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Background. Oral immunotherapy (OIT) is an emerging method for treating food allergy in children. However, data regarding adults undergoing this process is lacking. Methods. We retrospectively analyzed the medical records of patients with food allergy aged ≥17 years who completed OIT treatment between April 2010 to December 2020 at Shamir medical Center. Data was compared to that of children aged 4 to <11 years and adolescents aged ≥11 to 17 treated during the same time period. Results. A total of 96 adults at a median age of 22.3 years who underwent OIT for milk (n=53), peanut (n=18), sesame (n=7), egg (n=5) and tree nuts (n=13) were analyzed and compared to 1299 children and 309 adolescents. Adults experienced more adverse reactions requiring injectable epinephrine, both during in-clinic up-dosing (49% vs. 15.9% and 26.5% for children and adolescents respectively, p<0.0001) and during home treatment (22.9% vs. 10.5%, p=0.001 for children, and 14.2%, p=0.06 for adolescents). Most adults (61.5%) were fully desensitized, but rates of full desensitization were significantly lower compared to children (73.4%, p=0.013). Significantly more adults (28.3%) undergoing milk OIT failed treatment compared to children (14.3%, p=0.015) and adolescents (14.1%, p=0.022), while failure rates in adults undergoing OIT for other foods were low (9.3%) and comparable to children and adolescents. Conclusions. OIT is successful in desensitizing most adults with IgE-mediated food allergy. Adults undergoing milk OIT are at increased risk for severe reactions and for OIT failure while failure rates in adults undergoing OIT for other foods are low.

Kaili Wu

and 7 more

Objective: To explore the audiological characteristics of infant auditory neuropathy (AN) patients with cochlear microphonic (CM) recorded but no otoacoustic emission (OAE) response and clinically reduce the rate of missed diagnosis of AN. Design: Retrospective clinical study of medical data from 2003 to 2020. Setting: Otolaryngology head and neck surgery clinical hearing center. Participants: Eighteen infant AN patients with CM present and distortion product otoacoustic emission (DPOAE) absent in both ears were OAE absent group. Forty-four infant AN patients with CM and DPOAE present in both ears were OAE present group. Main outcome measures: Audiological characteristics. Results: 1. The age of onset in OAE absent group was 0.9 (0.02) years old, which was less than 1.11 (1.63) years old in OAE present group (P=0.041). 2. The CM threshold of OAE absent group was 80 (10) dB nHL, which was significantly higher (P<0.001) than OAE present group. CM amplitude were smaller (P<0.05), and CM duration were shorter (P<0.05) in OAE absent group. 3. The thresholds of auditory steady-state response (ASSR) at 0.5, 1, 2 and 4 kHz were 94 (10), 94 (10), 87 (20) and 81 (10) dB HL cg respectively in OAE absent group, which were higher than those in OAE present group (P<0.01). Conclusions: Infant AN patients with CM present and OAE absent showed earlier onset, worse hearing level and worse CM performance. The influencing factors and value of CM in AN patients still need to be explored in the future.

Emily Williams

and 3 more

Background Uterine artery embolization (UAE) and myomectomy are uterus-sparing treatments for uterine fibroids. Each carries a different risk and efficacy profile. Despite this there is a lack of direct comparison between the two techniques making treatment choice decisions difficult. Objectives To compare the therapeutic efficacy and complications of UAE versus myomectomy. Search strategy A systematic search of The Cochrane Library, Medline, and EMBASE databases was conducted using a pre-defined search strategy. The review was prospectively registered on PROSPERO (CRD42021259347). Selection Criteria All randomised controlled trials and cohort studies published between January 1995 and August 2021 directly comparing UAE and myomectomy were included. Data Collection and Analysis Meta-synthesis of raw data was performed using Review Manager 5.4.1 from the Cochrane Collaboration. A pooled estimate of efficacy was established using a fixed-effect model. Main results 8 studies were identified. UAE was associated with lower complication rates (OR 0.56; 95% CI 0.40-0.79), increased improvement in bleeding (OR 1.61 95% CI 1.07-2.43) and a shorter total recovery time (7.72 days versus 36.63 days). Whilst myomectomy was associated with a higher post-procedure quality of life (mean difference -10.56; 95% CI -15.34 - -5.79) and lower re-intervention rate (OR 5.16; 95% CI 2.41-11.04). No significant difference in procedural failure rate was seen (OR 0.67; 95% CI 0.30-1.50). Given concerns with UAE and future fertility limited post-procedure fertility outcomes were identified. Conclusions: Given differences in efficacy profiles a personalised approach to treatment discussions should be maintained. Funding: None Keywords: Uterine artery embolization, myomectomy, uterine fibroid

