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The role of antiphospholipid antibody pattern in the recurrence of thrombosis in patients with antiphospholipid syndrome
Full text linkThe antiphospholipid syndrome (APS) is a hypercoagulability condition of autoimmune origin clinically characterized by the development of arterial, venous and/or microvascular thrombosis and pregnancy complications (recurrent early miscarriages, fetal deaths after the 10th week of gestation and/or premature births) associated to the presence of antiphospholipid antibodies (aPL). It can occur either as an isolated condition (primary APS), or in the context of an underlying autoimmune disease, most commonly systemic lupus erythematosus (SLE). Three aPL are included in the current classification criteria: anti-cardiolipin IgG/IgM, anti-β2-glycoprotein I (β2GPI) IgG/IgM and lupus anticoagulant (LAC). Although several others have been identified, they are not tested in most laboratories. The standard of treatment is oral anticoagulation for thrombotic APS and prophylactic/therapeutic low molecular weight heparin plus low dose aspirin for obstetric APS. Nonetheless there is a high rate of recurrence of clinical manifestations in patients undergoing standard of care. Known risk factors for thrombotic recurrence are a previous arterial thrombosis, high risk aPL profiles such as triple aPL positivity and LA persistent positivity, association with SLE and presence of genetic and acquired risk factors for thrombosis. Moreover, aPL persistence over time seems to be associated with thrombotic recurrence, but data on the course of aPL tests over time are limited and mostly with a short follow-up. Recently a score system, named global APS score (GAPSS), that includes the three aPL plus anti-phosphatydilserine-prothrombin (aPS-PT) IgG/M, hypertension and dyslipidemia, has been proposed as a risk stratification tool for APS. Its “adjusted” (aGAPSS) does not include aPS-PT. Moreover, a score for measuring damage, named Damage Index for APS (DIAPS), has been devised. The aGAPSS is by its very nature dynamic, since both cardiovascular risk factors and aPL can change over time, and therefore needs to be monitored longitudinally at repeated time points. Furthermore, even though a disease activity index for APS is lacking, the aGAPSS, as a dynamic score that predispose to clinical manifestations, could be used a surrogate of disease activity and predictor of damage.
Starting from these premises, the objective of my thesis has been to analyze the pattern of aPL persistence over time and its association with clinical manifestations and the role of longitudinal monitoring of the aGAPSS as a predictor of clinical recurrence and a surrogate of disease activity predicting damage accrual, in a cohort of patients with APS.
In the first study we assessed the rate of aPL persistence in a cohort of 200 individuals with a diagnosis of APS. Median follow-up duration was 172.5 months (IQR 120-240). 56% of patients presented persistent aPL positivity, defined as positivity at medium-high titer in at least two thirds of total determinations. Higher aPL titers and multiple aPL positivity at baseline correlated with aPL persistence, while single aCL and LA positivity were associated with a transient aPL profile. Patients with persistent aPL presented a higher rate of recurrence of clinical manifestations (thrombosis and/or pregnancy morbidity) in comparison to patients with transient aPL (43.8% vs 23.9%) with an OR=2.48 (95% CI 1.34-4.58, p=0.003). The rate of thrombotic recurrence, analyzed separately, was also higher in patients with persistent aPL profile (40.2% vs 18.2%) with an OR=3.02 (95% CI 1.57-5.81, p<0.001). We therefore concluded that more than half of patients with APS maintained persistent aPL positivity over more than 14 years of follow-up. Multiple positivity at baseline increased the likelihood of aPL persistence in the follow-up. Persistent aPL increased the odds of thrombotic and thrombotic plus obstetric recurrence.
In the second study we aimed to assess if the one-time aGAPSS measured at baseline, presented a different association with recurrence of thrombosis and/or pregnancy morbidity in comparison to the average aGAPSS over time, measured as a mean of up to 6 yearly measurements (in patients without recurrence) or up the event in patients with recurrence, and to the delta of the aGAPSS, computed as the difference between the aGAPSS before clinical recurrence (if present) or at the end of follow-up (in case of no clinical recurrence) and the basal aGAPSS. Only patients with at least three annual determinations of the aGAPSS were included. In more than half of patients under VKA therapy, we tested the percentage of time spent within the therapeutic range (TTR) to verify that there was no difference between patients with and without thrombotic recurrence. In our cohort of 200 APS patients, we found a higher baseline, mean and delta aGAPSS in patients with recurrence than patients without. Conversely, when comparing patients with thrombotic recurrence to patients with only obstetric recurrence, the baseline aGAPSS was not significantly different, while both the mean aGAPSS and the delta were significantly higher in the first group. The mean aGAPSS was higher in patients with arterial thrombotic recurrence than venous recurrence. TTR was similar in patients under VKA who did or did not present thrombotic recurrence. When performing a cox regression analysis to find the best cut-off value for predicting recurrence of clinical manifestations, a mean aGAPSS > 13 had the highest HR for the event. We therefore concluded that periodic, at least annual monitoring of aPL and cardiovascular risk factors gives a more realistic picture to stratify the risk of recurrence in APS patients and predispose preventive strategies.
