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1.
J Bone Miner Res ; 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32119749

RESUMO

Odanacatib (ODN), a selective oral inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this analysis, the effects of ODN on bone remodeling/modeling and structure were examined in the randomized, double-blind, placebo-controlled, event-driven, Phase 3, Long-term Odanacatib Fracture Trial (LOFT; NCT00529373) and planned double-blind extension in postmenopausal women with osteoporosis. A total of 386 transilial bone biopsies, obtained from consenting patients at baseline (ODN n = 17, placebo n = 23), Month 24 (ODN n = 112, placebo n = 104), -36 (ODN n = 42, placebo n = 41), and - 60 (ODN n = 27, placebo n = 20), were assessed by dynamic and static bone histomorphometry. Patient characteristics at baseline and BMD changes over 5 years for this subset were comparable to the overall LOFT population. Qualitative assessment of biopsies revealed no abnormalities. Consistent with the mechanism of ODN, osteoclast number was higher with ODN versus placebo over time. Regarding bone remodeling, dynamic bone formation indices in trabecular, intracortical, and endocortical surfaces were generally similar in ODN- versus placebo-treated patients after 2 years' treatment. Regarding periosteal modeling, the proportion of patients with periosteal double labels and the bone formation indices increased over time in the ODN-treated patients compared with placebo. This finding supported the observed numerical increase in cortical thickness at Month 60 versus placebo. In conclusion, ODN treatment for 5 years did not reduce bone remodeling and increased the proportion of patients with periosteal bone formation. These results are consistent with the mechanism of action of ODN, and are associated with continued BMD increases and reduced risk of fractures compared with placebo in the LOFT Phase 3 fracture trial. This article is protected by copyright. All rights reserved.

2.
Cardiovasc J Afr ; 30(5): 279-284, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31512717

RESUMO

BACKGROUND: Alirocumab reduces low-density lipoprotein cholesterol (LDL-C) levels by up to 61%. The ODYSSEY Open-Label Extension study investigated the effect of alirocumab in patients with heterozygous familial hypercholesterolaemia (HeFH) over 144 weeks. METHODS: Eligible patients with HeFH had completed an earlier double-blind, randomised, placebo-controlled parent study. Patients were initiated on 75 mg alirocumab Q2W subcutaneous (SC) unless baseline LDL-C was > 8.9 mmol/l, in which case they received 150 mg alirocumab Q2W. Dose titration to 150 mg Q2W was at the investigator's discretion. RESULTS: The study enrolled 167 patients and the parent study mean (± SD) baseline LDL-C level was 3.65 ± 1.9 mmol/l. Mean LDL-C level was reduced by 48.7% at week 144; mean on-treatment LDL-C was 2.30 ± 1.24 mmol/l. Eight patients reported injection-site reactions, with one treatment discontinuation. Treatment emergent anti-drug antibodies were identified in five patients but these did not affect the efficacy. CONCLUSIONS: Alirocumab effectively and safely reduced LDL-C in these patients.

4.
Pediatr Blood Cancer ; 66(11): e27954, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31397075

RESUMO

INTRODUCTION: Sickle cell disease (SCD) is among the most common inherited hematologic diseases in sub-Saharan Africa (SSA). Historically, hydroxyurea administration in SSA has been restricted due to limited region-specific evidence for safety and efficacy. METHODS: We conducted a prospective observational cohort study of pediatric patients with SCD in Malawi. From January 2015 to November 2017, hydroxyurea at doses of 10-20 mg/kg/day was administered to children with clinically severe disease (targeted use policy). From December 2017 to July 2018, hydroxyurea was prescribed to all patients (universal use policy). RESULTS: Of 187 patients with SCD, seven (3.7%) died and 23 (12.3%) were lost to follow-up. The majority (135, 72.2%) were prescribed hydroxyurea, 59 (43.7%) under the targeted use policy and 76 (56.3%) under the universal use policy. There were no documented severe toxicities. Under the targeted use policy, children with SCD demonstrated absolute decreases in the rates of hospitalization (-4.1 per 1000 person-days; -7.2, -1.0; P = .004), fevers (-4.2 per 1000 person-days; -7.2, -1.1; P = .002), transfusions (-2.3 per 1000 person-days; 95% confidence interval: -4.9, 0.3; P = .06), and annual school absenteeism (-51.2 per person-year; -60.1, -42.3; P < .0001) within 6 months of hydroxyurea commencement. CONCLUSION: We successfully implemented universal administration of hydroxyurea to children with SCD at a tertiary hospital in Malawi. Similar to recently reported trials, hydroxyurea was safe and effective during routine programmatic experience, with clinical benefits particularly among high-risk children. This highlights the importance of continued widespread scale-up of hydroxyurea within SCD programs across SSA.


