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Prospective cohort studies of kidney equity are limited by a focus on advanced rather than early disease and selective recruitment. Whole population studies frequently rely on area-level measures of deprivation as opposed to individual measures of social disadvantage. Here, we linked kidney health and individual census records in the North of Scotland (Grampian area), 2011-2021 (GLOMMS-CORE) and identified incident kidney presentations at thresholds of estimated glomerular filtration rate (eGFR) under 60 (mild/early), under 45 (moderate), under 30 ml/min/1.73m2(advanced), and acute kidney disease (AKD). Household and neighborhood socioeconomic measures, living circumstances, and long-term mortality were compared. Case-mix adjusted multivariable logistic regression (living circumstances), and Cox models (mortality) incorporating an interaction between the household and the neighborhood were used. Among census respondents, there were 48546, 29081, 16116, 28097 incident presentations of each respective eGFR cohort and AKD. Classifications of socioeconomic position by household and neighborhood were related but complex, and frequently did not match. Compared to households of professionals, people with early kidney disease in unskilled or unemployed households had increased mortality (adjusted hazard ratios: 95% confidence intervals) of (1.26: 1.19-1.32) and (1.77: 1.60-1.96), respectively with adjustment for neighborhood indices making little difference. Those within either a deprived household or deprived neighborhood experienced greater mortality, but those within both had the poorest outcomes. Unskilled and unemployed households frequently reported being limited by illness, adverse mental health, living alone, basic accommodation, lack of car ownership, language difficulties, visual and hearing impairments. Thus, impacts of deprivation on kidney health are spread throughout society, complex, serious, and not confined to those living in deprived neighborhoods.
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PURPOSE: To identify structural markers of active retinopathy of prematurity (ROP) in foveal and parafoveal retinal layers using hand-held optical coherence tomography. METHODS: Hand-held optical coherence tomography images (n = 278) were acquired from a prospective mixed cross-sectional longitudinal observational study of 87 participants (23-36 weeks gestational age; n = 30 with ROP, n = 57 without ROP) between 31 and 44 weeks postmenstrual age excluding treated ROP and features of cystoid macular edema. Six retinal layer thicknesses from the fovea to the parafovea were analyzed at five locations up to 1,000 µ m, temporally and nasally. RESULTS: The mean outer retinal thickness during active ROP increased at the fovea and parafovea from postmenstrual age 33 weeks to 39 weeks ( P < 0.001), whereas the parafoveal inner nuclear layer and retinal nerve fiber layer reduced ( P < 0.001). Outer retinal thickness at the fovea from 33 weeks to 39 weeks postmenstrual age was consistently thicker in infants with ROP across all levels of prematurity (gestational age). CONCLUSION: Increased foveal and parafoveal outer retina measured using hand-held optical coherence tomography shows potential as a marker for ROP screening.
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Recém-Nascido Prematuro , Retinopatia da Prematuridade , Humanos , Recém-Nascido , Estudos Transversais , Idade Gestacional , Estudos Prospectivos , Retina/diagnóstico por imagem , Retinopatia da Prematuridade/diagnóstico , Tomografia de Coerência Óptica/métodos , Estudos Observacionais como AssuntoRESUMO
Importance: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that ß-blocker use may be associated with reduced risk of COPD exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission. Objective: To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations. Design, Setting, and Participants: The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023. Interventions: Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol. Main Outcomes and Measures: The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions. Results: Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean [SD] age, 68 [7.9] years; 274 men [53%]; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P = .72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P = .96). Conclusions and Relevance: Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both. Trial Registration: isrctn.org Identifier: ISRCTN10497306.
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Bisoprolol , Progressão da Doença , Doença Pulmonar Obstrutiva Crônica , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Corticosteroides/uso terapêutico , Corticosteroides/efeitos adversos , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Antagonistas de Receptores Adrenérgicos beta 1/efeitos adversos , Antibacterianos/uso terapêutico , Antibacterianos/efeitos adversos , Bisoprolol/uso terapêutico , Bisoprolol/efeitos adversos , Método Duplo-Cego , Volume Expiratório Forçado , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Medidas de Resultados Relatados pelo PacienteRESUMO
BACKGROUND: No single study contrasts the extent and consequences of inequity of kidney care across the clinical course of kidney disease. METHODS: This population study of Grampian (UK) followed incident presentations of acute kidney injury (AKI) and incident estimated glomerular filtration rate (eGFR) thresholds of <60, <45 and <30 mL/min/1.73 m2 in separate cohorts (2011-2021). The key exposure was area-level deprivation (lowest quintile of the Scottish Index of Multiple Deprivation). Outcomes were care processes (monitoring, prescribing, appointments, unscheduled care), long-term mortality and kidney failure. Modelling involved multivariable logistic regression, negative binomial regression and cause-specific Cox models with and without adjustment of comorbidities. RESULTS: There were 41 313, 51 190, 32 171 and 17 781 new presentations of AKI and eGFR thresholds <60, <45 and <30 mL/min/1.73 m2. A total of 6.1-7.8% of the population was from deprived areas and (versus all others) presented on average 5 years younger, with more diabetes and pulmonary and liver disease. Those from deprived areas were more likely to present initially in hospital, less likely to receive community monitoring, less likely to attend appointments and more likely to have an unplanned emergency department or hospital admission episode. Deprivation had the greatest association with long-term kidney failure at the eGFR <60 mL/min/1.73 m2 threshold {adjusted hazard ratio [HR] 1.48 [95% confidence interval (CI) 1.17-1.87]} and this association decreased with advancing disease severity [HR 1.09 (95% CI 0.93-1.28) at eGFR <30 mL/min/1.73 m2), with a similar pattern for mortality. Across all analyses the most detrimental associations of deprivation were an eGFR threshold <60 mL/min/1.73 m2, AKI, males and those <65 years of age. CONCLUSIONS: Even in a high-income country with universal healthcare, serious and consistent inequities in kidney care exist. The poorer care and outcomes with area-level deprivation were greater earlier in the disease course.
