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Monkeypox (MPOX), a zoonotic disease originating in Western and Central Africa in 1970, has seen a recent surge in outbreaks across 100+ countries. A comparative analysis of 404 Monkeypox virus (MPXV) genomes revealed notable changes in microsatellite abundance and density, especially within Clades I, IIa, and IIb. Each clade exhibited unique microsatellite motifs, with twenty-six conserved loci specific to MPXV, suggesting their potential as molecular markers in diagnostics. Additionally, nine genes in the MPXV genome featured ten variable hotspot microsatellite regions associated with surface protein synthesis and host control. Notably, gene OPG153, especially at the SSR locus '(ATC)n', exhibited the most pronounced variations among lineages over time and plays a role in virus pathogenesis within the host cell. These findings not only enhance our understanding of MPXV unique molecular profile but also offer valuable insights into potential pathogenic and evolutionary implications.
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BACKGROUND: Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab. METHODS: Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9. RESULTS: Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C. CONCLUSIONS: In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.
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Anticorpos Monoclonais Humanizados , Anticolesterolemiantes , LDL-Colesterol , Homozigoto , Hiperlipoproteinemia Tipo II , Inibidores de PCSK9 , Adolescente , Criança , Feminino , Humanos , Masculino , Fatores Etários , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , LDL-Colesterol/sangue , Quimioterapia Combinada , Ezetimiba/uso terapêutico , Ezetimiba/efeitos adversos , Predisposição Genética para Doença , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Fenótipo , Pró-Proteína Convertase 9/genética , Inibidores de Serina Proteinase/efeitos adversos , Inibidores de Serina Proteinase/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Estudos Clínicos como AssuntoRESUMO
AIMS: PCSK9 inhibition intensively lowers low density lipoprotein cholesterol and is well tolerated in adults and paediatric patients with familial hypercholesterolaemia (FH). HAUSER-RCT showed that 24 weeks of treatment with evolocumab in paediatric patients did not affect cognitive function. This study determined the effects of 80 additional weeks of evolocumab treatment on cognitive function in paediatric patients with heterozygous FH. METHODS AND RESULTS: HAUSER-OLE was an 80-week open-label extension of HAUSER-RCT, a randomized, double-blind, 24-week trial evaluating the efficacy and safety of evolocumab in paediatric patients (ages 10-17 years) with FH. During the OLE, all patients received monthly 420â mg subcutaneous evolocumab injections. Tests of psychomotor function, attention, visual learning, and executive function were administered at baseline and Weeks 24 and 80 of the OLE. Changes over time were analysed descriptively and using analysis of covariance. Cohen's d statistic was used to evaluate the magnitude of treatment effects. Analysis of covariance results indicated no decrease in performance across visits during 80 weeks of evolocumab treatment for Groton Maze Learning, One Card Learning accuracy, Identification speed, or Detection speed (all P > 0.05). Performance on all tasks was similar for those who received placebo or evolocumab in the RCT (all P > 0.05). For all tests, the least square mean differences between patients who received placebo vs. evolocumab in the parent study were trivial (all Cohen's d magnitude < 0.2). CONCLUSION: In paediatric patients with FH, 80 weeks of open-label evolocumab treatment had no negative impact on cognitive function. REGISTRATION: ClinicalTrials.gov identifier: NCT02624869.
Some children are born with a genetic disorder that causes high cholesterol, which leads to heart disease. Children with high cholesterol can be treated with evolocumab, a medication that lowers blood cholesterol. Because cholesterol is important for development and adequate function of the brain, there is a concern that lowering cholesterol in children may affect mental ability. In this study, we tested whether treating children with evolocumab for 80 weeks affected mental ability in performing several tasks. A battery of tests that measure executive function (Groton Maze Learning Test), visual learning (One Card Learning Test), visual attention (Identification Test), and psychomotor function (Detection Test) showed no decrease in performance across visits during 80 weeks of evolocumab treatment. Performance on all tasks was similar for the children who received placebo for the first 24 weeks then received evolocumab for an additional 80 weeks (placebo/evolocumab) and those who received evolocumab for 24 weeks then received evolocumab for an additional 80 weeks (evolocumab/evolocumab).
