTS: Eight hundred forty-three individuals were randomised: 21 withdrew, 3 lost contact, 32 indeterminate diagnosis, 2 missing outcome, and 785 were included in the analysis. Mean age was 81.4 (SD 6.4) years. 12.1% (95/785) had delirium by reference standard assessment, 14.3% (56/392) by 4AT, and 4.7% (18/384) by CAM. The 4AT had an area under the receiver operating characteristic curve of 0.90 (95% CI 0.84-0.96). The 4AT had a sensitivity of 76% (95% CI 61-87%) and a specificity of 94% (95% CI 92-97%). The CAM had a sensitivity of 40% (95% CI 26-57%) and a specificity of 100% (95% CI 98-100%). CONCLUSIONS: The 4AT is a short, pragmatic tool which can help improving detection rates of delirium in routine clinical care. TRIAL REGISTRATION: International standard randomised controlled trial number (ISRCTN) 53388093 . Date applied 30/05/2014; date assigned 02/06/2014.


Assuntos
Confusão/diagnóstico , Delírio/diagnóstico , Testes Diagnósticos de Rotina , Testes Neuropsicológicos , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Lista de Checagem/métodos , Lista de Checagem/normas , Testes Diagnósticos de Rotina/métodos , Testes Diagnósticos de Rotina/normas , Manual Diagnóstico e Estatístico de Transtornos Mentais , Serviço Hospitalar de Emergência , Feminino , Avaliação Geriátrica/métodos , Humanos , Pacientes Internados , Masculino , Testes Neuropsicológicos/normas , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
10.
EBioMedicine ; 46: 423-430, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31311721

RESUMO

BACKGROUND: The POP Trial was a phase 1, open-label, rising-dose, randomised study that explored the safety and tolerability of calmangafodipir (superoxide dismutase mimetic) co-treatment with n-acetylcysteine (NAC) for paracetamol overdose. METHODS: Patients were recruited at the Royal Infirmary of Edinburgh (8th June 2017-10th May 2018). Inclusion criterion: adults within 24 h of a paracetamol overdose that required NAC. Within each of 3 sequential cohorts, participants were randomly assigned, with concealed allocation, to NAC and a single intravenous calmangafodipir dose (n = 6) or NAC alone (n = 2). Calmangafodipir doses were 2, 5, or 10 µmol/kg. Participants, study and clinical teams were not blinded. The primary outcome was safety and tolerability. Secondary outcomes were alanine transaminase (ALT), international normalised ratio (INR), keratin-18, caspase-cleaved keratin-18 (ccK18), microRNA-122, and glutamate dehydrogenase (GLDH). (Clinicaltrials.gov:NCT03177395). FINDINGS: All 24 participants received their allocated drug doses and were analysed. Primary endpoints: all participants experienced ≥1 adverse event (AE), most commonly gastrointestinal. Patients experiencing ≥1 serious adverse event (SAE): NAC alone, 2/6; NAC + calmangafodipir (2 µmol/kg), 4/6; NAC + calmangafodipir (5 µmol/kg), 2/6; NAC + calmangafodipir (10 µmol/kg), 3/6. No AEs or SAEs were probably or definitely calmangafodipir-related. Secondary safety outcomes demonstrated no differences between groups. With NAC alone, 2/6 had ALT > 100 U/L; with NAC + calmangafodipir, 0/18. No INR difference. Keratin-18 and ccK18 increased in the NAC alone group more than with calmangafodipir (baseline to 20 h fold change, NAC + calmangafodipir (5 µmol/kg) compared to NAC alone: 0.48 (95%CI 0.28-0.83)). microRNA-122 changes were similar to K18, GLDH was frequently undetected. INTERPRETATION: Calmangafodipir was tolerated when combined with NAC and may reduce biomarkers of paracetamol toxicity.