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Injúria Renal Aguda , Insuficiência Renal Crônica , Masculino , Humanos , Assistência de Saúde Universal , Progressão da Doença , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/complicações , Taxa de Filtração Glomerular , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Fatores de RiscoRESUMO
The observational retrospective cohort Study on HEalthcare Resource utiLization (HCRU) related to exacerbatiOns in patients with COPD (SHERLOCK; D5980R00014) evaluated exacerbation-related HCRU and costs using the U.K. National Health Service Greater Glasgow and Clyde Health Board data. Patients (≥40 years) with COPD were stratified by exacerbations one year before the index date: Group A (none), B (1 moderate), C (1 severe) and D (≥2 moderate and/or severe). All-cause and COPD-related HCRU and costs were assessed over 36 months. Adjusted rate ratios (RRs) or relative costs versus Group A were estimated using generalized linear models with appropriate distributions and link functions. The study included 22 462 patients (Group A, n = 7788; B, n = 5151; C, n = 250 and D, n = 9273). At 12 months, RRs (95% CI) versus Group A for all-cause and COPD-related HCRU, respectively, were highest in Groups C (1.28 [1.18, 1.39] and 1.18 [1.09, 1.29]) and D (1.26 [1.23, 1.28] and 1.29 [1.26, 1.31]). General practitioner and outpatient visits, and general ward stays/days accounted for the greatest COPD-related HCRU. All-cause and COPD-related relative costs (95% CI) versus Group A at 12 months, respectively, were 1.03 (0.94, 1.12) and 1.06 (0.99, 1.13) in Group B; 1.47 (1.07, 2.01) and 1.54 (1.20, 1.97) in Group C; 1.47 (1.36, 1.58) and 1.63 (1.54, 1.73) in Group D. Increased HCRU and costs in patients with exacerbation histories persisted at 36 months, demonstrating the sustained impact of exacerbations. The study suggests the importance of management and prevention of exacerbations through intervention optimization and budgeting by payers for exacerbation-related costs.
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Doença Pulmonar Obstrutiva Crônica , Humanos , Estudos Retrospectivos , Medicina Estatal , Progressão da Doença , Atenção à SaúdeRESUMO
Importance: Bleeding is the most common cause of preventable death after trauma. Objective: To determine the effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) when used in the emergency department along with standard care vs standard care alone on mortality in trauma patients with exsanguinating hemorrhage. Design, Setting, and Participants: Pragmatic, bayesian, randomized clinical trial conducted at 16 major trauma centers in the UK. Patients aged 16 years or older with exsanguinating hemorrhage were enrolled between October 2017 and March 2022 and followed up for 90 days. Intervention: Patients were randomly assigned (1:1 allocation) to a strategy that included REBOA and standard care (n = 46) or standard care alone (n = 44). Main Outcomes and Measures: The primary outcome was all-cause mortality at 90 days. Ten secondary outcomes included mortality at 6 months, while in the hospital, and within 24 hours, 6 hours, or 3 hours; the need for definitive hemorrhage control procedures; time to commencement of definitive hemorrhage control procedures; complications; length of stay; blood product use; and cause of death. Results: Of the 90 patients (median age, 41 years [IQR, 31-59 years]; 62 [69%] were male; and the median Injury Severity Score was 41 [IQR, 29-50]) randomized, 89 were included in the primary outcome analysis because 1 patient in the standard care alone group declined to provide consent for continued participation and data collection 4 days after enrollment. At 90 days, 25 of 46 patients (54%) had experienced all-cause mortality in the REBOA and standard care group vs 18 of 43 patients (42%) in the standard care alone group (odds ratio [OR], 1.58 [95% credible interval, 0.72-3.52]; posterior probability of an OR >1 [indicating increased odds of death with REBOA], 86.9%). Among the 10 secondary outcomes, the ORs for mortality and the posterior probabilities of an OR greater than 1 for 6-month, in-hospital, and 24-, 6-, or 3-hour mortality were all increased in the REBOA and standard care group, and the ORs were increased with earlier mortality end points. There were more deaths due to bleeding in the REBOA and standard care group (8 of 25 patients [32%]) than in standard care alone group (3 of 18 patients [17%]), and most occurred within 24 hours. Conclusions and Relevance: In trauma patients with exsanguinating hemorrhage, a strategy of REBOA and standard care in the emergency department does not reduce, and may increase, mortality compared with standard care alone. Trial Registration: isrctn.org Identifier: ISRCTN16184981.
