Phenotypical heterogeneity in RAG-deficient patients from a highly consanguineous population

Mutations affecting recombination activation genes RAG1 and RAG2 are associated with variable phenotypes, depending on the residual recombinase activity. The aim of this study is to describe a variety of clinical phenotypes in RAG-deficient patients from the highly consanguineous Egyptian population. Thirty-one patients with RAG mutations (from 28 families) were included from 2013 to 2017. On the basis of clinical, immunological and genetic data, patients were subdivided into three groups; classical T B severe combined immunodeficiency (SCID), Omenn syndrome (OS) and atypical SCID. Nineteen patients presented with typical T B SCID; among these, five patients carried a homozygous RAG2 mutation G35V and five others carried two homozygous RAG2 mutations (T215I and R229Q) that were detected together. Four novel mutations were reported in the T B SCID group; three in RAG1 (A565P, N591Pfs*14 and K621E) and one in RAG2 (F29S). Seven patients presented with OS and a novel RAG2 mutation (C419W) was documented in one patient. The atypical SCID group comprised five patients. Two had normal B cell counts; one had a previously undescribed RAG2 mutation (V327D). The other three patients presented with autoimmune cytopaenias and features of combined immunodeficiency and were diagnosed at a relatively late age and with a substantial diagnostic delay; one patient had a novel RAG1 mutation (C335R). PID disorders are frequent among Egyptian children because of the high consanguinity. RAG mutations stand behind several variable phenotypes, including classical SCID, OS, atypical SCID with autoimmunity and T B CID

Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations

none313siBackground: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations. Objective: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts. Methods: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered. Results: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years. Conclusions: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.noneThalhammer J.; Kindle G.; Nieters A.; Rusch S.; Seppanen M.R.J.; Fischer A.; Grimbacher B.; Edgar D.; Buckland M.; Mahlaoui N.; Ehl S.; Boztug K.; Brunner J.; Demel U.F.; Forster-Waldl E.; Gasteiger L.M.; Goschl L.; Kojic M.; Schroll A.; Seidel M.G.; Wintergerst U.; Wisgrill L.; Sharapova S.O.; Goffard J.-C.; Kerre T.; Meyts I.; Roosens F.; Smet J.; Haerynck F.; Eric Z.P.; Milenova V.; Gagro A.; Richter D.; Chovancova Z.; Hlavackova E.; Litzman J.; Milota T.; Sediva A.; Elaziz D.A.; Alkady R.S.; El Sayed El Hawary R.; Eldash A.S.; Galal N.; Lotfy S.; Meshaal S.S.; Reda S.M.; Sobh A.; Elmarsafy A.; Brosselin P.; Courteille V.; De Vergnes N.; Kracker S.; Pergent M.; Randrianomenjanahary P.; Ahrenstorf G.; Albert M.H.; Ankermann T.; Atschekzei F.; Baumann U.; Becker B.C.; Behrends U.; Belohradsky B.H.; Biegner A.-K.; Binder N.; Bode S.F.N.; Boesecke C.; Boetticher B.; Borte M.; Borte S.; Classen C.F.; Dirks J.; Duckers G.; El-Helou S.; Ernst D.; Fasshauer M.; Fecker G.; Felgentreff K.; Foell D.; Ghosh S.; Girschick H.J.; Goldacker S.; Graf N.; Graf D.; Greil J.; Hanitsch L.G.; Hauck F.; Heeg M.; Heine S.I.; Henes J.C.; Hoenig M.; Holzer U.; Holzinger D.; Horneff G.; Hundsdoerfer P.; Jablonka A.; Jakoby D.; Joean O.; Kaiser-Labusch P.; Klemann C.; Kobbe R.; Korholz J.; Kramm C.M.; Kruger R.; Landwehr-Kenzel S.; Lehmberg K.; Liese J.G.; Lippert C.F.; Maccari M.E.; Masjosthusmann K.; Meinhardt A.; Metzler M.; Morbach H.; Muller I.; Naumann-Bartsch N.; Neubert J.; Niehues T.; Peter H.-H.; Rieber N.; Ritterbusch H.; Rockstroh J.K.; Roesler J.; Schauer U.; Scheible R.; Schmalzing M.; Schmidt R.E.; Schneider D.T.; Schreiber S.; Schuetz C.; Schulz A.; Schulze-Koops H.; Schulze-Sturm U.; Schuster V.; Schwaneck E.C.; Schwarz K.; Schwarze-Zander C.; Sirin M.; Skapenko A.; Sogkas G.; Sparber-Sauer M.; Speckmann C.; Steinmann S.; Stiehler S.; Tenbrock K.; von Bernuth H.; Warnatz K.; Wasmuth J.-C.; Weiss M.; Witte T.; Wittke K.; Wittkowski H.; Zeuner R.A.; Farmaki E.; Hatzistilianou M.N.; Kakkas I.; Kanariou M.G.; Kapousouzi A.; Liatsis E.; Maggina P.; Papadopoulou-Alataki E.; Raptaki M.; Speletas M.; Tantou S.; Goda V.; Krivan G.; Marodi L.; Abolhassani H.; Aghamohammadi A.; Rezaei N.; Feighery C.; Leahy T.R.; Ryan P.; Batzir N.A.; Garty B.Z.; Tamary H.; Aiuti A.; Amodio D.; Azzari C.; Barzaghi F.; Baselli L.A.; Cancrini C.; Carrabba M.; Cazzaniga M.; Cesaro S.; Chinello M.; Danieli M.G.; Dellepiane R.M.; Fabio G.; Gambineri E.; Lodi L.; Lougaris V.; Marasco C.; Martire B.; Marzollo A.; Milito C.; Moschese V.; Pignata C.; Plebani A.; Porta F.; Quinti I.; Ricci S.; Soresina A.; Tommasini A.; Vacca A.; Vanessa C.; Blaziene