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Maximal oxygen consumption ( V̇ O 2max ) is impaired in heart (HTx), kidney (KTx), and liver (LTx) transplanted recipients and the contribution of the cardiovascular, central, and peripheral (muscular) factors in affecting V̇ O 2max improvement after endurance training (ET) has never been quantified in these patients. ET protocols involving single leg cycling (SL) elicit larger improvements of the peripheral factors affecting O 2 diffusion and utilization than the double leg (DL) cycling ET. Therefore, this study aimed to compare the effects of SL-ET vs DL-ET on V̇ O 2max . We determined the DL- V̇ O 2max and maximal cardiac output before and after 24 SL-ET vs DL-ET sessions on 33 patients (HTx = 13, KTx = 11 and LTx = 9). The DL- V̇ O 2max increased by 13.8% ± 8.7 ( p  < 0.001) following the SL-ET, due to a larger maximal O 2 systemic extraction; meanwhile, V̇ O 2max in DL-ET increased by 18.6% ± 12.7 ( p  < 0.001) because of concomitant central and peripheral adaptations. We speculate that in transplanted recipients, SL-ET is as effective as DL-ET to improve V̇ O 2max and that the impaired peripheral O 2 extraction and/or utilization play an important role in limiting V̇ O 2max in these types of patients. Novelty: SL-ET increases V̇ O 2max in transplanted recipients because of improved peripheral O 2 extraction and/or utilization. SL-ET is as successful as DL-ET to improve the cardiorespiratory fitness in transplanted recipients. The model of V̇ O 2max limitation indicates the peripheral factors as a remarkable limitation to the V̇ O 2max in these patients.

Antiphospholipid antibodies (aPL) can induce fetal loss in experimental animal models. Human studies did find hypocomplementemia associated with pregnancy complications in patients with antiphospholipid syndrome (APS), but these results are not unanimously confirmed. To investigate if the detection of low C3/C4 could be considered a risk factor for adverse pregnancy outcomes (APO) in APS and aPL carriers' pregnancies we performed a multicenter study including 503 pregnancies from 11 Italian and 1 Russian centers. Data in women with APS and asymptomatic carriers with persistently positive aPL and preconception complement levels were available for 260 pregnancies. In pregnancies with low preconception C3/C4, a significantly higher prevalence of pregnancy losses was observed ( p = 0.008). A subgroup analysis focusing on triple aPL-positive patients found that preconception low C3 and/or C4 levels were associated with an increased rate of pregnancy loss ( p = 0.05). Our findings confirm that decreased complement levels before pregnancy are associated with increased risk of APO. This has been seen only in women with triple aPL positivity, indeed single or double positivity does not show this trend. Complement levels are cheap and easy to be measured therefore they could represent a useful aid to identify patients at increased risk of pregnancy loss.

Aims: We aimed to describe how treatment of patients in cardiogenic shock bridged to heart transplantation with mechanical circulatory support, using either biventricular assist devices (BVADs) or extracorporeal life support (ECLS), has evolved in the last 20 years in our centre., Methods: Since 1998, 72 patients with refractory heart failure and indication for heart transplantation have received mechanical circulatory support: 40 had an ECLS system and 32 a BVAD., Results: Early mortality was similar (17.5 vs. 9.4%, P = 0.25) regardless of the type of support. After a median support time of 8 (1-27) vs. 34 (0-385) days (P < 0.01), 70 vs. 65.6% (P = 0.69) of patients underwent transplantation in the two groups. Prior to transplantation, BVAD patients were more stable with lower need for mechanical ventilation (9 vs. 57%, P < 0.01) and dialysis (0 vs. 38%, P < 0.01). Thirty-day mortality after transplantation was similar (18 vs. 14%, P = 0.53). Patients with extracorporeal support had higher rates of renal (P = 0.02) and respiratory failure (P = 0.03), infections (P = 0.02), atrial fibrillation (P = 0.03) and longer ICU stay (P = 0.01). Late survival was similar, while 5-year freedom from coronary vasculopathy was higher in those with BVAD (P = 0.03)., Conclusion: Although ECLS provides faster and simpler assistance compared with BVADs, no differences in early and medium-term outcomes in the last 20 years were observed in patients with cardiogenic shock. However, BVADs provided longer duration of support, better multiorgan recovery allowing more adequate graft selection, resulting in a lower rate of posttransplant complications., (Copyright © 2020 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Objectives: Patients with mechanical circulatory support bridged to a heart transplant (HTx) are at higher risk of postoperative graft dysfunction. In this subset, a mode of graft preservation that shortens graft ischaemia should be beneficial., Methods: The outcomes of 38 patients on mechanical circulatory support (extracorporeal life support, left ventricular assist device and biventricular assist device) who received a HTx between 2015 and 2020 were analysed according to the method of graft preservation: cold storage (CS) group, 24 (63%) or ex vivo perfusion (EVP) group, 14 (37%)., Results: The median age was 57 (range 30-73) vs 64 (35-75) years (P = 0.10); 88% were men (P = 0.28); extracorporeal life support was more frequent in the CS group (54% vs 36%; P = 0.27) versus left ventricular and biventricular assist devices in the EVP group (46% vs 64%; P = 0.27). Clamping time was shorter in the EVP group (P < 0.001) and ischaemic time >4 h was higher in the CS group (P = 0.01). Thirty-day mortality was 13% (0-27%) in the CS group and 0% (P = 0.28) in the EVP group. A significantly lower primary graft failure [7% (0-23%) vs 42% (20-63%); P = 0.03] was observed in the EVP group. Survival at 1 year was 79 ± 8% (63-95%) in the CS group and 84 ± 10% (64-104%) in the EVP group (P = 0.95)., Conclusions: Our results support the use of ex vivo graft perfusion in patients on mechanical circulatory support as a bridge to a HTx. This technique, by shortening graft ischaemic time, seems to improve post-HTx outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: The prognosis for patients affected by light-chain cardiac amyloidosis and acquired transthyretin-related (TTR) amyloidosis is poor. Heart transplantation (HTx) could improve prognosis also enabling autologous stem cell transplantation (ASCT) in the first group., Methods and Results: A total of 36 patients affected by systemic amyloidosis have been referred to our centre from 2009 to 2019. Of these, nine had cardiac involvement: seven by light-chain amyloidosis and two by acquired TTR amyloidosis. None died while waiting for HTx. A specific internal protocol useful to select candidates and to monitor the organ involvement after HTx was developed. Median age at diagnosis was 54 years and 66% were male. The most common short-term complication after HTx was renal failure (44%), followed by acute cardiac rejection more than 2R (22%). ASCT was performed in six out of seven light-chain cardiac amyloidosis patients, with a median time of 6 months after HTx. Two patients affected by light-chain cardiac amyloidosis died due to amyloidosis relapse: one before undergoing ASCT. After a median follow-up of 31 (7-124) months, 1- and 5-year survival was 88 and 66% in the cardiac light-chain amyloidosis group. Conversely, 1- and 5-year survival was 100% in the acquired TTR amyloidosis group., Conclusion: HTx may represent a valuable option in carefully selected patients. ASCT after HTx is an effective treatment that could decrease amyloidosis relapse in light-chain cardiac amyloidosis patients. A multidisciplinary approach is mandatory to select the best candidates and to obtain the most effective results with a specific surveillance follow-up protocol., (Copyright © 2020 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Objective: The APS ACTION Registry studies long-term outcomes in persistently antiphospholipid antibody (aPL)-positive patients. Our primary objective was to determine whether clinically meaningful aPL profiles at baseline remain stable over time. Our secondary objectives were to determine (1) whether baseline characteristics differ between patients with stable and unstable aPL profiles, and (2) predictors of unstable aPL profiles over time., Methods: A clinically meaningful aPL profile was defined as positive lupus anticoagulant (LAC) test and/or anticardiolipin (aCL)/anti-β 2 glycoprotein-I (anti-β 2 -GPI) IgG/M ≥ 40 U. Stable aPL profile was defined as a clinically meaningful aPL profile in at least two-thirds of follow-up measurements. Generalized linear mixed models with logit link were used for primary objective analysis., Results: Of 472 patients with clinically meaningful aPL profile at baseline (median follow-up 5.1 yrs), 366/472 (78%) patients had stable aPL profiles over time, 54 (11%) unstable, and 52 (11%) inconclusive. Time did not significantly affect odds of maintaining a clinically meaningful aPL profile at follow-up in univariate ( P = 0.906) and multivariable analysis ( P = 0.790). Baseline triple aPL positivity decreased (OR 0.25, 95% CI 0.10-0.64, P = 0.004) and isolated LAC test positivity increased (OR 3.3, 95% CI 1.53-7.13, P = 0.002) the odds of an unstable aPL profile over time., Conclusion: Approximately 80% of our international cohort patients with clinically meaningful aPL profiles at baseline remain stable at a median follow-up of 5 years; triple aPL-positivity increase the odds of a stable aPL profile. These results will guide future validation studies of stored blood samples through APS ACTION Core Laboratories., (Copyright © 2021 by the Journal of Rheumatology.)