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Anticorpos Monoclonais Humanizados , Anticolesterolemiantes , Hiperlipoproteinemia Tipo II , Adulto , Humanos , Criança , Pró-Proteína Convertase 9 , Anticolesterolemiantes/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Cognição , Resultado do Tratamento , Método Duplo-CegoRESUMO
BACKGROUND: The reduction of low-density lipoprotein cholesterol (LDL-C) with evolocumab, a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9i), reduces the risk of major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease (ASCVD) with a prior MI, prior stroke, or symptomatic peripheral artery disease, with no offsetting safety concerns. The effect of evolocumab on CV outcomes in lower risk patients without a history of MI or stroke has not been explored. STUDY DESIGN: VESALIUS-CV is a randomized, double-blind, placebo-controlled, global clinical trial designed to evaluate the effect of evolocumab on the risk of major cardiovascular events in patients at high cardiovascular risk but without a prior ischemic event. The study population consists of 12,301 patients with atherosclerosis or high-risk diabetes mellitus without a prior MI or stroke; an LDL-C ≥ 90 mg/dL, or non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 120 mg/dL, or apolipoprotein B ≥ 80 mg/dL; and treated with optimized lipid-lowering therapy. Patients were randomized in a 1:1 ratio to evolocumab 140 mg subcutaneously every 2 weeks or matching placebo. The primary efficacy objective is to assess whether evolocumab reduces the risk of the dual primary composite endpoints of coronary heart disease (CHD) death, myocardial infarction (MI), or ischemic stroke (triple primary endpoint) and of CHD death, MI, ischemic stroke, or ischemia-driven arterial revascularization (quadruple primary endpoint). Recruitment began in June 2019 and completed in November 2021. The trial is planned to continue until at least 751 patients experience an adjudicated triple endpoint, at least 1254 experience an adjudicated quadruple endpoint, and the median follow-up is ≥4.5 years. CONCLUSION: VESALIUS-CV will determine whether the addition of evolocumab to optimized lipid-lowering therapy reduces cardiovascular events in patients at high cardiovascular risk without a prior MI or stroke. TRIAL REGISTRATION: NCT03872401.
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Anticorpos Monoclonais Humanizados , Anticolesterolemiantes , Aterosclerose , Doenças Cardiovasculares , AVC Isquêmico , Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/induzido quimicamente , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol , Inibidores de PCSK9 , Fatores de Risco , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Aterosclerose/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/induzido quimicamente , Pró-Proteína Convertase 9 , Fatores de Risco de Doenças Cardíacas , AVC Isquêmico/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: The HAUSER-RCT study showed that 24 weeks of evolocumab (a proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor) in paediatric patients with heterozygous familial hypercholesterolaemia was safe and improved lipid parameters compared to placebo. Here, we aimed to evaluate the safety and efficacy of evolocumab in this population for an additional 80 weeks. METHODS: HAUSER-OLE was an 80-week, single-arm, open-label extension of HAUSER-RCT, a randomised controlled trial, and was conducted at 46 centres in 23 countries. Paediatric patients aged 10-17 years with heterozygous familial hypercholesterolaemia who completed 24 weeks of monthly treatment with subcutaneously administered placebo or 420 mg evolocumab in HAUSER-RCT with no serious treatment-emergent adverse events were eligible to enrol in HAUSER-OLE. All patients received open-label subcutaneous evolocumab 420 mg monthly with background statins with or without ezetimibe for 80 additional weeks. The primary endpoint was treatment-emergent adverse events. Efficacy was evaluated by changes in lipids from the baseline of HAUSER-RCT to the end of HAUSER-OLE (104 weeks). This study is registered with ClinicalTrials.gov (NCT02624869) and is now completed. FINDINGS: Between Sept 10, 2016, and Nov 25, 2019, 157 patients were enrolled in HAUSER-RCT and received randomised treatment; 150 continued to HAUSER-OLE, received evolocumab treatment, and were included in the full analysis set, presented here. 146 (97%) of 150 patients completed the open-label extension. The incidence of treatment-emergent adverse events in HAUSER-OLE was 70% (105 of 150). Overall, the most common treatment-emergent adverse events were nasopharyngitis (22 [15%] of 150), headache (14 [9%]), and influenza-like illness (13 [9%]). Serious treatment-emergent adverse events occurred in four (3%) of 150 patients (perforated appendicitis and peritonitis, wrist fracture, anorexia nervosa, and headache); none was considered related to evolocumab. No treatment-emergent adverse events led to treatment discontinuation. At week 80, the mean percentage change from baseline in LDL cholesterol was -35·3% (SD 28·0). INTERPRETATION: After 80 weeks of treatment, evolocumab was safe, well tolerated, and led to sustained reductions in LDL cholesterol in paediatric patients with heterozygous familial hypercholesterolaemia. When lipid goals cannot be achieved with conventional treatments, evolocumab is an effective add-on therapy in paediatric patients. FUNDING: Amgen. TRANSLATIONS: For the French, Spanish, Spanish, Portuguese, Italian and Dutch translations of the abstract see Supplementary Materials section.