Eric Bongelli

and 4 more

We used the Qamanirjuaq, Bathurst, and George River barren-ground caribou sine cycles to project numbers (Nt), calculate subpopulation annual growth rates (λt) and calculate logistic carrying capacity (Kt). Maximum annual growth rate was 1.196 and maximum annual rate of decline was 0.836 for the harvested Qamanirjuaq subpopulation sine cycle. However, the maximum annual subpopulation growth rates for both the harvested Bathurst and George River subpopulation sine cycles were greater than the biologically possible maximum intrinsic rate of increase during the eruption phase. Subpopulation numbers for Qamanirjuaq, Bathurst and George River barren-ground caribou subpopulations all closely tracked carrying capacity for one complete cycle with lag times between Nt and Kt ranging from < 1-year to approximately 5-years. The short lag times observed indicates that Qamanirjuaq, Bathurst and George River barren-ground caribou subpopulations closely track their range condition. Range condition drives barren-ground caribou subpopulation cycles, but range condition also cycles; presumably because annual barren-ground caribou grazing rates are proportional to barren-ground caribou numbers and eventually exceed range annual growth rates. Immigration from adjacent subpopulations plays a role in the initiation and acceleration of the eruption period in some subpopulations, but not all of them. Numerical synchrony and asynchrony with adjacent subpopulation cycles can affect the timing of the eruption phase through mediation of immigration. Once subpopulation range has recovered, the rapid recovery of subpopulation numbers suggest that subpopulations are not restricted by other factors. The regularity and symmetry of both the increase and decline phases of these cycles suggests that the barren-ground caribou cycle is both stable and resilient. Continuation of barren-ground caribou cycles at historical levels is likely if habitat conservation measures are adopted so that annual migration patterns are not disrupted, summer and winter range remain undisturbed and common-sense harvest management policies are adopted when caribou are at low numbers.
Aim: To evaluate the treatments used in patients diagnosed with SARS-CoV-2 infection hospitalized in critical care service, through a prescription indication study. Methods: A longitudinal observational study of medication use, of the indication-prescription type with elements of the therapeutic scheme and practical consequences, was carried out. The sample was characterized from the sociodemographic, clinical, and pharmacotherapeutic points of view. The prescription was evaluated through the indicators: indication, therapeutic scheme, treatment individualization, and drug combinations. The detected adverse reactions were classified according to their causality by the Naranjo Algorithm, their severity, their clinical significance, and according to their mechanism by Rawlins and Thompson. Results: In the sample (N=77), the male gender predominated (79%) between 27-59 years old (64%), alcohol consumer (62%), hypertensive (33%) with long hospital stay (51%). 417 medications were analyzed, being antibiotics (50.6%) being the most prescribed. 73.4% of the therapeutic schemes were correct, however, 26.6% had problems with the therapeutic schemes due to the use of incorrect doses, intervals, and duration of treatment, as well as risky interactions. Two probable adverse reactions were detected, mild, non-serious, and type A and B according to Rawlins and Thompson. Conclusions: The results obtained will allow the pharmaceutical professional to create risk matrices that guarantee a timely intervention in the health team to contribute to the rational and safe use of medicines in patients infected with SARS-CoV-2.