The management of reproductive issues in women with inflammatory arthritis has greatly changed over decades. In the 1980-1990s, women with refractory forms of arthritis were either not able to get pregnant or did choose not to get pregnant because of their disabling disease. Hence, the traditional belief that pregnancy can induce a remission of arthritis. The availability of biologic agents has allowed a good control of aggressive forms of arthritis. The main topic of discussion during preconception counselling is the use of drugs during pregnancy and breastfeeding. Physicians are now supported by international recommendations released by the European League Against Rheumatism and the American College of Rheumatology, but still they must face with cultural reluctance in accepting that a pregnant woman can take medications. Patient-physician communication should be centered on the message that active maternal disease during pregnancy is detrimental to fetal health. Keeping maternal disease under control with drugs which are not harmful to the fetus is the best way to ensure the best possible outcome for both the mother and the baby. However, there might be concerns about the influence of the in utero exposure to medications on the newborn's health conditions. Particularly, studies suggesting an increased risk of autism-spectrum-disorders in children born to women with rheumatoid arthritis has raised questions about neuropsychological impairment in the offspring of women with chronic arthritis. As a multidisciplinary group of rheumatologists and child neuropsychiatrists, we conducted a study on 16 women with chronic forms of arthritis whose diagnosis was determined before pregnancy and their 18 school-age children. The children underwent a complete neurological examination and validated tests/questionnaires. Behavioral aspects of somatization and anxiety/depression (internalizing problem) or an "adult profile" were found in nearly one third of children. Children at a high risk of neurodevelopmental problems were born to mothers with a longer history of arthritis and were breastfeed for less than 6 months of age or were not breastfeed at all. No association was found with other maternal characteristics such as autoantibody existence and disease activity during and after the pregnancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co. authorship with several of the authors CN, LA, FF, AT, SP, and MGL., (Copyright © 2021 Nalli, Galli, Lini, Merlini, Piantoni, Lazzaroni, Bitsadze, Khizroeva, Zatti, Andreoli, Fazzi, Franceschini, Makatsariya, Shoenfeld and Tincani.)

Problem: Antibody-mediated autoimmune diseases, such as autoimmune thyroid diseases (ATD), systemic lupus erythematosus (SLE), and antiphospholipid syndrome (APS), often are associated with recurrent fetal loss. One of the ATD is Hashimoto's thyroiditis which recently showed association with complications of pregnancy with increased levels of circulating autoantibodies reactive with epitopes on thyroid tissue such as thyroid peroxidase (anti-TPO). In retrospective study of sera analyses in patients with Hashimoto's thyroiditis, all patients had mainly elevated circulating anti-TPO autoantibodies., Aim: We assessed the potential of human anti-TPO highly positive IgG, derived from patients with Hashimoto's thyroiditis sera associated with complications of pregnancy, to cause directly complications of pregnancy in murine model., Method of Study: Naïve ICR female mice, infused intravenously with 100 μg of anti-TPO-positive IgG, showed increased fetal loss and embryo small for date (P < .001) in comparison with mice passively transferred with commercial IgG or PBS. Moreover, we observed embryos small for date in the mice passively transferred with anti-TPO-positive IgG, exemplified by reduced weight of embryos and placentae (P = .001). Histopathological examination revealed delay in fetal development in 50% cases of anti-TPO-positive IgG-treated mice. Importantly, pathological changes in the transition zone, state of glycogen cells, and significant structural changes in the labyrinth part of placenta were observed in all anti-TPO-positive IgG samples., Conclusion: The current study shows in the first time, a direct proof of concept, on the association of human TPO-positive IgG from Hashimoto's thyroiditis patients on fetal loss induction in murine model., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

To study disease activity during pregnancy and obstetric outcomes in patients with juvenile idiopathic arthritis (JIA) upon different subsets and with focus on medication use. Retrospective observational study of 22 pregnancies in 16 JIA patients (95.5% Caucasian) who were followed between 2010 and 2018. Disease activity, flares and medications were recorded before conception, during each trimester and postpartum period. Pregnancies occurred in 10 (45.5%) oligoarticular extended (OLA-E), 6 (27.3%) in polyarticular (PLA), 4 in (18.2%) systemic (SYS), 1 (4.5%) in oligoarticular persistent (OLA-P) and 1 (4.5%) in enthesitis-related arthritis (ERA) JIA patients. The median age at disease diagnosis and at conception was 5.5 and 28 years (respectively). The median disease duration was 20 years. Nineteen (95%) pregnancies started in a period of stable disease remission. Among the 22 pregnancies, 20 ended with a live birth (90.9%). No spontaneous miscarriages occurred; two voluntary interruption of pregnancy were performed. There were 7 flares in 6/20 pregnancies (35%) and 8 flares (8/22, 36.4%) occurred in postpartum period, all of them in OLA-E and PLA patients. Seven patients (35%) were taking biological disease-modifying anti-rheumatic drugs (bDMARDs) at conception, and 6 of them stopped this treatment at positive pregnancy test. Five patients resumed bDMARDs either during pregnancy (3 exposed during the third trimester) or puerperium due to a flare. Four preterm deliveries (20%) were recorded, all in patients who had a flare during pregnancy. The preconception counselling should include the evaluation of disease subset, as OLA-E and PLA may flare more than other subsets, especially if bDMARDs are discontinued at positive pregnancy test. Continuation of bDMARDs during pregnancy should be considered to minimize the risk of adverse pregnancy outcomes, particularly preterm delivery. Key Points • In our cohort, all the flares during pregnancy and 75% of postpartum flares were observed in patients who withdrew bDMARDs and cDMARDs at the beginning of pregnancy. • Flares were observed only in PLA and OLA-E patients. • Preterm delivery occurred in 20% of the pregnancies; all of these patients had a disease flare during pregnancy.

Objective: The long-term outcome of children born to SLE mothers still represents a controversial topic in literature, with some studies reporting a possible increased prevalence of different neurologic and psychiatric diseases (NPD), including neurodevelopmental disorders (ND), and in particular learning disorders (LD). Different risk factors have been advocated, such as the in utero exposure to auto-antibodies and drugs, particularly Azathioprine (AZA). Methods: A case-control study was designed to compare pregnancies treated with AZA (cases) with those not treated with AZA (controls). All the pregnancies had been prospectively followed in two Italian centers. The match was based upon renal involvement, antiphospholipid (aPL) status, maternal age at pregnancy (±5 years) and child's age at the time of the study (±2 years). SLE mothers were interviewed by a telephone survey, particularly focused on the presence of a certified NPD in their children ≥6 years of age. Results: Twenty-seven cases and 65 controls were similar in terms of demographic, immunological and clinical features, except for a higher rate of SLE flares during pregnancy in cases (22.2% vs. 10.8%, p :0.191). The 92 children had a mean age of 14.0 years at the time of the survey; 11 had at least one NPD (12.0%). The frequency of each single NPD was similar to that of the general pediatric population and no association was found with either the in utero exposure to AZA, or other specific factors (auto-antibodies, disease activity, obstetric complications, prematurity). Conclusion: The long-term neuropsychiatric outcome of the children born to SLE mothers did not show neither an increased frequency of NPD as compared to the general pediatric population nor a specific pattern of NPD. The in utero exposure to AZA was not associated with the development of NPD in this case-control study of prospectively-followed pregnancies. NPD are complex conditions and large prospective studies are needed to capture the wide range of variables that may contribute to their development in the offspring of SLE women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with several of the authors LA and AT., (Copyright © 2020 Lazzaroni, Andreoli, Crisafulli, Tamborini, Debeni, Binda, Nalli, Galli, Fazzi, Moroni, Franceschini and Tincani.)