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Anticolesterolemiantes , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/uso terapêutico , Criança , LDL-Colesterol , Método Duplo-Cego , Ezetimiba/uso terapêutico , Cefaleia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pró-Proteína Convertase 9 , Subtilisinas/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: Pediatric cardiac Extracorporeal Membrane Oxygenation (ECMO) is effective, however, bleeding and clotting issues continue to cause significant morbidity and mortality. The objective of this study was to assess the correlation between measures of anticoagulation, the heparin dose in pediatric cardiac ECMO patients as well as to assess covert coagulopathy as measured by thromboelastography (TEG). METHODS: Retrospective study of cardiac ECMO patients in a large, academic referral center using anticoagulation data during the ECMO support. RESULTS: Five hundred and eighty-four sets of anticoagulation tests and 343 TEG from 100 patients with median age of 26 days were reviewed. ECMO was post-surgical for congenital heart disease in 94% with resuscitation (ECPR) in 38% of the cases. Mean duration of support was 6.3 days. Overall survival to discharge was 35%. There was low but statistically significant correlation between individual anticoagulation measures and low correlation between Anti-Xa levels and heparin dose. There was no correlation between PTT and heparin dose. 343 TEG with Heparinase were reviewed to assess covert coagulopathy which was present in 25% of these. The coagulopathy noted was pro-hemorrhagic in almost all of the cases with high values of reaction time and kinetics and low values for angle and maximum amplitude. CONCLUSION: Coagulation monitoring on ECMO may benefit from addition of Heparinase TEG to diagnose covert coagulopathy which can contribute to significant hemorrhagic complications. There is a need for a prospective, thromboelastography guided intervention trial to reduce coagulopathy related morbidity and mortality in ECMO.
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Oxigenação por Membrana Extracorpórea , Anticoagulantes/efeitos adversos , Coagulação Sanguínea , Criança , Oxigenação por Membrana Extracorpórea/efeitos adversos , Heparina/farmacologia , Humanos , Estudos RetrospectivosRESUMO
INTRODUCTION: Nucleated red blood cells (NRBCs) are immature red cells that under normal conditions are not present in the peripheral circulation. Several studies have suggested an association between elevated NRBC and poor outcome in critically ill adults and neonates. We sought to determine if elevations in NRBC value following cardiac surgery and following clinical events during the hospital stay can be used as a biomarker to monitor for mortality risk in neonates post-cardiac surgery. MATERIALS AND METHODS: We constructed a retrospective study of 264 neonates who underwent cardiac surgery at Children's Hospital, New Orleans between 2011 and 2020. Variables included mortality and NRBC value were recorded following cardiac surgery and following peri-operative clinical events. The study was approved by LSU Health IRB. Sensitivity, specificity, receiver operating characteristic (ROC) curves with area under the curve (AUC) and logistic regression analysis were performed. RESULTS: Thirty-six patients (13.6%) died, of which 32 had an NRBC value ≥10/100 white blood cell (WBC) during hospitalisation. Multi-variable analysis found extracorporeal membrane oxygenation use (OR 10, 95% CI 2.9-33, p=<0.001), NRBC ≥10/100 WBC (OR 16.1, CI 4.1-62.5, p ≤ 0.001) and peak NRBC in the 14-day period post-cardiac surgery (continuous variable, OR 1.05, 95% CI 1.0-1.09, p = 0.03), to be independently associated with mortality. Using a cut-off NRBC value of 10/100 WBC, there was an 88.9% sensitivity and a 90.8% specificity, with ROC curve showing an AUC of 0.9 and 0.914 for peak NRBC value in 14 days post-surgery and entire hospitalisation, respectively. CONCLUSIONS: NRBC ≥10/100 WBC post-cardiac surgery is strongly associated with mortality. Additionally, NRBC trend appears to show promise as an accurate biomarker for mortality.
