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1.
Ann Neurol ; 2024 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-39177219

RESUMEN

OBJECTIVE: There is currently scarce data on the electroclinical characteristics of epilepsy associated with synapsin 1 (SYN1) pathogenic variations. We examined clinical and electro-encephalographic (EEG) features in patients with epilepsy and SYN1 variants, with the aim of identifying a distinctive electroclinical pattern. METHODS: In this retrospective multicenter study, we collected and reviewed demographic, genetic, and epilepsy data of 19 male patients with SYN1 variants. Specifically, we analyzed interictal EEG data for all patients, and electro-clinical data from 10 epileptic seizures in 5 patients, using prolonged video-EEG monitoring recordings. Inter-ictal EEG functional connectivity parameters and frequency spectrum of the 10 patients over 12 years of age, were computed and compared with those of 56 age- and sex-matched controls. RESULTS: The main electroclinical features of epilepsy in patients with SYN1 were (1) EEG background and organization mainly normal; (2) interictal abnormalities are often rare or not visible on EEG; (3) more than 60% of patients had reflex seizures (cutaneous contact with water and defecation being the main triggers) isolated or associated with spontaneous seizures; (4) electro-clinical semiology of seizures was mainly temporal or temporo-insulo/perisylvian with a notable autonomic component; and (5) ictal EEG showed a characteristic rhythmic theta/delta activity predominating in temporo-perisylvian regions at the beginning of most seizures. Comparing patients with SYN1 to healthy subjects, we observed a shift to lower frequency bands in power spectrum of interictal EEG and an increased connectivity in both temporal regions. INTERPRETATION: A distinct epilepsy syndrome emerges in patients with SYN1, with a rather characteristic clinical and EEG pattern suggesting predominant temporo-insular involvement. ANN NEUROL 2024.

2.
Infection ; 51(4): 1169-1173, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36735196

RESUMEN

INTRODUCTION: Between May 2022 and January 2023, a global mpox outbreak affected more than 84,000 patients across all continents. Transmission of mpox occurs through large respiratory droplets and direct contact with skin lesions. CASE PRESENTATION: We present the case of a 31-year-old previously healthy male with mpox-Infection following occupational exposure to mpox from a needle stick injury with a sterile needle through a contaminated glove. The patient presented with a three-day history of fever, malaise, and an increasing erythema and swelling of one fingertip. The patient works as a medical doctor with regular exposure to patients infected with mpox. Mpox-PCR from a swab of the lesion and an oro-pharyngeal swab were positive. The lesion on his finger evolved into a necrotic skin lesion finally healing, leaving a scar. He did not develop any secondary pox on his skin and recovered fully. DISCUSSION: Only a minority of patients with mpox infection develop illness with pronounced local complications as in this case. CONCLUSION: Mpox can potentially be transmitted in an occupational context. Medical personnel should be informed about this possible route of transmission.


Asunto(s)
Mpox , Humanos , Masculino , Adulto , Brotes de Enfermedades , Piel , Fiebre , Dedos
3.
J Endovasc Ther ; : 15266028221113745, 2022 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-35980088

RESUMEN

PURPOSE: The purpose of this study was to report the closure of iliac arteriovenous fistulas associated with a post-thrombotic iliac vein occlusion by iliac venous stent recanalization. CASE REPORT: An 80-year-old woman presented with a worsening painful swelling of her left leg after an iliofemoral deep vein thrombosis 6 months ago. Duplex ultrasound and magnetic resonance venography revealed a post-thrombotic obstruction of her iliac veins as well as several arteriovenous fistulas between branches of her left external and internal iliac arteries and adjacent diseased venous segments. In a first attempt, coil embolization did not sustainably close these iliac arteriovenous fistulas. Direct stent recanalization of the chronically diseased iliofemoral venous segment, however, resulted in an immediate closure of arteriovenous shunt flow and subsequent improvement of clinical symptoms. Six months after iliac vein stent recanalization, still no fistulas could be detected any more, venous stents were fully patent, and the patient was free of symptoms. CONCLUSION: Post-thrombotic iliofemoral obstructions might be associated with the development of arteriovenous fistulas. Direct stent recanalization of the chronically occluded veins results in closure of related arteriovenous fistulas. CLINICAL IMPACT: This case suggests that the combined occurrence of post-thrombotic venous obstructions with arteriovenous fistulas, which are related to aforementioned venous lesions, should be evaluated for primary venous stent recanalization rather than fistula embolization.

