tbuckley/cabot-search huggingface dataset:
PB1883 GLYCOPROTEIN STRUCTURES OF LEUKEMIC B‐LYMPHOCYTES AND CD38 EXPRESSION IN CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: O. Shalay, H. Lebed, V. Barilka, O. Zotova, M. Valchuk, V. Loginsky
Journal: HemaSphere (2019)

Background: Glycoprotein cell structures (glycocode) play an important part in intercellular interaction. Changes in their structure may determine the ability of leukemic cells to spread (expansion), and impact the exposure of membrane antigen, which transmit pro‐ and antiapoptotic signals. Aims: The aim of this study was to conduct research of leukemic lymphocytes glycocode in chronic lymphocytic leukemia (CLL) and its interconnection with the expression of prognostically significant CD38 antigen. Methods: Carbohydrate determinants of leukemic lymphocyte membrane were studied in 65 CLL patients using panel of 12 lectins with main carbohydrate specificity, and CD38 expression. Results: 27% of lymphocytes of CLL patients were identified as containing Thomsen–Friedenreich antigen (PNA+), absent in normal lymphocytes. Leukemic lymphocytes are characterized by a significantly lower level of I and II type N‐glycans’ glycosidic chains (RCA). The lymphocytes of the CLL patients reacted weaker with GalNAca‐specific SBA lectin, Mana‐specific PSL lectin and GlcNAcb‐specific lectins (WGA і STL), polyspecific lectin PHA. We researched the correlation between lectin receptors expression level and CD38 antigen. The patients were divided into groups with low and increased antigen expression level. In the low CD38 expression level group (≤30%) no statistically significant changes in interaction with lectins were detected as compared to the general patients group. Leukemic lymphocytes with increased CD 38 expression (&gt;30% CD38 + cells) exhibit a significantly higher interaction level with PNA lectin (T antigen) and decreased interaction level with RCA; they have more terminal Fucα residues (H antigen, LAL lectin). A correlation analysis has been done between the percentage of leukemic cells that bind lectins and the number of CD38+ lymphocytes. A high level of CD38 expression correlates with increased A antigen disaccharide content (GalNAAcα1→3Galβ; SBA lectin), decrease of GlcNAcβ sialylated residues (WGA lectin, r = –0,702; STL lectin, r = –0,503), and sialic acid (SNL lectin). They have less polyantennae N‐glycans (PHA lectin, r = –0,701). Summary/Conclusion: A higher CD 38 expression level is accompanied with an increased number of cells containing Thomsen‐Friedenreich antigen (PNA lectin) and corelates positively with antigen A level (SBA lectin) and terminal Fucα (LAL lectin) and a decreased level of Galβ glycosidic residues (RCA lectin); it correlates negatively with a decrease of GlcNAcβ sialylated residues (WGA, STL lectin), and residues of neuraminic acid (NANA, SNL lectin) and polyantennae N‐glycans (PHA‐L lectin).
“Bonkers” paperwork required for non-EU doctors to work in the NHS needs reform, says GMC chief
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The UK government should legislate to make it easier for doctors from outside Europe to work in the NHS, the chief executive of the GMC has said.

Charlie Massey said that the existing “equivalence” process that requires doctors from outside the European Economic Area to fill in “about 1000 pages of paperwork” to demonstrate that their experience and training meets the standard for the UK was “bonkers.”