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Oclusão com Balão , Exsanguinação , Humanos , Masculino , Adulto , Feminino , Exsanguinação/complicações , Teorema de Bayes , Estudos Retrospectivos , Hemorragia/etiologia , Hemorragia/terapia , Aorta , Oclusão com Balão/efeitos adversos , Oclusão com Balão/métodos , Ressuscitação/métodos , Escala de Gravidade do Ferimento , Serviço Hospitalar de Emergência , Reino UnidoRESUMO
RATIONALE & OBJECTIVE: The population burden and long-term implications of hyperkalemia have not been comprehensively studied. We studied how often and where hyperkalemia occurs as well as its independent association with survival and long-term cardiac and kidney health. STUDY DESIGN: Population-based cohort study of adult residents of Grampian, United Kingdom. SETTING & PARTICIPANTS: Among the 468,594 adult residents (2012-2014), 302,630 people with at least 1 blood test were followed until 2019. EXPOSURE: Hyperkalemia was defined as serum potassium ≥ 5.5 mmol/L. Adjustment for comorbidities, demographics, measures of acute and chronic kidney function, and medications prescribed before measurement of serum potassium. OUTCOME: All-cause mortality, cardiac events, and kidney failure. ANALYTICAL APPROACH: Description of the annual incidence of hyperkalemia and the characteristics associated with its occurrence, and adjusted Cox proportional hazards (PH) analysis to evaluate the independent long-term association of hyperkalemia with all-cause mortality among people who survived ≥90 days after blood testing. Cause-specific PH models were fit to evaluate the association of hyperkalemia with cardiac events/death, noncardiac death, and kidney failure. Effect modification by level of estimated glomerular filtration rate (eGFR) at the time of blood testing was explored. RESULTS: The annual population incidence of hyperkalemia was 0.96 per 100 person-years. This represented 2.3%, 2.1%, and 1.9% of people with at least one blood test in 2012, 2013, and 2014, respectively. Two-thirds of episodes of hyperkalemia occurred in the community. The hyperkalemia rate was 2-fold higher for each 10-year greater age. Those with hyperkalemia were 20 times more likely to have concurrent acute kidney injury (AKI), and 17 times more likely to have an eGFR of <30 mL/min/1.73 m2. Throughout 5 years of follow-up evaluation (2,483,452 person-years), hyperkalemia was associated with poorer health outcomes. This association held across all levels of kidney function and was irrespective of concurrent AKI, but was stronger among those with a baseline eGFR of ≥60 mL/min/1.73 m2 (P for interaction < 0.001). The adjusted HRs (hyperkalemia vs no hyperkalemia) for people with eGFR ≥60 mL/min/1.73 m2 and eGFR <30 mL/min/1.73 m2 were 2.3 (95% CI, 2.2-2.5) and 1.5 (95% CI, 1.3-1.6) for mortality; 1.8 (95% CI, 1.6-1.9) and 1.4 (95% CI, 1.2-1.6) for cardiac events; and 17.0 (95% CI, 9.3-31.1) and 2.0 (95% CI, 1.5-2.8) for kidney failure, respectively. LIMITATIONS: The observational nature of this study limits evaluation of causal relationships. CONCLUSIONS: There is a substantial burden of hyperkalemia in the general population. Hyperkalemia is associated with poorer long-term health outcomes, especially kidney outcomes, that are independent of other established risk factors.
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Hiperpotassemia , Adulto , Estudos de Coortes , Taxa de Filtração Glomerular , Humanos , Hiperpotassemia/epidemiologia , Rim , Avaliação de Resultados em Cuidados de Saúde , Fatores de RiscoRESUMO
INTRODUCTION: Increasing blood pressure variability has been reported following acute stroke, but there is uncertainty about how best to measure it and about the impact on prognosis following acute ischaemic stroke and transient ischaemic attack. METHODS: Enhanced casual blood pressure and ambulatory blood pressure monitoring were completed at baseline (≤48 h post symptom onset). Blood pressure variability was defined by standard deviation and coefficient of variation of systolic, diastolic, mean arterial pressure, and pulse pressure. Modified Rankin scale score ≥3 described poor functional outcome assessed at 1- and 12-months post-stroke. Multivariable logistic regression models incorporating blood pressure variability measurement and other factors were performed, and odds ratio and 95% confidence intervals reported. RESULTS: 232 patients were recruited; 45 were dependent at 1-month, and 37 at 12-months. Dependent patients were more likely to be older, with a higher burden of pre-morbid conditions, and with increased blood pressure variability. Enhanced casual standard deviations of diastolic blood pressure [1.19 (1.02 to 1.39)] and mean arterial pressure [1.20 (1.00 to 1.43)] predicted dependency at 1-month. Predictors of 12-month dependency included: enhanced casual standard deviation of mean arterial pressure [1.21 (1.0-1.46)]; 24 h ambulatory monitor standard deviations of diastolic blood pressure [2.30 (1.08-4.90)] and mean arterial pressure [1.72 (1.09-2.72)], and the coefficient of variation of mean arterial pressure [1.76 (1.05-2.94)]; day-time ambulatory monitor coefficient of variation of systolic blood pressure [1.44 (1.02-2.03)] and mean arterial pressure [1.46 (1.02-2.08)]; and night-time ambulatory standard deviation of diastolic blood pressure [1.65 (1.03 -2.63)], and the coefficient of variation of mean arterial pressure and [1.38 (1.00- 1.90)] and pulse pressure [1.29 (1.00-1.65)]. CONCLUSION: Increasing blood pressure variability is independently and modestly associated with poor functional outcome at 1- and 12-months following acute stroke.