4.
Int J Mol Sci ; 23(23)2022 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-36499313

RESUMEN

Cenerimod, a sphingosine-1-phosphate 1 receptor modulator, is in development for the treatment of systemic lupus erythematosus, a disease mainly affecting women of childbearing potential. The effect of cenerimod on the pharmacokinetics (PK) of a combined oral contraceptive (COC, 100 µg levonorgestrel and 20 µg ethinylestradiol (EE)) was investigated. A randomized, double-blind, parallel-group study was performed in 24 healthy male and female subjects. A single oral dose of COC was administered alone and after 35 days of once daily (o.d.) administration of cenerimod 0.5 (n = 10) or 4 (n = 14) mg. Exposure to EE alone or in combination with cenerimod was comparable as reflected by the geometric mean ratios and the respective 90% confidence intervals, while a slight increase in exposure (approximately 10-25%) to levonorgestrel was observed at clinically relevant concentrations of cenerimod. Overall, COC alone or in combination with cenerimod was safe and well tolerated. Two subjects reported one adverse event each (one headache after COC alone, and gastroenteritis in combination with cenerimod 4 mg). In conclusion, cenerimod does not affect the PK of levonorgestrel or EE to a clinically relevant extent. Therefore, COC can be selected as method of contraception during and after cenerimod therapy without the risk of interaction.


Asunto(s)
Anticonceptivos Orales Combinados , Glicoles de Propileno , Femenino , Humanos , Masculino , Anticonceptivos Orales Combinados/farmacocinética , Etinilestradiol , Factores Inmunológicos , Levonorgestrel , Glicoles de Propileno/efectos adversos
5.
Vox Sang ; 115(1): 60-71, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31709562

RESUMEN

BACKGROUND AND OBJECTIVES: Patient Blood Management (PBM) aims to optimize the care of patients who might need a blood transfusion. The International Consensus Conference on PBM (ICC-PBM) aimed to develop evidence-based recommendations on three topics: preoperative anaemia, red blood cell transfusion thresholds and implementation of PBM programmes. This paper reports how evidence-based methodologies and technologies were used to enhance shared decision-making in formulating recommendations during the ICC-PBM. MATERIALS & METHODS: Systematic reviews on 17 PICO (Population, Intervention, Comparison, Outcomes) questions were conducted by a Scientific Committee (22 international topic experts and one methodologist) according to GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methodology. Evidence-based recommendations were formulated using Consensus Development Conference methodology. RESULTS: We screened 17 607 references and included 145 studies. The overall certainty in the evidence of effect estimates was generally low or very low. During the ICC, plenary sessions (100-200 stakeholders from a range of clinical disciplines and community representatives) were followed by closed sessions where multidisciplinary decision-making panels (>50 experts and patient organizations) formulated recommendations. Two chairs (content-expert and methodologist) moderated each session and two rapporteurs documented the discussions. The Evidence-to-Decision template (GRADEpro software) was used as the central basis in the process of formulating recommendations. CONCLUSION: This ICC-PBM resulted in 10 clinical and 12 research recommendations supported by an international stakeholder group of experts in blood transfusion. Systematic, rigorous and transparent evidence-based methodology in a formal consensus format should be the new standard to evaluate (cost-) effectiveness of medical treatments, such as blood transfusion.


Asunto(s)
Anemia/terapia , Transfusión Sanguínea/normas , Transfusión de Eritrocitos/normas , Humanos
6.
Infection ; 48(3): 453-461, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32394345

RESUMEN

PURPOSE: Current German/Austrian antiretroviral treatment guidelines recommend more than 20 combination regimens for first-line therapy, without a preference. Regimens include two nucleoside reverse transcriptase inhibitors (NRTIs) plus either an integrase strand transfer inhibitor (INSTI), a non-NRTI (NNRTI) or a boosted protease inhibitor (PI). The objective was to examine the outcomes of recommended first-line ART in Germany. METHODS: This nationwide observational study included treatment-naïve chronically HIV-1 infected patients receiving one of the recommended first-line regimens. Patients were allocated to three arms (INSTI, NNRTI, PI) and were prospectively followed for 24 months. Delayed treatment initiation was defined by a baseline CD4 T-cell count of < 350/µl or CDC clinical stage C. RESULTS: Among a total of 434 patients enrolled, virologic failure was rare and occurred in 4.3% (6/141) in the PI arm, in 3.3% (4/122) in the NNRTI arm and in 0.6% (1/171) in the INSTI arm (p = 0.10). De novo drug resistance mutations developed in only two patients in the NNRTI arm. Nonetheless, treatment modifications were frequent (51%) and mostly performed for strategic reasons. Retention on all initial compounds at month 24 was 64%, 49%, and 22% in the INSTI, NNRTI and PI arms respectively. Delayed treatment initiation was common (47%) and more frequently observed in patients in the PI arm. It was not associated with virological failure. CONCLUSION: High efficacy and low virological failure rates were observed with recommended first-line regimens independent of delayed treatment initiation, chosen regimen and subsequent treatment modifications, demonstrating the validity of the current treatment guidelines.