In the third study we tested if the mean aGAPSS over time, calculated in an identic fashion as the previous study, can be used as a predictor of damage accrual measured through DIAPS change during follow-up (calculated as the difference between the DIAPS at the end of follow-up and the basal DIAPS). aGAPSS showed a positive linear correlation with DIAPS change over time in the multivariate analysis. When comparing patients with high vs low damage accrual (setting a cut-off of 1 point of DIAPS increase during follow-up) we found that mean aGAPSS over time was higher in patients with high damage. Moreover, in the multivariate logistic regression analysis aGAPSS was a predictor of high damage accrual. Lastly, when analyzing the association between DIAPS and mortality, we found that baseline DIAPS correlated with increased odds of death during follow-up. We could therefore conclude that mean aGAPSS over time could serve as a predictor of damage accrual in APS patients.
The overall conclusions of the present thesis are therefore that:
1. aPL persistence was associated with multiple positivity and higher aPL titers at baseline and correlated with recurrence of clinical manifestations.
2. aGAPSS longitudinal monitoring, assessed as a mean or delta, compared to one-time assessment of the score, better defined the risk for recurrence of clinical manifestations. A persistently high aGAPSS and an aGAPSS increasing over time were predictors of thrombotic recurrence.
3. Mean aGAPSS over time linearly correlated with DIAPS change and was associated with high damage. Considering its dynamic nature, it can be used as a surrogate of disease activity and a predictor of damage accrual in APS patients.
4. In light of our results results, periodic monitoring of aPL and cardiovascular risk factors is highly recommended in APS patients
sj-pdf-1-lup-10.1177_09612033211070973 – Supplemental Material for Cost-effectiveness analysis of treatments for the first episode of catastrophic antiphospholipid syndrome: A study based on the catastrophic antiphospholipid syndrome registry
No full textSupplemental Material, sj-pdf-1-lup-10.1177_09612033211070973 for Cost-effectiveness analysis of treatments for the first episode of catastrophic antiphospholipid syndrome: A study based on the catastrophic antiphospholipid syndrome registry by Gerardo Quintana-López, Ignasi Rodríguez-Pintó, Kevin Maldonado-Cañón, Gerard Espinosa, Jorge Diaz-Rojas and Ricard Cervera in Lupus</p
Does seronegative antiphospholipid syndrome really exist?
No full textThe diagnosis of seronegative (SN-) antiphospholipid syndrome (APS) has been suggested for patients with clinical manifestations indicative of APS but with persistently negative results in the commonly used assays to detect anti-cardiolipin (aCL) antibodies, anti-β2 Glycoprotein I antibodies (aβ2GPI), and lupus anticoagulant (LA). To date the best management of these patients is still unclear. New emerging anti-phospholipid (aPL) assays could improve our ability in diagnosing APS. However, the availability of aPL assays in routine laboratory practice is limited. In fact, even aβ2GPI is routinely tested in only a small number of laboratories, and other aPL, such as anti-prothrombin or anti-annexin antibodies, in only a few research laboratories. On the other hand transient or false negative aPL assay and other genetic or acquired pro-thrombotic conditions can further complicate this issue. This paper is focused on the arguments for and against the diagnosis of SN-APS and is aimed to help the clinician when approaching a patient with clinical manifestations consistent with APS diagnosis but with negative aPL using the commonly available tests. © 2011 Elsevier B.V
Supplemental Material - The clinical significance of low complement levels in patients with catastrophic antiphospholipid syndrome: A descriptive analysis of 73 patients from the “Catastrophic antiphospholipid syndrome registry”
No full textSupplemental Material for The clinical significance of low complement levels in patients with catastrophic antiphospholipid syndrome: A descriptive analysis of 73 patients from the “Catastrophic antiphospholipid syndrome registry” by Ana Ponce, Ignasi Rodríguez-Pintó, José M Basauli, Gerard Espinosa, Doruk Erkan, Yehuda Shoenfeld, Ricard Cervera and On Behalf the CAPS Registry Project Group/European Forum on Antiphospholipid Antibodies in Lupus</p
Heart Valve Surgery and the Antiphospholipid Syndrome
No full textFor more than 5 decades, cardiac surgery has developed at a
fast and steady pace. Since the early days of complex and
cumbersome procedures initially developed at targeting the
correction in congenital intracardiac defects [1, 2], all types
of intra- and extracardiac procedures have been performed
worldwide on a routine basis at all institutions that meet the
minimum requirements for intrathoracic surgery according
to international standards [3]. The lack of appropriate diagnostic
tools and advanced equipment for intracardiac surgery
is a stimulus for progression. The initial era of cardiac surgery
was defined by the development of basic technology for
diagnosis and treatment and marked by the enormous progression
in clinical experience.