Assuntos
Anemia Falciforme/tratamento farmacológico , Países em Desenvolvimento , Hidroxiureia/uso terapêutico , Absenteísmo , Adolescente , Anemia Falciforme/epidemiologia , Transfusão de Sangue/estatística & dados numéricos , Criança , Pré-Escolar , Terapia Combinada , Feminino , Febre/epidemiologia , Febre/etiologia , Hemoglobinas/análise , Hospitalização/estatística & dados numéricos , Hospitais Públicos/estatística & dados numéricos , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/provisão & distribução , Lactente , Cooperação Internacional , Malaui/epidemiologia , Masculino , North Carolina , Pacientes Desistentes do Tratamento , Utilização de Procedimentos e Técnicas , Estudos Prospectivos , Centros de Atenção Terciária/estatística & dados numéricos
5.
J R Coll Physicians Edinb ; 49(2): 105-111, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31188337

RESUMO

BACKGROUND: This scoping survey is a preliminary part of the Scottish Care of Older People (SCoOP) audit programme, which aims to assess specialist service provision for older people with frailty in Scotland, and provide benchmarking data for improving services. METHODS: The survey was distributed to nominated consultant geriatricians based in 12 of the 14 Scottish health boards who completed data to the 'best of their knowledge'. Data collected were: consultant and specialty doctor level workforce; days of frailty unit operation; multidisciplinary team discussion frequency; and, physiotherapy and occupational therapy availability. Consultant cover was correlated with population data, and scores for service components used to derive separate acute and community service provision scores. RESULTS: Consultant geriatrician availability varies widely across Scottish health boards with a median of 1.45 [range: 0.54-2.40; interquartile range (IQR): 0.71-2.28] full-time equivalent consultant geriatricians per 10,000 people ≥65 years. Variation was also present in the service provision scores [score range 0 (none) to 1.0 (very good)]: for acute services, the median national service provision score was 0.81 (range: 0.50-0.89; IQR: 0.75-0.85) and for community services 0.60 (range: 0.48-0.82; IQR: 0.52-0.65). CONCLUSIONS: This report clearly demonstrates mismatch between workforce and services in both acute and community settings in the context of the population size. Future surveys will build on this preliminary information to audit service provision for older people at an individual hospital level.