Speaking at the NHS Confederation Conference in …
SAT0186 Ω MORTALITY IN CHILDREN WITH JUVENILE SYSTEMIC LUPUS ERYTHEMATOSUS IN AN ARGENTINE PEDIATRIC CENTRE.
Authors: Cristina Battagliotti
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Juvenile systemic lupus erythematosus (JSLE) is a complex multisystemic autoimmune disease, often causing irreversible damage, reduced quality of life and life expectancy. Data on causes of death and time trends in infant lupus mortality are limited. <h3>Objectives:</h3> The aim of this study was to determine mortality in a pediatric cohort. <h3>Methods:</h3> This retrospective study included patients with childhood onset lupus (fulfilling ACR 1997) who were diagnosed at the Paediatric centre in Santa Fe Argentine, Alassia Children Hospital from 1991 to 2018 and had 15 years of age at presentation. <h3>Results:</h3> This study includes 54 JSLE children (F:M=12,5 :1) with a mean age of onset lupus 12 years (range 4-15 years). During a mean follow-up in our centre of 3 years (range 12m–10 years), 12 patients (24%) was died; 5 during the follow-up in our centre and 7 in adult centre,4 lost to follow-up. The average age of death was16 years (range 10-29 years) and the average since diagnose time was 17 months (range 3m-15 years). The principal system involved was renal (100%). 10 patients with diffuse proliferative lupus nephritis (WHO class IV), 2 membranous lupus nephritis (WHO class V), 5 patients (41.6%) with hematological disorders (2 pancytopenia, 2 leukopenia,1 Macrophage Activation Syndrome). 3 patients had thrombosis. 5 patients (41.6%) with neurological involvement (4 psychosis, 1 depression). One patient with liver dysfunction. There one death related to renal biopsy. The principal cause of mortality was active disease and infection. Meningococcal meningitis, Klebsiella peritonitis, Pneumococcal cellulitis of the neck, peritonitis and 1 patient with disseminated tuberculosis. 11 patients (91,6%) had received intravenous steroids as pulses and Cyclophosphamide pulse therapy, azathioprine or mycophenolate mofetil, hydroxychloroquine immunoglobulins. In some patients peritoned dialysis and ventilation. 8 patients (66%) with bad socioeconomic environment. Four patients (33%) with poor adherence to treatment. <h3>Conclusion:</h3> In this single-center study, childhood onset lupus was associated with a mortality of 24%. With higher frequency of aggressive renal disease and higher requirement for steroids and immunosuppressive drugs. Pediatric care should consider transition to adult’s centers and ensure continuity of treatment. <h3>Reference</h3> [1] Childhood systemic lupus erythematosus in Latin America. The GLADEL experience in 230 children. February 2008 Lupus 17(6):596-604 DOI: 10.1177/0961203307088006 <h3>Acknowledgement:</h3> Hospital de Niños Dr Orlando Alassia <h3>Disclosure of Interests:</h3> None declared
Robust Estimation of Recent Effective Population Size from Number of Independent Origins in Soft Sweeps
Authors: Bhavin S Khatri, Austin Burt
Journal: Molecular Biology and Evolution (2019)

Estimating recent effective population size is of great importance in characterizing and predicting the evolution of natural populations. Methods based on nucleotide diversity may underestimate current day effective population sizes due to historical bottlenecks, whereas methods that reconstruct demographic history typically only detect long-term variations. However, soft selective sweeps, which leave a fingerprint of mutational history by recurrent mutations on independent haplotype backgrounds, holds promise of an estimate more representative of recent population history. Here, we present a simple and robust method of estimation based only on knowledge of the number of independent recurrent origins and the current frequency of the beneficial allele in a population sample, independent of the strength of selection and age of the mutation. Using a forward-time theoretical framework, we show the mean number of origins is a function of θ=2Nμ and current allele frequency, through a simple equation, and the distribution is approximately Poisson. This estimate is robust to whether mutants preexisted before selection arose and is equally accurate for diploid populations with incomplete dominance. For fast (e.g., seasonal) demographic changes compared with time scale for fixation of the mutant allele, and for moderate peak-to-trough ratios, we show our constant population size estimate can be used to bound the maximum and minimum population size. Applied to the Vgsc gene of Anopheles gambiae, we estimate an effective population size of roughly 6×107, and including seasonal demographic oscillations, a minimum effective population size >3×107, and a maximum <6×109, suggesting a mean ∼109.
Dipeptidyl Peptidase 4 Inhibitors and the Risk of Bullous Pemphigoid Among Patients With Type 2 Diabetes
Authors: Antonios Douros, Julie Rouette, Hui Yin, Oriana Hoi Yun Yu, Kristian B. Filion, Laurent Azoulay
Journal: Diabetes Care (2019)