Background: Antiphospholipid antibody syndrome (APS) is an autoimmune disease that affects women in childbearing age. In recent years, great improvements were achieved in the management of pregnancies in these women. Prematurity could be an issue in these pregnancies, mainly due to the direct pathogenic effect of antiphospholipid antibodies (aPL) on the placental surface. Maternal IgG aPL can cross the placenta and theoretically interact with the growing fetus; it could reach the fetal brain because of the incompleteness of the fetal blood-brain barrier: whether this can have an effect on brain development is still debated. Neonatal thrombosis episodes have been described in children positive for aPL, not always associated with maternal antibody positivity, suggesting the hypothesis of a possible aPL de novo synthesis in fetus and neonates., Methods: A keyword-based literature search was conducted. We also described a case of neonatal catastrophic antiphospholipid syndrome (CAPS)., Results: Offspring of patients with APS are generally healthy but the occurrence of neonatal thrombosis or minor neurological disorders were reported., Conclusions: The limited number of the available data on this sensitive issue supports the need for further studies. Clinical follow-up of children of mothers with APS seems to be important to exclude, in the neonatal period, the occurrence of aPL associated pathological events such as thrombosis, and in the long-term, impairment in learning skills or behavioral problems.

To evaluate the impact of donor-recipient age matching on clinical outcomes after heart transplantation, a total of 509 patients (January 1990-December 2018, mean follow-up 111 ± 80 months) were stratified into 4 groups (young-R/young-D, young-R/old-D, old-R/young-D, old-R/old-D) according to the recipient (young-R < 60, old-R ≥ 60 years) and the donor (young-D < 50, old-D ≥ 50 years) age. No difference was found among 30-day mortality (P = .11) and postoperative complications between groups. Both unadjusted and adjusted survival was significantly higher for group young-R/young-D than that of other groups, in which survival was similar [adjusted HR for mortality of 2.0(1.2-3.4), 2.1(1.4-3.8) and 2.5(1.6-4.1) for groups old-R/young-D, young-R/old-D, old-R/old-D, respectively]. Compared to other groups, the incidence of grade ≥ 2 CAV was significantly lower in old-R/young-D group [adjusted HR 0.4(0.2-0.7)]. Among young recipients, the rate of acute grade ≥ 2 rejection episodes was higher in those receiving an old donor graft (P = .04). Old recipient groups were more affected by neoplasms and severe renal failure than young recipient groups (P < .01). Employment of hearts from donors ≥50 years of age adversely affects survival in recipients <60 years of age but does not influence outcomes in older recipients. Also, donor and recipient ages seem to have opposite effects on incidence of rejections and CAV of high grade., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: This study aimed to use cluster analysis (CA) to identify different clinical phenotypes among antiphospholipid antibodies (aPL)-positive patients., Methods: The Alliance for Clinical Trials and International Networking (APS ACTION) Registry includes persistently positive aPL of any isotype based on the Sydney antiphospholipid syndrome (APS) classification criteria. We performed CA on the baseline characteristics collected retrospectively at the time of the registry entry of the first 500 patients included in the registry. A total of 30 clinical data points were included in the primary CA to cover the broad spectrum of aPL-positive patients., Results: A total of 497 patients from international centres were analysed, resulting in three main exclusive clusters: (a) female patients with no other autoimmune diseases but with venous thromboembolism (VTE) and triple-aPL positivity; (b) female patients with systemic lupus erythematosus, VTE, aPL nephropathy, thrombocytopaenia, haemolytic anaemia and a positive lupus anticoagulant test; and (c) older men with arterial thrombosis, heart valve disease, livedo, skin ulcers, neurological manifestations and cardiovascular disease (CVD) risk factors., Conclusions: Based on our hierarchical cluster analysis, we identified different clinical phenotypes of aPL-positive patients discriminated by aPL profile, lupus or CVD risk factors. Our results, while supporting the heterogeneity of aPL-positive patients, also provide a foundation to understand disease mechanisms, create new approaches for APS classification and ultimately develop new management approaches.

Autoimmune diseases often affect young women and this may represent a problem in family planning. Pregnancies in these patients may carry several complications but nowadays the continued amelioration in treatment and management has greatly improved the pregnancy outcome. The main concern of these women obviously is the short- and long-term outcome of their children. A child born from a woman with autoimmune disease is potentially exposed in utero to maternal autoantibodies, cytokines, and drugs, and each item could impair his or her development. In addition, the maternal genetic heritage can favor autoimmunity. All these items could have a role, for example, in the development of autoimmune diseases (the same as the mother or different ones) or neurological disorders. Data in literature are controversial. This review will gather the available data possibly providing a useful tool for counseling future mothers., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest., (Copyright © 2019. Published by Elsevier Ltd.)

Infertility consists by definition in" failure to achieve a clinical pregnancy after 12 months or more of regular unprotected intercourse" while the term subfertility means a delay to achieve pregnancy. Several factors can contribute to infertility or subfertility in patients with systemic autoimmune diseases. The association of systemic autoimmune conditions with endometriosis, celiac disease and thyroid autoimmunity that are well known causes of infertility and/or subfertility need to be taken in consideration when difficulties in the onset of pregnancy is reported. The majority of the used antirheumatic drugs do not interfere with fertility. However, the use of cyclophosphamide, limited to severe disease, can provoke premature ovarian failure; to preserve fertility a preventive treatment is available. Nonsteroidal anti-inflammatory drugs can cause temporary infertility and corticosteroids are associated to a prolonged time to pregnancy in some rheumatic diseases. Data on the association of antiphospholipid antibodies (aPL) with infertility are still debated but in general an increased rate of aPL is described patients undergoing medically assisted reproductive techniques. In systemic lupus erythematosus aPL and other autoantibodies (i.e. anti-oocytes) can contribute to the infertility of some patients. Subfertility, rather than infertility, is observed in patients with rheumatoid arthritis; the particular physical conditions of these women can also account for this. Physicians should not forget the patients' age, that is mandatory in order to preserve their chance to have children., (Copyright © 2019. Published by Elsevier Ltd.)

Pregnancy in autoimmune diseases remains an argument of debate. In last years great improvements were done and with the correct medical support women with disease such as Systemic Lupus Erythematosus or Antiphospholipid Syndrome can afford a pregnancy and have healthy babies. The starting point is a good counselling. Women should be informed about risks that can occur taking some medications while pregnant and, on the other hand, that there are medications that can be safety assumed during pregnancy. Furthermore, there are known maternal risks factor such as the presence of antiphospholipid antibodies or anti-Ro/SSA antibodies that must be carefully manage by both rheumatologists and obstetrics. In addition, also disease activity during pregnancy can represent an issue. For all these reason, a multidisciplinary approach is mandatory in order to give our patients an optimal medical support, before, during and after pregnancy., (Copyright © 2019. Published by Elsevier Ltd.)