Assuntos
Acetaminofen/administração & dosagem , Acetaminofen/efeitos adversos , Acetilcisteína/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ácido Edético/análogos & derivados , Substâncias Protetoras/uso terapêutico , Fosfato de Piridoxal/análogos & derivados , Adulto , Biomarcadores , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Interações de Medicamentos , Overdose de Drogas , Ácido Edético/uso terapêutico , Feminino , Humanos , Masculino , Fosfato de Piridoxal/uso terapêutico , Fatores de Tempo , Adulto Jovem
12.
BMC Med Res Methodol ; 19(1): 18, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30658575

RESUMO

INTRODUCTION: The continual reassessment method (CRM) is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design, which is used in most phase I trials. Furthermore, the CRM has been shown to assign more trial participants at or close to the MTD than the 3 + 3 design. However, the CRM's uptake in clinical research has been incredibly slow, putting trial participants, drug development and patients at risk. Barriers to increasing the use of the CRM have been identified, most notably a lack of knowledge amongst clinicians and statisticians on how to apply new designs in practice. No recent tutorial, guidelines, or recommendations for clinicians on conducting dose-finding studies using the CRM are available. Furthermore, practical resources to support clinicians considering the CRM for their trials are scarce. METHODS: To help overcome these barriers, we present a structured framework for designing a dose-finding study using the CRM. We give recommendations for key design parameters and advise on conducting pre-trial simulation work to tailor the design to a specific trial. We provide practical tools to support clinicians and statisticians, including software recommendations, and template text and tables that can be edited and inserted into a trial protocol. We also give guidance on how to conduct and report dose-finding studies using the CRM. RESULTS: An initial set of design recommendations are provided to kick-start the design process. To complement these and the additional resources, we describe two published dose-finding trials that used the CRM. We discuss their designs, how they were conducted and analysed, and compare them to what would have happened under a 3 + 3 design. CONCLUSIONS: The framework and resources we provide are aimed at clinicians and statisticians new to the CRM design. Provision of key resources in this contemporary guidance paper will hopefully improve the uptake of the CRM in phase I dose-finding trials.


Assuntos
Ensaios Clínicos Fase I como Assunto/métodos , Relação Dose-Resposta a Droga , Dose Máxima Tolerável , Projetos de Pesquisa , Simulação por Computador , Humanos
14.
BMC Med ; 16(1): 210, 2018 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-30442137

RESUMO

BACKGROUND: Adequate reporting of adaptive designs (ADs) maximises their potential benefits in the conduct of clinical trials. Transparent reporting can help address some obstacles and concerns relating to the use of ADs. Currently, there are deficiencies in the reporting of AD trials. To overcome this, we have developed a consensus-driven extension to the CONSORT statement for randomised trials using an AD. This paper describes the processes and methods used to develop this extension rather than detailed explanation of the guideline. METHODS: We developed the guideline in seven overlapping stages: 1) Building on prior research to inform the need for a guideline; 2) A scoping literature review to inform future stages; 3) Drafting the first checklist version involving an External Expert Panel; 4) A two-round Delphi process involving international, multidisciplinary, and cross-sector key stakeholders; 5) A consensus meeting to advise which reporting items to retain through voting, and to discuss the structure of what to include in the supporting explanation and elaboration (E&E) document; 6) Refining and finalising the checklist; and 7) Writing-up and dissemination of the E&E document. The CONSORT Executive Group oversaw the entire development process. RESULTS: Delphi survey response rates were 94/143 (66%), 114/156 (73%), and 79/143 (55%) in rounds 1, 2, and across both rounds, respectively. Twenty-seven delegates from Europe, the USA, and Asia attended the consensus meeting. The main checklist has seven new and nine modified items and six unchanged items with expanded E&E text to clarify further considerations for ADs. The abstract checklist has one new and one modified item together with an unchanged item with expanded E&E text. The E&E document will describe the scope of the guideline, the definition of an AD, and some types of ADs and trial adaptations and explain each reporting item in detail including case studies. CONCLUSIONS: We hope that making the development processes, methods, and all supporting information that aided decision-making transparent will enhance the acceptability and quick uptake of the guideline. This will also help other groups when developing similar CONSORT extensions. The guideline is applicable to all randomised trials with an AD and contains minimum reporting requirements.