OBJECTIVE There are uncertainties regarding the association between dipeptidyl peptidase 4 (DPP-4) inhibitors and bullous pemphigoid (BP), a potentially severe autoimmune skin disease. Thus, we conducted a population-based study to determine whether use of DPP-4 inhibitors, when compared with other second- to third-line antidiabetic drugs, is associated with an increased risk of BP in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Using the U.K. Clinical Practice Research Datalink, we conducted a cohort study among 168,774 patients initiating antidiabetic drugs between January 2007 and March 2018. Using time-dependent Cox proportional hazards models, we estimated adjusted hazard ratios (HRs) with 95% CIs of incident BP associated with current use of DPP-4 inhibitors, compared with current use of other second- to third-line antidiabetic drugs. We also conducted a propensity score–matched analysis to assess the impact of residual confounding. RESULTS During 711,311 person-years of follow-up, 150 patients were newly diagnosed with BP (crude incidence rate, 21.1 per 100,000 person-years). Current use of DPP-4 inhibitors was associated with an increased risk of BP (47.3 vs. 20.0 per 100,000 person-years; HR 2.21 [95% CI 1.45–3.38]). HRs gradually increased with longer durations of use, reaching a peak after 20 months (HR 3.60 [95% CI 2.11–6.16]). Similar results were obtained in the propensity score–matched analysis (HR 2.40 [95% CI 1.13–4.66]). CONCLUSIONS In this large population-based study, use of DPP-4 inhibitors was associated with an at least doubling of the risk of BP in patients with type 2 diabetes, albeit the absolute risk was low.
Abstract 1058: The Athlete’s Heart - Gender Aspects
Authors: Katarina Steding, Henrik Engblom, Marcus Carlsson, Henrik Mosén, Torsten Buhre, Björn Wohlfart, Håkan Arheden
Journal: Circulation (2008)

Training induced morphological changes to the heart in male subjects has previously been well described. Only a few studies include females. The aim of this study was to investigate if the morphological response to training differs between male and female athletes. Eighteen triathletes (6 female) and 59 controls (19 female) underwent cardiac magnetic resonance imaging (CMR). Total heart volume (THV), left ventricular mass (LVM) and end diastolic volume (EDV) was calculated using planimetry derived from steady state free precession cine images. Mann-Whitney non-parametric t-test was used to compare THV/body surface area (BSA), LVM/THV and EDV/THV in the four groups. THV/BSA was significantly higher in athletes, both for males and females (p&lt;0.0001, p&lt;0.001 respectively). Male controls had a significantly higher THV/BSA when compared to female controls (p=0.004) and also LVM/THV (p=0.001). However, there were no significant differences between male and female athletes for any of the variables studied. Long term endurance training increases THV in the same order of magnitude in both male and female athletes. The differences seen between male and female control subjects are not found in male and female athletes.
Comment on editorial ‘Pathogenic effector functions of ACPA: where do we stand?’
Authors: Rikard Holmdahl
Journal: Annals of the Rheumatic Diseases (2019)

Comment on editorial 'Pathogenic effector functions of ACPA: where do we stand?'The recently published paper by Ge et al 1 has led to both retractions 2 and correction notes of papers 3 4 that have so far been a basis of the current understanding of anti-citrullinated protein antibodies (ACPAs).The recent and well-written editorial by Toes and Pisetsky 5 confirms the importance of this twist.However, there is one statement in the editorial that needs to be clarified: 'Notably, the authors who described the monoclonal ACPA with osteoclastogenic and pain-inducing potential notified the community that, in reassessing the original data, the antibodies in question showed 'no measurable affinity for the tested citrullinated peptides' as detailed in a recent correction and retraction note; in other words, the monoclonal antibodies studied were not ACPA.This observation is in line with crystallographic studies of some of these monoclonal antibodies that could not confirm the binding of citrullinated peptides'.The crystal structures and the discovery that the monoclonal antibodies D10 and B02 did not have any citrulline specificity were already made in 2013, just after the now retracted Amara et al 2 paper was published, and this information was at this time communicated to the authors both through discussions and through written notice.To our disappointment, they decided not to retract the paper.Instead, they used these antibodies to prove functions of ACPAs in new papers.This was also the reason that, several years later, we decided to include the old data of the B02 and D10 antibodies in our paper, showing for the first time the structural interactions between ACPA and citrullinated peptides. 1It was only after this paper was made public, in August 2018, that the Amara et al paper was finally retracted.It should also be noted that two papers based on these two previous 'ACPA' monoclonal B02 and D10 antibodies have been corrected, stating that it is not possible to conclude on the given data that ACPA specifically induces bone erosions.However, the authors continue to refer to these papers, iterating this statement as a proof.It is obviously critical for the future of rheumatology that published data are correct, and if this turns out not to be the case, it should be corrected as soon as proper information is available.
PS1593 AIHA IN HEMATOLOGICAL DISEASES - CHALLENGES FOR IMMUNOCHEMATOLOGY AND RISK-MANAGEMENT OF TRANSFUSION THERAPY
Authors: Y. Lazarova, S. Ivanova
Journal: HemaSphere (2019)