Objective: The reproductive choices of women affected by rheumatic diseases (RD) can be influenced by several factors, including the quality of physician-patient communication. We conducted a survey on reproductive issues aiming at exploring the unmet needs of women with RD during childbearing age., Methods: We administered 65 multiple-choice and 12 open-answer questions about pregnancy counselling, contraception, use of drugs during pregnancy and other women reproductive issues to 477 consecutive women with RD aged 18-55 years followed-up in 24 rheumatology centres in Italy. Analysis was restricted to 398 patients who received their diagnosis of RD before the age of 45. According to the RD diagnosis, patients were subdivided into 2 groups: connective tissue diseases (n = 249) and chronic arthritis (n = 149)., Results: At the time of interview, women in both groups had a mean age of 40 years. Nearly one third of patients in each group declared not to have received any counselling about either pregnancy desire nor contraception. A smaller family size than desired was reported by nearly 37% of patients, because of concerns related to maternal disease in one fourth of the cases. A "Disease Knowledge Index" (DKI) was created to investigate the degree of patients' information about the implications of their RD on reproductive issues. Having received counselling was associated with higher DKI values and with a positive impact on family planning., Conclusion: Italian women of childbearing age affected by RD reported several unmet needs in their knowledge about reproductive issues. Strategies are needed to implement and facilitate physician-patient communication., (Copyright © 2018. Published by Elsevier Masson SAS.)

Background: The APS ACTION International Clinical Database and Repository includes a secure web-based data capture system storing patient information including demographics, antiphospholipid antibodies (aPL)-related medical history, and aPL tests. Despite efforts at harmonization, inter-assay variability remains a problem in aPL testing. As a clinical repository open to researchers, ensuring comparability between assays and consistency in results between APS ACTION laboratories is essential to the validity of studies emerging from this network., Objective: To assess the level of agreement between an aPL-registry inclusion and core laboratory (core lab) anticardiolipin antibody (aCL) and anti-β 2 -glycoprotein-I antibody (aβ 2 GPI) ELISA testing results., Methods: Patients are recruited from 25 international centers based on positive aPL tests at inclusion. All samples are retested at the corresponding national APS ACTION core lab to confirm aPL positivity based on standard validated protocols. We analysed the categorical agreement, degree of linear association, and correlation between inclusion (local laboratory) and core lab aPL tests. Samples were included in this study only if results of aPL testing with ELISA at baseline were available., Results: 497 registry samples underwent confirmatory aPL tests. Categorical agreement between the inclusion and core lab values, as expressed by Cohen's kappa coefficients, ranged between 0.61 and 0.80 (as substantial agreement). The correlation between quantitative results in the aCL and aβ 2 GPI was better for IgM and IgA compared to IgG (Spearman rho 0.789 and 0.666 vs. 0.600 for aCL and rho 0.892 and 0.744 vs. 0.432 for aβ 2 GPI)., Conclusions: The results of inclusion for aCL and aβ 2 GPI tests used for recruitment into the registry were in agreement to the results obtained by the APS ACTION core laboratories; aCL and aβ 2 GPI results showed very good categorical agreement. This agreement increased when considering high titer (>40 units) samples. APS ACTION is a reliable and useful research resource for APS., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Red blood cell distribution width (RDW) has been emerging as a strong predictor of mortality among patients with cardiovascular disease. The aim of this study was to verify if RDW is able to predict survival after heart transplantation (HTx)., Methods: Two hundred and eighteen recipients who underwent HTx between 2000 and 2013 were classified into three groups according to the pre-HTx RDW tertile values (14.6 and 16.4%), and their outcomes were compared. Mean follow-up was 6.6 ± 4.2 years., Results: RDW correlated with other markers of chronic pathological conditions, such as the Index for Mortality Prediction after Cardiac Transplantation (IMPACT) score (P = 0.002) and Charlson Comorbidity Index (P < 0.001), and with creatinine levels (P = 0.007), previous cardiac surgery (P < 0.001), diabetes mellitus (P = 0.02), haemoglobin value (P = 0.004), pulmonary capillary wedge and central venous pressures (P = 0.019 and 0.01, respectively), systolic and mean pulmonary artery pressures (P = 0.002 and 0.014, respectively). The rate of 30-day mortality from the lowest to the highest RDW tertile was 1.4, 4 and 9% (P = 0.02), respectively.Long-term mortality correlated at multivariate analysis with recipient age [hazard ratio 1.06, 95% confidence interval (95% CI) 1.02-1.09], donor age (hazard ratio 1.02, 95% CI 1.0-1.04) and RDW (hazard ratio 1.13, 95% CI 1.04-1.23). The survival probability at 4, 8 and 12 years was 90, 84 and 74% for recipients with RDW less than 14.6%, while it was 72, 60 and 42% for recipients with RDW more than 16.4% (hazard ratio 3.29, 95% CI 1.74-6.24). No differences were found between causes of death., Conclusion: RDW correlated with survival in HTx recipients. This marker of blood cell size may represent a surrogate of disease and a helpful tool in the risk-assessment process.

Antiphospholipid syndrome (APS) is a rare disease characterised by venous and/or arterial thrombosis, pregnancy complications and the presence of specific autoantibodies called antiphospholipid antibodies. This review aims to identify existing clinical practice guidelines (CPG) as part of the ERN ReCONNET project, aimed at evaluating existing CPGs or recommendations in rare and complex diseases. Seventeen papers providing important data were identified; however, the literature search highlighted the scarceness of reliable clinical data to develop CPGs. With no formal clinical guidelines in place, diagnosis and treatment of APS is largely based on consensus and expert opinion. Patients' unmet need refers to the understanding of the disease and its clinical picture and implications, the need of education for patients, family members and healthcare providers, as well as to the development of monitoring pathways involving multiple healthcare providers., Competing Interests: Competing interests: None declared.

Antibodies against β2 glycoprotein I (anti-β2GPI) have been identified as the main pathogenic autoantibody subset in anti-phospholipid syndrome (APS); the most relevant epitope is a cryptic and conformation-dependent structure on β2GPI domain (D) 1. Anti-β2GPI domain profiling has been investigated in thrombotic APS, leading to the identification of antibodies targeting D1 as the main subpopulation. In contrast, scarce attention has been paid to obstetric APS, hence this study aimed at characterizing the domain reactivity with regards to pregnancy morbidity (PM). To this end, 135 women with persistently positive, medium/high titre anti-β2GPI IgG, without any associated systemic autoimmune diseases and at least one previous pregnancy were included: 27 asymptomatic carriers; 53 women with obstetric APS; 20 women with thrombotic APS; and 35 women with both thrombotic and obstetric complications. Anti-D1 and anti-D4/5 antibodies were tested using a chemiluminescent immunoassay and a research ELISA assay, respectively (QUANTA Flash ® β2GPI Domain 1 IgG and QUANTA Lite ® β2GPI D4/5 IgG, Inova Diagnostics). Positivity for anti-D1 antibodies, but not anti-D4/5 antibodies, was differently distributed across the 4 subgroups of patients (p < 0.0001) and significantly correlated with thrombosis (χ2 = 17.28, p < 0.0001) and PM (χ2 = 4.28, p = 0.039). Patients with triple positivity for anti-phospholipid antibodies displayed higher anti-D1 titres and lower anti-D4/5 titres compared to women with one or two positive tests (p < 0.0001 and p = 0.005, respectively). Reactivity against D1 was identified as a predictor for PM (OR 2.4, 95% confidence interval [CI] 1.2-5.0, p = 0.017); in particular, anti-D1 antibodies were predictive of late PM, conveying an odds ratio of 7.3 (95% CI 2.1-25.5, p = 0.022). Positivity for anti-D1 antibodies was not associated with early pregnancy loss. Anti-D4/5 antibodies were not associated with clinical APS manifestations. As a whole, our data suggest that anti-D1 antibodies are significantly associated not only with thrombosis, but also with late PM, while positive anti-D4/5 antibodies are not predictive of thrombosis or PM., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Anti-phospholipid antibodies (aPL) analyzed by line immunoassay (LIA) can recognize beta 2 -glycoprotein I (β 2 GPI) domain 1 (D1) epitopes depending on β 2 GPI binding to distinct phospholipids. The aPL LIA was compared with consensus ELISA to investigate whether both techniques can discriminate anti-phospholipid syndrome (APS) patients from aPL-positive, systemic autoimmune rheumatic diseases (SARD) patients without clinical symptoms of APS and controls., Methods: Thirty-four APS patients (14 arterial/venous thrombosis, 16 pregnancy morbidity, and 4 both), 41 patients with SARD lacking clinical APS criteria but demonstrating positivity for anti-β 2 GPI (aβ 2 GPI) IgG, and 20 healthy subjects (HS) were tested for aPL to cardiolipin (aCL), phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol (aPG), phosphatidylinositol, phosphatidylserine, β 2 GPI, prothrombin, and annexin V by LIA. Samples were also tested for aCL, aβ 2 GPI, aβ 2 GPI-domain 1 (aD1), and aβ 2 GPI-domains 4-5 (aD4-5) by ELISA and for lupus anti-coagulant., Results: Comparison of LIA with ELISA revealed a good agreement for the consensus criteria aPL aβ 2 GPI and aCL IgG (kappa = 0.69, 0.68, respectively) and a moderate agreement for IgM (kappa = 0.52, 0.49, respectively). Regarding ELISA, aD1/aD4-5 demonstrated the best performance of differentiating APS from asymptomatic SARD [area under the curve (AUC): 0.76]. aPG IgG had the best performance by LIA (AUC: 0.72) not significantly different from aD1/aD4-5. There was a good agreement for aPG IgG with aD1/aD4-5 (kappa = 0.71)., Conclusions: aD1/aD4-5 (ELISA) and aPG IgG (LIA) differentiate APS from SARD patients. PG appears to interact with β 2 GPI of APS patients and exposes D1 thereof for disease-specific aPL binding in LIA.

