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1.
BMC Womens Health ; 20(1): 41, 2020 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-32131802

RESUMEN

BACKGROUND: Hypertensive disorders of pregnancy (HDP), such as preeclampsia (PE) or the Hemolysis Elevated Liver enzymes and Low Platelets (HELLP) syndrome are associated with elevated cardiovascular disease (CVD) risks, but standardized prevention guidelines after such pregnancies are lacking. Hypertension is the first emerging risk factor after PE/HELLP pregnancies and is a major risk factor for CVD. Hypertension before the age of 55 years may lead to various manifestations of end-organ damage at relatively young age. Therefore, timely treatment of elevated blood pressure is mandatory, but many of these high-risk women have long-term undetected and untreated hypertension before adequate treatment is initiated. AIM: The aim of our study is to assess whether home blood pressure monitoring (HBPM) in women with a previous PE/HELLP pregnancy is a valuable tool for the early detection of hypertension. METHODS: Women with a history of both early and late PE/HELLP syndrome aged 40-60 years are invited to participate. Patients with a history of CVD, known hypertension and/or use of antihypertensive medication are excluded. Women are randomized between HPBM or 'usual care'. The primary outcome is feasibility and usability of HBPM after 1 year of follow-up. Secondary outcomes will be the effectiveness of HPBM to detect hypertension, the efficacy of BP treatment, quality of life, health-related symptoms, work ability, and life-style behaviour. The results of this study will provide better strategies for timely detection and prevention of hypertension in women after PE/HELLP. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03228082. Registered June 15, 2017.


Asunto(s)
Monitoreo Ambulatorio de la Presión Arterial , Presión Sanguínea/fisiología , Síndrome HELLP/fisiopatología , Hipertensión/prevención & control , Preeclampsia/diagnóstico , Calidad de Vida/psicología , Adulto , Factores de Edad , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/complicaciones , Persona de Mediana Edad , Embarazo , Complicaciones del Embarazo , Resultado del Embarazo
2.
Lancet ; 392(10143): 232-243, 2018 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-30047376

RESUMEN

BACKGROUND: More than 1·8 million new cases of HIV-1 infection were diagnosed worldwide in 2016. No licensed prophylactic HIV-1 vaccine exists. A major limitation to date has been the lack of direct comparability between clinical trials and preclinical studies. We aimed to evaluate mosaic adenovirus serotype 26 (Ad26)-based HIV-1 vaccine candidates in parallel studies in humans and rhesus monkeys to define the optimal vaccine regimen to advance into clinical efficacy trials. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled phase 1/2a trial (APPROACH). Participants were recruited from 12 clinics in east Africa, South Africa, Thailand, and the USA. We included healthy, HIV-1-uninfected participants (aged 18-50 years) who were considered at low risk for HIV-1 infection. We randomly assigned participants to one of eight study groups, stratified by region. Participants and investigators were blinded to the treatment allocation throughout the study. We primed participants at weeks 0 and 12 with Ad26.Mos.HIV (5 × 1010 viral particles per 0·5 mL) expressing mosaic HIV-1 envelope (Env)/Gag/Pol antigens and gave boosters at weeks 24 and 48 with Ad26.Mos.HIV or modified vaccinia Ankara (MVA; 108 plaque-forming units per 0·5 mL) vectors with or without high-dose (250 µg) or low-dose (50 µg) aluminium adjuvanted clade C Env gp140 protein. Those in the control group received 0·9% saline. All study interventions were administered intramuscularly. Primary endpoints were safety and tolerability of the vaccine regimens and Env-specific binding antibody responses at week 28. Safety and immunogenicity were also assessed at week 52. All participants who received at least one vaccine dose or placebo were included in the safety analysis; immunogenicity was analysed using the per-protocol population. We also did a parallel study in rhesus monkeys (NHP 13-19) to assess the immunogenicity and protective efficacy of these vaccine regimens against a series of six repetitive, heterologous, intrarectal challenges with a rhesus peripheral blood mononuclear cell-derived challenge stock of simian-human immunodeficiency virus (SHIV-SF162P3). The APPROACH trial is registered with ClinicalTrials.gov, number NCT02315703. FINDINGS: Between Feb 24, 2015, and Oct 16, 2015, we randomly assigned 393 participants to receive at least one dose of study vaccine or placebo in the APPROACH trial. All vaccine regimens demonstrated favourable safety and tolerability. The most commonly reported solicited local adverse event was mild-to-moderate pain at the injection site (varying from 69% to 88% between the different active groups vs 49% in the placebo group). Five (1%) of 393 participants reported at least one grade 3 adverse event considered related to the vaccines: abdominal pain and diarrhoea (in the same participant), increased aspartate aminotransferase, postural dizziness, back pain, and malaise. The mosaic Ad26/Ad26 plus high-dose gp140 boost vaccine was the most immunogenic in humans; it elicited Env-specific binding antibody responses (100%) and antibody-dependent cellular phagocytosis responses (80%) at week 52, and T-cell responses at week 50 (83%). We also randomly assigned 72 rhesus monkeys to receive one of five different vaccine regimens or placebo in the NHP 13-19 study. Ad26/Ad26 plus gp140 boost induced similar magnitude, durability, and phenotype of immune responses in rhesus monkeys as compared with humans and afforded 67% protection against acquisition of SHIV-SF162P3 infection (two-sided Fisher's exact test p=0·007). Env-specific ELISA and enzyme-linked immunospot assay responses were the principal immune correlates of protection against SHIV challenge in monkeys. INTERPRETATION: The mosaic Ad26/Ad26 plus gp140 HIV-1 vaccine induced comparable and robust immune responses in humans and rhesus monkeys, and it provided significant protection against repetitive heterologous SHIV challenges in rhesus monkeys. This vaccine concept is currently being evaluated in a phase 2b clinical efficacy study in sub-Saharan Africa (NCT03060629). FUNDING: Janssen Vaccines & Prevention BV, National Institutes of Health, Ragon Institute of MGH, MIT and Harvard, Henry M Jackson Foundation for the Advancement of Military Medicine, US Department of Defense, and International AIDS Vaccine Initiative.