Asunto(s)
Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Adulto , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos
7.
Eur Heart J ; 40(5): 422-440, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30608523

RESUMEN

Transcatheter heart valve interventions have transformed the outcomes of patients with valvular heart disease (VHD) who are unfavourable candidates for surgery. Technological advances have allowed extension of these interventions to younger or lower risk patients and those with other forms of VHD and may in the future permit earlier treatment of VHD in less symptomatic patients or those with moderate disease. The balance of risks and benefits is likely to differ between lower and higher risk patients, and more evidence is needed to evaluate the net benefit of transcatheter technology in these groups. As academic researchers, clinicians, industry, and patient stakeholders collaborate to research these broader indications for transcatheter valve interventions, it is essential to address (i) device durability and deliverability, (ii) specific anatomical needs (e.g. bicuspid aortic valves, aortic regurgitation, mitral and tricuspid valve disease), (iii) operator training, and (iv) the reinforced importance of the multidisciplinary Heart Team.


Asunto(s)
Enfermedades de las Válvulas Cardíacas/cirugía , Implantación de Prótesis de Válvulas Cardíacas/métodos , Prótesis Valvulares Cardíacas , Válvulas Cardíacas/cirugía , Implantación de Prótesis de Válvulas Cardíacas/instrumentación , Implantación de Prótesis de Válvulas Cardíacas/tendencias , Humanos , Supervivencia sin Progresión , Diseño de Prótesis , Reemplazo de la Válvula Aórtica Transcatéter/tendencias
8.
Tumour Biol ; 41(3): 1010428319827223, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30907281

RESUMEN

Prostate cancer represents a major cause of cancer death in men worldwide. Novel non-invasive methods are still required for differentiation of non-aggressive from aggressive tumors. Recently, changes in prostate-specific antigen glycosylation pattern, such as core-fucosylation, have been described in prostate cancer. The objective of this study was to evaluate whether the core-fucosylation determinant of serum prostate-specific antigen may serve as refined marker for differentiation between benign prostate hyperplasia and prostate cancer or identification of aggressive prostate cancer. A previously developed liquid chromatography-mass spectrometry/mass spectrometry-based strategy was used for multiplex analysis of core-fucosylated prostate-specific antigen (fuc-PSA) and total prostate-specific antigen levels in sera from 50 benign prostate hyperplasia and 100 prostate cancer patients of different aggressiveness (Gleason scores, 5-10) covering the critical gray area (2-10 ng/mL). For identification of aggressive prostate cancer, the ratio of fuc-PSA to total prostate-specific antigen (%-fuc-PSA) yielded a 5%-8% increase in the area under the curve (0.60) compared to the currently used total prostate-specific antigen (area under the curve = 0.52) and %-free prostate-specific antigen (area under the curve = 0.55) tests. However, our data showed that aggressive prostate cancer (Gleason score > 6) and non-aggressive prostate cancer (Gleason score ≤ 6) could not significantly (p-value = 0.08) be differentiated by usage of %-fuc-PSA. In addition, both non-standardized fuc-PSA and standardized %-fuc-PSA had no diagnostic value for differentiation of benign prostate hyperplasia from prostate cancer. The %-fuc-PSA serum levels could not improve the differentiation of non-aggressive and aggressive prostate cancer compared to conventional diagnostic prostate cancer markers. Still, it is unclear whether these limitations come from the biomarker, the used patient cohort, or the imprecision of the applied method itself. Therefore, %-fuc-PSA should be further investigated, especially by more precise methods whether it could be clinically used in prostate cancer diagnosis.


Asunto(s)
Biomarcadores de Tumor/química , Antígeno Prostático Específico/química , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/patología , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Cromatografía Liquida , Diagnóstico Diferencial , Glicosilación , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Próstata/patología , Antígeno Prostático Específico/sangre , Espectrometría de Masas en Tándem
9.
JAMA ; 321(10): 983-997, 2019 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-30860564