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Procedimentos Cirúrgicos Cardíacos , Eritrócitos , Adulto , Biomarcadores , Criança , Contagem de Eritrócitos , Humanos , Recém-Nascido , Estudos RetrospectivosRESUMO
OBJECTIVE: Rheumatoid arthritis (RA) is a chronic condition characterized by articular and non-articular features. Patients with RA have an increased risk of developing cardiovascular disease. This study aimed to ascertain what patients with RA know about their numbers (biomedical data, including blood pressure, cholesterol, disease activity score-28 joints [DAS28], and body mass index [BMI]) and to understand the barriers to patients knowing these health indicators and how their knowledge can be improved. METHODS: A total of 50 consecutive patients from a clinic were approached to complete an anonymous survey in a nurse-led clinic. The questionnaire included 10 questions that assessed the demographic data, knowledge of biomedical data, importance of these data, and how their awareness could be increased. RESULTS: A total of 40 patients responded to the questionnaire; the estimated mean age was 58.1±13.4 (mean±standard deviation) years. Most respondents were females (87%). The highest disease category duration was 2-5 years (40% patients). Moreover, 30% of respondents were aware of the "know your numbers" concept; 90% did not know their BMI, and 75% did not know about their DAS28 score. Furthermore, 40% reported that they were not informed about their biomedical data; 95% of patients revealed that they would like to know their numbers; 27.5% suggested that a regularly updated and explained written record would be appropriate, and 35% proposed that a multidisciplinary input would be useful in regularly informing them of the numbers. CONCLUSION: This study has shown that although patients are not very familiar with all of their biomedical data, they are interested in knowing them. Knowing their biomedical data may encourage them to be more concerned about their health and even lead to improved RA self-management and health outcomes.
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BACKGROUND AND OBJECTIVE: Omecamtiv mecarbil (OM) is a cardiac myosin activator under clinical development for the treatment of heart failure. Two modified-release (MR) novel OM minitablet formulations were developed to support the planned investigation of chronic heart failure in pediatric patients. The primary objective of this study was to determine the bioavailability of the minitablets relative to the adult matrix MR formulation tablets. METHODS: In a randomized, 5-period, crossover study, 20 healthy subjects received each of the following treatments orally: one 25-mg adult matrix MR tablet, 25 1-mg slow-release minitablets, 25 1-mg fast-release minitablets, six 1-mg slow-release minitablets, or six 1-mg fast-release minitablets after an overnight fast of at least 10 h with a minimum washout of 7 days between treatments. Blood samples were collected for up to 168 h. OM pharmacokinetic parameters were estimated using non-compartmental methods. RESULTS: When OM was administered as 25 1-mg OM slow-release minitablets, AUClast, AUCinf, and Cmax were 0.998-, 1.00-, and 1.29-fold of a single 25-mg OM matrix MR tablet, respectively. When OM was administered as 25 1-mg OM fast-release minitablets, AUClast, AUCinf, and Cmax were 1.26-, 1.25-, and 2.21-fold of a single 25-mg OM matrix MR tablet, respectively. The slow- and fast-release minitablets display approximately dose-proportional pharmacokinetics. There were no serious adverse events or treatment-emergent adverse events leading to discontinuation from the study. CONCLUSIONS: Relative bioavailability of slow-release minitablets was demonstrated to be similar to the adult matrix MR formulation.
