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PURPOSE: This case study aims to demonstrate the strengths of the Lean Six Sigma (LSS) methodology to improve the acute ischemic stroke (AIS) treatment rates and reduce process lead time at Baruch Padeh Medical Center (BPMC), a rural hospital in the Galilee region of Northern Israel. The LSS project redefined the BPMC stroke care pathway and increased its efficacy. DESIGN/METHODOLOGY/APPROACH: The LSS methodology was implemented in September 2017 by integrating lean principles and the Six Sigma DMAIC (Define-Measure-Analyze-Improve-Control). Existing procedures, field observation, ad hoc measurement and in-depth interviews were utilized, and the GEMBA method was implemented to identify root cause and improve actions optimizing the stroke pathway. FINDINGS: The presented case shows the usefulness of the LSS methodology in improving quality performance in a rural hospital. The intervention allowed the BPMC to improve the intravenous tissue plasminogen activator (IV-tPA) administration rate (+15.2%), reducing the process lead time. The lead time of door-to-computer tomography decreased from 52 to 26 min, and the door-to-needle time decreased from 94 to 75 min. ORIGINALITY/VALUE: The present case study shows the implementation of the LSS methodology aimed to improve the IV-tPA administration rate and reduce the stroke pathway lead time in a rural hospital. The case demonstrates the potential for the LSS methodology to support the AIS pathway optimization and represents a guide for healthcare organizations located in rural areas.
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Isquemia Encefálica , Acidente Vascular Cerebral , Hospitais Rurais , Humanos , Melhoria de Qualidade , Acidente Vascular Cerebral/terapia , Ativador de Plasminogênio Tecidual , Gestão da Qualidade TotalRESUMO
BACKGROUND AND AIMS: The accumulation of fat increases the formation of lipid peroxides, which are partly scavenged by alpha-tocopherol (α-TOH). Here, we aimed to investigate the associations between different measures of (abdominal) fat and levels of urinary α-TOH metabolites in middle-aged individuals. METHODS AND RESULTS: In this cross-sectional analysis in the Netherlands Epidemiology of Obesity study (N = 511, 53% women; mean [SD] age of 55 [6.1] years), serum α-TOH and α-TOH metabolites from 24-h urine were measured as alpha-tocopheronolactone hydroquinone (α-TLHQ, oxidized) and alpha-carboxymethyl-hydroxychroman (α-CEHC, enzymatically converted) using liquid-chromatography-tandem mass spectrometry. Body mass index and total body fat were measured, and abdominal subcutaneous and visceral adipose tissue (aSAT and VAT) were assessed using magnetic resonance imaging. Using multivariable-adjusted linear regression analyses, we analysed the associations of BMI, TBF, aSAT and VAT with levels of urinary α-TOH metabolites, adjusted for confounders. We observed no evidence for associations between body fat measures and serum α-TOH. Higher BMI and TBF were associated with lower urinary levels of TLHQ (0.95 [95%CI: 0.90, 1.00] and 0.94 [0.88, 1.01] times per SD, respectively) and with lower TLHQ relative to CEHC (0.93 [0.90, 0.98] and 0.93 [0.87, 0.98] times per SD, respectively). We observed similar associations for VAT (TLHQ: 0.94 [0.89, 0.99] times per SD), but not for aSAT. CONCLUSIONS: Opposite to our research hypothesis, higher abdominal adiposity was moderately associated with lower levels of oxidized α-TOH metabolites, which might reflect lower vitamin E antioxidative activity in individuals with higher abdominal fat instead.
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Adiposidade , Gordura Intra-Abdominal/fisiopatologia , Obesidade Abdominal/sangue , Obesidade Abdominal/fisiopatologia , alfa-Tocoferol/sangue , Fatores Etários , Biomarcadores/sangue , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Gordura Intra-Abdominal/metabolismo , Peroxidação de Lipídeos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Obesidade Abdominal/diagnóstico , Obesidade Abdominal/epidemiologiaRESUMO
OBJECTIVES: Low socioeconomic status (SES) is associated with cardiovascular risk factors and increased coronary artery disease (CAD) risk. We tested whether SES is an effect modifier of the association between classical cardiovascular risk factors and CAD using SES-stratified Mendelian Randomization in European-ancestry participants from UK Biobank. STUDY DESIGN AND SETTING: We calculated weighted genetic risk scores (GRS) for the risk factors body mass index (BMI), systolic blood pressure, low-density lipoprotein cholesterol, and triglycerides. Participants were stratified by Townsend deprivation index score. Logistic regression models were used to investigate associations between GRSs and CAD occurrence. Additionally, stratification based on GRS-adjusted Townsend deprivation index residuals was conducted to correct for possible collider-stratification bias. RESULTS: In a total sample size of N = 446,485, with 52,946 cases, the risk for CAD per standard deviation increase in genetically influenced BMI was highest in the group with the lowest 25% SES (odds ratio: 1.126, 95% confidence interval: 1.106-1.145; odds ratio: 1.081, 95% confidence interval: 1.059-1.103 in high SES), remaining similar after controlling for possible collider-stratification bias. The effects of genetically influenced systolic blood pressure, low-density lipoprotein cholesterol, and triglyceride on CAD were similar between SES groups. CONCLUSION: CAD risk attributable to increased BMI is not homogenous and could be modified by SES. This emphasizes the need of tailor-made approaches for BMI-associated CAD risk reduction.