RESUMEN

IMPORTANCE: Blood transfusion is one of the most frequently used therapies worldwide and is associated with benefits, risks, and costs. OBJECTIVE: To develop a set of evidence-based recommendations for patient blood management (PBM) and for research. EVIDENCE REVIEW: The scientific committee developed 17 Population/Intervention/Comparison/Outcome (PICO) questions for red blood cell (RBC) transfusion in adult patients in 3 areas: preoperative anemia (3 questions), RBC transfusion thresholds (11 questions), and implementation of PBM programs (3 questions). These questions guided the literature search in 4 biomedical databases (MEDLINE, EMBASE, Cochrane Library, Transfusion Evidence Library), searched from inception to January 2018. Meta-analyses were conducted with the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology and the Evidence-to-Decision framework by 3 panels including clinical and scientific experts, nurses, patient representatives, and methodologists, to develop clinical recommendations during a consensus conference in Frankfurt/Main, Germany, in April 2018. FINDINGS: From 17 607 literature citations associated with the 17 PICO questions, 145 studies, including 63 randomized clinical trials with 23 143 patients and 82 observational studies with more than 4 million patients, were analyzed. For preoperative anemia, 4 clinical and 3 research recommendations were developed, including the strong recommendation to detect and manage anemia sufficiently early before major elective surgery. For RBC transfusion thresholds, 4 clinical and 6 research recommendations were developed, including 2 strong clinical recommendations for critically ill but clinically stable intensive care patients with or without septic shock (recommended threshold for RBC transfusion, hemoglobin concentration <7 g/dL) as well as for patients undergoing cardiac surgery (recommended threshold for RBC transfusion, hemoglobin concentration <7.5 g/dL). For implementation of PBM programs, 2 clinical and 3 research recommendations were developed, including recommendations to implement comprehensive PBM programs and to use electronic decision support systems (both conditional recommendations) to improve appropriate RBC utilization. CONCLUSIONS AND RELEVANCE: The 2018 PBM International Consensus Conference defined the current status of the PBM evidence base for practice and research purposes and established 10 clinical recommendations and 12 research recommendations for preoperative anemia, RBC transfusion thresholds for adults, and implementation of PBM programs. The relative paucity of strong evidence to answer many of the PICO questions supports the need for additional research and an international consensus for accepted definitions and hemoglobin thresholds, as well as clinically meaningful end points for multicenter trials.


Asunto(s)
Anemia Ferropénica/diagnóstico , Anemia Ferropénica/tratamiento farmacológico , Transfusión Sanguínea , Transfusión de Eritrocitos/normas , Hemoglobinas/análisis , Cuidados Preoperatorios/normas , Anemia/diagnóstico , Pérdida de Sangre Quirúrgica/prevención & control , Transfusión Sanguínea/normas , Procedimientos Quirúrgicos Cardíacos , Cuidados Críticos , Hemorragia Gastrointestinal/terapia , Hematínicos/uso terapéutico , Fracturas de Cadera , Humanos , Hierro/uso terapéutico
10.
Circulation ; 133(5): 509-17, 2016 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-26733605

RESUMEN

BACKGROUND: In incipient Raynaud phenomenon, nailfold capillaroscopy and autoantibody tests are obtained to screen for an emerging connective tissue disease. Whether the presence of abnormal nailfold capillaries and autoantibodies are related to mortality in patients with incipient Raynaud phenomenon is not known. METHODS AND RESULTS: In 2958 consecutive patients (78% women, median age 45 years) with incipient Raynaud phenomenon without previously known connective tissue disease, nailfold capillaroscopy and laboratory tests for antinuclear antibodies (ANA) and ANA subsets were obtained at initial presentation. During a median follow-up period of 9.3 years, 227 women (9.9% of female patients) and 129 men (20% of male patients) with Raynaud phenomenon died. In comparison with a demographically matched standard population, survival was poorer in patients with Raynaud phenomenon (log-rank test P<0.0001). In patients with Raynaud phenomenon, mortality was higher in men than in women (P<0.0001, Cox proportional hazards model). In women, the presence of abnormal nailfold capillaries, ANA, and anti-Scl-70 antibodies were related to an increase in all-cause mortality. The conjoint presence of abnormal nailfold capillaries and autoantibodies was associated with the highest mortality rates. In men, abnormal nailfold capillaries, and ANA and ANA subsets, as well, were not related to survival. In both sexes, patients' age and serum creatinine were associated with mortality. CONCLUSIONS: In Raynaud phenomenon, male sex, age, and serum creatinine are related to mortality. Abnormal nailfold capillaries and autoantibodies are associated with an increase in all-cause mortality in female patients, but not in male patients with Raynaud phenomenon.