6.
BMJ Open ; 9(5): e023350, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072849

RESUMO

OBJECTIVES: To compare the characteristics of populations admitted to hospital-at-home services with the population admitted to hospital and assess the association of these services with healthcare costs and mortality. DESIGN: In a retrospective observational cohort study of linked patient level data, we used propensity score matching in combination with regression analysis. PARTICIPANTS: Patients aged 65 years and older admitted to hospital-at-home or hospital. INTERVENTIONS: Three geriatrician-led admission avoidance hospital-at-home services in Scotland. OUTCOME MEASURES: Healthcare costs and mortality. RESULTS: Patients in hospital-at-home were older and more socioeconomically disadvantaged, had higher rates of previous hospitalisation and there was a greater proportion of women and people with several chronic conditions compared with the population admitted to hospital. The cost of providing hospital-at-home varied between the three sites from £628 to £2928 per admission. Hospital-at-home was associated with 18% lower costs during the follow-up period in site 1 (ratio of means 0.82; 95% CI: 0.76 to 0.89). Limiting the analysis to costs during the 6 months following index discharge, patients in the hospital-at-home cohorts had 27% higher costs (ratio of means 1.27; 95% CI: 1.14 to 1.41) in site 1, 9% (ratio of means 1.09; 95% CI: 0.95 to 1.24) in site 2 and 70% in site 3 (ratio of means 1.70; 95% CI: 1.40 to 2.07) compared with patients in the control cohorts. Admission to hospital-at-home was associated with an increased risk of death during the follow-up period in all three sites (1.09, 95% CI: 1.00 to 1.19 site 1; 1.29, 95% CI: 1.15 to 1.44 site 2; 1.27, 95% CI: 1.06 to 1.54 site 3). CONCLUSIONS: Our findings indicate that in these three cohorts, the populations admitted to hospital-at-home and hospital differ. We cannot rule out the risk of residual confounding, as our analysis relied on an administrative data set and we lacked data on disease severity and type of hospitalised care received in the control cohorts.

7.
Age Ageing ; 48(4): 498-505, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30855656

RESUMO

Geriatric medicine is a speciality that has historically relied on team working to best serve patients. The nature of frailty in older people means that people present with numerous comorbidities, which in turn require a team-based approach to be managed, including allied health professionals, social work and nursing alongside medicine. The 'engine room' of the speciality has thus for many years been the multidisciplinary team (MDT) meeting-something other specialities have discovered only recently. Yet, rather paradoxically, the speciality has been slow compared to others (e.g. trauma, surgery, cancer) to reflect more formally on how team working can be enhanced, trained and supported in geriatric teams. This paper is a reflective review, grounded on our respective expertise in geriatric medicine and improvement science, on practice and its changing patterns within geriatric medicine, and the role of MDTs within it (Part 1). It offers a perspective from behavioural safety science, which has been studying team-working in healthcare for the last 20 years (Part 2) and concludes with practical suggestions, based on evidence, on how to integrate evidence and best practice into modern geriatric medicine-to address current and future challenges (Part 3).

9.
Blood Adv ; 2(21): 3035-3044, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30425067

RESUMO

In sub-Saharan Africa, inherited causes of anemia are common, but data are limited regarding the geographical prevalence and coinheritance of these conditions and their overall contributions to childhood anemia. To address these questions in Malawi, we performed a secondary analysis of the 2015-2016 Malawi Micronutrient Survey, a nationally and regionally representative survey that estimated the prevalence of micronutrient deficiencies and evaluated both inherited and noninherited determinants of anemia. Children age 6 to 59 months were sampled from 105 clusters within the 2015-2016 Malawi Demographic Health Survey. Hemoglobin, ferritin, retinol binding protein, malaria, and inflammatory biomarkers were measured from venous blood. Molecular studies were performed using dried blood spots to determine the presence of sickle cell disease or trait, α-thalassemia trait, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Of 1279 eligible children, 1071 were included in the final analysis. Anemia, iron deficiency, and malaria were common, affecting 30.9%, 21.5%, and 27.8% of the participating children, respectively. α-Thalassemia trait was common (>40% of children demonstrating deletion of 1 [33.1%] or 2 [10.0%] α-globin genes) and associated with higher prevalence of anemia (P < .001). Approximately 20% of males had G6PD deficiency, which was associated with a 1.0 g/dL protection in hemoglobin decline during malaria infection (P = .02). These data document that inherited blood disorders are common and likely play an important role in the prevalence of anemia and malaria in Malawian children.