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Pressão Arterial , Monitorização Ambulatorial da Pressão Arterial , Ataque Isquêmico Transitório/diagnóstico , AVC Isquêmico/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Avaliação da Deficiência , Inglaterra , Feminino , Estado Funcional , Humanos , Ataque Isquêmico Transitório/fisiopatologia , Ataque Isquêmico Transitório/reabilitação , AVC Isquêmico/fisiopatologia , AVC Isquêmico/reabilitação , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Reabilitação do Acidente Vascular Cerebral , Fatores de TempoRESUMO
BACKGROUND: Genome-wide association studies have identified chromosome 14q32 as a locus for coronary artery disease. The disease-associated variants fall in a hitherto uncharacterized gene called HHIPL1 (hedgehog interacting protein-like 1), which encodes a sequence homolog of an antagonist of hedgehog signaling. The function of HHIPL1 and its role in atherosclerosis are unknown. METHODS: HHIPL1 cellular localization, interaction with sonic hedgehog (SHH), and influence on hedgehog signaling were tested. HHIPL1 expression was measured in coronary artery disease-relevant human cells, and protein localization was assessed in wild-type and Apoe-/- (apolipoprotein E deficient) mice. Human aortic smooth muscle cell phenotypes and hedgehog signaling were investigated after gene knockdown. Hhipl1-/- mice were generated and aortic smooth muscle cells collected for phenotypic analysis and assessment of hedgehog signaling activity. Hhipl1-/- mice were bred onto both the Apoe-/- and Ldlr-/- (low-density lipoprotein receptor deficient) knockout strains, and the extent of atherosclerosis was quantified after 12 weeks of high-fat diet. Cellular composition and collagen content of aortic plaques were assessed by immunohistochemistry. RESULTS: In vitro analyses revealed that HHIPL1 is a secreted protein that interacts with SHH and increases hedgehog signaling activity. HHIPL1 expression was detected in human smooth muscle cells and in smooth muscle within atherosclerotic plaques of Apoe-/- mice. The expression of Hhipl1 increased with disease progression in aortic roots of Apoe-/- mice. Proliferation and migration were reduced in Hhipl1 knockout mouse and HHIPL1 knockdown aortic smooth muscle cells, and hedgehog signaling was decreased in HHIPL1-deficient cells. Hhipl1 knockout caused a reduction of >50% in atherosclerosis burden on both Apoe-/- and Ldlr-/- knockout backgrounds, and lesions were characterized by reduced smooth muscle cell content. CONCLUSIONS: HHIPL1 is a secreted proatherogenic protein that enhances hedgehog signaling and regulates smooth muscle cell proliferation and migration. Inhibition of HHIPL1 protein function might offer a novel therapeutic strategy for coronary artery disease.
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Aterosclerose/genética , Cromossomos Humanos Par 14/genética , Doença das Coronárias/genética , Proteínas Hedgehog/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Animais , Aterosclerose/patologia , Divisão Celular , Movimento Celular , Células Cultivadas , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Camundongos Knockout para ApoE , Miócitos de Músculo Liso/metabolismo , Placa Aterosclerótica/patologia , Receptores de LDL/deficiência , Transdução de SinaisRESUMO
PURPOSE: To investigate dynamic foveal morphology with postmenstrual age, in preterm infants with and without retinopathy of prematurity using hand-held optical coherence tomography, adjusting for gestational age (GA) and birthweight (BW). METHODS: Prospective mixed cross-sectional/longitudinal observational study of 87 participants (23-36 weeks GA; n = 30 with, n = 57 without retinopathy of prematurity) using hand-held optical coherence tomography images (n = 278) acquired between 31 weeks and 44 weeks postmenstrual age excluding treated retinopathy of prematurity. Measurements included foveal width, area, depth, central foveal thickness, maximum slope, and parafoveal retinal thickness at 1,000 µm nasal and temporal to the central fovea. RESULTS: Retinopathy of prematurity was significantly correlated with only foveal width in either GA or BW adjusted statistical models. In contrast, severity of prematurity (GA, BW) correlated with foveal area (P < 0.005), depth (P ≤ 0.001), and slope (P < 0.01), although central foveal thickness (P = 0.007) and parafoveal retinal thickness (P < 0.001) correlated with GA, but not with BW. CONCLUSION: Foveal width is independent of GA and BW with potential in retinopathy of prematurity screening assessment using hand-held optical coherence tomography. Foveal morphology could be graded in prematurity during development, with possible implications for future management of preterm infants.
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Fóvea Central/patologia , Recém-Nascido Prematuro , Retinopatia da Prematuridade/diagnóstico , Tomografia de Coerência Óptica , Peso ao Nascer , Estudos Transversais , Feminino , Fóvea Central/diagnóstico por imagem , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Triagem Neonatal , Estudos Prospectivos , Acuidade Visual/fisiologiaRESUMO
BACKGROUND: In an apparent paradox, morbidity and mortality are lower in obese patients undergoing cardiac surgery, although the nature of this association is unclear. We sought to determine whether the obesity paradox observed in cardiac surgery is attributable to reverse epidemiology, bias, or confounding. METHODS: Data from the National Adult Cardiac Surgery registry for all cardiac surgical procedures performed between April 2002 and March 2013 were extracted. A parallel systematic review and meta-analysis (MEDLINE, Embase, SCOPUS, Cochrane Library) through June 2015 were also accomplished. Exposure of interest was body mass index categorized into 6 groups according to the World Health Organization classification. RESULTS: A total of 401 227 adult patients in the cohort study and 557 720 patients in the systematic review were included. A U-shaped association between mortality and body mass index classes was observed in both studies, with lower mortality in overweight (adjusted odds ratio, 0.79; 95% confidence interval, 0.76-0.83) and obese class I and II (odds ratio, 0.81; 95% confidence interval, 0.76-0.86; and odds ratio, 0.83; 95% confidence interval, 0.74-0.94) patients relative to normal-weight patients and increased mortality in underweight individuals (odds ratio, 1.51; 95% confidence interval, 1.41-1.62). In the cohort study, a U-shaped relationship was observed for stroke and low cardiac output syndrome but not for renal replacement therapy or deep sternal wound infection. Counter to the reverse epidemiology hypotheses, the protective effects of obesity were less in patients with severe chronic renal, lung, or cardiac disease and greater in older patients and in those with complications of obesity, including the metabolic syndrome and atherosclerosis. Adjustments for important confounders did not alter our results. CONCLUSIONS: Obesity is associated with lower risks after cardiac surgery, with consistent effects noted in multiple analyses attempting to address residual confounding and reverse causation.