Asunto(s)
Vacunas contra el SIDA/administración & dosificación , VIH-1/inmunología , Vacunas contra el SIDA/efectos adversos , Dolor Abdominal/etiología , Adenoviridae , Adolescente , Adulto , Animales , Aspartato Aminotransferasas/análisis , Dolor de Espalda/etiología , Diarrea/etiología , Mareo/etiología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Fatiga/etiología , Vectores Genéticos , Voluntarios Sanos , Humanos , Inmunidad Celular , Inmunidad Humoral , Macaca mulatta , Persona de Mediana Edad , Adulto Joven
3.
Cardiovasc Diabetol ; 16(1): 67, 2017 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-28526033

RESUMEN

BACKGROUND: Multiple bloodglucose-lowering agents have been linked to cardiovascular events. Preliminary studies showed improvement in left ventricular (LV) function during glucagon-like peptide-1 receptor agonist administration. Underlying mechanisms, however, are unclear. The purpose of this study was to investigate myocardial perfusion and oxidative metabolism in type 2 diabetic (T2DM) patients with LV systolic dysfunction as compared to healthy controls. Furthermore, effects of 26-weeks of exenatide versus insulin glargine administration on cardiac function, perfusion and oxidative metabolism in T2DM patients with LV dysfunction were explored. METHODS AND RESULTS: Twenty-six T2DM patients with LV systolic dysfunction (cardiac magnetic resonance (CMR) derived LV ejection fraction (LVEF) of 47 ± 13%) and 10 controls (LVEF of 59 ± 4%, P < 0.01 as compared to patients) were analyzed. Both myocardial perfusion during adenosine-induced hyperemia (P < 0.01), and coronary flow reserve (P < 0.01), measured by [15O]H2O positron emission tomography (PET), were impaired in T2DM patients as compared to healthy controls. Myocardial oxygen consumption and myocardial efficiency, measured using [11C]acetate PET and CMR derived stroke volume, were not different between the groups. Eleven patients in the exenatide group and 12 patients in the insulin glargine group completed the trial. Systemic metabolic control was improved after both treatments, although, no changes in cardiac function, perfusion and metabolism were seen after exenatide or insulin glargine. CONCLUSIONS: T2DM patients with LV systolic dysfunction did not have altered myocardial efficiency as compared to healthy controls. Exenatide or insulin glargine had no effects on cardiac function, perfusion or oxidative metabolism. Trial registration NCT00766857.


Asunto(s)
Circulación Coronaria/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cardiomiopatías Diabéticas/tratamiento farmacológico , Metabolismo Energético/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Incretinas/uso terapéutico , Insulina Glargina/uso terapéutico , Miocardio/metabolismo , Péptidos/uso terapéutico , Ponzoñas/uso terapéutico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Función Ventricular Izquierda/efectos de los fármacos , Anciano , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Cardiomiopatías Diabéticas/diagnóstico por imagen , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/fisiopatología , Exenatida , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Incretinas/efectos adversos , Insulina Glargina/efectos adversos , Imagen por Resonancia Cinemagnética , Masculino , Persona de Mediana Edad , Imagen de Perfusión Miocárdica/métodos , Miocardio/patología , Países Bajos , Oxidación-Reducción , Consumo de Oxígeno , Péptidos/efectos adversos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Recuperación de la Función , Volumen Sistólico , Sístole , Factores de Tiempo , Resultado del Tratamiento , Ponzoñas/efectos adversos , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/fisiopatología
4.
Acta Obstet Gynecol Scand ; 96(2): 158-165, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27861697

