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In this cohort of patients with pulmonary arterial hypertension (PAH), we investigate metabolomic associations with comprehensive right ventricular (RV) functional measurements derived from multibeat RV pressure-volume loop analysis. Our results show that tryptophan metabolism, particularly the kynurenine pathway, is linked to intrinsic RV function and PAH pathobiology. Findings also highlight the importance of arginine bioavailability in the cardiopulmonary system’s response to exercise stress. Metabolite profiles selected via unbiased analysis outperformed N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) in predicting load-independent measures of RV function at rest and cardiopulmonary system performance under stress. Overall, this work suggests the potential for select metabolites to function as disease-specific biomarkers, offers insights into PAH pathobiology, and informs discovery of potentially targetable RV-centric pathways.

Purpose To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. Patients and Methods In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. Results Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. Conclusion Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.

Prior studies of post-thyroidectomy vocal cord paralysis (VCP) present static and limited evaluations. We comprehensively assessed the experience of patients with VCP post-thyroidectomy over 1 year.Voice Handicap Index (VHI), Eating Assessment Tool (EAT-10), 12-Item Short Form Survey (SF-12), and qualitative interviews were assessed preoperatively, and 2-weeks, 6-weeks, 6-months, and 1-year postoperatively.7 of 44 patients (15.9%) had postoperative VCP. Compared to those without complication, mean VHI scores for VCP patients increased significantly from baseline at 2-weeks (27.9 point increase vs 1.6, p 0.01) and 6-weeks (26.3 vs. -0.3, p 0.01) postoperative. There were no significant differences between groups in SF-12 or EAT-10 scores at any point. Qualitative interviews showed that both groups noted bothersome voice symptoms at 2-weeks; however, by 6-weeks, only VCP patients noted voice symptoms negatively affecting their life.While both patients with and without VCP reported subjective voice symptoms immediately postoperatively, those with VCP had worse quantitative measures. Understanding the longitudinal experience of VCP can help providers tailor counseling for these patients.

To date, it remains unclear whether recent changes in the management of patients with systemic sclerosis-associated pulmonary hypertension (SSc-PH) have improved survival.To describe a cohort of SSc-PH patients and compare their characteristics and survival between the last two decades.SSc-PH patients prospectively enrolled in the Johns Hopkins PH Center Registry were grouped into two cohorts based on the date of diagnostic right heart catheterization: cohort A included patients diagnosed between 1999 and 2010, and cohort B included those diagnosed between 2010 and 2021. Patients' characteristics were compared between the two cohorts.Of 504 SSc-PH patients distributed almost equally between the two cohorts, 308 (61%) had World Symposium on Pulmonary Hypertension (WSPH) Group 1, 43 (9%) had Group 2, and 151 (30%) had Group 3. Patients with Group 1 disease in cohort B had significantly better clinical and hemodynamic characteristics at diagnosis, were more likely to receive upfront combination pulmonary arterial hypertension therapy, and had a nearly 4-year increase in median transplant-free survival in univariable analysis compared to those in cohort A (P0.01). Improved transplant-free survival was still observed after adjusting for patients' baseline characteristics. In contrast, for Group 2 or 3 SSc-PH patients, there were no differences in baseline clinical, hemodynamic, or survival characteristics between the two cohorts.This is the largest single-center study that compares clinical characteristics of SSc-PH patients between the last two decades. Transplant-free survival has improved significantly for those with Group 1 disease over the last decade, possibly secondary to earlier detection and better therapeutic management. Conversely, those with Group 2 or 3 disease continue to have dismal prognosis.

Uma das funções do Observatório de Museus e Centros de Ciência e Tecnologia - OMCC&T é o acompanhamento sistemático da visitação aos museus parceiros: conhecer para contar. Nesse estudo, apresentamos a análise dos dados coletados em dez instituições de ciência e tecnologia da região metropolitana do Rio de Janeiro, na perspectiva da visitação a esses espaços como prática de lazer cultural. As informações, obtidas em 4.606 questionários voluntariamente autorrespondidos, registram o perfil sociocultural e a opinião do público de visitação espontânea, com mais de 15 anos. Foi criado um indicador que revela a relação de cada museu com a população de sua vizinhança. Os visitantes de primeira vez são a maioria dos entrevistados, que ficaram sabendo do espaço principalmente por recomendação de amigos. Conhecer o museu é o que os motiva à visita, que pode levar de alguns meses a mais de dois anos para se efetivar. A ida aos museus estudados, como atividade de lazer, ocorre em grupos de duas a cinco pessoas, caracterizando uma prática de alta sociabilidade. Identificamos que os entrevistados com maior escolaridade e renda são frequentadores mais assíduos. O principal dificultador da visita é a falta de divulgação. O “boca a boca” é a forma de comunicação mais eficiente dentre as fontes de informação sobre a existência dos museus investigados, embora o espaço virtual venha ganhando protagonismo nesse papel.

