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1.
Cerebrovasc Dis ; : 1-10, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496366

RESUMO

INTRODUCTION: The 5-year recurrence risk after ischaemic stroke and transient ischaemic attack (TIA) is 25-30%. Although inflammation may be a target for prevention trials, the contribution of plaque inflammation to acute cerebrovascular events remains unclear. We investigated the association of acute inflammatory cytokines and high-sensitivity C-reactive protein (CRP) with recently symptomatic carotid atherosclerosis in a prospective cohort study. METHODS: Blood and Imaging markers of TIA BIO-TIA) is a multicentre prospective study of imaging and inflammatory markers in patients with TIA. Exclusion criteria were infection and other co-morbid illnesses associated with inflammation. CRP and serum cytokines (interleukin [IL]-6, IL-1ß, IL-8, IL-10, IL-12, interferon-γ [IFN-γ] and tumour necrosis factor-α [TNF-α]) were measured. All patients had carotid imaging. RESULTS: Two hundred and thirty-eight TIA cases and 64 controls (TIA mimics) were included. Forty-nine (20.6%) cases had symptomatic internal carotid artery stenosis. Pro-inflammatory cytokine levels increased in a dose-dependent manner across controls, TIA without carotid stenosis (CS), and TIA with CS (IL-1ß, ptrend = 0.03; IL-6, ptrend < 0.0001; IL-8, ptrend = 0.01; interferon (IFN)-γ, ptrend = 0.005; TNF-α, ptrend = 0.003). Results were unchanged when DWI-positive cases were excluded. On multivariable linear regression, only age (p = 0.01) and CS (p = 0.04) independently predicted log-IL-6. On multivariable Cox regression, CRP was the only independent predictor of 90-day stroke recurrence (adjusted hazard ratio per 1-unit increase 1.03 [95% CI: 1.01-1.05], p = 0.003). CONCLUSION: Symptomatic carotid atherosclerosis was associated with elevated cytokines in TIA patients after controlling for other sources of inflammation. High-sensitivity CRP was associated with recurrent ischaemic stroke at 90 days. These findings implicate acute plaque inflammation in the pathogenesis of cerebral thromboembolism and support a rationale for randomized trials of anti-inflammatory therapy for stroke patients, who were excluded from coronary trials.

2.
Stroke ; : STROKEAHA121034005, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34496624

RESUMO

BACKGROUND AND PURPOSE: Cognitive impairment no dementia (CIND) and dementia are common stroke outcomes, with significant health and societal implications for aging populations. These outcomes are not included in current epidemiological models. We aimed to develop an epidemiological model to project incidence and prevalence of stroke, poststroke CIND and dementia, and life expectancy, in Ireland to 2035, informing policy and service planning. METHODS: We developed a probabilistic Markov model (the StrokeCog model) applied to the Irish population aged 40 to 89 years to 2035. Data sources included official population and hospital-episode statistics, longitudinal cohort studies, and published estimates. Key assumptions were varied in sensitivity analysis. Results were externally validated against independent sources. The model tracks poststroke progression into health states characterized by no cognitive impairment, CIND, dementia, disability, stroke recurrence, and death. RESULTS: We projected 69 051 people with prevalent stroke in Ireland in 2035 (22.0 per 1000 population [95% CI, 20.8-23.1]), with 25 274 (8.0 per 1000 population [95% CI, 7.1-9.0]) of those projected to have poststroke CIND, and 12 442 having poststroke dementia (4.0 per 1000 population [95% CI, 3.2-4.8]). We projected 8725 annual incident strokes in 2035 (2.8 per 1000 population [95% CI, 2.7-2.9]), with 3832 of these having CIND (1.2 per 1000 population [95% CI, 1.1-1.3]), and 1715 with dementia (0.5 per 1000 population [95% CI, 0.5-0.6]). Life expectancy for stroke survivors at age 50 was 23.4 years (95% CI, 22.3-24.5) for women and 20.7 (95% CI, 19.5-21.9) for men. CONCLUSIONS: This novel epidemiological model of stroke, poststroke CIND, and dementia draws on the best available evidence. Sensitivity analysis indicated that findings were robust to assumptions, and where there was uncertainty a conservative approach was taken. The StrokeCog model is a useful tool for service planning and cost-effectiveness analysis and is available for adaptation to other national contexts.