Nowadays, most of the young women affected by Systemic Lupus Erythematosus (SLE) can carry out one or more pregnancies thanks to the improvement in treatment and the consequent reduction in morbidity and mortality. Pregnancy outcome in these women has also greatly improved in the last decades. A correct timing for pregnancy (tailored on disease activity and established during a preconception counselling), together with a tight monitoring during the three trimesters and the post-partum period (to timely identify and treat possible obstetric complications or maternal disease flares), as well as the concept of multidisciplinary management, are currently milestones of the management of pregnancy in SLE patients. Nevertheless, the increasing knowledge on the compatibility of drugs with pregnancy has allowed a better treatment of these patients, by choosing medications that control maternal disease activity without harming the foetus. However, particular attention and strict monitoring should be dedicated to SLE pregnant women in particular clinical settings: patients with lupus nephritis and patients with aPL positivity or Antiphospholipid syndrome, who are at higher risk for maternal and foetal complications, but also patients with anti-Ro/SSA and/or anti-La/SSB antibodies, because of the risk of neonatal lupus. A discussion on family planning, as well as counselling on contraception, should be part of the everyday-practice for physicians caring for SLE women during their reproductive age. Another issue is the possible reduction of fertility in these women, that can be due to different reasons. Consequently, the request for assisted reproduction techniques has been increasing in the last years, so that rheumatologists and gynaecologists should be prepared to counsel SLE patients also in this particular setting., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: Improvement of clinical results in heart transplantation (HTx) has favoured the expansion of indication criteria towards aged population. The impact of increasing recipient age is controversial and, owing to donor shortage, the debate still remains whether HTx is justified for older patients. We analysed age as a prognostic factor at long-term after HTx and if it should be a determinant in organ allocation., Methods: Data of 364 consecutive patients who underwent cardiac transplantation between 1999 and 2014 at the University Hospital of Udine were analysed. Patients were divided into three groups according to age (Group 1: 18-40, Group 2: 41-59, Group 3: ≥ 60 years) and survival and major complications were evaluated at long-term (mean follow-up 6.7 ± 4.5 years, range 1-15.7 years)., Results: Preoperatively, renal failure (2.9, 16.1, 39.5%, P < 0.01) and cardiovascular factors such as diabetes (1.2, 17.1, 36.4%, P < 0.01), systemic hypertension (5.9, 31.5, 40.8%, P < 0.01) and dyslipidaemia (5.9, 40.3, 42.9%, P < 0.01) were more common in older patients (Group 3), as well as ischaemic cardiopathy (0, 42.6, 49.7%, P < 0.01). Donor age was lower in younger recipients (Group 1) (33 ± 15, 39 ± 14, 45 ± 14 years, P < 0.01). Older patients showed a worse long-term survival (hazard ratio 1.7; 1.1-2.5), also after adjusting for major cardiovascular risk factors, renal failure and donor age. In fact, 15-year survival was 100% in Group 1, while at 1, 5, 10 and 15 years survival was 88, 78, 69 and 56% in Group 2, and 87, 68, 49 and 43% in Group 3, respectively. Even major long-term complications were less frequent in younger patients in terms of neoplasms (P < 0.01), rehospitalizations (P < 0.01) and a tendency to higher freedom from other complications such as cytomegalovirus infections, renal failure and dialysis., Conclusions: Our results showed a significantly different outcome according to recipient age, even when adjusted for major risk factors. Notably, patients younger than 40 years showed 100% long-term survival, and apparent lower rate of complications due to immunosuppression. Since 15-year survival in patients ≤40 years is twice that of patients ≥60 years, recipient age should be taken into account in organ allocation., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: The treatment of complicated aortic endocarditis with periannular abscesses and root disarrangement is a surgical challenge, and includes left ventricular outflow tract (LVOT) reconstruction with the patch technique or homograft implantation. The results of a simplified technique to reconstruct the LVOT in destructive endocarditis of either the aortic native valve or valve prosthesis with the Sorin Pericarbon Freedom stentless valve are reported., Methods: Since August 2007, 40 patients with destructive endocarditis (mean age: 69 ± 12, 75% males, European System for Cardiac Operative Risk Evaluation II (EuroSCORE II): 19 ± 13, New York Heart Association (NYHA) class: ≥3 in all cases) have undergone LVOT reconstruction with a Sorin Pericarbon Freedom stentless bioprosthesis. Seven patients (17.5%) were in septic or cardiogenic shock preoperatively, and 18 patients (45%) suffered from moderate or severe aortic regurgitation. Eleven patients (27.5%) experienced preoperative systemic embolizations. Thirty-six cases (90%) were valve redos and 9 patients (22.5%) had concomitant procedures. The mean follow-up was 26 ± 25 months., Results: One patient (2.5%) died early (<30 days) and another 3 patients never discharged died due to multiorgan failure and septic shock. Actuarial survival rate was 85 ± 6% at 1 year, and 76 ± 8% at 3 and 5 years, respectively. Twelve patients (30%) required pacemaker implantation because of atrioventricular block and 20 patients (50%) developed or showed a progression of renal failure. One patient (2.5%) had an endocarditis relapse, and 1 (2.5%) showed a mild paraprosthetic aortic leak. No patient needed reoperation. At the last echocardiographic evaluation, mean gradient, peak gradient and left ventricular ejection fraction were 7.9 ± 5.0 mmHg, 15.1 ± 7.2 mmHg and 63.3 ± 9.3%, respectively., Conclusions: The Sorin Pericarbon Freedom stentless prosthesis, with the modified technique herein described, seems to be a good option in most of cases of destructive aortic valve endocarditis. It is promptly available in different sizes, easy to implant and, due to its pericardial inflow skirt, ideal for extensive reconstruction of the LVOT with good haemodynamic performance and low risk of relapse., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Since patient compliance following organ transplantation is considered a limiting factor for long-term outcome, psychosocial assessment is commonly employed to evaluate suitability for organ transplantation. We analysed the impact of psychosocial characteristics on long-term outcome after heart transplantation in our institution., Methods: The outcomes of 345 patients (82% male, mean age: 56 ± 11 years) who had undergone a heart transplant since 1999 were evaluated taking into consideration major clinical and psychosocial findings. The impact on survival of the psychological habitus, substance abuse, economic status, education level, presence of caregivers and distance from the hospital (Area 1: <100 km, Area 2: ≥100 and <500 km, Area 3: ≥500 km) were considered in an univariate and multivariate analysis., Results: Univariate analysis showed that only retired patients had an increased risk of mortality. In fact, survival at 1, 5 and 10 years in unemployed versus retired versus employed people was 94 ± 3% vs 91 ± 2% vs 88 ± 3%; 86 ± 5% vs 75 ± 3% vs 80 ± 5%; 72 ± 8% vs 57 ± 5% vs 76 ± 5%, respectively (P = 0.05). Unemployed and employed patients were younger than retired patients. In multivariate analysis, after correction of clinical data, no psychosocial characteristics were found to be risk factors for long-term mortality: psychological problems [hazard ratio (HR) = 0.87; 0.56-1.33]; smoking (HR = 0.96; 0.61-1.54); alcohol abuse (HR = 1.62; 0.73-3.61); absence of caregivers (HR = 0.9; 0.44-1.83); critical economical condition (HR = 1.12; 0.65-1.93); lower school degree (HR = 0.95; 0.60-1.51); unemployment (HR = 1.00; 0.58-1.73) and distance from hospital (HR = 1.12; 0.76-1.98). At the same time, no psychosocial factors were identified as risk factors for coronary allograft vasculopathy, acute rejection and infection., Conclusions: The psychosocial factors analysed in our study seem to have no impact on patient outcome, and should not preclude candidates from listing for heart transplantation; on the other hand psychosocial assessment should be utilized to identify patients requiring more specific surveillance to obtain the best outcome., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