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Cardiopatias/mortalidade , Índice de Massa Corporal , Procedimentos Cirúrgicos Cardíacos , Comorbidade , Bases de Dados Factuais , Cardiopatias/patologia , Cardiopatias/cirurgia , Mortalidade Hospitalar , Humanos , Obesidade/complicações , Obesidade/diagnóstico , Razão de Chances , Fatores de RiscoRESUMO
BACKGROUND: Adult height is associated with risk of several diseases, but the breadth of such associations and whether these associations are primary or due to confounding are unclear. We examined the association of adult height with 50 diseases spanning multiple body systems using both epidemiological and genetic approaches, the latter to identify un-confounded associations and possible underlying mechanisms. METHODS: We examined the associations for adult height (using logistic regression adjusted for potential confounders) and genetically determined height (using a two-sample Mendelian randomisation approach with height-associated genetic variants as instrumental variables) in 417,434 individuals of white ethnic background participating in the UK Biobank. We undertook pathway analysis of height-associated genes to identify biological processes that could link height and specific diseases. RESULTS: Height was associated with 32 diseases and genetically determined height associated with 12 diseases. Of these, 11 diseases showed a concordant association in both analyses, with taller height associated with reduced risks of coronary artery disease (odds ratio per standard deviation (SD) increase in height ORepi = 0.80, 95% CI 0.78-0.81; OR per SD increase in genetically determined height ORgen = 0.86, 95% CI 0.82-0.90), hypertension (ORepi = 0.83, 95% CI 0.82-0.84; ORgen = 0.88, 95% CI 0.85-0.91), gastro-oesophageal reflux disease (ORepi = 0.85, 95% CI 0.84-0.86; ORgen = 0.94, 95% CI 0.92-0.97), diaphragmatic hernia (ORepi = 0.81, 95% CI 0.79-0.82; ORgen = 0.91, 95% CI 0.88-0.94), but increased risks of atrial fibrillation (ORepi = 1.42, 95% CI 1.38-1.45; ORgen = 1.33, 95% CI 1.26-1.40), venous thromboembolism (ORepi = 1.18, 95% CI 1.16-1.21; ORgen = 1.15, 95% CI 1.11-1.19), intervertebral disc disorder (ORepi = 1.15, 95% CI 1.13-1.18; ORgen = 1.14, 95% CI 1.09-1.20), hip fracture (ORepi = 1.19, 95% CI 1.12-1.26; ORgen = 1.27, 95% CI 1.17-1.39), vasculitis (ORepi = 1.15, 95% CI 1.11-1.19; ORgen = 1.20, 95% CI 1.14-1.28), cancer overall (ORepi = 1.09, 95% CI 1.08-1.11; ORgen = 1.06, 95% CI 1.04-1.08) and breast cancer (ORepi = 1.08, 95% CI 1.06-1.10; ORgen = 1.07, 95% CI 1.03-1.11). Pathway analysis showed multiple height-associated pathways associating with individual diseases. CONCLUSIONS: Adult height is associated with risk of a range of diseases. We confirmed previously reported height associations for coronary artery disease, atrial fibrillation, venous thromboembolism, intervertebral disc disorder, hip fracture and cancer and identified potential novel associations for gastro-oesophageal reflux disease, diaphragmatic hernia and vasculitis. Multiple biological mechanisms affecting height may affect the risks of these diseases.
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Estatura/genética , Doença/genética , Testes Genéticos/métodos , Análise da Randomização Mendeliana/métodos , Adulto , Idoso , Doença/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Dynamic cerebral autoregulation (CA), the transient response of cerebral blood flow (CBF) to rapid changes in arterial blood pressure (BP), is usually modeled as a linear mechanism. We tested the hypothesis that dynamic CA can display nonlinear behavior resulting from differential efficiency dependent on the direction of BP changes. Cerebral blood velocity (CBV) (transcranial Doppler), heart rate (HR) (three-lead ECG), continuous BP (Finometer), and end-tidal CO2 (capnograph) were measured in 10 healthy young subjects during 15 squat-stand maneuvers (SSM) with a frequency of 0.05 Hz. The protocol was repeated with a median (interquartile range) of 44 (35-64) days apart. Dynamic CA was assessed with the autoregulation index (ARI) obtained from CBV step responses estimated with an autoregressive moving-average model. Mean BP, HR, and CBV were different (all P < 0.001) between squat and stand, regardless of visits. ARI showed a strong interaction ( P < 0.001) of SSM with the progression of transients; in general, the mean ARI was higher for the squat phase compared with standing. The changes in ARI were partially explained by concomitant changes in CBV ( P = 0.023) and pulse pressure ( P < 0.001), but there was no evidence that ARI differed between visits ( P = 0.277). These results demonstrate that dynamic CA is dependent on the direction of BP change, but further work is needed to confirm if this finding can be generalized to other physiological conditions and also to assess its dependency on age, sex and pathology.