Assuntos
Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Projetos de Pesquisa/normas , Ásia , Lista de Checagem , Consenso , Técnicas de Apoio para a Decisão , Europa (Continente) , Humanos
15.
Lancet ; 392(10158): 1629-1638, 2018 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-30269876

RESUMO

BACKGROUND: 2·6 million pregnancies were estimated to have ended in stillbirth in 2015. The aim of the AFFIRM study was to test the hypothesis that introduction of a reduced fetal movement (RFM), care package for pregnant women and clinicians that increased women's awareness of the need for prompt reporting of RFM and that standardised management, including timely delivery, would alter the incidence of stillbirth. METHODS: This stepped wedge, cluster-randomised trial was done in the UK and Ireland. Participating maternity hospitals were grouped and randomised, using a computer-generated allocation scheme, to one of nine intervention implementation dates (at 3 month intervals). This date was concealed from clusters and the trial team until 3 months before the implementation date. Each participating hospital had three observation periods: a control period from Jan 1, 2014, until randomised date of intervention initiation; a washout period from the implementation date and for 2 months; and the intervention period from the end of the washout period until Dec 31, 2016. Treatment allocation was not concealed from participating women and caregivers. Data were derived from observational maternity data. The primary outcome was incidence of stillbirth. The primary analysis was done according to the intention-to-treat principle, with births analysed according to whether they took place during the control or intervention periods, irrespective of whether the intervention had been implemented as planned. This study is registered with www.ClinicalTrials.gov, number NCT01777022. FINDINGS: 37 hospitals were enrolled in the study. Four hospitals declined participation, and 33 hospitals were randomly assigned to an intervention implementation date. Between Jan 1, 2014, and Dec, 31, 2016, data were collected from 409 175 pregnancies (157 692 deliveries during the control period, 23 623 deliveries in the washout period, and 227 860 deliveries in the intervention period). The incidence of stillbirth was 4·40 per 1000 births during the control period and 4·06 per 1000 births in the intervention period (adjusted odds ratio [aOR] 0·90, 95% CI 0·75-1·07; p=0·23). INTERPRETATION: The RFM care package did not reduce the risk of stillbirths. The benefits of a policy that promotes awareness of RFM remains unproven. FUNDING: Chief Scientist Office, Scottish Government (CZH/4/882), Tommy's Centre for Maternal and Fetal Health, Sands.


Assuntos
Conscientização , Morte Fetal/prevenção & controle , Movimento Fetal , Gravidez/psicologia , Cuidado Pré-Natal/métodos , Adulto , Feminino , Humanos , Irlanda/epidemiologia , Natimorto/epidemiologia , Reino Unido/epidemiologia
16.
Intensive Care Med ; 44(11): 1836-1848, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30291379