Joshua Sink

and 1 more

Employing New Criteria for Confirmation of Conduction Pacing – Achieving True Left Bundle Branch Pacing May Be Harder Than Meets the EyeJoshua Sink, MD1, Nishant Verma, MD, MPH2Northwestern University, Feinberg School of Medicine, Department of Internal MedicineNorthwestern University, Feinberg School of Medicine, Division of CardiologyCorresponding Author:Nishant Verma, MD, MPH251 East Huron Street, Feinberg 8-503Chicago, IL 60611312-926-2148Nishant.Verma@nm.orgFunding: NoneDisclosures: Dr. Sink has nothing to disclose. Dr. Verma receives speaker honoraria from Medtronic, Biotronik and Baylis Medical and consulting fees from Boston Scientific, Biosense Webster, AltaThera Pharmaceuticals and Knowledge 2 Practice.Word Count: 1200In recent years, conduction system pacing (CSP) has garnered significant attention from the electrophysiology (EP) community. This movement has been driven by the hypothesis that using the natural conduction system activation is desirable and clinically beneficial in patients with advanced conduction disease and ventricular desynchrony. Permanent His-bundle pacing (PHBP) is generally seen as the purest form of conduction system activation. (Figure 1) PHBP was first described over 20 years ago but the idea has attracted substantial investigative effort in recent years. When successfully achieved, His bundle pacing has been associated with reduction in mortality, reduction in heart failure (HF) admissions, and improvement in left ventricular (LV) function compared to right ventricular (RV) pacing.1 Despite this, consistent achievability in real-world practice remains limited due to a variety of factors including narrow anatomic targetability, lead stability, high pacing thresholds, low ventricular sensing, and inability to correct the QRS in bundle branch block.2Thus, while waiting for the next iteration of improved delivery techniques, pacing leads and programming algorithms,, alternative methods of conductive system pacing have emerged, with the potential to surmount the challenges described.Left bundle branch pacing (LBBP) has recently emerged as an alternative method of CSP. The technique was first described by Huang et al. in 2017 and has seen a momentous rise in interest since.3 In 2019, Huang et al. produced a user manual for a successful LBBP procedure, and in it they attempted to develop the first iteration of criteria for the confirmation of LBBP.4 Utilizing these criteria, or close variations of them, a number of studies were published afterwards that demonstrated preliminary safety, feasibility, and efficacy of LBBP.5,6,7 LBBP became an attractive alternative to His bundle pacing because of the lower thresholds, improved lead stability, and higher procedural success rates. When compared against RV pacing in patients requiring a high burden of pacing, LBBP has demonstrated reduced mortality, HF admissions, and need for upgrade to a BiV device.8 In a small, non-randomized patient sample, LBBP showed greater improvement in LV ejection fraction (EF) compared to BiV pacing.9 Most notably, perhaps, is the astonishing rate of lead placement success, with achievement rates reported as high as 98% in sizable studies.6Differences between the two forms of CSP were apparent from the beginning, including in the appropriate QRS morphology after a successful case. Unlike PHBP, LBBP did not reproduce the native QRS and the QRS duration was often greater than at baseline (Figure 2). The arena of LBBP underwent a notable shift in the Fall of 2021 when Wu et al. proposed new criteria to prove LBBP.10 In this study, they presented an exquisite display of fundamental electrophysiologic principles by using mapping catheters positioned on the His and LV septum during LBB lead placement. Through this painstaking work, they clarified the difference between true LBBP and left bundle branch area pacing (LBBAP), which can incorporate both LBBP and left ventricular septal pacing (LVSP). In their proposed framework, without the presence of a His or LV septum mapping catheter, output dependent QRS transition from non-selective (NS-LBBP) to selective-LBBP (S-LBBP) or LVSP is necessary to prove LBBP and had a sensitivity and specificity of 100%.The present study by Shimeno et al, published in the current issue of the Journal of Cardiovascular Electrophysiology , is the first known effort to document achievement rates of LBBP by utilizing the modified criteria proposed by Wu et al.11 The primary finding of the study is that achieving true LBBP with an acceptable pacing threshold is likely harder than previously realized. As expected, there was improvement after a learning curve, but even in the last third of patients enrolled, the achievement rate of LBBP was only 50%. This is dramatically lower than previously reported achievement rates using the original Huang et al. criteria, and it suggests that not all patients in the previously described studies were actually achieving true LBBP. An unknown subset of patients in these studies was likely only achieving LVSP. This is probably due to a prior reliance on indicators such as a paced right bundle branch block (RBBB) pattern, identification of an intrinsic LBB potential, and/or use of V6 R-wave peak time cutoffs (RWPT) without clear output-dependent QRS transition. It is also worth noting that a variety of RWPT cutoffs have been used seemingly arbitrarily as ‘evidence of LBBP’. This presents a major dilemma and highlights the need for a clear set of LBBP criteria to be defined by the collective EP community. Despite these caveats, many of these previous studies did not fully confirm LBBP in their patients, yet the outcomes from these studies were still clinically promising. This raises the obvious question, does obtaining true LBBP matter? Future studies will need to explore the differences in clinical outcomes between true LBBP and LVSP.Secondarily, Shimeno et al. have provided a