Assuntos
Anemia/diagnóstico , Transtornos Herdados da Coagulação Sanguínea/diagnóstico , Malária/diagnóstico , Anemia/complicações , Anemia/epidemiologia , Anemia/patologia , Anemia Falciforme/complicações , Anemia Falciforme/diagnóstico , Transtornos Herdados da Coagulação Sanguínea/complicações , Transtornos Herdados da Coagulação Sanguínea/epidemiologia , Pré-Escolar , Análise Discriminante , Feminino , Genótipo , Deficiência de Glucosefosfato Desidrogenase/complicações , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Deficiência de Glucosefosfato Desidrogenase/genética , Humanos , Malária/complicações , Malária/epidemiologia , Malaui/epidemiologia , Masculino , Prevalência , Índice de Gravidade de Doença , Talassemia alfa/complicações , Talassemia alfa/diagnóstico , Talassemia alfa/genética
10.
Trials ; 19(1): 569, 2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30340618

RESUMO

BACKGROUND: Attempts to design services to support the delivery of healthcare closer to home have taken various forms as countries respond to an increase in hospital admission rates for older people, who are at risk of hospital-acquired morbidity, prolonged lengths of stay and readmission. Evidence to support the development of these services is limited. We are conducting a process evaluation, alongside a UK multi-site randomised trial, to understand the contexts and practices of implementing geriatrician-led admission avoidance hospital at home services and to explore ways that the intervention might be effective, under what conditions, for whom, and how it differs from inpatient care. METHODS: We are interviewing patients and their caregivers, from sites that are purposively sampled from participating National Health Service (NHS) trusts across the UK. We are also visiting sites to observe local processes and discuss the establishment and running of services with a range of multidisciplinary staff, managers, commissioners, primary care and social services representatives. We aim to interview approximately 36 patients and their caregivers with experience of hospital at home or inpatient services; 12 at each of three sites. We will use a content analysis approach to explore data across participants, services and sites. DISCUSSION: This process evaluation will enable evaluation of implementation processes prior to knowing trial outcomes. We encompass domains of reach, delivery, change, context and response to the intervention by patients, their carers, health professionals and the health system. TRIAL REGISTRATION: ISRCTN60477865 . Registered on 10 March 2014. Trial sponsor: University of Oxford. Version 3.1, registered on 14 June 2016.


Assuntos
Avaliação Geriátrica , Geriatras , Serviços de Assistência Domiciliar , Ensaios Clínicos Controlados Aleatórios como Assunto , Idoso de 80 Anos ou mais , Cuidadores , Análise de Dados , Humanos , Pacientes Internados , Estudos Multicêntricos como Assunto , Admissão do Paciente , Pesquisa Qualitativa
11.
Toxicol Sci ; 165(1): 170-185, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29860528

RESUMO

Cosmetic regulations prohibit animal testing for the purpose of safety assessment and recent registration, evaluation and authorization of chemicals guidance states that the local lymph node assay (LLNA) in mice shall only be conducted if in vitro data cannot give sufficient information for classification and labeling. However, Quantitative Risk Assessment for fragrance ingredients requires an NESIL (no expected sensitization induction level), a dose not expected to cause induction of skin sensitization in humans. In absence of human data, this is derived from the LLNA and it remains a key challenge for risk assessors to derive this value from nonanimal data. Here we present a workflow using structural information, reactivity data and KeratinoSens results to predict an LLNA result as a point of departure. Specific additional tests (metabolic activation, complementary reactivity tests) are applied in selected cases depending on the chemical domain of a molecule. Finally, in vitro and in vivo data on close analogues are used to estimate uncertainty of the prediction in the specific chemical domain. This approach was applied to three molecules which were subsequently tested in the LLNA and 22 molecules with available and sometimes discordant human and LLNA data. Four additional case studies illustrate how this approach is being applied to recently developed molecules in the absence of animal data. Estimation of uncertainty and how this can be applied to determine a final NESIL for risk assessment is discussed. We conclude that, in the data-rich domain of fragrance ingredients, sensitization risk assessment without animal testing is possible in most cases by this integrated approach.