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Doenças Cardiovasculares , Doença da Artéria Coronariana , Humanos , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Fatores de Risco , Doenças Cardiovasculares/epidemiologia , Análise da Randomização Mendeliana , Fatores de Risco de Doenças Cardíacas , Triglicerídeos , Lipoproteínas LDL/genética , Colesterol , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Oxidative stress has been proposed as a key contributor to lifestyle- and age-related diseases. Because free radicals play an important role in various processes such as immune responses and cellular signaling, the body possesses an arsenal of different enzymatic and non-enzymatic antioxidant defense mechanisms. Oxidative stress is, among others, the result of an imbalance between the production of various reactive oxygen species (ROS) and antioxidant defense mechanisms including vitamin E (α-tocopherol) as a non-enzymatic antioxidant. Dietary vitamins, such as vitamin C and E, can also be taken in as supplements. It has been postulated that increasing antioxidant levels through supplementation may delay and/or ameliorate outcomes of lifestyle- and age-related diseases that have been linked to oxidative stress. Although supported by many animal experiments and observational studies, randomized clinical trials in humans have failed to demonstrate any clinical benefit from antioxidant supplementation. Nevertheless, possible explanations for this discrepancy remain underreported. This review aims to provide an overview of recent developments and novel research techniques used to clarify the existing controversy on the benefits of antioxidant supplementation in health and disease, focusing on α-tocopherol as antioxidant. Based on the currently available literature, we propose that examining the difference between antioxidant activity and capacity, by considering the catabolism of antioxidants, will provide crucial knowledge on the preventative and therapeutical use of antioxidant supplementation in oxidative stress-related diseases.
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BACKGROUND AND AIMS: Mitochondrial dysfunction is associated with increased reactive oxygen species (ROS) that are thought to drive disease risk, including stroke. We investigated the association between mtDNA abundance, as a proxy measure of mitochondrial function, and incident stroke, using multivariable-adjusted survival and Mendelian Randomization (MR) analyses. METHODS: Cox-proportional hazard model analyses were conducted to assess the association between mtDNA abundance, and incident ischemic and hemorrhagic stroke over a maximum of 14-year follow-up in European-ancestry participants from UK Biobank. MR was conducted using independent (R2 < 0.001) lead variants for mtDNA abundance (p < 5 × 10-8) as instrumental variables. Single-nucleotide polymorphism (SNP)-ischemic stroke associations were derived from three published open source European-ancestry results databases (cases/controls): MEGASTROKE (60,341/454,450), UK Biobank (2404/368,771) and FinnGen (10,551/202,223). MR was performed per study, and results were subsequently meta-analyzed. RESULTS: In total, 288,572 unrelated participants (46% men) with mean (SD) age of 57 (8) years were included in the Cox-proportional hazard analyses. After correction for considered confounders (BMI, hypertension, cholesterol, T2D), no association was found between low versus high mtDNA abundance and ischemic (HR: 1.06 [95% CI: 0.95, 1.18]) or hemorrhagic (HR: 0.97 [95% CI: 0.82, 1.15]) stroke. However, in the MR analyses after removal of platelet count-associated SNPs, we found evidence for an association between genetically-influenced mtDNA abundance and ischemic stroke (odds ratio, 1.17; confidence interval, 1.03, 1.32). CONCLUSIONS: Although the results from both multivariable-adjusted prospective and basis MR analyses did not show an association between low mtDNA and increased risk of ischemic stroke, in-depth MR sensitivity analyses may suggest evidence for a causal relationship.