useful tool in identifying that LBB potential to QRS-onset ≥ 22ms had a specificity of 98% in predicting LBBP.11 This target measure can help future operators ensure proximal enough engagement of the LBB conduction system. Additionally, the group took a close look at validating a RWPT cutoff time for the prediction of LBBP. Unfortunately, a RWPT cutoff of 68 ms (in non-LBBB patients), determined by the ROC curve, was not highly predictive. This runs contrary to previous reports by Wu et al. and Jastrzebski et al., which reported higher predictive value of RWPT cutoffs10,12 Looking at the data surrounding RWPT cutoffs as a collective, it likely should not be used as a primary metric for confirming LBBP due to imperfect sensitivity and specificity, but it may be an alternative if output dependent QRS transition or change in RWPT of ≥10 ms is not observed. Additionally, in the event that capture thresholds are similar between the LBB and the adjacent myocardium, programmed stimulation is an option to try to reveal a QRS transition by exploiting differences in refractory periods.This study also highlighted one of the unique complications of LBBP by demonstrating a high rate of septal perforation. Paradoxically, more perforations were seen with increased experience, likely highlighting that deeper penetration into the septum is often sought as operators become more familiar with the procedure. The long-term clinical implications of this complication are, thus far, unknown.Looking forward, clear guidelines for confirmation of LBBP need to be defined. This is necessary to ensure quality before undertaking multi-center randomized controlled trials to assess LBBP in comparison to current pacing methods. To date, Wu et al. seem to have provided the best framework to achieve this.10 That said, there are concerns given that this has only been validated in 30 patients (and only 9 with LBBB). In an ideal world, these criteria would be validated in a larger population, though the work to accomplish this would be meticulous given the current gold standard of using an LV septal mapping catheter to prove conduction system capture. Shimeno et al. should be congratulated for their effort in putting this framework to practice. In their work, they have demonstrated that achieving true LBBP as defined by Wu et al. may be harder than meets the eye, and this is very important in assessing the practicality of using LBBP as a widespread alternative to other pacing methods.References:Abdelrahman M, Subzposh FA, Beer D, et al. Clinical Outcomes of His Bundle Pacing Compared to Right Ventricular Pacing. J Am Coll Cardiol . 2018;71(20):2319-2330. doi:10.1016/j.jacc.2018.02.048Zanon F, Abdelrahman M, Marcantoni L, et al. Long term performance and safety of His bundle pacing: A multicenter experience. J Cardiovasc Electrophysiol . 2019;30(9):1594-1601. doi:10.1111/jce.14063Huang W, Su L, Wu S, et al. A Novel Pacing Strategy With Low and Stable Output: Pacing the Left Bundle Branch Immediately Beyond the Conduction Block. Can J Cardiol . 2017;33(12):1736.e1-1736.e3. doi:10.1016/j.cjca.2017.09.013Huang W, Chen X, Su L, Wu S, Xia X, Vijayaraman P. A beginner’s guide to permanent left bundle branch pacing. Heart Rhythm . 2019;16(12):1791-1796. doi:10.1016/j.hrthm.2019.06.016Padala SK, Master VM, Terricabras M, et al. Initial Experience, Safety, and Feasibility of Left Bundle Branch Area Pacing: A Multicenter Prospective Study. JACC Clin Electrophysiol . 2020;6(14):1773-1782. doi:10.1016/j.jacep.2020.07.004Su L, Wang S, Wu S, et al. Long-Term Safety and Feasibility of Left Bundle Branch Pacing in a Large Single-Center Study. Circ Arrhythm Electrophysiol . 2021;14(2):e009261. doi:10.1161/CIRCEP.120.009261Huang W, Wu S, Vijayaraman P, et al. Cardiac Resynchronization Therapy in Patients With Nonischemic Cardiomyopathy Using Left Bundle Branch Pacing. JACC Clin Electrophysiol . 2020;6(7):849-858. doi:10.1016/j.jacep.2020.04.011Sharma PS, Patel NR, Ravi V, et al. Clinical outcomes of left bundle branch area pacing compared to right ventricular pacing: Results from the Geisinger-Rush Conduction System Pacing Registry. Heart Rhythm . 2022;19(1):3-11. doi:10.1016/j.hrthm.2021.08.033Wu S, Su L, Vijayaraman P, et al. Left Bundle Branch Pacing for Cardiac Resynchronization Therapy: Nonrandomized On-Treatment Comparison With His Bundle Pacing and Biventricular Pacing. Can J Cardiol . 2021;37(2):319-328. doi:10.1016/j.cjca.2020.04.037Wu S, Chen X, Wang S, et al. Evaluation of the Criteria to Distinguish Left Bundle Branch Pacing From Left Ventricular Septal Pacing. JACC Clin Electrophysiol . 2021;7(9):1166-1177. doi:10.1016/j.jacep.2021.02.018Shimeno K, Tamura S, Hayashi Y, et al. Achievement Rate and Learning Curve of Left Bundle Branch Capture in Left Bundle Branch Area Pacing Procedure Performed to Demonstrate Output-Dependent QRS Transition.J Cardiovasc Electrophysiol . 2022Jastrzębski M, Kiełbasa G, Curila K, et al. Physiology-based electrocardiographic criteria for left bundle branch capture. Heart Rhythm . 2021;18(6):935-943. doi:10.1016/j.hrthm.2021.02.021Figure LegendsFigure 1: Permanent His Bundle PacingPanel A: A 12-lead electrocardiogram (EKG) shows baseline conduction in a patient with exertional intolerance. The PR interval is markedly prolonged and, with exercise, this patient developed AV block. A permanent His-bundle pacemaker was implantedPanel B: An EKG demonstrating permanent His-bundle pacing in the same patient as panel A. Selective His-bundle capture results in reproduction of the intrinsic QRS complex.Figure 2: Non-Selective Left Bundle Branch PacingA 12-Lead electrocardiogram showing non-selective left bundle branch pacing. The paced QRS morphology is not a direct match for native conduction and the QRS duration is longer than at baseline. However, conduction system capture was confirmed with an output dependent QRS morphology change.FiguresFigure 1: Permanent His-Bundle Pacing