To prevent thrombotic events after angioplasty, current guidelines recommend dual antiplatelet therapy with aspirin and thienopyridine. Clopidogrel is the only thienopyridine currently available in the Brazilian National Health System. The purpose of this study was to determine the cost-effectiveness of prasugrel, an alternative thienopyridine, compared with clopidogrel in patients with acute coronary syndrome and diabetes mellitus who underwent angioplasty.A state-transition Markov model was created to simulate the progression of diabetic patients after angioplasty. The model had a lifetime horizon and discounted outcomes at a 5% annual rate. The risks of myocardial infarction and death were calculated using data from the diabetes subgroup, and the risks of bleeding were calculated using data from the overall group from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction 38 trial. Direct costs were estimated using official Brazilian open data. Quality of life values were obtained through literature search. Univariate and multivariate sensitivity analyses were performed.Prasugrel was associated with more quality-adjusted life-years (QALYs) (5.03 vs 4.94) and higher costs (US$975.11 vs US$575.97), resulting in an incremental cost-utility ratio (ICUR) of US$4303.86/QALY. In one-way sensitivity analysis, the costs of prasugrel had the greatest impact on ICUR, followed by the initial age entering the cohort. In the probabilistic sensitivity analysis, all ICUR values simulations were less than one Brazilian gross domestic product per capita/QALY (US $5802.86).Given the appealing economic profile, the clinical debate between reducing the risk of myocardial infarction and increasing the risk of bleeding may overcome economic concerns in the Brazilian National Health System.

Este trabalho tem por objetivo verificar a relação entre a taxa básica de juros brasileira e os custos de capital de terceiros definidos pela ANEEL para os leilões para implantação, operação e manutenção de infraestruturas de transmissão de energia elétrica. A metodologia de pesquisa consiste no levantamento dos custos de capital de terceiros dos leilões de transmissão realizados no horizonte de 2006 a 2020 e comparação destes à taxa SELIC. Os resultados apontam que em boa parte do período analisado o custo de capital de terceiros foi inferior a taxa SELIC em função de estar atrelado a juros subsidiados pelo Banco Nacional de Desenvolvimento Econômico e Social- BNDES. A referida situação se inverteu a partir de meados de 2015.

Objective The objective is to describe the main characteristics of patients with systemic lupus erythematosus (SLE) in Argentina and to examine the influence of ethnicity on the expression of the disease. Patients and methods RELESSAR is a multicentre register carried out by 106 researchers from 67 rheumatologic Argentine centres. It is a cross-sectional study of SLE (1982/1997 ACR) patients. RELESSAR electronic database includes demographic, cumulative SLE manifestations, SELENA-SLEDAI, SLICC-SDI, Katz’s severity and Charlson’s comorbidity indexes and treatment patterns. Results We included 1,610 patients, 91.7% were female with a median age at diagnosis of 28.1 ± 12.8; 96.2% met ≥4 ACR 1982/97 criteria. Frequent manifestations were arthritis (83.5%), malar rash (79.5%), photosensitivity (75.3%), haematological (63.8%) and renal disease (47.4%), antinuclear antibodies (96%), anti-dsDNA (66.5%) and anti-Smith antibodies (29%). The mean Selena-SLEDAI score at last visit was 3.18 (SD 4.3) and mean SDI was 1 (SD 1.3). The accumulated treatments most frequently used were antimalarials (90.4%), corticosteroids (90%), azathioprine (31.8%), intravenous cyclophosphamide (30.2%), mycophenolate mofetil or mycophenolic acid (24.5%), methotrexate (19.3%), belimumab 5.3% and rituximab 5.1%. Refractory lupus was diagnosed in 9.3% of the cases. The main causes of death were lupus activity (25.0%), activity and concomitant infections (25.0%), infections (18.2%), vascular disease (13.6%) and cancer (4.5%). Mortality was associated with higher SLEDAI, Katz, damage indexes and comorbidities. Of the 1610 patients included, 44.6% were Caucasian, 44.5% Mestizo, 8.1% Amerindian and 1.2% Afro-Latin American. Mestizo patients had higher male representation, low socioeconomic status, more inadequate medical coverage, fewer formal years of education and shorter disease duration. Polyadenopathies and Raynaud’s phenomenon were more frequent in Caucasians. In the logistic regression analysis higher damage index (OR 1.28, CI 95% 1.02–1.61, p = 0.03) remained associated to mestizo ethnicity. Conclusions This study represents the largest number of adult patients with SLE studied in Argentina. Caucasian patients were differentiated by having Raynaud’s phenomenon and polyadenopathy more frequently, while patients of Mestizo origin had higher damage indexes.