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Preparações de Ação Retardada/química , Comprimidos/química , Ureia/análogos & derivados , Administração Oral , Adolescente , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Composição de Medicamentos , Feminino , Meia-Vida , Voluntários Saudáveis , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Mialgia/etiologia , Ureia/efeitos adversos , Ureia/sangue , Ureia/farmacocinética , Ureia/uso terapêutico , Adulto JovemRESUMO
Despite improved outcomes following modifications to the Fontan technique, significant morbidity and mortality persist. We sought to determine if abnormal pre-Fontan catheterization hemodynamic data will predict postoperative prolonged hospital stay (PHLOS) and adverse post-discharge outcomes. This is a retrospective study of patients who underwent the Fontan procedure at Children's Hospital of New Orleans from 2008 to 2018. PHLOS was defined as ≥ 14 and ≥ 21 days to discharge post Fontan. We defined post-discharge adverse outcomes as thromboembolic phenomena requiring anticoagulation therapy, protein-losing enteropathy, plastic bronchitis, transplantation, persistent chylous effusion requiring fenestration creation, or death. Statistical analysis was performed using student t test, Chi-square test, and multivariable logistic regression analysis using IBM SPSS version 22. Ninety-seven patients underwent extracardiac Fontan. Forty-one patients (42.3%) experienced hospitalization ≥ 14 days, 31 patients (32%) experienced hospitalization ≥ 21 days, and 14 patients (14.4%) experienced adverse post-discharge outcome. Elevated end-diastolic pressure (EDP) ≥ 10 mmHg (p = 0.005, OR 4.2, CI 1.5-11.4) was independently associated with ≥ 14 days of hospitalization, while a CI < 4 L/minute/meters2 combined with one abnormal catheterization variable was associated with PHLOS and post-discharge adverse outcomes (p = 0.03, OR 2.8, CI 1.1-7.3 and p = 0.043, OR 6.42, OR 1.1-38.9, respectively). The absence of fenestration was also associated with post-discharge adverse outcomes (p = 0.007, OR 5.8, CI1.6-20.7). Elevated EDP may be associated with PHLOS, while CI < 4 L/minute/meters2 combined with abnormal catheterization hemodynamics may be associated with PHLOS and adverse post-discharge outcomes, while absence of fenestration may be associated with post-discharge adverse events.
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Cateterismo Cardíaco/métodos , Técnica de Fontan/efeitos adversos , Cardiopatias Congênitas/cirurgia , Tempo de Internação/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Adolescente , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Feminino , Técnica de Fontan/mortalidade , Cardiopatias Congênitas/mortalidade , Hemodinâmica , Humanos , Lactente , Masculino , Nova Orleans , Alta do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: For many elderly patients, a disproportionate amount of health care resources and expenditures is spent during the last year of life, despite the discomfort and reduced quality of life associated with many aggressive medical approaches. However, few prognostic tools have focused on predicting all-cause 1-year mortality among elderly patients at a statewide level, an issue that has implications for improving quality of life while distributing scarce resources fairly. OBJECTIVE: Using data from a statewide elderly population (aged ≥65 years), we sought to prospectively validate an algorithm to identify patients at risk for dying in the next year for the purpose of minimizing decision uncertainty, improving quality of life, and reducing futile treatment. METHODS: Analysis was performed using electronic medical records from the Health Information Exchange in the state of Maine, which covered records of nearly 95% of the statewide population. The model was developed from 125,896 patients aged at least 65 years who were discharged from any care facility in the Health Information Exchange network from September 5, 2013, to September 4, 2015. Validation was conducted using 153,199 patients with same inclusion and exclusion criteria from September 5, 2014, to September 4, 2016. Patients were stratified into risk groups. The association between all-cause 1-year mortality and risk factors was screened by chi-squared test and manually reviewed by 2 clinicians. We calculated risk scores for individual patients using a gradient tree-based boost algorithm, which measured the probability of mortality within the next year based on the preceding 1-year clinical profile. RESULTS: The development sample included 125,896 patients (72,572 women, 57.64%; mean 74.2 [SD 7.7] years). The final validation cohort included 153,199 patients (88,177 women, 57.56%; mean 74.3 [SD 7.8] years). The c-statistic for discrimination was 0.96 (95% CI 0.93-0.98) in the development group and 0.91 (95% CI 0.90-0.94) in the validation cohort. The mortality was 0.99% in the low-risk group, 16.75% in the intermediate-risk group, and 72.12% in the high-risk group. A total of 99 independent risk factors (n=99) for mortality were identified (reported as odds ratios; 95% CI). Age was on the top of list (1.41; 1.06-1.48); congestive heart failure (20.90; 15.41-28.08) and different tumor sites were also recognized as driving risk factors, such as cancer of the ovaries (14.42; 2.24-53.04), colon (14.07; 10.08-19.08), and stomach (13.64; 3.26-86.57). Disparities were also found in patients' social determinants like respiratory hazard index (1.24; 0.92-1.40) and unemployment rate (1.18; 0.98-1.24). Among high-risk patients who expired in our dataset, cerebrovascular accident, amputation, and type 1 diabetes were the top 3 diseases in terms of average cost in the last year of life. CONCLUSIONS: Our study prospectively validated an accurate 1-year risk prediction model and stratification for the elderly population (≥65 years) at risk of mortality with statewide electronic medical record datasets. It should be a valuable adjunct for helping patients to make better quality-of-life choices and alerting care givers to target high-risk elderly for appropriate care and discussions, thus cutting back on futile treatment.