Background: Heavy AIHAs are a problem for transfusion medicine because they make it difficult to treat the underlying disease, and because of the high risk of hemolytic post-transfusion reactions. The safety and effectiveness of transfusion therapy in severe AIHAs depends entirely on: Ig class of auto-antierytrocite antibodies, t optimum of activity, activity, and specificity. Aims: Frequency, evolution, and severity of AIHA in hematological diseases: AML, ALL, CLL, NHL, MH, MM, MDS, MAA; An. Cooley, Myelofibrosis, ITP, B12-deficiency, choice of blood transfusion approach Methods: Materials: Number of AIHAs - 136 cases in adults for the period 2014–2018, evolution in the course of the underlying disease, Ig class of auto-antierytrocite antibodies, activity, specificity, transfusion therapy - with or without complications (presentation of 3 severe clinical cases of AIHA in MM, MDS, after allogeneic ABO-compatibility HSCT). Methods: Routine manual technique, column-agglutination technique for blood typing, screening and identification of anti-erythrocyte antibodies (agglutination, enzyme, indirect antiglobulin test), in vitro compatibility tests on all methods and techniques, absorption and elution by standard techniques, if necessary. Results: AIHA was found in 136 cases: male-39.7%, female-52.94%; AML-11.77%, ALL-3.69%, CLL-16.92%, NHL-25%, MH-3.67%, MM-6.62%, MDS-16.18%, An.Cooley-1.47%, MAA-4.41%, Myelofibrosis-2.21 %, B12 deficit-2.95%, ITP-3.67%; AIHA at the expense of IgG −41.91%, IgG + C3d-26.47%, C3d-12.5%, 19.2% are atypical; autoantibody specificity-22.8%; mixed autoimmune disease-5.15%, major approach to severe AIHA-retention of blood transfusion due to the effect of immunosuppressive therapy, transfusion therapy was performed only in severe AIHA (IgG + C3d, CAD) with Hb values <45 G / L and the blood transfusion without reactions and complications for the patients.Summary/Conclusion: The severe AIHA in the evolution of the underlying disease are the challenge of transfusion medicine and the choice of approach/risk management in transfusion therapy/retention of blood transfusion or blood transfusion only at low critical levels of Hb <45 G / L are favorable for the patient. The favorable evolution of hematological disease depends on good transfusion support.
PF789 8‐YEARS’ OVERALL AND EVENT FREE SURVIVAL IS SUBOPTIMAL IN A LARGE GROUP OF TRANSFUSION‐DEPENDENT THALASSEMIC PATIENTS
Authors: A. Kattamis, A. Mikelatou, K. Koumasi, E. Nitsa, E. Rigatou, D. Kyriakopoulou
Journal: HemaSphere (2019)