3.
Pediatr Res ; 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103679

RESUMO

BACKGROUND: States which reduce foetal oxygen delivery are associated with impaired intrauterine growth. Hypoxia results when barometric pressure falls with ascent to altitude, and with it the partial pressure of inspired oxygen ('hypobaric hypoxia'). birthweight is reduced when native lowlanders gestate at such high altitude (HA)-an effect mitigated in native (millennia) HA populations. Studying HA populations offer a route to explore the mechanisms by which hypoxia impacts foetal growth. METHODS: Between February 2017 and January 2019, we prospectively studied 316 pregnant women, in Leh, Ladakh (altitude 3524 m, where oxygen partial pressure is reduced by 1/3) and 101 pregnant women living in Delhi (low altitude, 216 m above sea level). RESULTS: Of Ladakhi HA newborns, 14% were small for gestational age (<10th birthweight centile) vs 19% of newborn at low altitude. At HA, increased maternal body mass index, age, and uterine artery (UtA) diameter were positively associated with growth >10th weight centile. CONCLUSIONS: This study showed that Ladakhi offspring birthweight is relatively spared from the expected adverse HA effects. Furthermore, maternal body composition and greater UtA size may be physiological HA adaptations and warrant further study, as they offer potential mechanisms to overcome hypoxia-related growth issues. IMPACT: Reduced foetal oxygen delivery seen in native lowlanders who gestate at HA causes foetal growth restriction-an effect thought to be mitigated in native HA populations. We found that greater maternal body mass and UtA diameter were associated with increased offspring birthweight in a (Ladakh) HA population. This supports a role for them as physiological mediators of adaptation and provides insights into potential mechanisms that may treat hypoxia-related growth issues.

5.
J Patient Saf ; 17(2): 141-148, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33395019

RESUMO

OBJECTIVE: This study aimed to determine if the implementation of large-scale patient safety initiatives have been successful in reducing overall and preventable adverse event rates in hospital inpatients. DESIGN: The design used in this study was systematic review and meta-analysis. DATA RESOURCES: We followed our published protocol (PROSPERO [CRD42019140058]) and searched the following databases: PubMed, CINAHL, PsycINFO, Cochrane Library, and Embase from inception to February 2020. The reference lists of eligible studies were also searched. ELIGIBILITY: All longitudinal retrospective record review studies that examined adverse event rates before and after the introduction of patient safety initiatives in hospital inpatients were included. DATA EXTRACTION: Data extraction, quality, and risk of bias assessment were carried out by 2 independent reviewers. Information on study design, setting, demographics, interventions, and safety outcome measures was extracted. RESULTS: A total of 3894 articles were screened, and 7 articles met the eligibility criteria for our systematic review with 5 of these providing sufficient information for inclusion in the meta-analysis. The degree of heterogeneity was high among studies. The meta-analysis demonstrated a minimal risk reduction in overall adverse event rates of 0.017 (95% confidence interval, 0.002-0.032) when the lower-quality studies were excluded, with one adverse event being prevented for every 59 hospital admissions. CONCLUSIONS: These findings are significant when the large numbers of admissions to a hospital every year are considered. Given the low numbers of large-scale implementation studies, there is a need for more research on the effectiveness of patient safety initiatives to further assess the impact of such initiatives on adverse events.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Hospitais/tendências , Humanos , Estudos Longitudinais , Avaliação de Resultados em Cuidados de Saúde , Estudos Retrospectivos
6.
BMJ Qual Saf ; 30(7): 547-558, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33436402

RESUMO

OBJECTIVES: To quantify the prevalence and nature of adverse events in acute Irish hospitals in 2015 and to assess the impact of the National Clinical Programmes and the National Clinical Guidelines on the prevalence of adverse events by comparing these results with the previously published data from 2009. DESIGN AND METHODS: A retrospective chart review of 1605 admissions to eight Irish hospitals in 2015, using identical methods to those used in 2009. RESULTS: The percentage of admissions associated with one or more adverse events was unchanged (p=0.48) at 14% (95% CI=10.4% to 18.4%) in 2015 compared with 12.2% (95% CI=9.5% to 15.5%) in 2009. Similarly, the prevalence of preventable adverse events was unchanged (p=0.3) at 7.4% (95% CI=5.3% to 10.5%) in 2015 compared with 9.1% (95% CI=6.9% to 11.9%) in 2009. The incidence densities of preventable adverse events were 5.6 adverse events per 100 admissions (95% CI=3.4 to 8.0) in 2015 and 7.7 adverse events per 100 admissions (95% CI=5.8 to 9.6) in 2009 (p=0.23). However, the percentage of preventable adverse events due to hospital-associated infections decreased to 22.2% (95% CI=15.2% to 31.1%) in 2015 from 33.1% (95% CI=25.6% to 41.6%) in 2009 (p=0.01). CONCLUSION: Adverse event rates remained stable between 2009 and 2015. The percentage of preventable adverse events related to hospital-associated infection decreased, which may represent a positive impact of the related national programmes and guidelines.