RationalePulmonary arterial hypertension (PAH) is a rare disease characterised by limited survival despite remarkable improvements in therapy. The causes, clinical burden and outcomes of patients admitted to the intensive care unit (ICU) remain poorly characterised. The aim of this study was to describe patient characteristics, causes of ICU hospitalisation, and risk factors for ICU and 1-year mortality.MethodsData from patients enrolled in the Johns Hopkins Pulmonary Hypertension Registry were analysed for the period between January 2010 and December 2020. Clinical, functional, haemodynamic and laboratory data were collected.Measurements and main results102 adult patients with 155 consecutive ICU hospitalisations were included. The leading causes for admission were right heart failure (RHF, 53.3%), infection (17.4%) and arrhythmia (11.0%). ICU mortality was 27.1%. Mortality risk factors included Na −1 (OR: 3.10, 95% CI: 1.41–6.82), elevated pro-B-type natriuretic peptide (proBNP) (OR: 1.75, 95% CI: 1.03–2.98), hyperbilirubinaemia (OR: 1.40, 95% CI: 1.09–1.80), hyperlactaemia (OR: 1.42, 95% CI: 1.05–1.93), and need for vasopressors/inotropes (OR: 5.29, 95% CI: 2.28–12.28), mechanical ventilation (OR: 3.76, 95% CI: 1.63–8.76) and renal replacement therapy (OR: 5.57, 95% CI: 1.25–24.76). Mortality rates at 3, 6 and 12 months were 17.5%, 27.6% and 39.0%, respectively. Connective tissue disease-associated PAH has lower 1-year survival compared to idiopathic PAH (51.4% versus 79.8%, log-rank test p=0.019).ConclusionsRHF is the most common cause for ICU admission. In-hospital and 1-year mortality remain exceedingly high despite improved ICU care. Recognising specific risk factors on admission can help identifying patients at risk for poor outcomes.

Right ventricular function has prognostic significance in patients with pulmonary hypertension. We evaluated whether cardiac magnetic resonance-derived strain and strain rate parameters could reliably reflect right ventricular systolic and diastolic function in precapillary pulmonary hypertension. End-systolic elastance and the time constant of right ventricular relaxation tau, both derived from invasive high-fidelity micromanometer catheter measurements, were used as gold standards for assessing systolic and diastolic right ventricular function, respectively. Nineteen consecutive precapillary pulmonary hypertension patients underwent cardiac magnetic resonance and right heart catheterization prospectively. Cardiac magnetic resonance data were compared with those of 19 control subjects. In pulmonary hypertension patients, associations between strain- and strain rate-related parameters and invasive hemodynamic parameters were evaluated. Longitudinal peak systolic strain, strain rate, and early diastolic strain rate were lower in PAH patients than in controls; peak atrial-diastolic strain rate was higher in pulmonary hypertension patients. Similarly, circumferential peak systolic strain rate was lower and peak atrial-diastolic strain rate was higher in pulmonary hypertension. In pulmonary hypertension, no correlations existed between cardiac magnetic resonance-derived and hemodynamically derived measures of systolic right ventricular function. Regarding diastolic parameters, tau was significantly correlated with peak longitudinal atrial-diastolic strain rate ( r = −0.61), deceleration time ( r = 0.75), longitudinal systolic to diastolic time ratio ( r = 0.59), early diastolic strain rate ( r = −0.5), circumferential peak atrial-diastolic strain rate ( r = −0.52), and deceleration time ( r = 0.62). Strain analysis of the right ventricular diastolic phase is a reliable non-invasive method for detecting right ventricular diastolic dysfunction in PAH.