Assuntos
Alternativas aos Testes com Animais/métodos , Dermatite Alérgica de Contato/etiologia , Perfumes , Animais , Humanos , Ensaio Local de Linfonodo , Nível de Efeito Adverso não Observado , Perfumes/administração & dosagem , Perfumes/química , Perfumes/toxicidade , Medição de Risco
12.
Pediatr Blood Cancer ; 65(6): e26993, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29411937

RESUMO

BACKGROUND: Glomerulopathy is an increasingly identified complication in young patients with sickle cell disease (SCD). Hyperfiltration and albuminuria followed by declining glomerular filtration rates and eventual end-stage renal disease (ESRD) is assumed to be the typical progression of glomerular disease. There are only a few reported biomarkers to identify early-stage renal disease in SCD. PROCEDURES: We detail the renal profile of 101 children with SCD in Malawi and propose a novel urinary biomarker for the identification of early renal disease. RESULTS: Among children with sickle cell anemia, 24.8% had a urine albumin-creatinine ratio of 30 mg/g or above. In univariate analysis, only patients with higher urinary nephrin, a urinary marker of glomerular injury, had significantly greater odds of having albuminuria. In multivariable analysis, nephrin remained significantly associated with albuminuria. A nephrin-creatinine ratio (NCR) cut-point of 622 ng/mg, the 50th percentile, was associated with a 45.8 times greater odds of having albuminuria in children with nephrinuria above this value. Further analysis revealed this urinary NCR cut-point to have 96% sensitivity, 64% specificity, 47% positive predictive value, and 98% negative predictive value for the presence of albuminuria. CONCLUSIONS: These data suggest that a substantial number of children with SCD in Malawi have renal disease and could be at risk for worsening nephropathy and ESRD as they age. Our data suggest that urinary nephrin could be utilized as an early marker of glomerular disease in SCD.


Assuntos
Albuminúria/diagnóstico , Anemia Falciforme/complicações , Biomarcadores/urina , Nefropatias/diagnóstico , Proteínas de Membrana/urina , Adolescente , Albuminúria/etiologia , Albuminúria/urina , Criança , Estudos Transversais , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Nefropatias/etiologia , Nefropatias/urina , Testes de Função Renal , Malaui , Masculino , Prognóstico
13.
Cardiovasc Diabetol ; 16(1): 141, 2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-29096623

RESUMO

BACKGROUND: We have previously shown that many chronic, inflammatory diseases are accompanied, and possibly partly caused or exacerbated, by various coagulopathies, manifested as anomalous clots in the form of 'dense matted deposits'. More recently, we have shown that these clots can be amyloid in nature, and that the plasma of healthy controls can be induced to form such clots by the addition of tiny amounts of bacterial lipopolysaccharide or lipoteichoic acid. Type 2 diabetes (T2D) is also accompanied by raised levels of LPS. METHODS: We use superresolution and confocal microscopies to investigate the amyloid nature of clots from healthy and T2D individuals. RESULTS: We show here, with the established stain thioflavin T and the novel stains Amytracker™ 480 and 680, that the clotting of plasma from type 2 diabetics is also amyloid in nature, and that this may be prevented by the addition of suitable concentrations of LPS-binding protein. CONCLUSION: This implies strongly that there is indeed a microbial component to the development of type 2 diabetes, and suggests that LBP might be used as treatment for it and its sequelae.


Assuntos
Amiloide/sangue , Corantes/metabolismo , Diabetes Mellitus Tipo 2/sangue , Fibrina/metabolismo , Corantes Fluorescentes/metabolismo , Adolescente , Adulto , Idoso , Amiloide/análise , Corantes/análise , Feminino , Fibrina/análise , Corantes Fluorescentes/análise , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Toxicol Sci ; 160(2): 244-255, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973542