Asunto(s)
Autoanticuerpos/sangre , Capilares , Angioscopía Microscópica/mortalidad , Enfermedad de Raynaud/sangre , Enfermedad de Raynaud/mortalidad , Adulto , Capilares/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Angioscopía Microscópica/métodos , Persona de Mediana Edad , Mortalidad/tendencias , Estudios Prospectivos , Enfermedad de Raynaud/diagnóstico
11.
Ann Surg ; 264(2): 203-11, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27163948

RESUMEN

OBJECTIVE: To determine whether the implementation of patient blood management (PBM) is effective to decrease the use of red blood cell without impairment of patient's safety. BACKGROUND: The World Health Organization encouraged all member states to implement PBM programs employing multiple combined strategies to increase and preserve autologous erythrocyte volume to minimize red blood cell transfusions. Data regarding safety issues are not sufficiently available. METHODS: In this prospective, multicenter study, surgical inpatients from four German University Hospitals were analyzed before (pre-PBM) and after the implementation of PBM. PBM program included multiple measures (ie, preoperative optimization of hemoglobin levels, blood-sparing techniques, and standardization of transfusion practice). Primary aim was to show noninferiority of the PBM cohort with a margin of 0.5%. Secondary endpoints included red blood cell utilization. RESULTS: A total of 129,719 patients discharged between July 2012 and June 2015 with different inclusion periods for pre-PBM (54,513 patients) and PBM (75,206 patients) were analyzed. The primary endpoint was 6.53% in the pre-PBM versus 6.34% in the PBM cohort. The noninferiority aim was achieved (P < 0.001). Incidence of acute renal failure decreased in the PBM cohort (2.39% vs 1.67%; P < 0.001, regression model). The mean number of red blood cell transfused per patient was reduced from 1.21 ±â€Š0.05 to 1.00 ±â€Š0.05 (relative change by 17%, P < 0.001). CONCLUSIONS: The data presented show that implementation of PBM with a more conscious handling of transfusion practice can be achieved even in large hospitals without impairment of patient's safety. Further studies should elucidate which PBM measures are most clinically and cost effective. TRIAL REGISTRATION: PBM-Study ClinicalTrials.gov, NCT01820949.


Asunto(s)
Anemia/prevención & control , Transfusión de Eritrocitos , Complicaciones Posoperatorias/prevención & control , Anemia/diagnóstico , Anemia/etiología , Protocolos Clínicos , Estudios Controlados Antes y Después , Femenino , Alemania , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Seguridad del Paciente , Selección de Paciente , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Estudios Prospectivos
12.
J Endovasc Ther ; 23(5): 738-43, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27328913

RESUMEN

PURPOSE: To prospectively investigate the associations of serum cholinesterase (CHE) levels with ischemic outcomes after angioplasty and stenting for lower limb peripheral artery disease (PAD). METHODS: A prospective cohort study enrolled 108 patients with Rutherford category 2-3 ischemia who had successful primary unilateral angioplasty and self-expanding bare metal stent implantation for superficial femoral artery (SFA) stenosis. The primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke or transient ischemic attack, cardiovascular death, or >80% target lesion restenosis within 2 years after peripheral angioplasty. Target lesion restenosis (restenosis endpoint) and the composite of the aforementioned atherothrombotic events (atherothrombotic endpoint) within 2-year follow-up were defined as secondary endpoints. RESULTS: CHE levels were not available in 4 patients due to technical problems and 4 patients were lost to follow-up. The remaining 100 patients (median age 65 years; 62 men) met the minimum sample size requirement for statistical analysis. Median CHE levels were significantly lower in patients who subsequently experienced the primary endpoint compared with patients without ischemic events [7.1 (IQR 6.3-8.1) vs 8 (IQR 7-9.3) kU/L, p=0.007]. A CHE level <8.3 kU/L was identified as the best cutoff value to predict the primary endpoint, providing an 82.1% sensitivity and 44.3% specificity. The primary endpoint occurred significantly more often in patients with low CHE <8.3 kU/L than in patients with higher CHE levels (32 vs 7 patients, p=0.01). In multivariable Cox regression analysis, low CHE was associated with a 2.6-fold increased risk (95% CI 1.1 to 5.9, p=0.03) of the primary endpoint. Moreover, patients who suffered the secondary restenosis endpoint had significantly lower median CHE levels than patients without restenosis [7.1 (IQR 6.3-8.2) vs 7.9 (IQR 7-8.9) kU/L, p=0.02], and restenosis occurred more frequently in patients with low CHE compared with those with higher CHE levels (27 vs 7 patients, p=0.04). CONCLUSION: Low CHE is associated with an increased risk of long-term adverse ischemic events following SFA angioplasty with stent implantation for PAD.