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AVC Isquêmico , Acidente Vascular Cerebral , DNA Mitocondrial/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Isquemia/complicações , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Mitocôndrias , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genéticaRESUMO
Vitamin E (α-tocopherol [α-TOH]) is transported in lipoprotein particles in blood, but little is known about the transportation of its oxidized metabolites. In the Netherlands Epidemiology of Obesity Study, we aimed to investigate the associations of 147 circulating metabolomic measures obtained through targeted nuclear magnetic resonance with serum α-TOH and its urinary enzymatic (α-CEHC) and oxidized (α-TLHQ) metabolites from 24-h urine quantified by liquid chromatography with tandem mass spectrometry. Multivariable linear regression analyses, in which multiple testing was taken into account, were performed to assess associations between metabolomic measures (determinants; standardized to mean = 0, SD = 1) and vitamin E metabolites (outcomes), adjusted for demographic factors. We analyzed 474 individuals (55% women, 45% men) with a mean (SD) age of 55.7 (6.0) y. Out of 147 metabolomic measures, 106 were associated (P < 1.34 × 10-3) with serum α-TOH (median ß [interquartile range] = 0.416 [0.383-0.466]), predominantly lipoproteins associated with higher α-TOH. The associations of metabolomic measures with urinary α-CEHC have directions similar to those with α-TOH, but effect sizes were smaller and non-significant (median ß [interquartile range] = 0.065 [0.047-0.084]). However, associations of metabolomic measures with urinary α-TLHQ were markedly different from those with both serum α-TOH and urinary α-CEHC, with negative and small-to-null relations to most very-low-density lipoproteins and amino acids. Therefore, our results highlight the differences in the lipoproteins involved in the transportation of circulating α-TOH and oxidized vitamin E metabolites. This indicates that circulating α-TOH may be representative of the enzymatic but not the antioxidative function of vitamin E.
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Metaboloma , Vitamina E , alfa-Tocoferol , Antioxidantes , Feminino , Humanos , Lipoproteínas , Masculino , Pessoa de Meia-Idade , Oxirredução , Vitamina E/sangue , Vitamina E/urina , alfa-Tocoferol/sangue , alfa-Tocoferol/urinaRESUMO
Background Dietary intake and blood concentrations of vitamins E and C, lycopene, and carotenoids have been associated with a lower risk of incident (ischemic) stroke. However, causality cannot be inferred from these associations. Here, we investigated causality by analyzing the associations between genetically influenced antioxidant levels in blood and ischemic stroke using Mendelian randomization. Methods and Results For each circulating antioxidant (vitamins E and C, lycopene, ß-carotene, and retinol), which were assessed as either absolute blood levels and/or high-throughput metabolite levels, independent genetic instrumental variables were selected from earlier genome-wide association studies (P<5×10-8). We used summary statistics for single-nucleotide polymorphisms-stroke associations from 3 European-ancestry cohorts (cases/controls): MEGASTROKE (60 341/454 450), UK Biobank (2404/368 771), and the FinnGen study (8046/164 286). Mendelian randomization analyses were performed on each exposure per outcome cohort using inverse variance-weighted analyses and subsequently meta-analyzed. In a combined sample of 1 058 298 individuals (70 791 cases), none of the genetically influenced absolute antioxidants or antioxidant metabolite concentrations were causally associated with a lower risk of ischemic stroke. For absolute antioxidants levels, the odds ratios (ORs) ranged between 0.94 (95% CI, 0.85-1.05) for vitamin C and 1.04 (95% CI, 0.99-1.08) for lycopene. For metabolites, ORs ranged between 1.01 (95% CI, 0.98-1.03) for retinol and 1.12 (95% CI, 0.88-1.42) for vitamin E. Conclusions This study did not provide evidence for a causal association between dietary-derived antioxidant levels and ischemic stroke. Therefore, antioxidant supplements to increase circulating levels are unlikely to be of clinical benefit to prevent ischemic stroke.