7.
Ir J Med Sci ; 190(1): 335-344, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32562218

RESUMO

BACKGROUND: There are no previously published reports regarding the epidemiology and characteristics of moyamoya disease or syndrome in Ireland. AIMS: To examine patient demographics, mode of presentation and the outcomes of extracranial-intracranial bypass surgery in the treatment of moyamoya disease and syndrome in Ireland. METHODS: All patients with moyamoya disease and syndrome referred to the National Neurosurgical Centre during January 2012-January 2019 were identified through a prospective database. Demographics, clinical presentation, radiological findings, surgical procedures, postoperative complications and any strokes during follow-up were recorded. RESULTS: Twenty-one patients were identified. Sixteen underwent surgery. Median age at diagnosis was 19 years. Fifteen were female. Mode of presentation was ischaemic stroke in nine, haemodynamic TIAs in eight, haemorrhage in three and incidental in one. Sixteen patients had Moyamoya disease, whereas five patients had moyamoya syndrome. Surgery was performed on 19 hemispheres in 16 patients. The surgical procedures consisted of ten direct (STA-MCA) bypasses, five indirect bypasses and four multiple burr holes. Postoperative complications included ischaemic stroke in one patient and subdural haematoma in one patient. The median follow-up period in the surgical group was 52 months; there was one new stroke during this period. Two patients required further revascularisation following recurrent TIAs. One patient died during follow-up secondary to tumour progression associated with neurofibromatosis type 1. CONCLUSIONS: Moyamoya is rare but occurs in Caucasians in Ireland. It most commonly presents with ischaemic symptoms. Surgical intervention in the form of direct and indirect bypass is an effective treatment in the majority of cases.


Assuntos
Revascularização Cerebral/métodos , Doença de Moyamoya/epidemiologia , Doença de Moyamoya/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Irlanda , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Síndrome , Resultado do Tratamento , Adulto Jovem
8.
Age Ageing ; 50(4): 1144-1150, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-33367538

RESUMO

INTRODUCTION: Hyponatraemia is associated with increased morbidity and mortality; the aetiology and outcomes of hyponatraemia in older patients have not been defined in prospective studies. METHODS: A single-centre 9-month prospective observational study in which clinical outcomes in hospitalised patients ≥ 65 years (older patients with hyponatraemia (OP-HN)) and those <65 years (young patients with hyponatraemia (YP-HN)) with hyponatraemia were analysed, and compared with eunatraemic controls (older patients with normonatraemia (OP-NN) and young patients with normonatraemia (YP-NN)). RESULTS: In total, 1,321 episodes of hyponatraemia in 1,086 patients were included; 437 YP-HN, median age 54 years (IQR 44,60) and 884 OP-HN, median age 77 years (IQR 71,82). A total of 1,120 consecutive eunatraemic control patients were simultaneously recruited; 690 OP-NN, median age 77 years (IQR 71,83) and 430 YP-NN, median age 52 years (IQR 41,58). Euvolaemic hyponatraemia was the commonest cause of hyponatraemia in both age groups (48% in YP-HN and 46% in OP-HN). Sixty-two percent of OP-HN received hyponatraemia-directed treatment within the initial 48 h, compared with 55% of YP-HN, P = 0.01. Despite the greater treatment rates in OP-HN, younger patients were 24% more likely to be discharged with normal plasma sodium concentration (pNa) compared with older patients, relative risk (RR) 1.24 (95% confidence interval (CI) 1.12-1.37), P < 0.001.Using OP-NN as the reference group, the RR of in-hospital death in OP-HN was 2.15 (95% CI 1.3-3.56), P = 0.002. Using YP-NN as the reference group, the RR of in-hospital death in YP-HN was 4.34 (95% CI 1.98-9.56), P < 0.001. CONCLUSION: Despite greater rates of HN-targeted treatment, the risk of in-hospital death is increased in older hyponatraemic patients compared with older eunatraemic controls. The impact of hyponatraemia on mortality is even greater in younger patients.


Assuntos
Hiponatremia , Adulto , Idoso , Idoso de 80 Anos ou mais , Mortalidade Hospitalar , Humanos , Hiponatremia/diagnóstico , Hiponatremia/terapia , Pessoa de Meia-Idade , Estudos Prospectivos
9.
Artigo em Inglês | MEDLINE | ID: mdl-33019730