RESUMO

Several aromatic aldehydes such as 3-(4-tert-butylphenyl)-2-methylpropanal were shown to adversely affect the reproductive system in male rats following oral gavage dose of ≥ 25 mg/kg bw/d. It was hypothesized that these aldehydes are metabolized to benzoic acids such as p-tert-butylbenzoic acid as key toxic principle and that Coenzyme A (CoA) conjugates may be formed from such acids. Here we performed a detailed structure activity relationship study on the formation of benzoic acids from p-alkyl-phenylpropanals and related chemicals in rat hepatocytes in suspension. Formation of CoA conjugates from either p-alkyl-phenylpropanals directly or from their benzoic acid metabolites was further assessed in plated rat hepatocytes using high resolution LC-MS. All of the test chemicals causing reproductive adverse effects in male rats formed p-alkyl-benzoic acids in rat hepatocytes in suspension. Compounds metabolized to p-alkyl-benzoic acids led to accumulation of p-alkyl-benzoyl-CoA conjugates at high and steady levels in plated rat hepatocytes, whereas CoA conjugates of most other xenobiotic acids were only transiently detected in this in vitro system. The correlation between this metabolic fate and the toxic outcome may indicate that accumulation of the alkyl-benzoyl-CoA conjugates in testicular cells could impair male reproduction by adversely affecting CoA-dependent processes required for spermatogenesis. This hypothesis prompted a search for new p-alkyl-phenylpropanal derivatives which do not form benzoic acid metabolites and the corresponding CoA conjugates. It was found that such metabolism did not occur with a derivative containing an o-methyl substituent, ie, 3-(4-isobutyl-2-methylphenyl)propanal. This congener preserved the fragrance quality but lacked the male reproductive toxicity in a 28-day rat study, as predicted from its in vitro metabolism.


Assuntos
Aldeídos/toxicidade , Hepatócitos/metabolismo , Hidrocarbonetos Aromáticos/toxicidade , Perfumes/toxicidade , Reprodução/efeitos dos fármacos , Testículo/efeitos dos fármacos , Aldeídos/química , Aldeídos/metabolismo , Animais , Benzoatos/química , Benzoatos/metabolismo , Benzoatos/toxicidade , Biotransformação , Células Cultivadas , Coenzima A/química , Coenzima A/metabolismo , Coenzima A/toxicidade , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/metabolismo , Masculino , Estrutura Molecular , Perfumes/química , Perfumes/metabolismo , Ratos Sprague-Dawley , Medição de Risco , Testículo/metabolismo , Testículo/patologia , Fatores de Tempo , Testes de Toxicidade Subcrônica
15.
Trials ; 18(1): 491, 2017 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-29061154

RESUMO

BACKGROUND: There is concern that existing models of acute hospital care will become unworkable as the health service admits an increasing number of frail older people with complex health needs, and that there is inadequate evidence to guide the planning of acute hospital level services. We aim to evaluate whether geriatrician-led admission avoidance to hospital at home is an effective alternative to hospital admission. METHODS/DESIGN: We are conducting a multi-site randomised open trial of geriatrician-led admission avoidance hospital at home, compared with admission to hospital. We are recruiting older people with markers of frailty or prior dependence who have been referred to admission avoidance hospital at home for an acute medical event. This includes patients presenting with delirium, functional decline, dependence, falls, immobility or a background of dementia presenting with physical disease. Participants are randomised using a computerised random number generator to geriatrician-led admission avoidance hospital at home or a control group of inpatient admission in a 2:1 ratio in favour of the intervention. The primary endpoint 'living at home' (the inverse of death or living in a residential care setting) is measured at 6 months follow-up, and we also collect data on this outcome at 12 months. Secondary outcomes include the incidence of delirium, mortality, new long-term residential care, cognitive impairment, activities of daily living, quality of life and quality-adjusted survival, length of stay, readmission or transfer to hospital. We will conduct a parallel economic evaluation, and a process evaluation that includes an interview study to explore the experiences of patients and carers. DISCUSSION: Health systems around the world are examining how to provide acute hospital-level care to older adults in greater numbers with a fixed or shrinking hospital resource. This trial is the first large multi-site randomised trial of geriatrician-led admission avoidance hospital at home, and will provide evidence on alternative models of healthcare for older people who require hospital admission. TRIAL REGISTRATION: ISRCTN60477865 : Registered on 10 March 2014. Trial Sponsor: University of Oxford. Version 3.1, 14/06/2016.