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Antioxidantes , Dieta , AVC Isquêmico , Antioxidantes/administração & dosagem , Antioxidantes/análise , Dieta/estatística & dados numéricos , Estudo de Associação Genômica Ampla , Humanos , AVC Isquêmico/sangue , AVC Isquêmico/epidemiologia , AVC Isquêmico/genética , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Medição de RiscoRESUMO
BACKGROUND & AIMS: Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (α-tocopherol, α-TOH) competitively reacts with lipid peroxyl radicals to mitigate oxidative damage, and forms oxidized vitamin E metabolites. Accordingly, we aimed to investigate the associations between α-TOH metabolites (oxidized and enzymatic) in both circulation and urine and measures of glucose homeostasis in the general middle-aged population. METHODS: This cross-sectional study was embedded in the population-based Netherlands Epidemiology of Obesity (NEO) Study. α-TOH metabolites in blood (α-TOH and α-CEHC-SO3) and urine [sulfate (SO3) and glucuronide (GLU) of both α-TLHQ (oxidized) and α-CEHC (enzymatic)] were quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MS-MS). Measures of glucose homeostasis (HOMA-B, HOMA-IR, Insulinogenic index and Matsuda index) were obtained from fasting and postprandial blood samples. Multivariable linear regression analyses were performed to assess the associations of α-TOH metabolites and measures of glucose homeostasis. RESULTS: We included 498 participants (45% men) with mean (SD) age of 55.8 (6.1) years who did not use glucose-lowering medication. While blood α-TOH was not associated with measures of glucose homeostasis, urinary oxidized metabolites (α-TLHQ-SO3/GLU) were associated with HOMA-IR and Matsuda index. For example, a one-SD higher α-TLHQ-SO3 was associated with 0.92 (95% CI: 0.87, 0.97) fold lower HOMA-IR and 1.06 (1.01, 1.11) fold higher Matsuda index, respectively. Similar results were obtained for the urinary α-TLHQ to α-CEHC ratio as a measure of oxidized-over-enzymatic conversion of α-TOH. CONCLUSION: Higher urinary levels of oxidized α-TOH metabolites as well as higher oxidized-to-enzymatic α-TOH metabolite ratio, but not circulating α-TOH or enzymatic metabolites, were associated with lower insulin resistance. Rather than circulating α-TOH, estimates of the conversion of α-TOH might be informative in relation to health and disease.
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Glicemia/metabolismo , Homeostase/fisiologia , Urina/química , Vitamina E/análogos & derivados , alfa-Tocoferol/análogos & derivados , Idoso , Índice de Massa Corporal , Cromanos/sangue , Cromanos/urina , Estudos Transversais , Feminino , Voluntários Saudáveis , Humanos , Resistência à Insulina/fisiologia , Modelos Lineares , Peroxidação de Lipídeos , Masculino , Pessoa de Meia-Idade , Países Baixos , Oxirredução , Propionatos/sangue , Propionatos/urina , Estudos ProspectivosRESUMO
The antioxidant vitamin E (α-tocopherol, α-TOH) protects lipids from oxidation by reactive oxygen species. We hypothesized that lifestyle factors associate with vitamin E metabolism marked by urinary α-tocopheronolactone hydroquinone (α-TLHQ) and α-carboxymethyl-hydroxychroman (α-CEHC levels), as potential reflection of lipid oxidation. We conducted a cross-sectional study in the Netherlands Epidemiology of Obesity Study. Serum α-TOH, and urinary α-TLHQ and α-CEHC were quantified by liquid chromatography coupled with tandem mass spectrometry. Information on the lifestyle factors (sleep, physical activity (PA), smoking and alcohol) were collected through questionnaires. Multivariable linear regression analyses were performed to assess the associations between the lifestyle factors and α-TOH measures. A total of 530 participants (46% men) were included with mean (SD) age of 56 (6) years. Of the examined lifestyle factors, only poor sleep was associated with a higher serum α-TOH (mean difference: 4% (95% CI: 1, 7%)). Current smoking was associated with higher urinary α-CEHC (32%: (14%, 53%)), with evidence of a dose-response relationship with smoking intensity (low pack years, 24% (2, 52%); high pack years, 55% (25, 93%)). Moderate physical activity was associated with a lower α-TLHQ relative to α-CEHC (-17%: (-26, -6%), compared with low PA). Only specific lifestyle factors associate with vitamin E metabolism. Examining serum α-TOH does not provide complete insight in vitamin E antioxidant capacity.
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AIMS: To conduct a pilot study on the potential to optimise care pathways in syncope/Transient Loss of Consciousness management by using Lean Six Sigma methodology while maintaining compliance with ESC and/or NICE guidelines. METHODS: Five hospitals in four European countries took part. The Lean Six Sigma methodology consisted of 3 phases: 1) Assessment phase, in which baseline performance was mapped in each centre, processes were evaluated and a new operational model was developed with an improvement plan that included best practices and change management; 2) Improvement phase, in which optimisation pathways and standardised best practice tools and forms were developed and implemented. Staff were trained on new processes and change-management support provided; 3) Sustaining phase, which included support, refinement of tools and metrics. The impact of the implementation of new pathways was evaluated on number of tests performed, diagnostic yield, time to diagnosis and compliance with guidelines. One hospital with focus on geriatric populations was analysed separately from the other four. RESULTS: With the new pathways, there was a 59% reduction in the average time to diagnosis (pâ=â0.048) and a 75% increase in diagnostic yield (pâ=â0.007). There was a marked reduction in repetitions of diagnostic tests and improved prioritisation of indicated tests. CONCLUSIONS: Applying a structured Lean Six Sigma based methodology to pathways for syncope management has the potential to improve time to diagnosis and diagnostic yield.