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Recursos em Saúde/normas , Futilidade Médica/psicologia , Mortalidade/tendências , Qualidade de Vida/psicologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Estudos Prospectivos , Fatores de Risco , Fatores de TempoRESUMO
AIM: To assess utility and correlation of known anticoagulation parameters in the management of pediatric ventricular assist device (VAD). METHODS: Retrospective study of pediatric patients supported with a Berlin EXCOR VAD at a single pediatric tertiary care center during a single year. RESULTS: We demonstrated associations between activated thromboplastin time (aPTT) and R-thromboelastography (R-TEG) values (rs = 0.65, P < 0.001) and between anti-Xa assay and R-TEG values (rs = 0.54, P < 0.001). The strongest correlation was seen between aPTT and anti-Xa assays (rs = 0.71, P < 0.001). There was also a statistically significant correlation between platelet counts and the maximum amplitude of TEG (rs = 0.71, P < 0.001). Importantly, there was no association between dose of unfractionated heparin and either measure of anticoagulation (aPTT, anti-Xa or R-TEG value). CONCLUSION: This study suggests that while there is strong correlation between aPTT, anti-Xa assay and R-TEG values for patients requiring VAD support, there is a lack of relevant correlation between heparin dose and degree of effect. This raises concern as various guidelines continue to recommend using these parameters to titrate heparin therapy.
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The majority of thoracic aortic aneurysms (TAA) in the pediatric population are due to post repair etiology (iatrogenic). Although rare, underlying inheritable disease and congenital cardiac anomalies represent the most common non-iatrogenic cause of TAA among patients in this age group (1-21 years of age). Herein, we present a case series of 9aortic aneurysms with varying underlying etiology. We discuss the molecular genetic basis of these syndromes in conjunction with the radiological findings and histological description utilizing the newly published consensus criteria article.
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Aneurisma da Aorta Torácica/genética , Coartação Aórtica/complicações , Cútis Laxa/complicações , Anormalidades do Olho/complicações , Feminino , Humanos , Lactente , Recém-Nascido , Síndrome de Loeys-Dietz/complicações , Síndromes Neurocutâneas/complicações , Terminologia como AssuntoRESUMO
Histopathological whole-slide images (WSIs) have emerged as an objective and quantitative means for image-based disease diagnosis. However, WSIs may contain acquisition artifacts that affect downstream image feature extraction and quantitative disease diagnosis. We develop a method for detecting blur artifacts in WSIs using distributions of local blur metrics. As features, these distributions enable accurate classification of WSI regions as sharp or blurry. We evaluate our method using over 1000 portions of an endomyocardial biopsy (EMB) WSI. Results indicate that local blur metrics accurately detect blurry image regions.