Jia-hui Ma

and 9 more

Background and Purpose Chronic obstructive pulmonary diseases (COPD) are age-related, airflow-obstruction diseases mostly caused by cigarette smoke. However, the relationship between COPD and lung cellular senescence is still not fully understood. Here, we investigated how E3 ligase Pellino-1 mediated COPD and lung cellular senescence. Experimental Approach We used western blot, qPCR and co-IP assays to analyze the correlation of Pellino-1 and P21 in cells with or without silencing Pellino-1. Then we used flow cytometry, immunofluorescence staining and β- galactosidase assay to analyze the influences of silencing Pellino-1. Furthermore, we constructed COPD and aging models in vivo. Adenovirus of knock-down and overexpression Pellino-1 was used to infected mice. Immunohistochemistry and HE staining were used to analyze the lung pathology. Key Results Here, we first found that the E3 ubiquitin ligase Pellino-1 could bind to senescence marker p21 and modify p21 by K63-site ubiquitination and verified with silencing Pellino-1. Furthermore, we found that p21-mediated lung cellular senescence could be inhibited by silencing Pellino-1. Moreover, by constructing an adenovirus mouse model, we found that silencing Pellino-1 could inhibit COPD and inflammation via reduction of SASPs regulated by p21. Resistomycin, a potential Pellino-1 inhibitor, interrupts the interaction between Pellino-1 and p21, which accelerates the ubiquitin-dependent degradation of p21 and consequently inhibits lung cellular senescence and COPD progression. Conclusion and Implications Our study elucidated that inhibition of E3 ligase Pellino-1 exhibits therapeutic potential for treatment to attenuate the progression of lung cellular senescence and COPD.

Jawad Khalil

and 8 more

Background: Ticagrelor is labelled as a reversible, direct-acting platelet P2Y12 receptor (P2Y12R) antagonist that is indicated clinically for the prevention of thrombotic events in patients with acute coronary syndrome (ACS). As with many antiplatelet drugs, ticagrelor therapy increases bleeding risk in patients which in emergency situations requires platelet transfusion although there is ongoing debate on its effectiveness following ticagrelor therapy. The aim of this study was to further examine the reversibility of ticagrelor at the P2Y12R. Methods: Studies were performed in human platelets with both P2Y12R-stimulated GTPase activity and platelet aggregation assessed. Cell-based bioluminescence resonance energy transfer (BRET) assays were also undertaken to assess G protein subunit activation downstream of P2Y12R activation. Results: Initial studies revealed a range of P2Y12R ligands including ticagrelor displayed inverse agonist activity at the P2Y12R. Of these only ticagrelor was resistant to wash-out. In both human platelets and cell-based assays, washing failed to reverse ticagrelor-dependent inhibition of ADP-stimulated P2Y12R function in contrast to other P2Y12R antagonists. The P2Y12R agonist 2MeSADP, which was also resistant to wash-out, was able to effectively compete with ticagrelor. In silico docking revealed that ticagrelor and 2MeSADP penetrated more deeply into the orthosteric binding pocket of the P2Y12R than other P2Y12R ligands. Conclusion: Ticagrelor binding to the P2Y12R is prolonged and more akin to that of an irreversible antagonist especially versus the endogenous P2Y12R agonist ADP. This study highlights the potential clinical need for novel ticagrelor reversal strategies in patients with spontaneous major bleeding and bleeding associated with urgent invasive procedures.