RESUMEN

INTRODUCTION: Large practice variation exists in mode of delivery after cesarean section, suggesting variation in implementation of contemporary guidelines. We aim to evaluate this practice variation and to what extent this can be explained by risk factors at patient level. MATERIAL AND METHODS: This retrospective cohort study was performed among 17 Dutch hospitals in 2010. Women with one prior cesarean section without a contraindication for a trial of labor were included. We used multivariate logistic regression analysis to develop models for risk factor adjustments. One model was derived to adjust the elective repeat cesarean section rates; a second model to adjust vaginal birth after cesarean rates. Standardized rates of elective repeat cesarean section and vaginal birth after cesarean per hospital were compared. Pseudo-R2 measures were calculated to estimate the percentage of practice variation explained by the models. Secondary outcomes were differences in practice variation between hospital types and the correlation between standardized elective repeat cesarean section and vaginal birth after cesarean rates. RESULTS: In all, 1068 women had a history of cesarean section, of whom 71% were eligible for inclusion. A total of 515 women (67%) had a trial of labor, of whom 72% delivered vaginally. The elective repeat cesarean section rate at hospital level ranged from 6 to 54% (mean 29.8, standard deviation 11.8%). Vaginal birth after cesarean rates ranged from 50 to 90% (mean 71.8%, standard deviation 11.1%). More than 85% of this practice variation could not be explained by risk factors at patient level. CONCLUSION: A large practice variation exists in elective repeat cesarean section and vaginal birth after cesarean rates that can only partially be explained by risk factors at patient level.


Asunto(s)
Cesárea Repetida/estadística & datos numéricos , Parto Vaginal Después de Cesárea/estadística & datos numéricos , Adulto , Estudios de Cohortes , Femenino , Hospitales/estadística & datos numéricos , Humanos , Análisis Multivariante , Países Bajos/epidemiología , Pautas de la Práctica en Medicina/estadística & datos numéricos , Embarazo , Estudios Retrospectivos , Factores de Riesgo , Esfuerzo de Parto
5.
BMC Pregnancy Childbirth ; 17(1): 284, 2017 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-28870155

RESUMEN

BACKGROUND: Preterm birth is in quantity and in severity the most important topic in obstetric care in the developed world. Progestogens and cervical pessaries have been studied as potential preventive treatments with conflicting results. So far, no study has compared both treatments. METHODS/DESIGN: The Quadruple P study aims to compare the efficacy of vaginal progesterone and cervical pessary in the prevention of adverse perinatal outcome associated with preterm birth in asymptomatic women with a short cervix, in singleton and multiple pregnancies separately. It is a nationwide open-label multicentre randomized clinical trial (RCT) with a superiority design and will be accompanied by an economic analysis. Pregnant women undergoing the routine anomaly scan will be offered cervical length measurement between 18 and 22 weeks in a singleton and at 16-22 weeks in a multiple pregnancy. Women with a short cervix, defined as less than, or equal to 35 mm in a singleton and less than 38 mm in a multiple pregnancy, will be invited to participate in the study. Eligible women will be randomly allocated to receive either progesterone or a cervical pessary. Following randomization, the silicone cervical pessary will be placed during vaginal examination or 200 mg progesterone capsules will be daily self-administered vaginally. Both interventions will be continued until 36 weeks gestation or until delivery, whichever comes first. Primary outcome will be composite adverse perinatal outcome of perinatal mortality and perinatal morbidity including bronchopulmonary dysplasia, intraventricular haemorrhage grade III and IV, periventricular leukomalacia higher than grade I, necrotizing enterocolitis higher than stage I, Retinopathy of prematurity (ROP) or culture proven sepsis. These outcomes will be measured up until 10 weeks after the expected due date. Secondary outcomes will be, among others, time to delivery, preterm birth rate before 28, 32, 34 and 37 weeks, admission to neonatal intensive care unit, maternal morbidity, maternal admission days for threatened preterm labour and costs. DISCUSSION: This trial will provide evidence on whether vaginal progesterone or a cervical pessary is more effective in decreasing adverse perinatal outcome in both singletons and multiples. TRIAL REGISTRATION: Trial registration number: NTR 4414 . Date of registration January 29th 2014.