Asunto(s)
Angioplastia/instrumentación , Colinesterasas/sangre , Isquemia/terapia , Enfermedad Arterial Periférica/terapia , Stents Metálicos Autoexpandibles , Anciano , Angioplastia/efectos adversos , Angioplastia/mortalidad , Biomarcadores/sangre , Distribución de Chi-Cuadrado , Regulación hacia Abajo , Femenino , Humanos , Isquemia/sangre , Isquemia/diagnóstico , Isquemia/mortalidad , Ataque Isquémico Transitorio/etiología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Infarto del Miocardio/etiología , Enfermedad Arterial Periférica/sangre , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/mortalidad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Diseño de Prótesis , Recurrencia , Factores de Riesgo , Accidente Cerebrovascular/etiología , Factores de Tiempo , Resultado del Tratamiento
13.
J Math Biol ; 72(6): 1467-529, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26242360

RESUMEN

Population managers will often have to deal with problems of meeting multiple goals, for example, keeping at specific levels both the total population and population abundances in given stage-classes of a stratified population. In control engineering, such set-point regulation problems are commonly tackled using multi-input, multi-output proportional and integral (PI) feedback controllers. Building on our recent results for population management with single goals, we develop a PI control approach in a context of multi-objective population management. We show that robust set-point regulation is achieved by using a modified PI controller with saturation and anti-windup elements, both described in the paper, and illustrate the theory with examples. Our results apply more generally to linear control systems with positive state variables, including a class of infinite-dimensional systems, and thus have broader appeal.


Asunto(s)
Ecología/organización & administración , Ecosistema , Modelos Biológicos , Animales , Arecaceae , Artiodáctilos , Simulación por Computador , Ecología/estadística & datos numéricos , Femenino , Masculino , Conceptos Matemáticos , Dinámica Poblacional/estadística & datos numéricos
14.
Eur J Clin Invest ; 44(8): 766-74, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24942279

RESUMEN

BACKGROUND: Microcirculatory function can be assessed by postocclusive reactive hyperaemia (PORH) using laser Doppler fluxmetry. Previous studies have shown that PORH reveals microvascular damage at an early stage. In particular, at younger ages, PORH might depend on age and gender. To implement PORH into a larger scale of clinical studies, one has to be aware of the influence of age and gender on microcirculation. The aim of this study was to assess the impact of age and gender on microcirculatory function during adolescence. MATERIALS AND METHODS: Within the scope of an epidemiological project, 896 children and adolescents underwent assessment of PORH by laser Doppler fluxmetry. Microcirculatory parameters during PORH (baseline perfusion, biological zero, peak perfusion, time to peak perfusion and recovery time) were analysed in relation to age (by tertiles) and gender. RESULTS: Baseline perfusion, biological zero and peak perfusion were lower in children/adolescents in the upper age tertile (12·3-18·1 years) than in the middle (9·8-12·2 years) and lower (4·3-9·7 years) age tertiles (P < 0·0001). In the total of participants, baseline perfusion, biological zero and peak perfusion were higher in males than in females (P < 0·0001). Analysing microcirculatory parameters as a function of age and gender, the sex differences were only apparent in the upper and the middle age tertiles, but not in the lower. CONCLUSIONS: During adolescence, PORH is a function of age. At higher age, microvascular reactivity considerably depends on gender, whereas no sex differences are present at younger ages.


Asunto(s)
Envejecimiento/fisiología , Microcirculación/fisiología , Caracteres Sexuales , Adolescente , Niño , Preescolar , Femenino , Voluntarios Sanos , Humanos , Flujometría por Láser-Doppler , Ligadura , Masculino , Piel/irrigación sanguínea
15.
J Neurol Neurosurg Psychiatry ; 85(11): 1198-208, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24659797

RESUMEN

OBJECTIVE: This double-blind, placebo-controlled, dose-finding phase IIb study evaluated the efficacy and safety of ponesimod, an oral selective S1P1 receptor modulator, for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: 464 patients were randomised to receive once-daily oral ponesimod 10, 20 or 40 mg, or placebo for 24 weeks. The primary endpoint was the cumulative number of new T1 gadolinium-enhanced (T1 Gd+) lesions per patient recorded every 4 weeks from weeks 12 to 24 after study drug initiation. Secondary endpoints were the annualised confirmed relapse rate (ARR) and time to first confirmed relapse. Safety and tolerability were also evaluated. RESULTS: The mean cumulative number of new T1 Gd+ lesions at weeks 12-24 was significantly lower in the ponesimod 10 mg (3.5; rate ratio (RR) 0.57; p=0.0318), 20 mg (1.1; RR 0.17; p<0.0001) and 40 mg (1.4; RR 0.23; p<0.0001) groups compared with placebo (6.2). The mean ARR was lower with 40 mg ponesimod versus placebo, with a maximum reduction of 52% (0.25 vs 0.53; p=0.0363). The time to first confirmed relapse was increased with ponesimod compared with placebo. The proportion of patients with ≥ 1 treatment-emergent adverse events (AEs) was similar across ponesimod groups and the placebo group. Frequently reported AEs with higher incidence in the three ponesimod groups compared with placebo were anxiety, dizziness, dyspnoea, increased alanine aminotransferase, influenza, insomnia and peripheral oedema. CONCLUSIONS: Once-daily treatment with ponesimod 10, 20 or 40 mg significantly reduced the number of new T1 Gd+ lesions and showed a beneficial effect on clinical endpoints. Ponesimod was generally well tolerated, and further investigation of ponesimod for the treatment of RRMS is under consideration. TRIAL REGISTRATION NUMBER: NCT01006265.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Receptores de Lisoesfingolípidos/antagonistas & inhibidores , Tiazoles/uso terapéutico , Administración Oral , Adolescente , Adulto , Método Doble Ciego , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/patología , Índice de Severidad de la Enfermedad , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Adulto Joven
16.
J Cardiovasc Pharmacol ; 63(2): 120-31, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24126567