RESUMO

PURPOSE: Reliable biomarkers for predicting subsequent sepsis among patients with suspected acute infection are lacking. In patients presenting to emergency departments (EDs) with suspected acute infection, we aimed to evaluate the reliability and discriminant ability of 47 leukocyte biomarkers as predictors of sepsis (Sequential Organ Failure Assessment score ≥ 2 at 24 h and/or 72 h following ED presentation). METHODS: In a multi-centre cohort study in four EDs and intensive care units (ICUs), we standardised flow-cytometric leukocyte biomarker measurement and compared patients with suspected acute infection (cohort-1) with two comparator cohorts: ICU patients with established sepsis (cohort-2), and ED patients without infection or systemic inflammation but requiring hospitalization (cohort-3). RESULTS: Between January 2014 and February 2016, we recruited 272, 59 and 75 patients to cohorts 1, 2, and 3, respectively. Of 47 leukocyte biomarkers, 14 were non-reliable, and 17 did not discriminate between the three cohorts. Discriminant analyses for predicting sepsis within cohort-1 were undertaken for eight neutrophil (cluster of differentiation antigens (CD) CD15; CD24; CD35; CD64; CD312; CD11b; CD274; CD279), seven monocyte (CD35; CD64; CD312; CD11b; HLA-DR; CD274; CD279) and a CD8 T-lymphocyte biomarker (CD279). Individually, only higher neutrophil CD279 [OR 1.78 (95% CI 1.23-2.57); P = 0.002], higher monocyte CD279 [1.32 (1.03-1.70); P = 0.03], and lower monocyte HLA-DR [0.73 (0.55-0.97); P = 0.03] expression were associated with subsequent sepsis. With logistic regression the optimum biomarker combination was increased neutrophil CD24 and neutrophil CD279, and reduced monocyte HLA-DR expression, but no combination had clinically relevant predictive validity. CONCLUSIONS: From a large panel of leukocyte biomarkers, immunosuppression biomarkers were associated with subsequent sepsis in ED patients with suspected acute infection. CLINICAL TRIAL REGISTRATION: NCT02188992.


Assuntos
Antígenos CD/sangue , Leucócitos/fisiologia , Sepse/sangue , Sepse/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Coortes , Serviço Hospitalar de Emergência , Feminino , Antígenos HLA-DR/sangue , Humanos , Unidades de Terapia Intensiva , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
17.
PLoS One ; 13(10): e0204010, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30281643

RESUMO

BACKGROUND: Acute medical units (AMUs) receive the majority of acute medical patients presenting to hospital as an emergency in the United Kingdom (UK) and in other international settings. They have emerged as a result of local service innovation in the context of a limited evidence base. As such, the AMU model is not well characterised in terms of its boundaries, patient populations and components of care. This makes service optimisation and development through strategic resource planning, quality improvement and research challenging. AIM: This study aims to evaluate a national set of AMUs with the intent of characterising the AMU model. METHODS: Twenty-nine AMUs in Scotland were identified. Data were collected by semi-structured interviews with multidisciplinary healthcare professionals working in each AMU. A draft report was produced for each unit and verified by a unit representative. The unit reports were then analysed to develop a conceptual framework of key components of AMUs and a service definition of the boundaries of acute medical care. RESULTS: Acute medical care in Scotland can be described as being delivered in "acute medical services" rather than geographically distinct AMUs. Twelve key components of AMU care were identified: care areas, functions, populations, patient flow, support services, communication, nurse care, allied healthcare professional care, non-consultant medical care, consultant care, patient assessment and specialty care. DISCUSSION: This empirically derived characterisation of the AMU model is likely to be of utility to practitioners, managers, policy makers and researchers: it is relevant on an operational level, will aid quality improvement and is a foundation to needed further research into how best to deliver care in AMUs. This is important given the central role AMUs play in the journey of the majority of patients presenting to hospital acutely in Scotland, the UK and internationally.


Assuntos
Serviço Hospitalar de Emergência/organização & administração , Programas Nacionais de Saúde/organização & administração , Pessoal Técnico de Saúde , Comunicação , Consultores , Estudos Transversais , Pessoal de Saúde , Hospitais , Humanos , Cuidados de Enfermagem , Escócia
18.
BMJ Open ; 8(8): e021944, 2018 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-30166303

RESUMO

INTRODUCTION: The major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist). METHODS AND ANALYSIS: Patients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a sample size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland. ETHICS AND DISSEMINATION: MS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: NCT01910259; 2012-005394-31; ISRCTN28440672.