Este artigo tem por objetivo verificar algumas capturas de Receita Anual Permitida – RAP, que ocorreram após a edição da Medida Provisória nº 579/2012 e que são consideradas indevidas pelas concessionárias transmissão do setor elétrico. O horizonte do estudo englobará as referidas capturas de RAP iniciadas com o primeiro ciclo de revisão tarifária das empresas renovadas nos termos da MP 579/2012, a partir de 2018, e que podem ter afetado as empresas existentes ou às que obtiveram suas concessões por meio de licitação na modalidade leilão. Ao explorar tais capturas, o artigo verifica evidências de que o risco regulatório da captura de receitas no setor de transmissão de energia elétrica poderá culminar com a recuperação parcial do investimento realizado pelo investidor o que poderá afastá-lo dos futuros certames licitatórias.

Introducción: el lupus es una enfermedad compleja y varias veces de difícil abordaje. Alcanzar la remisión es uno de los objetivos, incorporando opciones terapéuticas. Objetivos: describir las características generales de los pacientes según el estado de la enfermedad y el uso de belimumab. Materiales y métodos: estudio de corte transversal, registro RELESSAR. Se definió el estado de la enfermedad como: remisión: SLEDAI=0 y sin corticoides; baja actividad de la enfermedad: SLEDAI >0 y ≤4 y sin corticoides; control no óptimo: SLEDAI >4 y cualquier dosis de corticoides. Resultados: se incluyeron 1.277 pacientes, 23,4% en remisión, 12,6% en baja actividad y 63,8% con control no óptimo. En este último grupo eran más jóvenes y con menor duración de la enfermedad; presentaban mayores índices de actividad y cronicidad, y mayor empleo de inmunosupresores. Solo el 22,3% de los pacientes con criterio potencial de uso de belimumab (lupus eritematoso sistémico activo a pesar del tratamiento estándar) lo recibía en ese momento. Las variables asociadas a hospitalizaciones fueron: terapia con corticoides, ciclofosfamida y mayor SLICC. Conclusiones: se refleja la complejidad del manejo de estos pacientes y se visualizan aspectos estructurales como la desigualdad. El uso del belimumab resultaría beneficioso en los pacientes seleccionados.

Purpose: Inhibition of the vascular endothelial growth factor (VEGF) axis is the basis of all currently approved antiangiogenic therapies. In preclinical models, anti-VEGF blocking antibodies have shown broad efficacy that is dependent on both tumor context and treatment duration. We aimed to characterize this activity and to evaluate the effects of discontinuation of treatment on the dynamics of tumor regrowth.Experimental Design: We evaluated the effects of anti-VEGF treatment on tumor growth and survival in 30 xenograft models and in genetic mouse models of cancer. Histologic analysis was used to evaluate the effects of treatment on tumor vasculature. We used a variety of treatment regimens to allow analysis of the effects of treatment duration and cessation on growth rate, survival, and vascular density.Results: Preclinical tumor models were characterized for their varied dependence on VEGF, thereby defining models for testing other agents that may complement or augment anti-VEGF therapy. We also found that longer exposure to anti-VEGF monoclonal antibodies delayed tumor growth and extended survival in established tumors from both cell transplants and genetic tumor models and prevented regrowth of a subset of residual tumors following cytoablative therapy. Discontinuation of anti-VEGF in established tumors resulted in regrowth at a rate slower than that in control-treated animals, with no evidence of accelerated tumor growth or rebound. However, more rapid regrowth was observed following discontinuation of certain chemotherapies. Concurrent administration of anti-VEGF seemed to normalize these accelerated growth rates.Conclusions: In diverse preclinical models, continuous VEGF suppression provides maximal benefit as a single agent, combined with chemotherapy, or as maintenance therapy once chemotherapy has been stopped. Clin Cancer Res; 16(15); 3887–900. ©2010 AACR.

PDF file, 54K, Estimation of percentage of patients to achieve TSC (15 ug/mL) at Ctrough ss with Q3W dose regimen.

PDF file, 3179K, Representative for visual predictive check.

PDF file, 20K, Effects of 30D8 on 4T1 cell migration in vitro.

PDF file, 239K, Intervention studies in the laser-induced choroidal neovascularization (CNV) model.

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Supplementary Data from Effects of Anti-VEGF Treatment Duration on Tumor Growth, Tumor Regrowth, and Treatment Efficacy

PDF file, 1199K, Tumor growth inhibition.