RESUMO

Post-stroke cognitive impairment (PSCI) is a common consequence of stroke. Epidemiological evidence indicates that, with an ageing population, stroke and PSCI are likely to increase in the coming decades. This may have considerable implications for the demand for nursing home placement. As prevalence estimates of both cognitive impairment and dementia on admission to nursing home among residents with and without stroke have not yet been compared, they were estimated and compared in this study. We performed a cross-sectional survey to establish the admission characteristics of 643 residents in 13 randomly selected nursing homes in Ireland. The survey collected data on resident's stroke and cognitive status at the time of nursing home admission. The survey found, among nursing home residents that experienced stroke prior to admission, prevalence estimates for cognitive impairment (83.8%; 95% CI = 76.9-90.6%) and dementia (66.7%; 95% CI = 57.9-75.4%) were significantly higher compared to residents that had not experienced stroke prior to admission (cognitive impairment: 56.6%; 95% CI = 52.4-60.8%; X2 (1) = 28.64; p < 0.001; dementia: 49.8%; 95% CI = 45.6-54.1%; X2 (1) = 10.47; p < 0.01). Since the prevalence of PSCI is likely to increase in the coming decades, the findings highlight an urgent need for health service planning for this increased demand for nursing home care to meet the care needs of these stroke survivors.


Assuntos
Disfunção Cognitiva , Casas de Saúde , Acidente Vascular Cerebral , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/epidemiologia , Estudos Transversais , Feminino , Humanos , Irlanda/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Acidente Vascular Cerebral/epidemiologia
10.
Lupus ; 29(12): 1571-1593, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33100166

RESUMO

Antiphospholipid syndrome (APS), an acquired autoimmune thrombophilia, is characterised by thrombosis and/or pregnancy morbidity in association with persistent antiphospholipid antibodies. The 16th International Congress on Antiphospholipid Antibodies Task Force on APS Treatment Trends reviewed the current status with regard to existing and novel treatment trends for APS, which is the focus of this Task Force report. The report addresses current treatments and developments since the last report, on the use of direct oral anticoagulants in patients with APS, antiplatelet agents, adjunctive therapies (hydroxychloroquine, statins and vitamin D), targeted treatment including rituximab, belimumab, and anti-TNF agents, complement inhibition and drugs based on peptides of beta-2-glycoprotein I. In addition, the report summarises potential new players, including coenzyme Q10, adenosine receptor agonists and adenosine potentiation. In each case, the report provides recommendations for clinicians, based on the current state of the art, and suggests a clinical research agenda. The initiation and development of appropriate clinical studies requires a focus on devising suitable outcome measures, including a disease activity index, an optimal damage index, and a specific quality of life index.

11.
PLoS Genet ; 16(10): e1009035, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33048947

RESUMO

Epidemiological research suggests that paternal obesity may increase the risk of fathering small for gestational age offspring. Studies in non-human mammals indicate that such associations could be mediated by DNA methylation changes in spermatozoa that influence offspring development in utero. Human obesity is associated with differential DNA methylation in peripheral blood. It is unclear, however, whether this differential DNA methylation is reflected in spermatozoa. We profiled genome-wide DNA methylation using the Illumina MethylationEPIC array in a cross-sectional study of matched human blood and sperm from lean (discovery n = 47; replication n = 21) and obese (n = 22) males to analyse tissue covariation of DNA methylation, and identify obesity-associated methylomic signatures. We found that DNA methylation signatures of human blood and spermatozoa are highly discordant, and methylation levels are correlated at only a minority of CpG sites (~1%). At the majority of these sites, DNA methylation appears to be influenced by genetic variation. Obesity-associated DNA methylation in blood was not generally reflected in spermatozoa, and obesity was not associated with altered covariation patterns or accelerated epigenetic ageing in the two tissues. However, one cross-tissue obesity-specific hypermethylated site (cg19357369; chr4:2429884; P = 8.95 × 10-8; 2% DNA methylation difference) was identified, warranting replication and further investigation. When compared to a wide range of human somatic tissue samples (n = 5,917), spermatozoa displayed differential DNA methylation across pathways enriched in transcriptional regulation. Overall, human sperm displays a unique DNA methylation profile that is highly discordant to, and practically uncorrelated with, that of matched peripheral blood. We observed that obesity was only nominally associated with differential DNA methylation in sperm, and therefore suggest that spermatozoal DNA methylation is an unlikely mediator of intergenerational effects of metabolic traits.


Assuntos
Metilação de DNA/genética , Epigenoma/genética , Obesidade/genética , Espermatozoides/metabolismo , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Ilhas de CpG/genética , Replicação do DNA/genética , Epigênese Genética/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Genoma Humano/genética , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/epidemiologia , Obesidade/patologia , Polimorfismo de Nucleotídeo Único/genética , Espermatozoides/crescimento & desenvolvimento , Espermatozoides/imunologia , Adulto Jovem
12.
Front Immunol ; 11: 572567, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101294