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Coração , Artefatos , Biópsia , HumanosRESUMO
The development of rK39-based rapid diagnostic tests (RDTs) has greatly aided the diagnosis of visceral leishmaniasis, especially in the Indian subcontinent and Brazil, by offering high sensitivity and specificity. However, these tests have been less sensitive and less specific in sub-Saharan Africa. To improve upon the performance of rK39 in Africa, we engineered the fusion molecule rK28, which retained some of the rK39 repeats and combined them with repeat sequences from two additional Leishmania genes. This polyprotein was used in the development of several prototype RDTs by different commercial manufacturers with the goal of assessing relative performance in inexpensive formats. Here, we report field studies showing that the rK28 antigen could be readily adapted to a variety of RDT formats to achieve high sensitivity, generally > 90%, and adequate specificity to aid in the diagnosis of human visceral leishmaniasis in East Africa, Asia, and South America.
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Leishmaniose Visceral/diagnóstico , Sistemas Automatizados de Assistência Junto ao Leito , África Oriental , Humanos , Sensibilidade e EspecificidadeRESUMO
Lyme disease, while still an uncommon disease in the UK, is on the increase. Case numbers have increased by 3.6-fold since 2001, with over 950 cases reported by the Health Protection Agency (HPA) in 2011, compared with less than 500 cases annually pre-2004. HPA indications of the true incidence are suggested to be closer to 3000 cases/year, of which around 82% of cases are indigenously acquired. Three genospecies, Borrelia burgdorferi sensu stricto, Borrelia afzelli and Borrelia garinii, represent the predominant pathogenic variants in the UK. Erythema migrans is the commonest manifestation, occurring in 60%-91% of cases. In the UK, neuroborelliosis is the most common complication, while myocarditis is unusual, and death from either conduction disease or carditis is extremely rare. The role of Borrelia infection in chronic dilated cardiomyopathy in the UK remains unproven. Controversy over the existence of either 'chronic Lyme disease' and/or 'post-Lyme disease syndrome' continues unabated. National medical societies, patient advocacy groups, insurance companies, lawyers, doctors, the private health medical sector and scientific journals have all become embroiled in this bitter controversy. New developments include diagnostic tests able to detect Lyme disease at an earlier stage, shorter durations of antibiotic therapy and potential advances in vaccines against Borrelia.
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Eritema Migrans Crônico/diagnóstico , Doença de Lyme/diagnóstico , Neuroborreliose de Lyme/diagnóstico , Pele/microbiologia , Picadas de Carrapatos/microbiologia , Doenças Transmitidas por Carrapatos/diagnóstico , Animais , Vacinas Bacterianas , Borrelia burgdorferi/isolamento & purificação , Grupo Borrelia Burgdorferi/isolamento & purificação , Eritema Migrans Crônico/epidemiologia , Eritema Migrans Crônico/microbiologia , Feminino , Humanos , Doença de Lyme/epidemiologia , Doença de Lyme/microbiologia , Neuroborreliose de Lyme/epidemiologia , Neuroborreliose de Lyme/microbiologia , Masculino , Kit de Reagentes para Diagnóstico , Pele/patologia , Doenças Transmitidas por Carrapatos/epidemiologia , Doenças Transmitidas por Carrapatos/microbiologia , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Soluble CD40 ligand (sCD40L) and matrix metalloproteinase 9 (MMP-9) are inflammation markers and have been poorly described in infectious disease. In this prospective study, we describe the sera kinetics of these two molecules in the course of treatment follow up in human visceral leishmaniasis (VL). METHODS: Sera from VL patients were collected before and during follow up of regular Antimony treatment. sCD40L and MMP-9 were measured by Luminex assay. Paired analysis by Wilcoxon signed test was used for comparison of values of the same subjects before and after initiation of treatment. Correlations between clinical data and parasite load with the serum levels of sCD40L and MMP-9 were performed by Spearman test. Tests were considered statistically significant if the probability of a type I error was less than 5% (p-value < 0.05). RESULTS: While sCD40L and MMP-9 were not observed in sera from non endemic controls which are at low risk of Leishmania chagasi infection, elevated levels were observed in sera from VL patients, and an increase in sCD40L and MMP-9 levels were detectable during the follow-up of VL patients undergoing antimony treatment. sCD40L levels were also high in individuals living in endemic settings at high risk of infection (endemic controls). Additionally, negative correlations were found between spleen sizes and MMP-9 before treatment and sCD40L at day 15 of treatment. Negative correlations were also found between parasite load with both sCD40L and MMP-9. CONCLUSION: Serum sCD40L and MMP-9 are identified as new and simple biomarkers in two situations: (i) monitoring the success of therapy and (ii) predicting favorable clinical outcome of human VL.