PDF file, 28K, Effects of 30D8 on CXCL12 and VEGF serum levels in HM7 tumor bearing mice.

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PDF file, 869K, Proliferation and apoptosis analysis by IF staining in EL4 tumor sections.

PDF file, 26K, Comparison of PK in Balb c/nude mice of three hamster antibodies with similar binding affinity toward human CXCL12.

PDF file, 38K, Sequence alignment of 30D8 and humanized 30D8 (hu30D8).

PDF file, 2424K, Observed individual concentration-time profile of onartuzumab in human in comparison with cyno-based prediction.

PDF file, 1651K, Representative individual fits.

PDF file, 2444K, Basic goodness-of-fit plots for PK-PD modeling in KP4 tumor-bearing mice.

Purpose: We characterized the pharmacokinetics of onartuzumab (MetMAb) in animals and determined a concentration–effect relationship in tumor-bearing mice to enable estimation of clinical pharmacokinetics and target doses.Experimental Design: A tumor growth inhibition model was used to estimate tumoristatic concentrations (TSC) in mice. Human pharmacokinetic parameters were projected from pharmacokinetics in cynomolgus monkeys by the species-invariant time method. Monte Carlo simulations predicted the percentage of patients achieving steady-state trough serum concentrations (Ctrough ss) ≥TSC for every 3-week (Q3W) dosing.Results: Onartuzumab clearance (CL) in the linear dose range was 21.1 and 12.2 mL/d/kg in mice and cynomolgus monkeys with elimination half-life at 6.10 and 3.37 days, respectively. The estimated TSC in KP4 pancreatic xenograft tumor-bearing mice was 15 μg/mL. Projected CL for humans in the linear dose range was 5.74 to 9.36 mL/d/kg with scaling exponents of CL at 0.75 to 0.9. Monte Carlo simulations projected a Q3W dose of 10 to 30 mg/kg to achieve Ctrough ss of 15 μg/mL in 95% or more of patients.Conclusions: Onartuzumab pharmacokinetics differed from typical bivalent glycosylated monoclonal antibodies with approximately 2-times faster CL in the linear dose range. Despite this higher CL, xenograft efficacy data supported dose flexibility with Q1W to Q3W dose regimens in the clinical setting with a TSC of 15 μg/mL as the Ctrough ss target. The projected human efficacious dose of 10 to 30 mg/kg Q3W should achieve the target TSC of 15 μg/mL. These data show effective pharmacokinetic/pharmacodynamic modeling to project doses to be tested in the clinic. Clin Cancer Res; 19(18); 5068–78. ©2013 AACR.

PDF file, 967K, Onartuzumab tumoristatic concentration range.

Purpose: Our goal was to develop a potent humanized antibody against mouse/human CXCL12. This report summarized its in vitro and in vivo activities.Experimental Design: Cell surface binding and cell migration assays were used to select neutralizing hamster antibodies, followed by testing in several animal models. Monoclonal antibody (mAb) 30D8 was selected for humanization based on its in vitro and in vivo activities.Results: 30D8, a hamster antibody against mouse and human CXCL12α, CXCL12β, and CXCL12γ, was shown to dose-dependently block CXCL12α binding to CXCR4 and CXCR7, and CXCL12α-induced Jurkat cell migration in vitro. Inhibition of primary tumor growth and/or metastasis was observed in several models. 30D8 alone significantly ameliorated arthritis in a mouse collagen-induced arthritis model (CIA). Combination with a TNF-α antagonist was additive. In addition, 30D8 inhibited 50% of laser-induced choroidal neovascularization (CNV) in mice. Humanized 30D8 (hu30D8) showed similar in vitro and in vivo activities as the parental hamster antibody. A crystal structure of the hu30D8 Fab/CXCL12α complex in combination with mutational analysis revealed a “hot spot” around residues Asn44/Asn45 of CXCL12α and part of the RFFESH region required for CXCL12α binding to CXCR4 and CXCR7. Finally, hu30D8 exhibited fast clearance in cynomolgus monkeys but not in rats.Conclusion: CXCL12 is an attractive target for treatment of cancer and inflammation-related diseases; hu30D8 is suitable for testing this hypothesis in humans. Clin Cancer Res; 19(16); 4433–45. ©2013 AACR.

Supplementary Figure 6 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Figure 2 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Figure 1 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Figure 4 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Figure Legends 1-6 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Figure 3 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Tables 1 - 4 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Figure 5 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life