The impact of rheumatic disease on fertility and reproduction can be remarkable. Many disease-related factors can influence patients' sexual functioning, perturb fertility and limit family planning. Antirheumatic pharmacological treatment can also have a crucial role in this field. Proper counselling, preferably provided by a multidisciplinary team of rheumatologists, obstetricians, gynaecologists and neonatologists, is recommended for patients taking antirheumatic drugs, not only at the beginning, but also during the course of treatment. Paternal exposure to antirheumatic drugs was not found to be specifically associated with congenital malformation and adverse pregnancy outcome, therefore discontinuation of these drugs while planning for conception should be weighed against the risk of disease flare. Drugs in Food and Drug Administration (FDA) category 'X' should be withdrawn in a timely manner in women who desire a pregnancy. Meanwhile, disease control can be achieved with anti-tumour necrosis factor (TNF)-α agents, which are not teratogenic drugs. If maternal disease control is permissive, they can be stopped as soon as the pregnancy test turns positive and be resumed during pregnancy in case of a flare.

Objectives: To evaluate the efficacy and safety of rituximab (RTX) in patients with systemic lupus erythematosus (SLE) refractory to standard therapy in the clinical practice setting., Methods: 145 SLE patients (ACR criteria) were treated with RTX in 11 Italian Centres: 118 with two infusions (1 g), two weeks apart; 27 with 4 infusions (375 mg/m2), one week apart, followed in 10 cases by two further doses, after 1 and 2 months. Systemic complete response (CR) was defined as European Consensus Lupus Activity Measurement (ECLAM) score ≤1 and partial response (PR) as 1< ECLAM ≤3. Renal CR (RCR) and renal PR (RPR) were defined according to EULAR recommendations for management of lupus nephritis., Results: Data from 134 (92.4%) patients were available. The mean±SD follow-up was 27.3±18.5 months. After the first course of RTX, CR or PR were observed in 85.8% and CR in 45.5% of cases; RCR or RPR in 94.1% and RCR in 30.9% of patients after 12-month follow-up. Disease flares occurred in 35.1% and renal flares in 31.2% of patients during observational period. Among patients retreated, CR or PR were observed in 84.4% and CR in 57.8% of cases. Adverse events, infections, and infusion reactions occurred after first RTX course in 23.8%, 16.4%, and 3.8% of patients and after retreatment in 33.3%, 22.2% and 11.1%, respectively. No severe infusion reactions or deaths occurred., Conclusions: Data from Italian multicentre RTX Registry confirmed the efficacy and safety of RTX in SLE patients refractory to standard treatment in clinical practice setting.

Objective: It has been suggested that only antibodies against domain 1 (D1) of β2 -glycoprotein I (β2 GPI) are pathogenic and diagnostic. The role of antibodies against other β2 GPI domains is still debated. This study was undertaken to evaluate the clinical relevance of domain specificity profiling of anti-β2 GPI IgG antibodies in antiphospholipid syndrome (APS) patients and in control groups of patients with systemic autoimmune rheumatic diseases and in asymptomatic antiphospholipid antibody (aPL) carriers., Methods: We evaluated 159 subjects with persistently positive, medium or high-titer anti-β2 GPI IgG, including 56 patients with thrombotic (obstetric or nonobstetric) primary APS, 31 women with obstetric primary APS, 42 aPL-positive patients with systemic autoimmune rheumatic diseases, and 30 asymptomatic aPL carriers. One hundred healthy donors were included. Anti-β2 GPI D1 and D4/5 IgG were tested on research enzyme-linked immunosorbent assays containing recombinant β2 GPI domains., Results: As compared to other groups, aPL carriers displayed higher frequency/titer of anti-D4/5 IgG. Unlike anti-D4/5, anti-D1 IgG antibodies were more frequent and at higher titer in triple than in single or double aPL-positive subjects. An anti-D1 to anti-D4/5 ratio of ≥1.5 was predictive of systemic autoimmunity (odds ratio 3.25 [95% confidence interval 1.45-7.49], P = 0.005). Neither anti-D1 nor anti-D4/5 antibodies were associated with APS clinical criteria., Conclusion: Anti-D1 IgG is the preferential specificity not only in vascular and obstetric primary APS, but also in patients with systemic autoimmune rheumatic disease with no clinical features of APS. Conversely, aPL carriers do not have a polarized profile toward D1. Combined testing for anti-β2 GPI IgG with different domain specificity allows a more accurate aPL profiling, with polarization toward anti-D1 IgG as a possible fingerprint of systemic autoimmunity., (© 2015, American College of Rheumatology.)

Aim: To analyse the clinical features, laboratory data, foetal-maternal outcomes, and follow-up in a cohort of 247 women with obstetric antiphospholipid syndrome (OAPS)., Methods: The European Registry on APS became a Registry within the framework of the European Forum on Antiphospholipid Antibody projects and placed on a website in June 2010. Cases with obstetric complaints related to aPL who tested positive for aPL prospectively and retrospectively were included. The three-year survey results are reported., Results: 338 women with 1253 pregnancy episodes were included; 915 were historical and 338 were latest episodes. All these women tested positive for aPL. 247 of the 338 fulfilled the Sydney criteria. According to the laboratory categories, 84/247 were in category I, 42 in IIa, 66 in IIb and 55 in IIc. Obstetric complications other than foetal losses, appeared in 129 cases (52.2%). 192 (77.7%) had a live birth and 55 (22.3%) did not. The latter group of only 38 cases (69%) received adequate treatment and 17 (31%) did not. 177/247 (72%) women were put on heparin plus LDA. Thrombosis appeared in two during pregnancy and in 14 during the puerperium. 7 (3%) women evolved to complete SLE., Conclusions: OAPS shows differential characteristics than classical APS. All laboratory test categories are needed to avoid false-negative diagnoses. In some cases, complement levels could act as a serological marker. OAPS has very good foetal-maternal outcomes when treated. Thrombosis and progression to SLE in mothers with OAPS are scarce compared with "classical APS", suggesting that they have different aPL-mediated pathogenic mechanisms., (Copyright © 2015 Elsevier B.V. All rights reserved.)