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Pressão Arterial , Circulação Cerebrovascular , Exercício Físico/fisiologia , Modelos Cardiovasculares , Contração Muscular , Postura , Velocidade do Fluxo Sanguíneo , Eletrocardiografia , Feminino , Frequência Cardíaca , Homeostase , Humanos , Masculino , Dinâmica não Linear , Posição Ortostática , Fatores de Tempo , Ultrassonografia Doppler Transcraniana , Adulto JovemRESUMO
BACKGROUND: We evaluated the effects of two interventions that modify the red cell storage lesion on kidney and lung injury in experimental models of transfusion. METHODS: White-landrace pigs (n = 32) were allocated to receive sham transfusion (crystalloid), 14-day stored allogeneic red cells, 14-day red cells washed using the red cells washing/salvage system (CATS; Fresenius, Germany), or 14-day red cells rejuvenated using the inosine solution (Rejuvesol solution; Zimmer Biomet, USA) and washed using the CATS device. Functional, biochemical, and histologic markers of organ injury were assessed for up to 24 h posttransfusion. RESULTS: Transfusion of 14 day red cells resulted in lung injury (lung injury score vs. sham, mean difference -0.3 (95% CI, -0.6 to -0.1; P = 0.02), pulmonary endothelial dysfunction, and tissue leukocyte sequestration. Mechanical washing reduced red cell-derived microvesicles but increased cell-free hemoglobin in 14-day red cell units. Transfusion of washed red cells reduced leukocyte sequestration but did not reduce the lung injury score (mean difference -0.2; 95% CI, -0.5 to 0.1; P = 0.19) relative to 14-day cells. Transfusion of washed red cells also increased endothelial activation and kidney injury. Rejuvenation restored adenosine triphosphate to that of fresh red cells and reduced microvesicle concentrations without increasing cell-free hemoglobin release. Transfusion of rejuvenated red cells reduced plasma cell-free hemoglobin, leukocyte sequestration, and endothelial dysfunction in recipients and reduced lung and kidney injury relative to 14-day or washed 14-day cells. CONCLUSIONS: Reversal of the red cell storage lesion by rejuvenation reduces transfusion-associated organ injury in swine.
Assuntos
Preservação de Sangue/métodos , Transfusão de Eritrócitos/métodos , Eritrócitos/citologia , Lesão Pulmonar/prevenção & controle , Animais , Soluções Cristaloides , Modelos Animais de Doenças , Feminino , Humanos , Soluções Isotônicas/administração & dosagem , SuínosRESUMO
BACKGROUND: The cerebroplacental ratio has been proposed as a marker of failure to reach growth potential near term. Low cerebroplacental ratio, regardless of the fetal size, is independently associated with the need for operative delivery for presumed fetal compromise and with neonatal unit admission at term. OBJECTIVE: The main aim of this study was to evaluate whether the cerebroplacental ratio at term is a marker of reduced fetal growth rate. The secondary aim was to investigate the relationship between a low cerebroplacental ratio at term, reduced fetal growth velocity, and adverse pregnancy outcome. STUDY DESIGN: This was a retrospective cohort study of singleton pregnancies in a tertiary referral center. The abdominal circumference was measured at 20-24 weeks' gestation and both abdominal circumference and fetal Dopplers recorded at or beyond 35 weeks, within 2 weeks of delivery. Abdominal circumference and birthweight values were converted into Z scores and centiles, respectively, and fetal Doppler parameters into multiples of median, adjusting for gestational age. Abdominal circumference growth velocity was quantified using the difference in the abdominal circumference Z score, comparing the scan at or beyond 35 weeks with the scan at 20-24 weeks. Both univariable and multivariable logistic regression analyses were performed to investigate the association between low cerebroplacental ratio and the low abdominal circumference growth velocity (in the lowest decile) and to identify and adjust for potential confounders. As a sensitivity analysis, we refitted the model excluding the data on pregnancies with small-for-gestational-age neonates. RESULTS: The study included 7944 pregnancies. Low cerebroplacental ratio multiples of median was significantly associated with both low abdominal circumference growth velocity (adjusted odds ratio, 2.10; 95% confidence interval, 1.71-2.57, P <0.001) and small for gestational age (adjusted odds ratio, 3.60; 95% confidence interval, 3.04-4.25, P < .001). After the exclusion of pregnancies resulting in small-for-gestational-age neonates, a low cerebroplacental ratio multiples of the median remained significantly associated with both low abdominal circumference growth velocity (adjusted odds ratio, 1.76; 95% confidence interval, 1.34-2.30, P < .001) and birthweight centile (adjusted odds ratio, 0.99; 95% confidence interval, 0.998-0.995, P < .001). The need for operative delivery for fetal compromise was significantly associated with a low cerebroplacental ratio (adjusted odds ratio, 1.40; 95% confidence interval, 1.10-1.78, P = .006), even after adjusting for both the umbilical artery pulsatility index multiples of the median and middle cerebral artery pulsatility index multiples of median. The results were similar, even after the exclusion of pregnancies resulting in small-for-gestational-age neonates (adjusted odds ratio, 1.39; 95% confidence interval, 1.06-1.84, P = .018). Low cerebroplacental ratio multiples of the median remained significantly associated with the risk of operative delivery for presumed fetal compromise (P < .001), even after adjusting for the known antenatal and intrapartum risk factors. These associations persisted, even after the exclusion of small-for-gestational-age births. In appropriate-for-gestational-age-sized fetuses, abdominal circumference growth velocity was significantly lower in those with a low cerebroplacental ratio multiples of the median than in those with normal cerebroplacental ratio multiples of the median (P < .001). CONCLUSION: The cerebroplacental ratio is a marker of impaired fetal growth velocity and adverse pregnancy outcome, even in fetuses whose size is considered appropriate using conventional biometry.