Assuntos
Fragilidade/terapia , Geriatras , Geriatria/métodos , Serviços Hospitalares de Assistência Domiciliar , Liderança , Admissão do Paciente , Papel Profissional , Atividades Cotidianas , Fatores Etários , Idoso , Envelhecimento , Protocolos Clínicos , Pesquisa Comparativa da Efetividade , Avaliação da Deficiência , Idoso Fragilizado , Fragilidade/diagnóstico , Fragilidade/fisiopatologia , Fragilidade/psicologia , Avaliação Geriátrica , Humanos , Masculino , Qualidade de Vida , Projetos de Pesquisa , Fatores de Tempo , Resultado do Tratamento , Reino Unido
16.
Cochrane Database Syst Rev ; 9: CD006211, 2017 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-28898390

RESUMO

BACKGROUND: Comprehensive geriatric assessment (CGA) is a multi-dimensional, multi-disciplinary diagnostic and therapeutic process conducted to determine the medical, mental, and functional problems of older people with frailty so that a co-ordinated and integrated plan for treatment and follow-up can be developed. This is an update of a previously published Cochrane review. OBJECTIVES: We sought to critically appraise and summarise current evidence on the effectiveness and resource use of CGA for older adults admitted to hospital, and to use these data to estimate its cost-effectiveness. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, three other databases, and two trials registers on 5 October 2016; we also checked reference lists and contacted study authors. SELECTION CRITERIA: We included randomised trials that compared inpatient CGA (delivered on geriatric wards or by mobile teams) versus usual care on a general medical ward or on a ward for older people, usually admitted to hospital for acute care or for inpatient rehabilitation after an acute admission. DATA COLLECTION AND ANALYSIS: We followed standard methodological procedures expected by Cochrane and Effective Practice and Organisation of Care (EPOC). We used the GRADE approach to assess the certainty of evidence for the most important outcomes. For this update, we requested individual patient data (IPD) from trialists, and we conducted a survey of trialists to obtain details of delivery of CGA. We calculated risk ratios (RRs), mean differences (MDs), or standardised mean differences (SMDs), and combined data using fixed-effect meta-analysis. We estimated cost-effectiveness by comparing inpatient CGA versus hospital admission without CGA in terms of cost per quality-adjusted life year (QALY) gained, cost per life year (LY) gained, and cost per life year living at home (LYLAH) gained. MAIN RESULTS: We included 29 trials recruiting 13,766 participants across nine, mostly high-income countries. CGA increases the likelihood that patients will be alive and in their own homes at 3 to 12 months' follow-up (risk ratio (RR) 1.06, 95% confidence interval (CI) 1.01 to 1.10; 16 trials, 6799 participants; high-certainty evidence), results in little or no difference in mortality at 3 to 12 months' follow-up (RR 1.00, 95% CI 0.93 to 1.07; 21 trials, 10,023 participants; high-certainty evidence), decreases the likelihood that patients will be admitted to a nursing home at 3 to 12 months follow-up (RR 0.80, 95% CI 0.72 to 0.89; 14 trials, 6285 participants; high-certainty evidence) and results in little or no difference in dependence (RR 0.97, 95% CI 0.89 to 1.04; 14 trials, 6551 participants; high-certainty evidence). CGA may make little or no difference to cognitive function (SMD ranged from -0.22 to 0.35 (5 trials, 3534 participants; low-certainty evidence)). Mean length of stay ranged from 1.63 days to 40.7 days in the intervention group, and ranged from 1.8 days to 42.8 days in the comparison group. Healthcare costs per participant in the CGA group were on average GBP 234 (95% CI GBP -144 to GBP 605) higher than in the usual care group (17 trials, 5303 participants; low-certainty evidence). CGA may lead to a slight increase in QALYs of 0.012 (95% CI -0.024 to 0.048) at GBP 19,802 per QALY gained (3 trials; low-certainty evidence), a slight increase in LYs of 0.037 (95% CI 0.001 to 0.073), at GBP 6305 per LY gained (4 trials; low-certainty evidence), and a slight increase in LYLAH of 0.019 (95% CI -0.019 to 0.155) at GBP 12,568 per LYLAH gained (2 trials; low-certainty evidence). The probability that CGA would be cost-effective at a GBP 20,000 ceiling ratio for QALY, LY, and LYLAH was 0.50, 0.89, and 0.47, respectively (17 trials, 5303 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Older patients are more likely to be alive and in their own homes at follow-up if they received CGA on admission to hospital. We are uncertain whether data show a difference in effect between wards and teams, as this analysis was underpowered. CGA may lead to a small increase in costs, and evidence for cost-effectiveness is of low-certainty due to imprecision and inconsistency among studies. Further research that reports cost estimates that are setting-specific across different sectors of care are required.