Assuntos
Antígenos CD40/sangue , Leishmaniose Visceral/sangue , Metaloproteinase 9 da Matriz/sangue , Adolescente , Adulto , Biomarcadores/sangue , Criança , Feminino , Humanos , Leishmaniose Visceral/diagnóstico , Masculino , Carga Parasitária , PrognósticoAssuntos
Anormalidades Múltiplas/patologia , Angiografia Coronária , Anomalias dos Vasos Coronários/patologia , Comunicação Interventricular/patologia , Artéria Pulmonar/anormalidades , Doença Aguda , Valva Aórtica/patologia , Cardiomegalia/etiologia , Anomalias dos Vasos Coronários/diagnóstico por imagem , Anomalias dos Vasos Coronários/fisiopatologia , Anomalias dos Vasos Coronários/cirurgia , Feminino , Comunicação Interventricular/fisiopatologia , Comunicação Interventricular/cirurgia , Humanos , Lactente , Insuficiência da Valva Mitral/complicações , Estenose da Valva Mitral/diagnóstico , Estenose da Valva Mitral/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Reimplante , Insuficiência Respiratória/etiologia , Síndrome , Ultrassonografia , Resistência Vascular , Disfunção Ventricular Esquerda/etiologiaRESUMO
BACKGROUND: Recombinant KSAC and L110f are promising Leishmania vaccine candidates. Both antigens formulated in stable emulsions (SE) with the natural TLR4 agonist MPL® and L110f with the synthetic TLR4 agonist GLA in SE protected BALB/c mice against L. major infection following needle challenge. Considering the virulence of vector-transmitted Leishmania infections, we vaccinated BALB/c mice with either KSAC+GLA-SE or L110f+GLA-SE to assess protection against L. major transmitted via its vector Phlebotomus duboscqi. METHODS: Mice receiving the KSAC or L110f vaccines were challenged by needle or L. major-infected sand flies. Weekly disease progression and terminal parasite loads were determined. Immunological responses to KSAC, L110f, or soluble Leishmania antigen (SLA) were assessed throughout vaccination, three and twelve weeks after immunization, and one week post-challenge. RESULTS: Following sand fly challenge, KSAC-vaccinated mice were protected while L110f-vaccinated animals showed partial protection. Protection correlated with the ability of SLA to induce IFN-γ-producing CD4(+)CD62L(low)CCR7(low) effector memory T cells pre- and post-sand fly challenge. CONCLUSIONS: This study demonstrates the protective efficacy of KSAC+GLA-SE against sand fly challenge; the importance of vector-transmitted challenge in evaluating vaccine candidates against Leishmania infection; and the necessity of a rapid potent Th1 response against Leishmania to attain true protection.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antígenos de Protozoários/imunologia , Leishmania major/imunologia , Vacinas contra Leishmaniose/imunologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/prevenção & controle , Animais , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/administração & dosagem , Modelos Animais de Doenças , Feminino , Interferon gama/metabolismo , Vacinas contra Leishmaniose/administração & dosagem , Leishmaniose Cutânea/patologia , Leishmaniose Cutânea/transmissão , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Phlebotomus/parasitologia , Linfócitos T/imunologiaRESUMO
A subunit vaccine using a defined antigen(s) may be one effective solution for controlling leishmaniasis. Because of genetic diversity in target populations, including both dogs and humans, a multiple-antigen vaccine will likely be essential. However, the cost of a vaccine to be used in developing countries must be considered. We describe herein a multiantigen vaccine candidate comprised of antigens known to be protective in animal models, including dogs, and to be recognized by humans immune to visceral leishmaniasis. The polyprotein (KSAC) formulated with monophosphoryl lipid A, a widely used adjuvant in human vaccines, was found to be immunogenic and capable of inducing protection against Leishmania infantum, responsible for human and canine visceral leishmaniasis, and against L. major, responsible for cutaneous leishmaniasis. The results demonstrate the feasibility of producing a practical, cost-effective leishmaniasis vaccine capable of protecting both humans and dogs against multiple Leishmania species.