Asunto(s)
Cuello del Útero/patología , Pesarios , Nacimiento Prematuro/prevención & control , Progesterona/administración & dosificación , Progestinas/administración & dosificación , Enfermedades del Cuello del Útero/complicaciones , Administración Intravaginal , Adolescente , Adulto , Medición de Longitud Cervical , Protocolos Clínicos , Femenino , Humanos , Embarazo , Resultado del Embarazo , Nacimiento Prematuro/etiología , Resultado del Tratamiento , Enfermedades del Cuello del Útero/diagnóstico por imagen , Enfermedades del Cuello del Útero/patología , Adulto Joven
6.
Psychogeriatrics ; 17(6): 356-363, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28417534

RESUMEN

BACKGROUND: Cognitive deficits have been reported in older cardiac patients. An underlying mechanism for these findings may be reduced cardiac function. The relationship between cardiac function as represented by different echocardiographic measures and different cognitive function domains in older cardiac patients remains unknown. METHODS: An older (≥70 years) heterogeneous group of 117 community-dwelling cardiac patients under medical supervision by a cardiologist underwent thorough echocardiographic assessment including left ventricular ejection fraction, cardiac index, left atrial volume index, left ventricular mass index, left ventricular diastolic function, and valvular calcification. During a home visit, a neuropsychological assessment was performed within 7.1 ± 3.8 months after echocardiographic assessment; the neuropsychological assessment included three subtests of a word-learning test (encoding, recall, recognition) to examine one memory function domain and three executive function tests, including digit span backwards, Trail Making Test B minus A, and the Stroop colour-word test. RESULTS: Regression analyses showed no significant linear or quadratic associations between any of the echocardiographic functions and the cognitive function measures. CONCLUSIONS: None of the echocardiographic measures as representative of cardiac function was correlated with memory or executive function in this group of community-dwelling older cardiac patients. These findings contrast with those of previous studies.


Asunto(s)
Enfermedades Cardiovasculares/fisiopatología , Cognición/fisiología , Ecocardiografía , Función Ejecutiva/fisiología , Memoria/fisiología , Pruebas Neuropsicológicas/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Vida Independiente , Masculino , Países Bajos , Análisis de Regresión
7.
Eur Respir J ; 48(3): 787-96, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27390285

RESUMEN

While beta-blockers are considered contraindicated in pulmonary arterial hypertension (PAH), the prognostic significance of sympathetic nervous system over-activity suggests a potential benefit of beta-blocker therapy. The aim of this randomised, placebo-controlled, crossover, single centre study was to determine the effects of bisoprolol on right ventricular ejection fraction (RVEF) in idiopathic PAH (iPAH) patients. Additional efficacy and safety parameters were explored.Patients with optimally treated, stable iPAH (New York Heart Association functional class II/III) were randomised to placebo or bisoprolol. Imaging and functional measurements were performed at baseline, crossover and end of study.18 iPAH patients were included, because inclusion faltered before enrolment of the targeted 25 patients. 17 patients completed 6 months of bisoprolol, 15 tolerated bisoprolol, one patient required intravenous diuretics. Bisoprolol was associated with a lower heart rate (17 beats per minute, p=0.0001) but RVEF remained unchanged. A drop in cardiac index (0.5 L·min(-1)·m(-2), p=0.015) was observed, along with a trend towards a decreased 6-min walking distance (6MWD).Although careful up-titration of bisoprolol was tolerated by most patients and resulted in a decreased heart rate, no benefit of bisoprolol in iPAH was demonstrated. Decreases in cardiac index and 6MWD suggest a deteriorated cardiac function. The results do not favour the use of bisoprolol in iPAH patients.


Asunto(s)
Antihipertensivos/uso terapéutico , Bisoprolol/uso terapéutico , Hipertensión Pulmonar Primaria Familiar/tratamiento farmacológico , Adulto , Anciano , Estudios Cruzados , Método Doble Ciego , Ejercicio Físico , Femenino , Insuficiencia Cardíaca/complicaciones , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Función Ventricular Izquierda , Función Ventricular Derecha , Caminata
8.
Am J Med Genet A ; 170(7): 1874-80, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27109146

RESUMEN

Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively. Including our patients, a total of 52 patients have been reported with Noonan syndrome caused by a RIT1 mutation. Our report contributes to the delineation of the phenotype associated with RIT1 mutations and underlines that lymphatic involvement is part of this spectrum. In addition, we provide an overview of the currently described Noonan syndrome patients with RIT1 mutations in literature. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Hidropesía Fetal/genética , Síndrome de Noonan/genética , Proteínas ras/genética , Femenino , Humanos , Hidropesía Fetal/fisiopatología , Extremidad Inferior/fisiopatología , Masculino , Mutación Missense , Síndrome de Noonan/fisiopatología , Fenotipo
9.
Lancet ; 382(9901): 1341-9, 2013 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-23924878