Assuntos
Desenvolvimento Fetal/fisiologia , Retardo do Crescimento Fetal/diagnóstico , Artéria Cerebral Média/embriologia , Resultado da Gravidez , Artérias Umbilicais/embriologia , Abdome/embriologia , Adulto , Peso ao Nascer , Estudos de Coortes , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Hipóxia Fetal/diagnóstico por imagem , Feto/anatomia & histologia , Idade Gestacional , Humanos , Recém-Nascido Pequeno para a Idade Gestacional , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/fisiopatologia , Gravidez , Fluxo Pulsátil , Estudos Retrospectivos , Ultrassonografia Pré-Natal , Artérias Umbilicais/diagnóstico por imagem , Artérias Umbilicais/fisiopatologiaRESUMO
AIMS: To quantify the difference in long-term survival and cardiovascular morbidity between women and men undergoing elective abdominal aortic aneurysm (AAA) repair at National Health Service hospitals in England. METHODS AND RESULTS: Patients having elective repair of AAA were reviewed using the Hospital Episode Statistics and Office for National Statistics (ONS) datasets. The primary outcome measure was 30-day mortality and the secondary outcomes were 1-year, 5-year, and aortic-related mortality and post-operative complication rates. We used logistic regression and survival models to assess risk factors on the primary and secondary outcomes. Between 1 April 2002 and 31 March 2013, a total of 31 090 patients (4795 women and 26 295 men) underwent open AAA repair. Between 1 January 2006 and 31 March 2013, a total of 16 777 patients (2036 women and 14 741 men) underwent endovascular aneurysm repair (EVAR). All-cause and aortic-related mortalities at 30 days, 1 year, and 5 years were all higher in women, despite a lower prevalence of pre-operative cardiovascular risk factors. Female sex was a significant independent risk factor for 30-day mortality in both open repair [odds ratio (OR) 1.39; 95% confidence interval (CI) 1.25-1.56; P < 0.001] and EVAR (OR 1.57; 95% CI 1.23-2.00; P < 0.001) groups. Based on an all-cause long-term survival model, conditional on 30-day survival, the estimated hazard for women in the open repair group was significantly (P = 0.006) higher than men, but the sex difference was not significant in the EVAR group (P = 0.356). In the open repair group, women had significantly (P < 0.001) higher cumulative incidence probabilities for both aortic-related mortality and other-cause mortality. In the EVAR group, women had significantly (P < 0.001) higher mean cumulative incidence probabilities for the aortic-related mortality compared with men, but not for the other-cause mortality (P = 0.235). CONCLUSION: Women undergoing elective AAA repair at National Health Service hospitals in England had increased short- and long-term mortality and post-operative morbidity compared with men. These findings can be used to improve pre-operative counselling for women undergoing AAA repair, and highlight the need for female-specific pre-, peri-, and post-operative management strategies.
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Aneurisma da Aorta Abdominal , Procedimentos Cirúrgicos Eletivos , Procedimentos Endovasculares , Inglaterra , Feminino , Humanos , Masculino , Programas Nacionais de Saúde , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Caracteres Sexuais , Resultado do TratamentoRESUMO
Sheep scab, caused by infestation with the mite Psoroptes ovis, is highly contagious, causing intense pruritus and represents a major welfare and economic concern. Disease control strategies rely upon chemotherapy, however, sustainability is questionable due to issues of chemical residues, eco-toxicity and acaricide resistance. Control by vaccination is supported by demonstration of protective immunity in sheep previously infested with P. ovis. We identified vaccine candidates for P. ovis based on: (1) antigens selected by their interaction with host signalling pathways and the host immune-response; and (2) those shown to be either immunogenic or involved in mite feeding. This resulted in the development and validation, in repeated immunisation and challenge trials, of a seven recombinant protein sub-unit cocktail vaccine. Sheep were inoculated on three occasions, 2 weeks apart, along with QuilA adjuvant. Vaccination resulted in highly significant reductions in both lesion size (up to 63%) and mite numbers (up to 56%) following challenge. Mean lesion size in vaccinates was significantly smaller than controls from 1 week post infestation (wpi) until the end of the experiment at 6 wpi. All antigens elicited serum IgG responses following immunisation and prior to infestation, whereas controls did not produce antigen-specific IgG during the pre-infestation period. Vaccinated animals showed an amnestic response, with levels of antigen-specific IgG against muGST, Pso o 1 and Pso o 2 increasing following infestation. This vaccine represents the greatest reduction in lesion size to date with a sheep scab vaccine, providing encouragement for future production of a commercially-viable means of immunoprophylaxis.