To analyze the glycosylation of anti-β2GP1, we investigated purified IgG from healthy children, patients with APS, and asymptomatic adult carriers of antiphospholipid antibodies. We observed that in the sera of healthy children and of patients with APS, IgG3 and IgG2 were predominant, respectively. The potentially protective anti-β2GP1-IgM was lower in the sera of healthy children. Although anti-β2GP1-associated C1q did not differ between children and patients with antiphospholipid syndrome, the associated C3c was significantly higher in the sera of healthy children. This indicates a more efficient clearance of anti-β2GP1 immune complexes in the healthy children. This clearance is not accompanied by inflammation or coagulatory events. It is likely that the most important pathogenic factor of the anti-β2GP1-IgG is related to the different glycosylation observed in healthy and diseased individuals. We detected a significantly higher sialylation of anti-β2GP1-IgG isolated from the sera of healthy children and asymptomatic adults when compared with that of patients with clinically apparent antiphospholipid syndrome. Low sialylated IgG reportedly ameliorates inflammation and inflammation promotes hyposialylation. Thus, both reactions create a vicious circle that precipitates the pathology of the antiphospholipid syndrome including thrombus-formation. We conclude that the increased sialylation of anti-β2GP1-IgG of sera of healthy individuals limits their pathogenicity.

One of the challenges of managing patients with antiphospholipid syndrome is the prevention of rethrombosis (secondary prophylaxis). Risk stratification, i.e. traditional cardiovascular and thrombosis risk factors, systemic autoimmune diseases, antiphospholipid antibody profile, and the intensity of anticoagulation are all relevant to the management of APS patients with recurrent thrombosis. The paper will review "state of the art" strategies for optimizing therapy for APS patients with recurrent thrombosis.

The Antiphospholipid Syndrome (APS) is characterized by thrombosis and pregnancy loss, clinical events mediated by pathogenic anti-phospholipid autoantibodies (aPL). β2-glycoprotein I (β2GPI) is the major autoantigens recognized by aPL. β2GPI is a cationic protein that binds to negatively charged surfaces such as those of apoptotic cells. This feature may lead to two major events: i) immunization with β2GPI fosters the Fc-receptor-mediated uptake by antigen presenting cells of apoptotic material decorated with β2GPI and the activation of β2GPI-specific T cells which in turn provide help to β2GPI-specific B cells for the production of anti-β2GPI; ii) apoptotic bodies decorated with β2GPI can be opsonized by anti-β2GPI and shifted towards a pro-inflammatory clearance by macrophages; epitope spread can occur with the generation of autoimmunity against nuclear autoantigens. In the presence of a predisposing genetic background and of a particular cytokine environment (type I interferons), the sequential emergence of autoantibodies can evolve into overt clinical disease. The spectrum of clinical phenotypes of the patients can be modulated by several factors affecting the pathogenicity of anti-β2GPI (e.g. domain specificity). We conclude that dying cells may play a dual role in APS: (I) as immunogen for the induction of aPL (etiology) and (II) as targets of aPL for the chronification of inflammation and the development of autoimmune diseases (pathology).

IgA antiphospholipid antibodies (aPL) are not currently recognized as formal laboratory criteria for the Antiphospholipid Syndrome (APS). This is mainly due to methodological issues (different study designs, use of various non-standardized IgA assays). However, there are experimental data showing the pathogenic role of IgA anti-cardiolipin antibodies (aCL) and IgA anti-β2glycoprotein I antibodies (anti-β2GPI). Isolated IgA aCL are not very common, therefore their testing could be useful in the case of strong suspicion of APS but negative results for other aPL tests. IgA anti-β2GPI seem to be the most prevalent isotype in patients with Systemic Lupus Erythematosus (SLE), with a significant association with thrombotic events. Such a clinical relevance has been recently recognized by the inclusion of these autoantibodies among the aPL tests in the novel SLICC classification criteria for SLE. Emerging interest has been raised by IgA anti-β2GPI against domain 4/5 as a novel subgroup of clinically relevant aPL.

Background: Elevated pulmonary vascular resistance (PVR) in heart transplant (HT) candidates is associated with poor survival after HT. This study assessed the effect of peri-operative sildenafil administration on pulmonary hemodynamics and clinical outcomes in patients with advanced heart failure who were considered high-risk for HT because of elevated PVR and transpulmonary gradient (TPG)., Methods: The study included 119 consecutive patients who underwent HT between 2004 and 2011. Fifteen patients (Group A) had severe pulmonary hypertension (PH), defined as mean pulmonary pressure (MPAP)>25 mm Hg and PVR>2.5 Wood units (WU), and/or TPG>12 mm Hg after vasodilator test or the continuous administration of inotropics drugs, and 104 patients (Group B) were without severe PH. Group A received sildenafil therapy. Pulmonary hemodynamics were evaluated before HT with and without sildenafil therapy. Right catheterization was performed early after HT with sildenafil therapy and late after HT without sildenafil. Survival after HT was compared between the groups., Results: The sildenafil dosage was 109±42 mg/day during 163±116 days before HT. After sildenafil therapy MPAP, PVR, and TPG decreased from 43.9±12.5 to 33.4±5.8 mm Hg, 5.0±1.1 to 3.0±1.6 WU, and 17.3±3.2 to 10.2±4.1 mm Hg, respectively (p<.01). All patients underwent successful HT. Sildenafil dosage was 140±70 mg/day for 43±45 days after HT. There were no differences in PVR and TPG with sildenafil therapy early after HT and without sildenafil 6 months after HT. Survival after HT was similar between the groups., Conclusion: Sildenafil therapy before and after HT in patients with severe PH is associated with improved pulmonary hemodynamics and successful HT, without an increase in post-HT mortality., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to evaluate the impact of adhering to a strict follow up regimen on mid-term efficacy of intraoperative radiofrequency ablation in maintaining sinus rhythm for patients with atrial fibrillation undergoing cardiac surgery., Methods: We enrolled 52 patients with atrial fibrillation and valve disease divided in 2 groups: group 1 (26 patients) underwent intraoperative radiofrequency ablation and was followed by a team of skilled cardiologists who treated recurrences with amiodarone and electrical cardioversion; group 2 (26 patients) was treated with intraoperative radiofrequency ablation but patients were thereafter treated by their local hospital or personal cardiologist., Results: There were no intraoperative deaths or complications related to radiofrequency ablation. Twenty four months after the operation, freedom from atrial fibrillation was 60% in group 1 and 32% in group 2 (p=0.02). Group 1 also showed a reduction in atrial volume (p≤0.05)., Conclusion: Postoperative follow up with electrical and pharmacologic cardioversion combined with radiofrequency ablation achieves higher rate of sinus rhythm maintenance. After ablation, electrical cardioversion is effective even in patients with enlarged left atrium, long history of atrial fibrillation, or previous failed electrical cardioversion., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Patients treated with continuous flow assist devices may have increased bleeding tendencies due to an induced high molecular weight von Willebrand factor (VWF) multimer deficiency. We report a patient supported with a HeartMate II (Thoratec, Pleasanton, CA) who developed severe gastrointestinal bleeding refractory to conventional therapy and needing a total of 60 transfusions. After documenting the lack of large VWF multimers, suggestive of a defective platelet function, the patient was switched from aspirin to warfarin therapy (target international normalized ratio between 1.5 and 2.0). Three days after changing the anticoagulant regimen, the patient stopped bleeding and required no further transfusion., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Glucocorticoid misuse is a common problem in northern Bihar. There is very little published literature regarding the magnitude of glucocorticoid misuse in South Asia. All inpatients and medical outpatients presenting to Duncan Hospital with suspected glucocorticoid abuse were screened over a six-month period. Patients presenting with iatrogenic Cushing's syndrome and hypoadrenal crisis were assessed clinically and biochemically for the side effects of glucocorticoid misuse. Twenty-two patients were seen in the hospital over a period of six months. Fifteen patients presented with iatrogenic Cushing's syndrome (68.2%) and seven with hypoadrenal crisis (31.8%). Ten were found to have cataracts, six had a recent onset of diabetes, five had a recent onset of hypertension and 12 had osteoporotic fractures of the spine. Glucocorticoid misuse is an important problem which has been inadequately addressed in the rural and semi-urban communities of northern Bihar.