RESUMEN

BACKGROUND: In women with a multiple pregnancy, spontaneous preterm delivery is the leading cause of perinatal morbidity and mortality. Interventions to reduce preterm birth in these women have not been successful. We assessed whether a cervical pessary could effectively prevent poor perinatal outcomes. METHODS: We undertook a multicentre, open-label randomised controlled trial in 40 hospitals in the Netherlands. We randomly assigned women with a multiple pregnancy between 12 and 20 weeks' gestation (1:1) to pessary or control groups, using a web-based application with a computer-generated list with random block sizes of two to four, stratified by hospital. Participants and investigators were aware of group allocation. For women in the pessary group, a midwife or obstetrician inserted a cervical pessary between 16 and 20 weeks' gestation. Women in the control group did not receive the pessary, but otherwise received similar obstetrical care to those in the pessary group. The primary outcome was a composite of poor perinatal outcome: stillbirth, periventricular leucomalacia, severe respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular haemorrhage, necrotising enterocolitis, proven sepsis, and neonatal death. Analyses were by modified intention to treat. This trial is registered in the Dutch trial registry, number NTR1858. FINDINGS: Between Sept 21, 2009, and March 9, 2012, 813 women underwent randomisation, of whom 808 were analysed (401 in the pessary group; 407 in the control group). At least one child of 53 women (13%) in the pessary group had poor perinatal outcome, compared with 55 (14%) in the control group (relative risk 0·98, 95% CI 0·69-1·39). INTERPRETATION: In unselected women with a multiple pregnancy, prophylactic use of a cervical pessary does not reduce poor perinatal outcome. FUNDING: The Netherlands Organisation for Health Research and Development.


Asunto(s)
Pesarios , Embarazo Múltiple , Nacimiento Prematuro/prevención & control , Adulto , Cuello del Útero , Remoción de Dispositivos/estadística & datos numéricos , Femenino , Humanos , Pesarios/efectos adversos , Embarazo , Resultado del Embarazo , Atención Prenatal/métodos
10.
J Cardiovasc Magn Reson ; 16: 28, 2014 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-24766828

RESUMEN

BACKGROUND: In hypertrophic cardiomyopathy (HCM), autopsy studies revealed both increased focal and diffuse deposition of collagen fibers. Late gadolinium enhancement imaging (LGE) detects focal fibrosis, but is unable to depict interstitial fibrosis. We hypothesized that with T1 mapping, which is employed to determine the myocardial extracellular volume fraction (ECV), can detect diffuse interstitial fibrosis in HCM patients. METHODS: T1 mapping with a modified Look-Locker Inversion Recovery (MOLLI) pulse sequence was used to calculate ECV in manifest HCM (n = 16) patients and in healthy controls (n = 14). ECV was determined in areas where focal fibrosis was excluded with LGE. RESULTS: The total group of HCM patients showed no significant changes in mean ECV values with respect to controls (0.26 ± 0.03 vs 0.26 ± 0.02, p = 0.83). Besides, ECV in LGE positive HCM patients was comparable with LGE negative HCM patients (0.27 ± 0.03 vs 0.25 ± 0.03, p = 0.12). CONCLUSIONS: This study showed that HCM patients have a similar ECV (e.g. interstitial fibrosis) in myocardium without LGE as healthy controls. Therefore, the additional clinical value of T1 mapping in HCM seems limited, but future larger studies are needed to establish the clinical and prognostic potential of this new technique within HCM.


Asunto(s)
Cardiomiopatía Hipertrófica/diagnóstico , Imagen por Resonancia Cinemagnética , Miocardio/patología , Adulto , Cardiomiopatía Hipertrófica/patología , Estudios de Casos y Controles , Femenino , Fibrosis , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas
11.
NPJ Vaccines ; 9(1): 179, 2024 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-39349488

RESUMEN

The failure of human vaccine efficacy trials assessing a mosaic HIV-1 vaccine calls into question the translatability of preclinical SHIV challenge studies that demonstrated high efficacy of this vaccine in primates. Here we present a post hoc immune correlates analysis of HIV-1 Env peptide-binding antibody responses from the NHP13-19 study identifying the V2 loop as the principal correlate of protection in primates. Moreover, we found high V2 loop sequence identity between the Mos1 vaccine component and the SHIV challenge strain, while the vaccine showed considerably lower V2 identity to globally circulating HIV-1 sequences. Thus, the induction of immune responses against the V2 epitope, which had exceptional identity between the vaccine and challenge Env strains, may have contributed to the high protection in primates.