Assuntos
Assistência Integral à Saúde/métodos , Idoso Fragilizado , Avaliação Geriátrica/métodos , Hospitalização , Idoso , Emergências , Humanos , Vida Independente/estatística & dados numéricos , Mortalidade
17.
N Engl J Med ; 376(26): 2534-2544, 2017 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-28402245

RESUMO

BACKGROUND: The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 µg daily, or 25 µg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). RESULTS: The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 µg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. CONCLUSIONS: Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .).


Assuntos
Hipotireoidismo/tratamento farmacológico , Tiroxina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Fadiga/etiologia , Feminino , Humanos , Hipotireoidismo/complicações , Análise de Intenção de Tratamento , Masculino , Qualidade de Vida , Tireotropina/sangue , Tiroxina/efeitos adversos , Tiroxina/sangue , Falha de Tratamento
19.
Regul Toxicol Pharmacol ; 73(1): 210-26, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26188116

RESUMO

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a workshop Knowledge sharing to facilitate regulatory decision-making. Fifty invited participants from the European Commission, national and European agencies and bodies, different industry sectors (chemicals, cosmetics, fragrances, pharmaceuticals, vaccines), and animal protection organizations attended the workshop. Four case studies exemplarily revealed which procedures are in place to obtain regulatory acceptance of new test methods in different sectors. Breakout groups discussed the status quo identifying the following facilitators for regulatory acceptance of alternatives to animal testing: Networking and communication (including cross-sector collaboration, international cooperation and harmonization); involvement of regulatory agencies from the initial stages of test method development on; certainty on prerequisites for test method acceptance including the establishment of specific criteria for regulatory acceptance. Data sharing and intellectual property issues affect many aspects of test method development, validation and regulatory acceptance. In principle, all activities should address replacement, reduction and refinement methods (albeit animal testing is generally prohibited in the cosmetics sector). Provision of financial resources and education support all activities aiming at facilitating the acceptance and use of alternatives to animal testing. Overall, workshop participants recommended building confidence in new methodologies by applying and gaining experience with them.


Assuntos
Alternativas aos Testes com Animais/métodos , Testes de Toxicidade/métodos , Animais , Cosméticos/química , Tomada de Decisões , Indústrias/métodos , Cooperação Internacional
20.
Chem Res Toxicol ; 28(6): 1205-8, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25942677

RESUMO

Hydroperoxides can act as specific haptens and oxidatively modify proteins. Terpene hydroperoxides trigger unusually high frequencies of positive skin reactions in human patients if tested at high concentrations. It is unknown whether this is due to specific hapten formation. Here, we show that both terpene hydroperoxides and the endogenous hydroperoxide formed from squalene can oxidatively modify tryptophan. Oxidative modifications of Trp were recently postulated to explain cross-sensitization between unrelated photosensitizers. Current observations may extend this hypothesis: Oxidative events triggered by endogenous hydroperoxides and hydroperoxides/oxidants derived from xenobiotics might lead to a sensitized state detected by patch tests with high concentrations of hydroperoxides.


Assuntos
Testes Diagnósticos de Rotina , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Triptofano/metabolismo , Estrutura Molecular , Oxirredução/efeitos dos fármacos
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