Assuntos
Infestações por Ácaros/veterinária , Psoroptidae/fisiologia , Doenças dos Ovinos/prevenção & controle , Vacinação/veterinária , Vacinas/uso terapêutico , Animais , Antígenos/imunologia , Proteínas de Artrópodes/imunologia , Infestações por Ácaros/parasitologia , Infestações por Ácaros/prevenção & controle , Ovinos , Doenças dos Ovinos/parasitologia , Vacinas de Subunidades Antigênicas/uso terapêutico , Vacinas Sintéticas/uso terapêuticoRESUMO
As clinical toxoplasmosis is not considered a problem in pigs, the main reason to implement a control strategy against Toxoplasma gondii (T. gondii) in this species is to reduce the establishment of T. gondii tissue cysts in pork, consequently reducing the risk of the parasite entering the human food chain. Consumption of T. gondii tissue cysts from raw or undercooked meat is one of the main sources of human infection, with infected pork being considered a high risk. This study incorporates a mouse bioassay with molecular detection of T. gondii DNA to study the effectiveness of vaccination (incomplete S48 strain) in its ability to reduce tissue cyst burden in pigs, following oocyst (M4 strain) challenge. Results from the mouse bioassay show that 100% of mice which had received porcine tissues from vaccinated and challenged pigs survived compared with 51.1% of mice which received tissues from non-vaccinated and challenged pigs. The presence (or absence) of T. gondii DNA from individual mouse brains also confirmed these results. This indicates a reduction in viable T. gondii tissue cysts within tissues from pigs which have been previously vaccinated with the S48 strain. In addition, the study demonstrated that the main predilection sites for the parasite were found to be brain and highly vascular muscles (such as tongue, diaphragm, heart and masseter) of pigs, while meat cuts used as human food such as chop, loin, left tricep and left semitendinosus, had a lower burden of T. gondii tissue cysts. These promising results highlight the potential of S48 strain tachyzoites for reducing the number of T. gondii tissues cysts in pork and thus improving food safety.
Assuntos
Carne/parasitologia , Vacinas Protozoárias/farmacologia , Doenças dos Suínos/prevenção & controle , Toxoplasma/imunologia , Toxoplasmose Animal/prevenção & controle , Animais , Feminino , Humanos , Masculino , Suínos , Doenças dos Suínos/parasitologia , Toxoplasmose Animal/parasitologia , Vacinas Atenuadas/farmacologiaRESUMO
High-dimensional radiomics features derived from pre-treatment positron emission tomography (PET) images offer prognostic insights for patients with head and neck squamous cell carcinoma (HNSCC). Using 124 PET radiomics features and clinical variables (age, sex, stage of cancer, site of cancer) from a cohort of 232 patients, we evaluated four survival models-penalized Cox model, random forest, gradient boosted model and support vector machine-to predict all-cause mortality (ACM), locoregional recurrence/residual disease (LR) and distant metastasis (DM) probability during 36, 24 and 24 months of follow-up, respectively. We developed models with five-fold cross-validation, selected the best-performing model for each outcome based on the concordance index (C-statistic) and the integrated Brier score (IBS) and validated them in an independent cohort of 102 patients. The penalized Cox model demonstrated better performance for ACM (C-statistic = 0.70, IBS = 0.12) and DM (C-statistic = 0.70, IBS = 0.08) while the random forest model displayed better performance for LR (C-statistic = 0.76, IBS = 0.07). We conclude that the ML-based prognostic model can aid clinicians in quantifying prognosis and determining effective treatment strategies, thereby improving favorable outcomes in HNSCC patients.
RESUMO
Background: Patients with breast cancer undergoing biological therapy and/or chemotherapy perform multiple radionuclide angiography (RNA) or multigated acquisition (MUGA) scans to assess cardiotoxicity. The association between RNA imaging parameters and left ventricular (LV) ejection fraction (LVEF) remains unclear. Objectives: This study aimed to extract and evaluate the association of several novel imaging biomarkers to detect changes in LVEF in patients with breast cancer undergoing chemotherapy. Methods: We developed and optimized a novel set of MATLAB routines called the "RNA Toolbox" to extract parameters from RNA images. The code was optimized using various statistical tests (e.g., ANOVA, Bland-Altman, and intraclass correlation tests). We quantitatively analyzed the images to determine the association between these parameters using regression models and receiver operating characteristic (ROC) curves. Results: The code was reproducible and showed good agreement with validated clinical software for the parameters extracted from both packages. The regression model and ROC results were statistically significant in predicting LVEF (R2 = 0.40, P < 0.001) (AUC = 0.78). Some time-based, shape-based, and count-based parameters were significantly associated with post-chemotherapy LVEF (ß = 0.09, P < 0.001), LVEF of phase image (ß = 4, P = 0.030), approximate entropy (ApEn) (ß = 11.6, P = 0.001), ApEn (diastolic and systolic) (ß = 39, P = 0.002) and LV systole size (ß = 0.03, P = 0.010). Conclusions: Despite the limited sample size, we observed evidence of associations between several parameters and LVEF. We believe that these parameters will be more beneficial than the current methods for patients undergoing cardiotoxic chemotherapy. Moreover, this approach can aid physicians in evaluating subclinical cardiac changes during chemotherapy, and in understanding the potential benefits of cardioprotective drugs.