12.
NPJ Vaccines ; 8(1): 40, 2023 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-36927774

RESUMEN

Since the original outbreak of the SARS-CoV-2 virus, several rapidly spreading SARS-CoV-2 variants of concern (VOC) have emerged. Here, we show that a single dose of Ad26.COV2.S (based on the Wuhan-Hu-1 spike variant) protects against the Gamma and Delta variants in naive hamsters, supporting the observed maintained vaccine efficacy in humans against these VOC. Adapted spike-based booster vaccines targeting Omicron variants have now been authorized in the absence of human efficacy data. We evaluated the immunogenicity and efficacy of Ad26.COV2.S.529 (encoding a stabilized Omicron BA.1 spike) in naive mice and in hamsters with pre-existing immunity to the Wuhan-Hu-1 spike. In naive mice, Ad26.COV2.S.529 elicited higher neutralizing antibody titers against SARS-CoV-2 Omicron BA.1 and BA.2, compared with Ad26.COV2.S. However, neutralizing titers against the SARS-CoV-2 B.1 (D614G) and Delta variants were lower after primary vaccination with Ad26.COV2.S.529 compared with Ad26.COV2.S. In contrast, we found comparable Omicron BA.1 and BA.2 neutralizing titers in hamsters with pre-existing Wuhan-Hu-1 spike immunity after vaccination with Ad26.COV2.S, Ad26.COV2.S.529 or a combination of the two vaccines. Moreover, all three vaccine modalities induced equivalent protection against Omicron BA.2 challenge in these animals. Overall, our data suggest that an Omicron BA.1-based booster in rodents does not improve immunogenicity and efficacy against Omicron BA.2 over an Ad26.COV2.S booster in a setting of pre-existing immunity to SARS-CoV-2.

14.
Eur Heart J ; 32(9): 1161-70, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21459882

RESUMEN

AIMS: We investigated the presence of a clinical diagnosis of hypertrophic cardiomyopathy (HCM), risk factors for sudden cardiac death (SCD), and cardiac events during follow-up in predictively tested-not known to have a clinical diagnosis of HCM before the DNA test-carriers of a sarcomeric gene mutation and associations with age and gender to determine the best cardiological screening strategy. METHODS AND RESULTS: One hundred and thirty-six (30%) of 446 mutation carriers were diagnosed with HCM at one or more cardiological evaluation(s). Male gender and higher age were associated with manifest disease. Incidence of newly diagnosed manifest HCM was <10% per person-year under the age of 40 years and >10% in older carriers, although numbers were small in carriers <15 years. Twenty-three percent of carriers, with and without manifest disease, had established risk factor(s) for SCD (no significant difference). During an average follow-up of 3.5 ± 1.7 years two carriers, both with manifest disease, died suddenly (0.13% per person-year). A high-risk status for SCD (≥2 risk factors and manifest HCM) was present in 17 carriers during follow-up (2.4% per person-year). Age but not gender was associated with a high-risk status for SCD. CONCLUSION: Thirty percent of carriers had or developed manifest HCM after predictive DNA testing and risk factors for SCD were frequently present. Our data suggest that the SCD risk is low and risk stratification for SCD can be omitted in carriers without manifest disease and that frequency of cardiological evaluations can possibly be decreased in carriers between 15 and 40 years as long as hypertrophy is absent.


Asunto(s)
Cardiomiopatía Hipertrófica Familiar/genética , Muerte Súbita Cardíaca/epidemiología , Mutación/genética , Adulto , Factores de Edad , Anciano , Cardiomiopatía Hipertrófica Familiar/mortalidad , Muerte Súbita Cardíaca/etiología , Diagnóstico Precoz , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Linaje , Factores de Riesgo , Factores Sexuales
15.
Cancer Immunol Immunother ; 60(2): 161-71, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20963411

RESUMEN

T cells with specificity for antigens derived from Wilms Tumor gene (WT1), Proteinase3 (Pr3), and mucin1 (MUC1) have been demonstrated to lyse acute myeloid leukemia (AML) blasts and multiple-myeloma (MM) cells, and strategies to enhance or induce such tumor-specific T cells by vaccination are currently being explored in multiple clinical trials. To test safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides and the pan HLA-DR T helper cell epitope (PADRE) or MUC1-helper epitopes in combination with CpG7909 and MontanideISA51, four patients with AML and five with MM were repetitively vaccinated. No clinical responses were observed. Neither pre-existing nor naive WT1-/Pr3-/MUC1-specific CD8+ T cells expanded in vivo by vaccination. In contrast, a significant decline in vaccine-specific CD8+ T cells was observed. An increase in PADRE-specific CD4+ T helper cells was observed after vaccination but these appeared unable to produce IL2, and CD4+ T cells with a regulatory phenotype increased. Taken into considerations that multiple clinical trials with identical antigens but different adjuvants induced vaccine-specific T cell responses, our data caution that a vaccination with leukemia-associated antigens can be detrimental when combined with MontanideISA51 and CpG7909. Reflecting the time-consuming efforts of clinical trials and the fact that 1/3 of ongoing peptide vaccination trails use CpG and/or Montanide, our data need to be taken into consideration.