Currently, cardiac surgery is a fully standardized specialty
covering all aspects of congenital and acquired cardiovascular
diseases. Up-to-date technological development combined
with massive accumulation of clinical work and
knowledge on intra- and postoperative management has led
to an increase in the complexity and condition of the patients
submitted for surgical correction of cardiac defects [4].
Antiphospholipid syndome (APS), an autoimmune disorder
characterized by venous and arterial thrombosis, fetal
loss, and thrombocytopenia, in the presence of antiphospholipid
antibodies (aPL), namely lupus anticoagulant (LA),
anticardiolipin antibodies (aCL), or anti-b2 glycoprotein-I
(b2GPI) antibodies [5], is an uncommon disease bringing
difficulties in establishing an appropriate diagnosis and
effective treatment.
APS belongs to a formally unclassified group of uncommon
or infrequent diseases such as infective endocarditis
(IE). As such, a number of cases might go underdiagnosed,
and, because of the specific pathophysiology, it might also
pose a number of problems at the time of the management.
Considering the specific impact of APS on thrombosis and
hemostasis, APS is an example of a challenging disease
when cardiovascular complications develop and surgical
treatment is indicated.
APS has been called to clinicians’ attention in recent years
as patients are increasingly being diagnosed at specifically
dedicated units [6] focusing on autoimmune disorders
Heart Valve Surgery and the Antiphospholipid Syndrome
No full textFor more than 5 decades, cardiac surgery has developed at a
fast and steady pace. Since the early days of complex and
cumbersome procedures initially developed at targeting the
correction in congenital intracardiac defects [1, 2], all types
of intra- and extracardiac procedures have been performed
worldwide on a routine basis at all institutions that meet the
minimum requirements for intrathoracic surgery according
to international standards [3]. The lack of appropriate diagnostic
tools and advanced equipment for intracardiac surgery
is a stimulus for progression. The initial era of cardiac surgery
was defined by the development of basic technology for
diagnosis and treatment and marked by the enormous progression
in clinical experience.
Currently, cardiac surgery is a fully standardized specialty
covering all aspects of congenital and acquired cardiovascular
diseases. Up-to-date technological development combined
with massive accumulation of clinical work and
knowledge on intra- and postoperative management has led
to an increase in the complexity and condition of the patients
submitted for surgical correction of cardiac defects [4].
Antiphospholipid syndome (APS), an autoimmune disorder
characterized by venous and arterial thrombosis, fetal
loss, and thrombocytopenia, in the presence of antiphospholipid
antibodies (aPL), namely lupus anticoagulant (LA),
anticardiolipin antibodies (aCL), or anti-b2 glycoprotein-I
(b2GPI) antibodies [5], is an uncommon disease bringing
difficulties in establishing an appropriate diagnosis and
effective treatment.
APS belongs to a formally unclassified group of uncommon
or infrequent diseases such as infective endocarditis
(IE). As such, a number of cases might go underdiagnosed,
and, because of the specific pathophysiology, it might also
pose a number of problems at the time of the management.
Considering the specific impact of APS on thrombosis and
hemostasis, APS is an example of a challenging disease
when cardiovascular complications develop and surgical
treatment is indicated.
APS has been called to clinicians’ attention in recent years
as patients are increasingly being diagnosed at specifically
dedicated units [6] focusing on autoimmune disorders
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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