RESUMO

Immunological adaptations in pregnancy allow maternal tolerance of the semi-allogeneic fetus but also increase maternal susceptibility to infection. At implantation, the endometrial stroma, glands, arteries and immune cells undergo anatomical and functional transformation to create the decidua, the specialized secretory endometrium of pregnancy. The maternal decidua and the invading fetal trophoblast constitute a dynamic junction that facilitates a complex immunological dialogue between the two. The decidual and peripheral immune systems together assume a pivotal role in regulating the critical balance between tolerance and defense against infection. Throughout pregnancy, this equilibrium is repeatedly subjected to microbial challenge. Acute viral infection in pregnancy is associated with a wide spectrum of adverse consequences for both mother and fetus. Vertical transmission from mother to fetus can cause developmental anomalies, growth restriction, preterm birth and stillbirth, while the mother is predisposed to heightened morbidity and maternal death. A rapid, effective response to invasive pathogens is therefore essential in order to avoid overwhelming maternal infection and consequent fetal compromise. This sentinel response is mediated by the innate immune system: a heritable, highly evolutionarily conserved system comprising physical barriers, antimicrobial peptides (AMP) and a variety of immune cells-principally neutrophils, macrophages, dendritic cells, and natural killer cells-which express pattern-receptors that detect invariant molecular signatures unique to pathogenic micro-organisms. Recognition of these signatures during acute infection triggers signaling cascades that enhance antimicrobial properties such as phagocytosis, secretion of pro-inflammatory cytokines and activation of the complement system. As well as coordinating the initial immune response, macrophages and dendritic cells present microbial antigens to lymphocytes, initiating and influencing the development of specific, long-lasting adaptive immunity. Despite extensive progress in unraveling the immunological adaptations of pregnancy, pregnant women remain particularly susceptible to certain acute viral infections and continue to experience mortality rates equivalent to those observed in pandemics several decades ago. Here, we focus specifically on the pregnancy-induced vulnerabilities in innate immunity that contribute to the disproportionately high maternal mortality observed in the following acute viral infections: Lassa fever, Ebola virus disease (EVD), dengue fever, hepatitis E, influenza, and novel coronavirus infections.


Assuntos
Decídua/imunologia , Placenta/imunologia , Viroses/imunologia , Imunidade Adaptativa/imunologia , COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Dengue/imunologia , Dengue/patologia , Feminino , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/patologia , Hepatite E/imunologia , Hepatite E/patologia , Humanos , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Influenza Humana/imunologia , Influenza Humana/patologia , Febre Lassa/imunologia , Febre Lassa/patologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Gravidez
13.
Sci Rep ; 10(1): 15444, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963294

RESUMO

Diets low in seafood omega-3 polyunsaturated fatty acids (PUFAs) are very prevalent. Such diets have recently been ranked as the sixth most important dietary risk factor-1.5 million deaths and 33 million disability-adjusted life-years worldwide are attributable to this deficiency. Wild oily fish stocks are insufficient to feed the world's population, and levels of eicosapentaenoic acid and docosahexaenoic acid (DHA) in farmed fish have more than halved in the last 20 years. Here we report on a double-blinded, controlled trial, where 161 healthy normotensive adults were randomly allocated to eat at least three portions/week of omega-3-PUFA enriched (or control) chicken-meat, and to eat at least three omega-3-PUFA enriched (or control) eggs/week, for 6 months. We show that regular consumption of omega-3-PUFA enriched chicken-meat and eggs significantly increased the primary outcome, the red cell omega-3 index (mean difference [98.75% confidence interval] from the group that ate both control foods, 1.7% [0.7, 2.6]). Numbers of subjects with a very high-risk omega-3 index (index < 4%) were more than halved amongst the group that ate both enriched foods. Furthermore, eating the enriched foods resulted in clinically relevant reductions in diastolic blood pressure (- 3.1 mmHg [- 5.8, - 0.3]). We conclude that chicken-meat and eggs, naturally enriched with algae-sourced omega-3-PUFAs, may serve as alternative dietary sources of these essential micronutrients. Unlike many lifestyle interventions, long-term population health benefits do not depend on willingness of individuals to make long-lasting difficult dietary changes, but on the availability of a range of commonly eaten, relatively inexpensive, omega-3-PUFA enriched foods.