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Yuval Shafir

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INTRODUCTION: Transvenous Lead Extraction (TLE) is usually performed via a superior approach. Predictors and outcomes of TLE requiring femoral vein bailout are poorly defined. We aimed to analyze predictors and consequences of TLE requiring femoral bailout. METHODS: A single tertiary center cohort of 421 consecutive patients who underwent TLE between May 2010 and February 2020 were analyzed. Venography was routinely performed before system upgrade to identify occluded veins. Patients were divided into 2 groups according to their need for femoral bailout extraction. RESULTS: A total of 928 leads were extracted with femoral bailout approach was needed in 71 leads(7.7%) among 49 patients(11.6%). A higher proportion of right ventricular(RV) leads required femoral bailout approach compared with right atrial(RA) leads[51/499(10.2%) vs 18/326(5.5%);p=0.02]. Femoral bailout was more common among younger patients, longer lead dwell time, more pocket entries, higher number of extracted leads, presence of abandoned leads and among patients with vascular occlusion. Following multivariate analysis, presence of abandoned leads, vascular occlusion and younger age remained a significant predictor for femoral bailout. Femoral bailout resulted in higher rates of major complications [5/49(10.2%) vs 12/372(3.2%);p=0.05] without intra-procedural mortality and no additional 30-day mortality[2/49(4.1%) vs 33/377(8.8%);p=0.39]. CONCLUSION: TLE of abandoned leads, occluded veins and younger age were found to be predictors of femoral bailout requirement. Despite higher rates of major complications in femoral TLE bailout, mortality was not increased. Venography prior to TLE should be considered for procedure planning.

Manuel E. Izquierdo

and 21 more

Background:  Heterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown. Objective: To determine whether potentially pathogenic  CFTR variants associate with disease severity and whether individuals with two potentially pathogenic variants exist in a severe asthma-enriched cohort . Methods: We analyzed sequencing data spanning a 190.5Kb region of  CFTR in participants from the Severe Asthma Research Program (SARP1-3). Potentially pathogenic, rare  CFTR variants (frequency<0.05) were classified as CF-causing or of varying clinical consequences (VVCC) (CFTR2.org). Regression-based models tested for association between  CFTR genotypes (0-2 potentially pathogenic variants) and severity outcomes. Results: Of 1401 participants, 9.5% (134) had one potentially pathogenic variant, occurring more frequently in non-Hispanic white (NHW, 10.1% [84 of 831]) compared to African American individuals (AA, 5.2% [22 of 426]). We found ≥2 potentially pathogenic  CFTR variants in 1.4% (19); 0.5% (4) of NHW and 2.8% (12) of AA. Potentially pathogenic  CFTR variant genotypes (≥1 or ≥2 variants) were not cumulatively associated with lung function or exacerbations. In NHW, we found three F508del compound heterozygotes with F508del and a VVCC (two 5T;TG12[c.1210-11T>G] and one Arg1070Trp) and a homozygote for the VVCC, 5T;TG12. Conclusions: We found potentially pathogenic  CFTR variants within a severe asthma-enriched cohort , including three compound heterozygote genotypes variably associated with CF in NHW individuals. These findings provide the rationale for  CFTR sequencing and phenotyping of CF-related traits in individuals with severe asthma.