Asunto(s)
Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/uso terapéutico , Leucemia Mieloide Aguda/terapia , Manitol/análogos & derivados , Mieloma Múltiple/terapia , Ácidos Oléicos , Oligodesoxirribonucleótidos , Péptidos/uso terapéutico , Adolescente , Antígenos de Neoplasias/química , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Femenino , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Masculino , Manitol/efectos adversos , Mucina-1/efectos adversos , Mucina-1/química , Mucina-1/inmunología , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Mieloblastina/efectos adversos , Mieloblastina/química , Mieloblastina/inmunología , Estadificación de Neoplasias , Neoplasia Residual/inmunología , Neoplasia Residual/patología , Neoplasia Residual/terapia , Ácidos Oléicos/efectos adversos , Oligodesoxirribonucleótidos/efectos adversos , Oligodesoxirribonucleótidos/inmunología , Péptidos/efectos adversos , Péptidos/inmunología , Proyectos Piloto , Resultado del Tratamiento , Proteínas WT1/efectos adversos , Proteínas WT1/química , Proteínas WT1/inmunología
16.
NPJ Vaccines ; 6(1): 39, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741993

RESUMEN

Previously we have shown that a single dose of recombinant adenovirus serotype 26 (Ad26) vaccine expressing a prefusion stabilized SARS-CoV-2 spike antigen (Ad26.COV2.S) is immunogenic and provides protection in Syrian hamster and non-human primate SARS-CoV-2 infection models. Here, we investigated the immunogenicity, protective efficacy, and potential for vaccine-associated enhanced respiratory disease (VAERD) mediated by Ad26.COV2.S in a moderate disease Syrian hamster challenge model, using the currently most prevalent G614 spike SARS-CoV-2 variant. Vaccine doses of 1 × 109 and 1 × 1010 VP elicited substantial neutralizing antibodies titers and completely protected over 80% of SARS-CoV-2 inoculated Syrian hamsters from lung infection and pneumonia but not upper respiratory tract infection. A second vaccine dose further increased neutralizing antibody titers that was associated with decreased infectious viral load in the upper respiratory tract after SARS-CoV-2 challenge. Suboptimal non-protective immune responses elicited by low-dose A26.COV2.S vaccination did not exacerbate respiratory disease in SARS-CoV-2-inoculated Syrian hamsters with breakthrough infection. In addition, dosing down the vaccine allowed to establish that binding and neutralizing antibody titers correlate with lower respiratory tract protection probability. Overall, these preclinical data confirm efficacy of a one-dose vaccine regimen with Ad26.COV2.S in this G614 spike SARS-CoV-2 virus variant Syrian hamster model, show the added benefit of a second vaccine dose, and demonstrate that there are no signs of VAERD under conditions of suboptimal immunity.

17.
Lancet ; 374(9694): 979-988, 2009 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-19656558

RESUMEN

BACKGROUND: Robust evidence to direct management of pregnant women with mild hypertensive disease at term is scarce. We investigated whether induction of labour in women with a singleton pregnancy complicated by gestational hypertension or mild pre-eclampsia reduces severe maternal morbidity. METHODS: We undertook a multicentre, parallel, open-label randomised controlled trial in six academic and 32 non-academic hospitals in the Netherlands between October, 2005, and March, 2008. We enrolled patients with a singleton pregnancy at 36-41 weeks' gestation, and who had gestational hypertension or mild pre-eclampsia. Participants were randomly allocated in a 1:1 ratio by block randomisation with a web-based application system to receive either induction of labour or expectant monitoring. Masking of intervention allocation was not possible. The primary outcome was a composite measure of poor maternal outcome--maternal mortality, maternal morbidity (eclampsia, HELLP syndrome, pulmonary oedema, thromboembolic disease, and placental abruption), progression to severe hypertension or proteinuria, and major post-partum haemorrhage (>1000 mL blood loss). Analysis was by intention to treat and treatment effect is presented as relative risk. This study is registered, number ISRCTN08132825. FINDINGS: 756 patients were allocated to receive induction of labour (n=377 patients) or expectant monitoring (n=379). 397 patients refused randomisation but authorised use of their medical records. Of women who were randomised, 117 (31%) allocated to induction of labour developed poor maternal outcome compared with 166 (44%) allocated to expectant monitoring (relative risk 0.71, 95% CI 0.59-0.86, p<0.0001). No cases of maternal or neonatal death or eclampsia were recorded. INTERPRETATION: Induction of labour is associated with improved maternal outcome and should be advised for women with mild hypertensive disease beyond 37 weeks' gestation. FUNDING: ZonMw.