Assuntos
Amilorida/uso terapêutico , Fluoxetina/uso terapêutico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Riluzol/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
19.
Lancet ; 392(10151): 919-928, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30170853

RESUMO

BACKGROUND: High-sensitivity cardiac troponin assays permit use of lower thresholds for the diagnosis of myocardial infarction, but whether this improves clinical outcomes is unknown. We aimed to determine whether the introduction of a high-sensitivity cardiac troponin I (hs-cTnI) assay with a sex-specific 99th centile diagnostic threshold would reduce subsequent myocardial infarction or cardiovascular death in patients with suspected acute coronary syndrome. METHODS: In this stepped-wedge, cluster-randomised controlled trial across ten secondary or tertiary care hospitals in Scotland, we evaluated the implementation of an hs-cTnI assay in consecutive patients who had been admitted to the hospitals' emergency departments with suspected acute coronary syndrome. Patients were eligible for inclusion if they presented with suspected acute coronary syndrome and had paired cardiac troponin measurements from the standard care and trial assays. During a validation phase of 6-12 months, results from the hs-cTnI assay were concealed from the attending clinician, and a contemporary cardiac troponin I (cTnI) assay was used to guide care. Hospitals were randomly allocated to early (n=5 hospitals) or late (n=5 hospitals) implementation, in which the high-sensitivity assay and sex-specific 99th centile diagnostic threshold was introduced immediately after the 6-month validation phase or was deferred for a further 6 months. Patients reclassified by the high-sensitivity assay were defined as those with an increased hs-cTnI concentration in whom cTnI concentrations were below the diagnostic threshold on the contemporary assay. The primary outcome was subsequent myocardial infarction or death from cardiovascular causes at 1 year after initial presentation. Outcomes were compared in patients reclassified by the high-sensitivity assay before and after its implementation by use of an adjusted generalised linear mixed model. This trial is registered with ClinicalTrials.gov, number NCT01852123. FINDINGS: Between June 10, 2013, and March 3, 2016, we enrolled 48 282 consecutive patients (61 [SD 17] years, 47% women) of whom 10 360 (21%) patients had cTnI concentrations greater than those of the 99th centile of the normal range of values, who were identified by the contemporary assay or the high-sensitivity assay. The high-sensitivity assay reclassified 1771 (17%) of 10 360 patients with myocardial injury or infarction who were not identified by the contemporary assay. In those reclassified, subsequent myocardial infarction or cardiovascular death within 1 year occurred in 105 (15%) of 720 patients in the validation phase and 131 (12%) of 1051 patients in the implementation phase (adjusted odds ratio for implementation vs validation phase 1·10, 95% CI 0·75 to 1·61; p=0·620). INTERPRETATION: Use of a high-sensitivity assay prompted reclassification of 1771 (17%) of 10 360 patients with myocardial injury or infarction, but was not associated with a lower subsequent incidence of myocardial infarction or cardiovascular death at 1 year. Our findings question whether the diagnostic threshold for myocardial infarction should be based on the 99th centile derived from a normal reference population. FUNDING: The British Heart Foundation.


Assuntos
Síndrome Coronariana Aguda/diagnóstico , Infarto do Miocárdio/diagnóstico , Troponina I/sangue , Síndrome Coronariana Aguda/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Valor Preditivo dos Testes
20.
Pharm Stat ; 17(6): 854-865, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30215881

RESUMO

It is often unclear what specific adaptive trial design features lead to an efficient design which is also feasible to implement. Before deciding on a particular design, it is generally advisable to carry out a simulation study to characterise the properties of candidate designs under a range of plausible assumptions. The implementation of such pre-trial simulation studies presents many challenges and requires considerable statistical programming effort and time. Despite the scale and complexity, there is little existing literature to guide the implementation of such projects using commonly available software. This Teacher's Corner article provides a practical step-by-step guide to implementing such simulation studies including how to specify and fit a Bayesian model in WinBUGS or OpenBUGS using SAS, and how results from the Bayesian analysis may be pulled back into SAS and used for adaptation of allocation probabilities before simulating subsequent stages of the trial. The interface between the two software platforms is described in detail along with useful tips and tricks. A key strength of our approach is that the entire exercise can be defined and controlled from within a single SAS program.


Assuntos
Teorema de Bayes , Ensaios Clínicos como Assunto , Guias de Prática Clínica como Assunto , Simulação por Computador , Humanos
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