Hanan Al-Abboh

and 2 more

A Novel MECOM Variant Associated with Congenital Amegakaryocytic Thrombocytopenia and Radioulnar Synostosis Hanan Al-Abboh1, Akmal Zahra1 and Adekunle Adekile1,2Pediatric Hematology Unit, Mubarak Hospital1 and Department of Pediatrics, Faculty of Medicine, Kuwait University2, Kuwait Address Correspondence to: Professor Adekunle Adekile Department of Pediatrics Faculty of Medicine Kuwait University PO Box 24923 Safat 13110 Kuwait Email: adekunle.adekile@ku.edu.kw Tel: +96525319486To the EditorCongenital radioulnar synostosis (RUS) is a rare developmental anomaly of proximal fusion of the radius and ulna, resulting in limited pronation and supination of the forearm. It may accompany other abnormalities in the skeleton, kidney, heart and aneuploidy syndromes1,2. A subset of patients with RUS present with bone marrow failure (BMF) syndromes, characterized by amegakaryocytic thrombocytopenia (RUSAT), progressing to myelodysplasia and pancytopenia2,3. The hematological manifestations are quite variable, with some presenting with severe BMF in childhood, while others are mild and may not present until adulthood.Heterozygous germline variants in the homeobox A11 (HOXA11) gene were the first to be associated with RUS and designated RUSAT14, but lately, several families have been described with variants in the MDS1 and EVI1 complex (MECOM) locus, and referred to as RUSAT22,5,6. Many of these variants appear de novo , while others follow an autosomal dominant inheritance. We, hereby, report the case of a Kuwaiti patient who presented with congenital amegakaryocytic thrombocytopenia (CAMT) in the neonatal period and later noticed to have RUS. Whole exome sequencing revealed a novel MECOM variant.A.A. is a male Kuwaiti, the first child of consanguineous parents and was first seen at the age of 36 days, following antenatal ultrasound diagnosis of bilateral hydronephrosis and right renal cyst. He was a product of induced vaginal delivery with a birth weight of 2.3 kg. After delivery, he was kept under observation in the neonatal intensive care unit. His CBC showed isolated thrombocytopenia (Plt 34 x109/L). He received several platelet transfusions, as well as IVIG twice. Postnatal abdominal ultrasound showed multicystic right kidney, in addition to bilateral hydronephrosis. The mother had no history of thrombocytopenia during pregnancy and there was no other pertinent family history.Physical examination at presentation showed 2 café-au-lait spots, one on the back, measuring 1x2 cm and another over the left leg, that was less than 0.6 cm. There were no obvious dysmorphic features and other systems were unremarkable. CBC showed WBC 11.2 x109/L Hb 10.4 g/dL, MCV 83fl, Plt 49 x109/L, ANC 1.8 x109/L. Renal function tests were normal. Blood film showed no abnormal cells; there was true thrombocytopenia with giant forms. Antiplatelet antibody was negative. Abdominal ultrasound at age 1 month showed complete replacement of the right kidney by cystic changes with left moderate hydronephrosis. Skeletal survey was reportedly normal.Bone marrow biopsy showed normal distribution of granulocytic and erythroid precursors, with severe suppression of megakaryocytosis, consistent with a bone marrow failure syndrome. Chromosomal breakage study was normal. The patient was diagnosed with right undescended testis, as well as right inguinal hernia that were operated at age 1 year and 10 months. At the age 2 and a half years, A.A. was noticed to have limited bilateral arm movement supination and pronation. The mother volunteered that she has a similar defect. X-rays confirmed that the child had bilateral radioulnar synostosis. Whole exome sequencing showed that the patient is heterozygous for a previously-unreported MECOM gene, c.2282A>G mutation. Unfortunately, the parents have not been screened for these mutations.The patient has been under follow up for 4 years, his platelet count has been stable, ranging between 40-50 x109/L, with no bleeding tendency. In spite of his limited arm rotation, he currently functions normally in his daily activities, however, his hand writing skills and ability to engage in sports are yet to be observed since he is still pre-school age. Platelet transfusion is reserved only for severe bleeding, which he has not had. Bone marrow transplant may be considered in future if his bone marrow failure worsens and/or his marrow shows dysplastic changes.Dokal et al3 were the first to report an association between RUS and late-onset BMF, while Thompson et al described its association with CAMT and linked it to the c.872delA ,p.Asn291Thrfs3 variant of the HOXA11gene4,7. More recently, several germline mutations in the MECOM locus have been reported and appear to be the more common cause of RUSAT. Indeed, no other cases of HOXA11 mutations linked to RUSAT have been described since the initial report. Niihori et al8 reported the first 3 heterozygous MECOMmutations in 3 sporadic patients. These variants and those subsequently reported by Walne et al2 are in a highly conserved cluster within 10 amino acids (aa750-760) and impact on either the highly conserved Cys2His2 zinc finger motif (zinc finger 8, aa733-755) or the adjacent linker motif (aa756-760). It has been shown that removal of the 8th zinc finger causes granulopoiesis arrest while mutations and deletions in other parts of the complex, outside the 8th and 9th fingers, are associated with hematological disorders without RUS9.MECOM codes for a zinc finger transcription factor with important roles in normal development and oncogenesis and is involved in the regulation of embryonic development and hematopoietic stem-cell renewal. Hence the phenotype in individuals with these mutations is very variable ranging from BMF to different skeletal, cardiac, renal malformations, B cell deficiency and sensorineural deafness.Our patient showed a previously unreported variant in the region of the 8th zinc finger of the MECOM locus. This c.2282A>G missense variant results in the tyrosine to cysteine substitution at codon 761 (p.Tyr761Cys). The amino acid is in the Zinc finger, C2H2 and Zinc finger, C2H2-like protein domains and is highly evolutionarily conserved. Unfortunately, the parents were not screened for the mutation, however, the mother shows RUS, with normal blood counts. This is consistent with the marked variability in the clinical phenotype. The father is also physically and hematologically normal.Apart from thrombocytopenia, our patient also had renal abnormalities – hydronephrosis and multicystic kidney disease. The natural history of his condition is that he may develop pancytopenia and/or myelodysplasia in the future. He is under close follow up and will be considered for bone marrow transplantation if his condition worsens. In the meantime, he remains hypomegakaryocytic with a platelet count at 30 – 50 x 109/l while other blood cellular elements are normal. His renal function and hearing are being monitored, but still remain normal.AcknowledgementsWe thank the patient’s family for allowing us to report this case. The whole exome sequencing was done at the Laboratory of Genetics and Genomics, Cincinnati Children’s Hospital, Cincinnati, Ohio.References1. Rizzo R, Pavone V, Corsello G, Sorge G, Neri G, Opitz JM. Autosomal dominant and sporadic radio-ulnar synostosis. Am J Med Genet.1997;68(2):127-134.2. Walne A, Tummala H, Ellison A, et al. Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease. Haematologica. 2018;103(7):e284-e287.3. Dokal I, Ganly P, Riebero I, et al. Late onset bone marrow failure associated with proximal fusion of radius and ulna: a new syndrome.Br J Haematol. 1989;71(2):277-280.4. Thompson AA, Nguyen LT. Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nat Genet. 2000;26(4):397-398.5. Germeshausen M, Ancliff P, Estrada J, et al. MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia. Blood Adv. 2018;2(6):586-596.6. Ripperger T, Hofmann W, Koch JC, et al. MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies. Haematologica. 2018;103(2):e55-e58.7. Thompson AA, Woodruff K, Feig SA, Nguyen LT, Schanen NC. Congenital thrombocytopenia and radio-ulnar synostosis: a new familial syndrome.Br J Haematol. 2001;113(4):866-870.8. Niihori T, Ouchi-Uchiyama M, Sasahara Y, et al. Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia. Am J Hum Genet.2015;97(6):848-854.9. Nielsen M, Vermont CL, Aten E, et al. Deletion of the 3q26 region including the EVI1 and MDS1 genes in a neonate with congenital thrombocytopenia and subsequent aplastic anaemia. J Med Genet.2012;49(9):598-600.