RESUMEN

ACT-280778 is a novel nondihydropyridine dual L/T-type calcium channel blocker. Two clinical studies (AC-067-101 and AC-067-102) were conducted to characterize its safety, tolerability, and pharmacokinetics in healthy male subjects after oral administration of single and multiple doses. Both trials were single-center, randomized, double-blind, placebo-controlled, adaptive design, ascending-dose studies, in which ACT-280778 was administrated as single doses of 2, 5, 15, or 40 mg, or as once-daily doses of 5 or 15 mg for 7 days. Single and multiple doses up to and including 15 mg were well tolerated, and no serious or severe adverse event was reported in either study. A single dose of 40 mg was associated with abnormal electrocardiogram findings resulting in the discontinuation of further treatment at this dose or higher doses. ACT-280778 was rapidly absorbed, and larger than dose-proportional increases of the maximum plasma concentration and area under the plasma concentration-time curve were observed. Food intake delayed the time to maximum plasma concentration and doubled exposure. Urinary excretion of unchanged ACT-280778 was negligible, and accumulation at steady state was modest. Overall, pharmacokinetic and tolerability profiles of ACT-280778 observed in these 2 studies warranted further evaluation of ACT-280778 in a proof-of-concept study in patients with hypertension.


Asunto(s)
Bencimidazoles/administración & dosificación , Compuestos Bicíclicos con Puentes/administración & dosificación , Bloqueadores de los Canales de Calcio/administración & dosificación , Canales de Calcio Tipo L/efectos de los fármacos , Canales de Calcio Tipo T/efectos de los fármacos , Administración Oral , Adulto , Área Bajo la Curva , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Compuestos Bicíclicos con Puentes/efectos adversos , Compuestos Bicíclicos con Puentes/farmacocinética , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Interacciones Alimento-Droga , Humanos , Masculino , Estudios Prospectivos , Adulto Joven
17.
J Clin Pharmacol ; 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-39141427

RESUMEN

Cenerimod is a sphingosine-1-phosphate receptor 1 modulator that reduces tissue availability of circulating lymphocytes. The compound is in Phase 3 development for the treatment of systemic lupus erythematosus. Its pharmacokinetic properties are characterized by slow absorption and multiphasic elimination with a long terminal half-life (t½), potentially caused by enterohepatic circulation (EHC). In this trial in healthy participants, oral cenerimod 0.5 and 4 mg once daily was administered for 50 days, followed by oral administration of activated charcoal (ie, 50 mg every 12 h for 11 days, starting 24 h after the last cenerimod dose), to investigate the potential EHC of cenerimod and assess whether elimination of cenerimod can be accelerated. The multiple-dose pharmacokinetics, pharmacodynamics, safety, and tolerability of cenerimod were also evaluated. For both doses, peak plasma concentrations were reached 6 and 7 h after dosing. Cenerimod accumulated approximately eightfold and (near) steady-state conditions were reached after 50 doses, resembling clinically meaningful exposure to cenerimod. The t½ following 0.5 and 4 mg of cenerimod was 767 and 799 h (ie, 32 and 33 days) and 720 and 780 h (ie, 30 and 33 days) with or without administration of charcoal, respectively, indicating no statistically significant difference. Therefore, charcoal did not accelerate cenerimod elimination suggesting that there is no EHC of cenerimod. A reversible, dose-dependent decrease in total lymphocyte count was observed. No safety concerns were identified; administration of charcoal was well tolerated.