Assuntos
Pressão Sanguínea , Dieta , Ingestão de Alimentos/fisiologia , Ovos/análise , Ácidos Graxos Ômega-3/análise , Alimentos Fortificados , Carne/análise , Adolescente , Adulto , Método Duplo-Cego , Ingestão de Energia , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Alimentos Marinhos/análise , Adulto Jovem
14.
Psychol Health ; : 1-18, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32924891

RESUMO

OBJECTIVE: To describe the process of developing a cognitive rehabilitation intervention for patients with post-stroke cognitive impairment (PSCI) and to describe the intervention prior to evaluation in a pilot randomised controlled trial (RCT). Method: The Medical Research Council framework, 'Developing and evaluating complex interventions', was used to develop the cognitive rehabilitation intervention. We conducted a combined analysis of the existing evidence base for PSCI rehabilitation alongside qualitative exploration of the perspectives of stroke survivors, their families, and healthcare professionals providing stroke care, on the necessary components for a cognitive rehabilitation intervention for PSCI. The Template for Intervention Description and Replication checklist was used as a structural framework for the description of the intervention. Results: The intervention comprises a five-week intervention integrating group-based activities, supported by a clinical neuropsychologist, with home-based activities to encourage self-efficacy through the practice of adjustment and compensatory strategies learned in the group format to achieve the patients' identified goals in managing their PSCI. Conclusion: A cognitive rehabilitation intervention for patients with PSCI has been developed and described. We are in the process of developing a structured intervention manual to standardise the content and delivery of the intervention for further testing in a pilot RCT.

15.
J Clin Endocrinol Metab ; 105(12)2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32879954

RESUMO

CONTEXT: Fluid restriction (FR) is the recommended first-line treatment for syndrome of inappropriate antidiuresis (SIAD), despite the lack of prospective data to support its efficacy. DESIGN: A prospective nonblinded randomized controlled trial of FR versus no treatment in chronic SIAD. INTERVENTIONS AND OUTCOME: A total of 46 patients with chronic asymptomatic SIAD were randomized to either FR (1 liter/day) or no specific hyponatremia treatment (NoTx) for 1 month. The primary endpoints were change in plasma sodium concentration (pNa) at days 4 and 30. RESULTS: Median baseline pNa was similar in the 2 groups [127 mmol/L (interquartile range [IQR] 126-129) FR and 128 mmol/L (IQR 126-129) NoTx, P = 0.36]. PNa rose by 3 mmol/L (IQR 2-4) after 3 days FR, compared with 1 mmol/L (IQR 0-3) NoTx, P = 0.005. There was minimal additional rise in pNa by day 30; median pNa increased from baseline by 4 mmol/L (IQR 2-6) in FR, compared with 1 mmol/L (IQR 0-1) NoTx, P = 0.04. After 3 days, 17% of FR had a rise in pNa of ≥5 mmol/L, compared with 4% NoTx, RR 4.0 (95% CI 0.66-25.69), P = 0.35. After 3 days, 61% of FR corrected pNa to ≥130 mmol/L, compared with 39% of NoTx, RR 1.56 (95% CI 0.87-2.94), P = 0.24. CONCLUSION: FR induces a modest early rise in pNa in patients with chronic SIAD, with minimal additional rise thereafter, and it is well-tolerated. More than one-third of patients fail to reach a pNa ≥130 mmol/L after 3 days of FR, emphasizing the clinical need for additional therapies for SIAD in some patients.


Assuntos
Hidratação/métodos , Síndrome de Secreção Inadequada de HAD/terapia , Privação de Água , Idoso , Idoso de 80 Anos ou mais , Líquidos Corporais/metabolismo , Doença Crônica , Feminino , Humanos , Hiponatremia/etiologia , Hiponatremia/terapia , Síndrome de Secreção Inadequada de HAD/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Privação de Água/fisiologia
16.
Cerebrovasc Dis ; 49(4): 404-411, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32777785

RESUMO

BACKGROUND: The harmful effects of outdoor air pollution on stroke incidence are becoming increasingly recognised. We examined the impact of different air pollutants (PM2.5, PM10, NO2, ozone, and SO2) on admission for all strokes in two Irish urban centres from 2013 to 2017. METHODS: Using an ecological time series design with Poisson regression models, we analysed daily hospitalisation for all strokes and is-chaemic stroke by residence in Dublin or Cork, with air pollution level monitoring data with a lag of 0-2 days from exposure. Splines of temperature, relative humidity, day of the week, and time were included as confounders. Analysis was also performed across all four seasons. Data are presented as relative risks (RRs) and 95% confidence intervals (95% CI) per interquartile range (IQR) increase in each pollutant. RESULTS: There was no significant association between all stroke admission and any individual air pollutant. On seasonal analysis, during winter in the larger urban centre (Dublin), we found an association between all stroke cases and an IQR increase in NO2 (RR 1.035, 95% CI: 1.003-1.069), PM10 (RR 1.032, 95% CI: 1.007-1.057), PM2.5 (RR 1.024, 95% CI: 1.011-1.039), and SO2 (RR 1.035, 95% CI: 1.001-1.071). There was no significant association found in the smaller urban area of Cork. On meta-analysis, there remained a significant association between NO2 (RR 1.013, 95% CI: 1.001-1.024) and PM2.5 (1.009, 95% CI 1.004-1.014) per IQR increase in each. DISCUSSION: Short-term air pollution in winter was found to be associated with hospitalisation for all strokes in a large urban centre in Ireland. As Ireland has relatively low air pollution internationally, this highlights the need to introduce policy changes to reduce air pollution in all countries.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Exposição Ambiental/efeitos adversos , Admissão do Paciente , Acidente Vascular Cerebral/epidemiologia , Humanos , Incidência , Irlanda/epidemiologia , Medição de Risco , Fatores de Risco , Estações do Ano , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/terapia , Fatores de Tempo , Saúde da População Urbana , Tempo (Meteorologia)
17.
Toxins (Basel) ; 12(2)2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093386