Hoda Abdelgawad

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57-years old man presented with exertional dyspnea. An early systolic murmur was heard over the aortic areas 2D and 3D Echocardiography revealed unicuspid , unicommissural aortic valve (UAV) with a characteristic “teardrop” lateral orifice (Figure A) and moderate valve stenosis (3D planimetered aortic valve area (AVA) is 1.1cm2) (Figure B) Continuous wave Doppler across aortic valve (AV) showed high peak and mean systolic gradients of 85 and 60mmHg respectively.(Figure C). 2D /3D Transesophageal Echocardiography (TOE) revealed a subaortic ridge attached to the posterior annulus (Arrow) (Figure D) Further En-face viewing of the aortic valve from the left ventricular outflow tract (LVOT) perspective showed a shelf-like ridge extending from the commissure to the cusp (Arrow) (Figure E) Zoomed mode of the aortic- LVOT junction confirmed the presence of the subaortic ridge seen attached to the posterior aortic annulus near the commissural opening (Figure F) The patient was referred for surgical consultation .. Unicupid aortic valve (UAV) is a rare congenital anomaly that has.2 subtypes ; unicomissural and acommissural subtypes. Both can present with variable degrees of the aortic stenosis (AS) and/or aortic valve regurgitation (AR).UAV has more early, accelerated and severe valvular degeneration in addition to smaller orifice in comparison with bicuspid and tricuspid aortic valve. Echocardiography is the gold standard for diagnosis and evaluation of the AV morphology and function and the associated disorders such as ventricular septal defect , aortopathy and subaortic obstruction.. Surgical aortic valve replacement (AVR) and repair of the associated anomalies are the most common treatment modality .

Esin Isik

and 7 more

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