Multidisciplinary approach and patient counselling have been the key points in the improvement of the management of pregnancy in women with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Most of these women can have successful pregnancy when thoroughly informed and instructed on several different issues. Disease activity should be in stable remission prior to pregnancy in order to reduce the chance for flare during pregnancy. To this purpose, medications must be modulated: "safe" drugs should be continued throughout pregnancy, embryotoxic/foetotoxic drugs should be withdrawn timely, and beneficial drugs such as low dose aspirin and heparin should be added for prophylaxis of maternal and foetal outcome, especially in the presence of antiphospholipid antibodies. The safety profile of anti-rheumatic drugs during pregnancy and breastfeeding should be kept constantly updated, as new data from inadvertent exposure accumulates and new drugs (especially biological agents) are available. Patients may carry autoantibodies that can negatively affect the baby, being neonatal lupus the prototypical case of passively acquired autoimmunity. Research has been greatly active in this field and more information on risk stratification and management are now available for counselling. The effect of both autoantibodies and drug exposure has been evaluated in the offspring: some concerns about learning disabilities have been raised, but these are treatable conditions that are likely to be overcome. To counsel a woman with SLE/APS during childbearing age means also to deal with contraception. Despite the "preferred choice" - combined oral contraceptive - may not be suitable for most of the patients, other options are available and should be offered and discussed with the patient. Fertility is not generally affected in SLE/APS patients, but those cases who require assisted reproduction techniques should be carefully evaluated and managed., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Anti-β₂-glycoprotein-I (anti-β₂GPI) were demonstrated to be pathogenic in the antiphospholipid syndrome (APS). However, they can be detected in patients with no features of APS, especially those affected by systemic autoimmune diseases (SAD), and so in healthy children. It has been suggested that anti-β₂GPI against domain 1 (D1) associate with thrombosis, while those recognising domain 4/5 (D4/5) are present in non-thrombotic conditions., Objective: To evaluate the fine specificity of anti-β₂GPI in adults and infants., Methods: Three groups were examined-group A: 57 1-year-old healthy children born to mothers with SAD; group B: 33 children with atopic dermatitis; group C: 64 patients with APS., Subjects: were selected based on positive anti-β₂GPI IgG results. Serum samples were tested for anti-β₂GPI IgG D1 and D4/5 using research ELISAs containing recombinant β₂GPI domain antigens., Results: Children (A and B) displayed preferential IgG reactivity for D4/5, whereas patients with APS were mainly positive for D1. No thrombotic events were recorded in groups A and B., Conclusions: The specificity for D4/5 suggests that anti-β₂GPI IgG production in children born to mothers with SAD is a process neither linked to systemic autoimmunity nor related to the maternal autoantibody status. This unusual fine specificity might, at least partially, account for the 'innocent' profile of such antibodies.

Objective: Anti-β2 GPI are a formal laboratory criterion for the antiphospholipid syndrome (APS). They were demonstrated to be a risk factor for thrombosis and fetal losses but can also be detected in patients with systemic autoimmune disease (SAD), in healthy adults individuals and pre-school children. It has been suggested that different subpopulations of anti-β2GPI may carry different pathogenetic potential: autoantibodies against Domain1 seem to be associated with thrombosis; autoantibodies against Domain4/5 have been identified in patients with non-thrombotic conditions., Methods: We studied 48 patients with SAD (32 systemic lupus erythematosus, 16 undifferentiated connettive tissue disease), 64 patients with APS, 57 one-year-old healthy children born to mother with SAD, 33 children with atopic dermatitis. All subjects were IgG anti-β2 GPI positive. The specificity of anti-β2 GPI was investigated using ELISA research products containing recombinant β2 GPI D1 and D4/5 antigens. Cut-off values are calculated as 95th percentile on 100 NHD. IgG anti-β2 GPI were tested at a validated home-made ELISA routinely performed in our laboratory. No thrombotic events were recordered in patients with SAD and in both groups of children., Results: Patients with SAD and APS showed prevalent reactivity for D1 while children in both groups preferentially recognize D4/5., Conclusions: IgG anti-β2 GPI against D1 seem to cluster in patients with systemic autoimmune conditions. Their pathogenic potential in determine APS manifestations may be mitigated by adequate prophylaxis.

Objective: Anti-β₂glycoprotein I antibodies (a-β₂GPI) are a laboratory criterion for the antiphospholipid syndrome (APS) and were demonstrated to be involved in the pathogenesis of APS. However, they can also be detected in asymptomatic subjects. It has been suggested that a-β₂GPI against Domain1 (D1) associate with thrombosis, while those recognizing Domain4/5 (D4/5) have been identified in non-thrombotic conditions. We evaluate the specificity of a-β₂GPI in different clinical situations., Methods: We studied 39 one-year-old healthy children born to mothers with systemic autoimmune diseases (SAD) (15 (38.4%) were born to mothers who were a-β₂GPI positive), 33 children with atopic dermatitis (AD) and 55 patients with APS (50 adults and 5 paediatrics). All subjects were IgG a-β₂GPI positive. IgG a-β₂GPI were performed by homemade ELISA, while IgG a-β₂GPI D1 and D4/5 were tested on research ELISAs containing recombinant β₂GPI domains antigens., Results: One-year-old children and AD children displayed preferential reactivity for D4/5; patients with APS recognized preferentially D1. We also found a good correlation between a-β₂GPI and D4/5 in one-year-old (r=0.853) and AD children (r=0.879) and between a-β₂GPI and D1 in the APS group (r=0.575). No thrombotic events were recorded in both groups of children., Conclusions: A-β₂GPI found in non-thrombotic conditions (healthy children born to mothers with SAD and AD children) mostly recognize D4/5, in contrast to the prevalent specificity for D1 in the APS group. The different specificity could at least partially explain the "innocent" profile of a-β₂GPI in children.

Patients with multivessel coronary artery disease and severe left ventricular dysfunction are considered to be at high risk for percutaneous coronary intervention, and often are poor surgical candidates because of severe comorbidity. We report a case of high-risk percutaneous coronary intervention in a 67-year-old man with a severe left ventricular dysfunction and three-vessel coronary artery disease using a novel left ventricular assist device.

Background: The plasma levels of brain natriuretic peptide, tumor necrosis factor-alpha, big endothelin-1 and cardiac troponins have been reported to correlate with the severity of heart failure., Methods: In a single population of 80 outpatients with mild to moderate chronic heart failure the correlation between the patient's functional capacity, as evaluated at a 6-min walk test, the clinical parameters and plasma levels of brain natriuretic peptide, tumor necrosis factor-alpha, big endothelin-1 and cardiac troponins was evaluated., Results: A significant inverse correlation was found with the patient's age (p < 0.0001), NYHA functional class (p < 0.0001), left ventricular dysfunction etiology (ischemic vs dilated cardiomyopathy, p < 0.0005), heart rate (p < 0.05), plasma levels of brain natriuretic peptide (p < 0.05) and of tumor necrosis factor-alpha (p < 0.0005). At multiple regression analysis a correlation was found between the 6-min walk test results and the patient's age (p < 0.05), NYHA functional class (p < 0.01), left ventricular dysfunction etiology (ischemic vs dilated cardiomyopathy, p < 0.05) and tumor necrosis factor-alpha plasma levels (p < 0.05)., Conclusions: In our patients with mild to moderate heart failure, a significant correlation was found between the results of the 6-min walk test and only the plasma concentrations of tumor necrosis factor-alpha among the laboratory parameters analyzed in this study.