A.; Sitkauskiene B.; Gowin E.; Heropolitanska-Pliszka E.; Pietrucha B.; Szaflarska A.; Wiesik-Szewczyk E.; Wolska-Kusnierz B.; Esteves I.; Faria E.; Marques L.H.; Neves J.F.; Silva S.L.; Teixeira C.; Pereira da Silva S.; Capilna B.R.; Guseva M.N.; Shcherbina A.; Bobcakova A.; Ciznar P.; Gabzdilova J.; Jesenak M.; Kapustova L.; Orosova J.; Petrovicova O.; Raffac S.; Kopac P.; Allende L.M.; Antoli A.; Blanch G.R.; Carbone J.; Dieli-Crimi R.; Garcia-Prat M.; Gil-Herrera J.; Gonzalez-Granado L.I.; Agullo P.L.; Olbrich P.; Parra-Martinez A.; Paz-Artal E.; Pleguezuelo D.E.; Rodriguez N.S.; Sanchez-Ramon S.; Santos-Perez J.L.; Solanich X.; Soler-Palacin P.; Gonzalez-Amores M.; Ekwall O.; Fasth A.; Bitzenhofer-Gruber M.; Candotti F.; Dimitriou F.; Heininger U.; Holbro A.; Jandus P.; Kolios A.G.A.; Marschall K.; Schmid J.P.; Posfay-Barbe K.M.; Prader S.; Reichenbach J.; Steiner U.C.; Truck J.; Bredius R.G.; de Kruijf- Bazen S.; de Vries E.; Henriet S.S.V.; Kuijpers T.W.; Potjewijd J.; Rutgers A.; Stol K.; van Aerde K.J.; Van den Berg J.M.; van de Ven A.A.J.M.; Montfrans J.; Aydemir S.; Baris S.; Dogu F.; Ikinciogullari A.; Karakoc-Aydiner E.; Kilic S.S.; Kiykim A.; Kokcu Karadag S.I.; Kutukculer N.; Ocak S.; UNAL E.; Boyarchuk O.; Hilfanova A.; Kostyuchenko L.V.; Alachkar H.; Arkwright P.D.; Baxendale H.E.; Bernatoniene J.; Coulter T.I.; Garcez T.; Goddard S.; Gompels M.M.; Grigoriadou S.; Herriot R.; Herwadkar A.; Huissoon A.; Ibberson L.; Nademi Z.; Noorani S.; Parvin S.; Steele C.L.; Thomas M.; Waruiru C.; Yong P.F.K.; Bourne H.Thalhammer, J.; Kindle, G.; Nieters, A.; Rusch, S.; Seppanen, M. R. J.; Fischer, A.; Grimbacher, B.; Edgar, D.; Buckland, M.; Mahlaoui, N.; Ehl, S.; Boztug, K.; Brunner, J.; Demel, U. F.; Forster-Waldl, E.; Gasteiger, L. M.; Goschl, L.; Kojic, M.; Schroll, A.; Seidel, M. G.; Wintergerst, U.; Wisgrill, L.; Sharapova, S. O.; Goffard, J. -C.; Kerre, T.; Meyts, I.; Roosens, F.; Smet, J.; Haerynck, F.; Eric, Z. P.; Milenova, V.; Gagro, A.; Richter, D.; Chovancova, Z.; Hlavackova, E.; Litzman, J.; Milota, T.; Sediva, A.; Elaziz, D. A.; Alkady, R. S.; El Sayed El Hawary, R.; Eldash, A. S.; Galal, N.; Lotfy, S.; Meshaal, S. S.; Reda, S. M.; Sobh, A.; Elmarsafy, A.; Brosselin, P.; Courteille, V.; De Vergnes, N.; Kracker, S.; Pergent, M.; Randrianomenjanahary, P.; Ahrenstorf, G.; Albert, M. H.; Ankermann, T.; Atschekzei, F.; Baumann, U.; Becker, B. C.; Behrends, U.; Belohradsky, B. H.; Biegner, A. -K.; Binder, N.; Bode, S. F. N.; Boesecke, C.; Boetticher, B.; Borte, M.; Borte, S.; Classen, C. F.; Dirks, J.; Duckers, G.; El-Helou, S.; Ernst, D.; Fasshauer, M.; Fecker, G.; Felgentreff, K.; Foell, D.; Ghosh, S.; Girschick, H. J.; Goldacker, S.; Graf, N.; Graf, D.; Greil, J.; Hanitsch, L. G.; Hauck, F.; Heeg, M.; Heine, S. I.; Henes, J. C.; Hoenig, M.; Holzer, U.; Holzinger, D.; Horneff, G.; Hundsdoerfer, P.; Jablonka, A.; Jakoby, D.; Joean, O.; Kaiser-Labusch, P.; Klemann, C.; Kobbe, R.; Korholz, J.; Kramm, C. M.; Kruger, R.; Landwehr-Kenzel, S.; Lehmberg, K.; Liese, J. G.; Lippert, C. F.; Maccari, M. E.; Masjosthusmann, K.; Meinhardt, A.; Metzler, M.; Morbach, H.; Muller, I.; Naumann-Bartsch, N.; Neubert, J.; Niehues, T.; Peter, H. -H.; Rieber, N.; Ritterbusch, H.; Rockstroh, J. K.; Roesler, J.; Schauer, U.; Scheible, R.; Schmalzing, M.; Schmidt, R. E.; Schneider, D. T.; Schreiber, S.; Schuetz, C.; Schulz, A.; Schulze-Koops, H.; Schulze-Sturm, U.; Schuster, V.; Schwaneck, E. C.; Schwarz, K.; Schwarze-Zander, C.; Sirin, M.; Skapenko, A.; Sogkas, G.; Sparber-Sauer, M.; Speckmann, C.; Steinmann, S.; Stiehler, S.; Tenbrock, K.; von Bernuth, H.; Warnatz, K.; Wasmuth, J. -C.; Weiss, M.; Witte, T.; Wittke, K.; Wittkowski, H.; Zeuner, R. A.; Farmaki, E.; Hatzistilianou, M. N.; Kakkas, I.; Kanariou, M. G.; Kapousouzi, A.; Liatsis, E.; Maggina, P.; Papadopoulou-Alataki, E.; Raptaki, M.; Speletas, M.; Tantou, S.; Goda, V.; Krivan, G.; Marodi, L.; Abolhassani, H.; Aghamohammadi, A.; Rezaei, N.; Feighery, C.; Leahy, T. R.; Ryan, P.; Batzir, N. A.; Garty, B. Z.; Tamary, H.; Aiuti, A.; Amodio, D.; Azzari, C.; Barzaghi, F.; Baselli, L. A.; Cancrini, C.; Carrabba, M.; Cazzaniga, M.; Cesaro, S.; Chinello, M.; Danieli, M. G.; Dellepiane, R. M.; Fabio, G.; Gambineri, E.; Lodi, L.; Lougaris, V.; Marasco, C.; Martire, B.; Marzollo, A.; Milito, C.; Moschese, V.; Pignata, C.; Plebani, A.; Porta, F.; Quinti, I.; Ricci, S.; Soresina, A.; Tommasini, A.; Vacca, A.; Vanessa, C.; Blaziene, A.; Sitkauskiene, B.; Gowin, E.; Heropolitanska-Pliszka, E.; Pietrucha, B.; Szaflarska, A.; Wiesik-Szewczyk, E.; Wolska-Kusnierz, B.; Esteves, I.; Faria, E.; Marques, L. H.; Neves, J. F.; Silva, S. L.; Teixeira, C.; Pereira da Silva, S.; Capilna, B. R.; Guseva, M. N.; Shcherbina, A.; Bobcakova, A.; Ciznar, P.; Gabzdilova, J.; Jesenak, M.; Kapustova, L.; Orosova, J.; Petrovicova, O.; Raffac, S.; Kopac, P.; Allende, L. M.; Antoli, A.; Blanch, G. R.; Carbone, J.; Dieli-Crimi, R.; Garcia-Prat, M.; Gil-Herrera, J.; Gonzalez-Granado, L. I.; Agullo, P. L.; Olbrich, P.; Parra-Martinez, A.; Paz-Artal, E.; Pleguezuelo, D. E.; Rodriguez, N. S.; Sanchez-Ramon, S.; Santos-Perez, J. L.; Solanich, X.; Soler-Palacin, P.; Gonzalez-Amores, M.; Ekwall, O.; Fasth, A.; Bitzenhofer-Gruber, M.; Candotti, F.; Dimitriou, F.; Heininger, U.; Holbro, A.; Jandus, P.; Kolios, A. G. A.; Marschall, K.; Schmid, J. P.; Posfay-Barbe, K. M.; Prader, S.; Reichenbach, J.; Steiner, U. C.; Truck, J.; Bredius, R. G.; de Kruijf- Bazen, S.; de Vries, E.; Henriet, S. S. V.; Kuijpers, T. W.; Potjewijd, J.; Rutgers, A.; Stol, K.; van Aerde, K. J.; Van den Berg, J. M.; van de Ven, A. A. J. M.; Montfrans, J.; Aydemir, S.; Baris, S.; Dogu, F.; Ikinciogullari, A.; Karakoc-Aydiner, E.; Kilic, S. S.; Kiykim, A.; Kokcu Karadag, S. I.; Kutukculer, N.; Ocak, S.; Unal, E.; Boyarchuk, O.; Hilfanova, A.; Kostyuchenko, L. V.; Alachkar, H.; Arkwright, P. D.; Baxendale, H. E.; Bernatoniene, J.; Coulter, T. I.; Garcez, T.; Goddard, S.; Gompels, M. M.; Grigoriadou, S.; Herriot, R.; Herwadkar, A.; Huissoon, A.; Ibberson, L.; Nademi, Z.; Noorani, S.; Parvin, S.; Steele, C. L.; Thomas, M.; Waruiru, C.; Yong, P. F. K.; Bourne, H