18.
Europace ; 15(11): 1540-56, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23981824

RESUMEN

The management of atrial fibrillation (AF) has seen marked changes in past years, with the introduction of new oral anticoagulants, new antiarrhythmic drugs, and the emergence of catheter ablation as a common intervention for rhythm control. Furthermore, new technologies enhance our ability to detect AF. Most clinical management decisions in AF patients can be based on validated parameters that encompass type of presentation, clinical factors, electrocardiogram analysis, and cardiac imaging. Despite these advances, patients with AF are still at increased risk for death, stroke, heart failure, and hospitalizations. During the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association (AFNET/EHRA) consensus conference, we identified the following opportunities to personalize management of AF in a better manner with a view to improve outcomes by integrating atrial morphology and damage, brain imaging, information on genetic predisposition, systemic or local inflammation, and markers for cardiac strain. Each of these promising avenues requires validation in the context of existing risk factors in patients. More importantly, a new taxonomy of AF may be needed based on the pathophysiological type of AF to allow personalized management of AF to come to full fruition. Continued translational research efforts are needed to personalize management of this prevalent disease in a better manner. All the efforts are expected to improve the management of patients with AF based on personalized therapy.


Asunto(s)
Fibrilación Atrial/terapia , Manejo de la Enfermedad , Medicina de Precisión/métodos , Medicina de Precisión/tendencias , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/genética , Biomarcadores/sangre , Encéfalo/patología , Ecocardiografía , Electrocardiografía , Humanos , Imagen por Resonancia Magnética , Factores de Riesgo , Resultado del Tratamiento
19.
RMD Open ; 9(1)2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36972928

RESUMEN

OBJECTIVE: To characterise associations between individual nailfold capillary aberrations with autoantibodies in a cross-sectional study on children and adults with Raynaud's phenomenon (RP). METHODS: Consecutive children and adults with RP and without previously known connective tissue disease (CTD) systemically underwent nailfold capillaroscopy and laboratory tests for the presence of antinuclear antibodies (ANA). The prevalence of individual nailfold capillary aberrations and ANA was assessed, and the associations between individual nailfold capillary aberrations and ANA were analysed separately in children and adolescents. RESULTS: In total, 113 children (median age 15 years) and 2858 adults (median age 48 years) with RP and without previously known CTD were assessed. At least one nailfold capillary aberration was detected in 72 (64%) of included children and in 2154 (75%) of included adults with RP (children vs adults p<0.05). An ANA titre ≥1:80, ≥1:160 or≥1:320 was observed in 29%, 21% or 16% of included children, and in 37%, 27% or 24% of screened adults, respectively. While the occurrence of individual nailfold capillary aberrations was related to the presence of an ANA titre of ≥1:80 in adults (reduced capillary density, avascular fields, haemorrhages, oedema, ramifications, dilations and giant capillaries: each p<0.001), no comparable association between nailfold capillary aberrations and ANA was observed in children with RP without previously known CTD. CONCLUSION: In contrast to adults, the association between nailfold capillary aberrations and ANA might be less pronounced in children. Further studies are warranted to validate these observations in children with RP.


Asunto(s)
Enfermedades del Tejido Conjuntivo , Enfermedad de Raynaud , Adolescente , Humanos , Adulto , Niño , Persona de Mediana Edad , Autoanticuerpos , Capilares , Estudios Transversales , Uñas/irrigación sanguínea , Enfermedad de Raynaud/diagnóstico , Enfermedad de Raynaud/etiología , Anticuerpos Antinucleares
20.
Expert Opin Biol Ther ; 23(8): 791-800, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37038897

RESUMEN

BACKGROUND: The objective of this non-interventional, observational prospective cohort study (CONNECT-IBD) was to assess the use of CT-P13 (Inflectra®) in the treatment of patients with Crohn's disease (CD) and ulcerative colitis (UC) in the context of treatment with reference infliximab (IFX; Remicade®). METHODS: Patients (recruited April 2015 to October 2018) at 150 sites across 13 European countries were followed for up to 2 years. Primary outcomes were safety, population characteristics, and drug utilization patterns. Secondary outcomes included clinical assessment of disease activity. Data were analyzed descriptively. RESULTS: Overall, 2543 patients (CD, n = 1676; UC, n = 867) were included. In the CT-P13 cohort (n = 1522), median disease duration was 63 (0-579) months and 30% of patients were IFX naïve; median duration of prior IFX treatment was 5 months. During the observation period, median duration of drug exposure was 14 (0-28) months. 41% of patients reported 912 all-causality treatment-emergent adverse events (TEAEs); 24% experienced treatment-related TEAEs. Most TEAEs were of mild-to-moderate severity. Treatment-emergent serious adverse events were reported by 17% of patients. CONCLUSION: Safety information for CT-P13 in this large study was consistent with the known safety profile for IFX and did not alter the established benefit-risk profile of CT-P13.


Asunto(s)
Biosimilares Farmacéuticos , Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Biosimilares Farmacéuticos/efectos adversos , Biosimilares Farmacéuticos/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/efectos adversos , Infliximab/uso terapéutico , Estudios Prospectivos , Inducción de Remisión , Resultado del Tratamiento
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