Background: Current therapeutic modalities with proper transfusion regimen and chelation therapy have dramatically increased life expectancy and decreased anemia and iron overload related complications in transfusion dependent thalassemic (TDT) patients. In many countries where thalassemia prevention programs were introduced, the majority of TDT population is of middle age. Data on morbidity and new complications on this ageing thalassemics are sparse. Aims: To determine the 8‐years’ overall survival (OS) and event‐free survival (EFS) and to examine factors affecting survival in a large group of TDT patients. Methods: This is a retrospective analysis of mortality and morbidity in a large group of homogenously –treated TDT patients in a single institution. Patients with TDT, regularly transfused in our unit on 31/12/2010, were followed for 8 years till 31/12/2018. ‘New event’ was defined as a new complication significant enough to require therapeutic intervention. The effect of different factors (like age, splenectomy, history of hepatitis C, burden of transfusions, iron overload, etc) on mortality and morbidity was evaluated. Burden of transfusion was evaluated as continuous (cc of transfused red blood cells/kg/year) and dichotomous variable (up to, and, more than 10 units/12 weeks). The majority of adult TDT patients (76.4%) received &gt;10 units/12 weeks. Results: 435 patients (mean 33.3 ± 7.9 years, max 52.3 years) were longitudinally followed. During an observation period of 8 years, 30 deaths occurred, corresponding to an 8‐years OS of 93.1%. Deaths significantly increased after the age of 40 years (figure). Splenectomy and history of hepatitis C were risk factors for death (O.R. 7.0 and 4.5, respectively, both p &lt; 0.05). Improvement of iron overload was noted between 2010 and 2018 (ferritin levels: 2108.6 ± 2098 vs. 1550.8 ± 1883.5 μg/l, respectively, p &lt; 0.05). During the observation period, percentages of patients experiencing new events were as follows: hypothyroidism 20.7%, cardiac complications 8.6%, glucose homeostasis disturbances 7.3%, hypogonadism 21.6%, significant osteoporosis 6.4%, renal failure 1%, neurological complications 5.5% and cancer 6.1%. 8 years’ EFS was 55%. Apart from age, no other factors were related to the occurrence of new events. Summary/Conclusion: Despite adequate transfusion regimen and improvement on iron overload, OS and EFS of TDT patients remain suboptimal, with mortality increasing significantly after the 4 th decade of life. Contributing factors to death, like splenectomy and history of hepatitis C, may be related to the initial treatment period. Effect of transfusion burden needs further evaluation. Ageing TDT population is likely to develop more complications with advanced age with the occurrence of malignancies being a major concern. image
THU0537 ANGIOMATOID FIBROUS HISTIOCYTOMA MIMICKING SYSTEMIC JIA VIA MUTATION-DRIVEN IL-6 PRODUCTION
Authors: Mark Friswell, Stephen Owens, Gail Halliday
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Angiomatoid Fibrous Histiocytoma mimicking Systemic JIA via mutation-driven IL-6 production: Angiomatoid Fibrous Histiocytoma (AFH) is a rare tumour associated with mutation-driven production of Interleukin-6 (IL-6) which causes a systemic inflammatory picture similar to Systemic Juvenile Idiopathic Arthritis (sJIA). <h3>Objectives</h3> A previously well 6-year old girl was referred with 6 weeks of abdominal pain, nausea, weight loss, night sweats, &amp; lethargy. Examination was unremarkable apart from a 2cm lump in the right popliteal fossa. This had been reported on USS 2 months earlier, at an external hospital, to be a Sebaceous cyst. There was no rash, organomegaly, lymphadenopathy, or synovitis. She had persistent recurrent fevers of &gt;39C, but not in the classical quotidian pattern of sJIA. <h3>Methods</h3> Bloods showed persistent Hb &lt;70, platelets &gt;600, ESR &gt;100, &amp; CRP &gt;200. Autoantibody &amp; full infection screens were negative. Urine HMMA:creatinine ratio was minimally raised at 7.2 (normal 1.8 - 5) Faecal calprotectin, upper &amp; lower GI endoscopy were normal. Bone-Marrow Aspiration was reported as being highly reactive but with no malignancy seen. Whole-body STIR MRI was reported as normal, but repeat localised USS &amp;MRI of the knee showed a 27x18x21mm well circumscribed, mixed cystic/solid lesion with marked vascularity. The lesion was then biopsied, and subsequently excised Plasma IL-6 levels were significantly elevated at 46.7pg/ml (normal range: 0-2), but normalised after excision. TNF and IL1b levels were normal <h3>Results</h3> Initial biopsy and FISH analysis confirmed the diagnosis of AFH with an abnormal EWSR1 signal pattern and classical EWSR1-CREB1 fusion. She went on to have a full excision, and staging investigations were negative. AFH is rare (&lt;0.3% of all soft-tissue tumours) and arises in the deep dermis/subcutis of the extremities of children &amp; young adults. It has been regularly described in the axilla &amp; popliteal fossa. It has a high (15%) local recurrence rate but rarely metastasises. In &gt;90% of cases AFH is associated with a characteristic translocation: t(2:22) (q33:q12). This forms the fusion gene EWSR1-CREB1 which in turn leads to continuous activation of CREB1. The promoter region of IL-6 has a CREB1 binding site thus causing IL-6 over-production and leading to the paraneoplastic syndrome. <h3>Conclusion</h3> Paraneoplastic immune dysregulation is a rare, but important cause of symptoms often otherwise associated with rheumatic diseases. Careful physical examination, and liaison with oncology teams, is needed, particularly before treatment with steroids or IL-6 inhibitors such as Tocilizumab are considered <h3><b>Disclosure of Interests:</b>&nbsp;</h3> Mark Friswell: None declared, Stephen Owens Consultant for: paid a consultancy fee by Chimerix to act as an advisor on a study of adenovirus in transplant patients, Gail Halliday: None declared&nbsp;