Reperfusion therapies and in-hospital outcomes for ST-elevation myocardial infarction in Europe: The ACVC-EAPCI EORP STEMI Registry of the European Society of Cardiology

Aims: The aim of this study was to determine the contemporary use of reperfusion therapy in the European Society of Cardiology (ESC) member and affiliated countries and adherence to ESC clinical practice guidelines in patients with ST-elevation myocardial infarction (STEMI). Methods and results: Prospective cohort (EURObservational Research Programme STEMI Registry) of hospitalized STEMI patients with symptom onset <24 h in 196 centres across 29 countries. A total of 11 462 patients were enrolled, for whom primary percutaneous coronary intervention (PCI) (total cohort frequency: 72.2%, country frequency range 0-100%), fibrinolysis (18.8%; 0-100%), and no reperfusion therapy (9.0%; 0-75%) were performed. Corresponding in-hospital mortality rates from any cause were 3.1%, 4.4%, and 14.1% and overall mortality was 4.4% (country range 2.5-5.9%). Achievement of quality indicators for reperfusion was reported for 92.7% (region range 84.8-97.5%) for the performance of reperfusion therapy of all patients with STEMI <12 h and 54.4% (region range 37.1-70.1%) for timely reperfusion. Conclusions: The use of reperfusion therapy for STEMI in the ESC member and affiliated countries was high. Primary PCI was the most frequently used treatment and associated total in-hospital mortality was below 5%. However, there was geographic variation in the use of primary PCI, which was associated with differences in in-hospital mortality

The ESC ACCA EAPCI EORP acute coronary syndrome ST-elevation myocardial infarction registry

Aims: The Acute Cardiac Care Association (ACCA)-European Association of Percutaneous Coronary Intervention (EAPCI) Registry on ST-elevation myocardial infarction (STEMI) of the EurObservational programme (EORP) of the European Society of Cardiology (ESC) registry aimed to determine the current state of the use of reperfusion therapy in ESC member and ESC affiliated countries and the adherence to ESC STEMI guidelines in patients with STEMI. Methods and results: Between 1 January 2015 and 31 March 2018, a total of 11 462 patients admitted with an initial diagnosis of STEMI according to the 2012 ESC STEMI guidelines were enrolled. Individual patient data were collected across 196 centres and 29 countries. Among the centres, there were 136 percutaneous coronary intervention centres and 91 with cardiac surgery on-site. The majority of centres (129/196) were part of a STEMI network. The main objective of this study was to describe the demographic, clinical, and angiographic characteristics of patients with STEMI. Other objectives include to assess management patterns and in particular the current use of reperfusion therapies and to evaluate how recommendations of most recent STEMI European guidelines regarding reperfusion therapies and adjunctive pharmacological and non-pharmacological treatments are adopted in clinical practice and how their application can impact on patients' outcomes. Patients will be followed for 1 year after admission. Conclusion: The ESC ACCA-EAPCI EORP ACS STEMI registry is an international registry of care and outcomes of patients hospitalized with STEMI. It will provide insights into the contemporary patient profile, management patterns, and 1-year outcome of patients with STEMI

Stoma-free Survival After Rectal Cancer Resection With Anastomotic Leakage: Development and Validation of a Prediction Model in a Large International Cohort.

Objective:To develop and validate a prediction model (STOMA score) for 1-year stoma-free survival in patients with rectal cancer (RC) with anastomotic leakage (AL).Background:AL after RC resection often results in a permanent stoma.Methods:This international retrospective cohort study (TENTACLE-Rectum) encompassed 216 participating centres and included patients who developed AL after RC surgery between 2014 and 2018. Clinically relevant predictors for 1-year stoma-free survival were included in uni and multivariable logistic regression models. The STOMA score was developed and internally validated in a cohort of patients operated between 2014 and 2017, with subsequent temporal validation in a 2018 cohort. The discriminative power and calibration of the models' performance were evaluated.Results:This study included 2499 patients with AL, 1954 in the development cohort and 545 in the validation cohort. Baseline characteristics were comparable. One-year stoma-free survival was 45.0% in the development cohort and 43.7% in the validation cohort. The following predictors were included in the STOMA score: sex, age, American Society of Anestesiologist classification, body mass index, clinical M-disease, neoadjuvant therapy, abdominal and transanal approach, primary defunctioning stoma, multivisceral resection, clinical setting in which AL was diagnosed, postoperative day of AL diagnosis, abdominal contamination, anastomotic defect circumference, bowel wall ischemia, anastomotic fistula, retraction, and reactivation leakage. The STOMA score showed good discrimination and calibration (c-index: 0.71, 95% CI: 0.66-0.76).Conclusions:The STOMA score consists of 18 clinically relevant factors and estimates the individual risk for 1-year stoma-free survival in patients with AL after RC surgery, which may improve patient counseling and give guidance when analyzing the efficacy of different treatment strategies in future studies