RESUMO

The phospholipase A2 (PLA2) inhibitor Varespladib (LY315920) and its orally bioavailable prodrug, methyl-Varespladib (LY333013) inhibit PLA2 activity of a wide variety of snake venoms. In this study, the ability of these two forms of Varespladib to halt or delay lethality of potent neurotoxic snake venoms was tested in a mouse model. The venoms of Notechis scutatus, Crotalus durissus terrificus, Bungarus multicinctus, and Oxyuranus scutellatus, all of which have potent presynaptically acting neurotoxic PLA2s of variable quaternary structure, were used to evaluate simple dosing regimens. A supralethal dose of each venom was injected subcutaneously in mice, followed by the bolus intravenous (LY315920) or oral (LY333013) administration of the inhibitors, immediately and at various time intervals after envenoming. Control mice receiving venom alone died within 3 h of envenoming. Mice injected with O. scutellatus venom and treated with LY315920 or LY333013 survived the 24 h observation period, whereas those receiving C. d. terrificus and B. multicinctus venoms survived at 3 h or 6 h with a single dose of either form of Varespladib, but not at 24 h. In contrast, mice receiving N. scutatus venom and then the inhibitors died within 3 h, similarly to the control animals injected with venom alone. LY315920 was able to reverse the severe paralytic manifestations in mice injected with venoms of O. scutellatus, B. multicinctus, and C. d. terrificus. Overall, results suggest that the two forms of Varespladib are effective in abrogating, or delaying, neurotoxic manifestations induced by some venoms whose neurotoxicity is mainly dependent on presynaptically acting PLA2s. LY315920 is able to reverse paralytic manifestations in severely envenomed mice, but further work is needed to understand the significance of species-specific differences in animal models as they compare to clinical syndromes in human and for potential use in veterinary medicine.


Assuntos
Acetatos/farmacologia , Indóis/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Inibidores de Fosfolipase A2/farmacologia , Mordeduras de Serpentes/tratamento farmacológico , Venenos de Serpentes/toxicidade , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Dose Letal Mediana , Camundongos , Fosfolipases A2/metabolismo , Venenos de Serpentes/enzimologia , Análise de Sobrevida , Fatores de Tempo
18.
Int J Adv Manuf Technol ; 106(3): 1085-1103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31983799

RESUMO

Establishing how to effectively manufacture cell therapies is an industry-level problem. Decentralised manufacturing is of increasing importance, and its challenges are recognised by healthcare regulators with deviations and comparability issues receiving specific attention from them. This paper is the first to report the deviations and other risks encountered when implementing the expansion of human pluripotent stem cells (hPSCs) in an automated three international site-decentralised manufacturing setting. An experimental demonstrator project expanded a human embryonal carcinoma cell line (2102Ep) at three development sites in France, Germany and the UK using the CompacT SelecT (Sartorius Stedim, Royston, UK) automated cell culture platform. Anticipated variations between sites spanned material input, features of the process itself and production system details including different quality management systems and personnel. Where possible, these were pre-addressed by implementing strategies including standardisation, cell bank mycoplasma testing and specific engineering and process improvements. However, despite such measures, unexpected deviations occurred between sites including software incompatibility and machine/process errors together with uncharacteristic contaminations. Many only became apparent during process proving or during the process run. Further, parameters including growth rate and viability discrepancies could only be determined post-run, preventing 'live' corrective measures. The work confirms the critical nature of approaches usually taken in Good Manufacturing Practice (GMP) manufacturing settings and especially emphasises the requirement for monitoring steps to be included within the production system. Real-time process monitoring coupled with carefully structured quality systems is essential for multiple site working including clarity of decision-making roles. Additionally, an over-reliance upon post-process visual microscopic comparisons has major limitations; it is difficult for non-experts to detect deleterious culture changes and such detection is slow.