Asunto(s)
Monitoreo Fetal/métodos , Hipertensión Inducida en el Embarazo/terapia , Trabajo de Parto Inducido/métodos , Preeclampsia/terapia , Desprendimiento Prematuro de la Placenta/epidemiología , Adulto , Eclampsia/epidemiología , Femenino , Edad Gestacional , Síndrome HELLP/epidemiología , Humanos , Hipertensión Inducida en el Embarazo/epidemiología , Modelos Logísticos , Mortalidad Materna , Países Bajos/epidemiología , Selección de Paciente , Hemorragia Posparto/epidemiología , Preeclampsia/epidemiología , Embarazo , Resultado del Embarazo/epidemiología , Edema Pulmonar/epidemiología , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Tromboembolia/epidemiología
18.
Pulm Circ ; 10(2): 2045894019873548, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32363028

RESUMEN

Right ventricular (RV) function and autonomic dysfunction are important determinants of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Although successful in animal studies, effects of beta-blocker therapy on RV function in clinical trials were disappointing. To understand this discrepancy, we studied whether beta-blocker therapy changes RV sympathetic activity. Idiopathic PAH (IPAH) patients received beta-blocker therapy (uptitrated to a maximal tolerated dose) and underwent cardiac magnetic resonance imaging, right heart catheterization, and a [11C]-hydroxyephedrine positron emission tomography ([11C]HED PET) scan at baseline to determine, respectively, RV ejection fraction (RVEF), RV pressures, and sympathetic activity. [11C]HED, a norepinephrine analogue, allows determination of sympathetic innervation of the RV. [11C]HED retention index reflects norepinephrine transporter activity. As a consequence of excessive catecholamine levels in the synaptic cleft, this transporter may be downregulated. Therefore, low [11C]HED retention index indicates high sympathetic activity. 13 IPAH patients underwent [11C]HED PET scans at baseline and after bisoprolol treatment. Although heart rate was reduced, systemic modulation of autonomic activity by bisoprolol did not affect local RV sympathetic nerve activity, RV function, or RV wall tension. In PAH patients, RV [11C]HED retention index was lower compared to LV tracer uptake (p<0.01) and was related to systolic wall tension (R2 = 0.4731, p<0.01) and RV function (R2 = 0.44, p = 0.01). In RV failure, the tolerated dosage of bisoprolol did not result in an improvement of RV function nor in a reduction in RV sympathetic activity.

19.
J Card Fail ; 15(4): 353-61, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19398085

RESUMEN

Besides stimulating erythropoiesis, erythropoietin (EPO) exerts powerful proangiogenic and antiapoptotic effects. These erythropoiesis-independent effects are potentially useful as a supplement for the treatment of chronic heart failure (CHF). EPO may improve microvascular capacity of ischemic myocardial tissue and could thereby (partially) restore myocardial function. In addition, EPO could protect cardiomyocytes from hypoxic damage and prevent them from apoptosis. However, the clinical value of these erythropoiesis-independent effects for the treatment of CHF remains to be elucidated. Small-sized trials evaluating the effects of EPO treatment on surrogate endpoints in patients with CHF showed positive effects in general; however, their mutual results are not always unambiguous. Moreover, increasing hematocrit levels with EPO has been associated with increased blood viscosity and an inherent risk of thromboembolic events. A currently running multicenter phase III trial is designed to provide clarity concerning the effects of EPO on outcome and safety in patients with CHF. Focusing primarily on outcome, however, does not provide insight into the mode of action and isolated benefits of the erythropoiesis-independent effects of EPO. Further exploration of these effects is a key issue to gain knowledge of the full potential of EPO for the treatment of CHF.


Asunto(s)
Anemia/fisiopatología , Apoptosis/fisiología , Eritropoyetina/fisiología , Insuficiencia Cardíaca/fisiopatología , Reperfusión Miocárdica , Anemia/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Enfermedad Crónica , Eritropoyetina/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Reperfusión Miocárdica/métodos
20.
Eur Heart J Case Rep ; 3(1): ytz005, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31020250

RESUMEN

BACKGROUND: Primary cardiac spindle cell sarcomas are extremely rare with only a few cases reported. They are frequently misdiagnosed on cardiac magnetic resonance (CMR) imaging as benign myxoma or thrombi and the suspicion of a malignant sarcoma arises only during surgery. This case report describes a case of cardiac spindle cell sarcoma diagnosed after surgery, where the initial diagnostic possibilities included an intramural thrombus and a cardiac myxoma. CASE SUMMARY: A 57-year-old woman was referred to our hospital for evaluation of a possible recurrent myxoma in the left atrium on echocardiography. Cardiac magnetic resonance imaging confirmed these masses as mural thrombotic masses, with a possible remnant of myxoma. After 2 months of anticoagulation therapy, the masses did not decrease in size on CMR imaging, and surgical removal was indicated. The atrial masses were surgically resected together with a large part of the left atrium. Histological examination showed spindle cell sarcoma. Unfortunately, the resection margins were positive and it was not possible to remove more atrium. PET-CT revealed metastasis in the right femur. The patient passed away 1 year after surgery. DISCUSSION: The rarity of spindle cell sarcoma and its similarities to benign cardiac myxoma and thrombi on echocardiography and CMR imaging present a diagnostic challenge when evaluating patients pre-operatively. Therefore, a malignant spindle cell sarcoma may only be diagnosed during surgery, after histological examination.

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