19.
Stroke ; 51(3): 838-845, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31948355

RESUMO

Background and Purpose- In randomized trials of symptomatic carotid endarterectomy, only modest benefit occurred in patients with moderate stenosis and important subgroups experienced no benefit. Carotid plaque 18F-fluorodeoxyglucose uptake on positron emission tomography, reflecting inflammation, independently predicts recurrent stroke. We investigated if a risk score combining stenosis and plaque 18F-fluorodeoxyglucose would improve the identification of early recurrent stroke. Methods- We derived the score in a prospective cohort study of recent (<30 days) non-severe (modified Rankin Scale score ≤3) stroke/transient ischemic attack. We derived the SCAIL (symptomatic carotid atheroma inflammation lumen-stenosis) score (range, 0-5) including 18F-fluorodeoxyglucose standardized uptake values (SUVmax <2 g/mL, 0 points; SUVmax 2-2.99 g/mL, 1 point; SUVmax 3-3.99 g/mL, 2 points; SUVmax ≥4 g/mL, 3 points) and stenosis (<50%, 0 points; 50%-69%, 1 point; ≥70%, 2 points). We validated the score in an independent pooled cohort of 2 studies. In the pooled cohorts, we investigated the SCAIL score to discriminate recurrent stroke after the index stroke/transient ischemic attack, after positron emission tomography-imaging, and in mild or moderate stenosis. Results- In the derivation cohort (109 patients), recurrent stroke risk increased with increasing SCAIL score (P=0.002, C statistic 0.71 [95% CI, 0.56-0.86]). The adjusted (age, sex, smoking, hypertension, diabetes mellitus, antiplatelets, and statins) hazard ratio per 1-point SCAIL increase was 2.4 (95% CI, 1.2-4.5, P=0.01). Findings were confirmed in the validation cohort (87 patients, adjusted hazard ratio, 2.9 [95% CI, 1.9-5], P<0.001; C statistic 0.77 [95% CI, 0.67-0.87]). The SCAIL score independently predicted recurrent stroke after positron emission tomography-imaging (adjusted hazard ratio, 4.52 [95% CI, 1.58-12.93], P=0.005). Compared with stenosis severity (C statistic, 0.63 [95% CI, 0.46-0.80]), prediction of post-positron emission tomography stroke recurrence was improved with the SCAIL score (C statistic, 0.82 [95% CI, 0.66-0.97], P=0.04). Findings were confirmed in mild or moderate stenosis (adjusted hazard ratio, 2.74 [95% CI, 1.39-5.39], P=0.004). Conclusions- The SCAIL score improved the identification of early recurrent stroke. Randomized trials are needed to test if a combined stenosis-inflammation strategy improves selection for carotid revascularization where benefit is currently uncertain.


Assuntos
Estenose das Carótidas , Placa Aterosclerótica , Tomografia por Emissão de Pósitrons , Acidente Vascular Cerebral , Idoso , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/fisiopatologia , Feminino , Fluordesoxiglucose F18/administração & dosagem , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/fisiopatologia , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia
20.
Hypertens Pregnancy ; 39(1): 56-63, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31910697

RESUMO

Objective: To determine whether family history of pre-eclampsia and cardiovascular disease is consistently associated with the occurrence of pre-eclampsia sub-phenotypes and fetal growth restriction (FGR).Material and Methods: We conducted a case-control study in which cases of pre-eclampsia and healthy pregnant controls were recruited at the time of delivery from eight Colombian cities between 2000 and 2012. Odds of pre-eclampsia among women with a positive family history of pre-eclampsia or cardiovascular disease were compared to women without affected relatives (logistic regression modeling and multinomial logistic regression model [Ajusted]).Results: A total of 3510 pre-eclampsia cases and 4512 controls with data on family history of pre-eclampsia were included in analyses. A subsample of 3086 cases and 3888 controls also provided information on family history of cardiovascular disease. Women whose mothers had pre-eclampsia had 3.38 (95% CI 2.89, 3.96) higher odds than those who did not, and having an affected sister increased pre-eclampsia odds by 2.43 (95% CI 2.02, 2.93). The effect of having both mother and sister affected with pre-eclampsia was stronger than the two independent risk factors (OR 4.17 [95% CI 2.60, 6.69]). Women with parental history of cardiovascular disease also had an increased risk of pre-eclampsia (OR 1.58 [95% CI 1.24, 2.01]).Conclusions: Family history of pre-eclampsia increased the risk of PE. The impact of family history of cardiovascular disease on pre-eclampsia was more conservative, but serves to support the hypothesis that pre-eclampsia may reflect the premature exposure of underlying cardiovascular dysfunction, precipitated by the stress test of pregnancy.


Assuntos
Doenças Cardiovasculares/etiologia , Interação Gene-Ambiente , Hereditariedade , Anamnese , Pré-Eclâmpsia/etiologia , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Pré-Eclâmpsia/diagnóstico , Gravidez , Fatores de Risco , Adulto Jovem
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