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This study aimed to investigate the impact of race on hospital length of stay (LOS) and hospital complications among pediatric patients with cervical/thoracic injury.A retrospective cohort was performed using the 2017 admission year from 753 facilities utilizing the National Trauma Data Bank. All pediatric patients with cervical/thoracic spine injuries were identified using the ICD-10-CM diagnosis coding system. These patients were segregated by their race, non-Hispanic white (NHW), non-Hispanic black (NHB), non-Hispanic Asian (NHA), and Hispanic (H). Demographic, hospital variable, hospital complications, and LOS data were collected. A linear and logistic multivariate regression analysis was performed to determine the risk ratio for hospital LOS as well as complication rate, respectively.A total of 4,125 pediatric patients were identified. NHB cohort had a greater prevalence of cervical-only injuries (NHW: 37.39% vs. NHB: 49.93% vs. NHA: 34.29% vs. H: 38.71%, P0.001). While transport accident was most common injury etiology for both cohorts, NHB cohort had a greater prevalence of assault (NHW: 1.53% vs. NHB: 17.40% vs. NHA: 2.86% vs. H: 6.58%, P0.001) than the other cohorts. Overall complication rates were significantly higher among NHB patients (NHW: 9.39% vs. NHB: 15.12% vs. NHA: 14.29% vs. H: 13.60%, P0.001). Compared with the NHW cohort, NHB, NHA, and H had significantly longer hospital LOS (NHW: 6.15 ± 9.03 days vs. NHB: 9.24 ± 20.78 days vs. NHA: 9.09 ± 13.28 days vs. H: 8.05 ± 11.45 days, P0.001). NHB race was identified as a significant predictor of increased LOS on multivariate regression analysis (risk ratio: 1.14, 95% confidence interval: 0.46, 1.82; P = 0.001) but not hospital complications (P = 0.345).Race may significantly impact health care resource utilization following pediatric cervical/thoracic spinal trauma.

In this retrospective study, we report 70 cases of Epstein-Barr virus (EBV)+ diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS) among 1696 DLBCL-NOS cases diagnosed between 2006 and 2019 (prevalence of 4.1%). At diagnosis, median age was 68.5 years; 79% of the cases presented with an advanced-stage disease (III-IV), 48% with extranodal lesions, and 14% with an hemophagocytic lymphohistiocytosis (HLH) (8 at diagnosis and 1 on therapy). A total of 46 cases presented a polymorphic pattern, and 21 were monomorphic. All had a non-germinal center B phenotype, with the majority of tumor cells expressing CD30 and programmed death ligand 1 (98% and 95%, respectively). Type II and III EBV latency was seen in 88% and 12% of the cases, respectively. Patients were treated with immunochemotherapy (59%) or chemotherapy (22%), and 19% received palliative care due to advanced age and altered performance status. After a median follow-up of 48 months, progression-free survival (PFS) and overall survival (OS) at 5 years were 52.7% and 54.8%, respectively. Older age (>50 years) and HLH were associated with shorter PFS and OS in multivariate analysis (PFS: hazard ratio [HR], 14.01; 95% confidence interval [CI], 2.34-83.97; and HR, 5.78; 95% CI, 2.35-14.23; OS: HR, 12.41; 95% CI, 1.65-93.53; and HR, 6.09; 95% CI, 2.42-15.30, respectively). Finally, using a control cohort of 425 EBV− DLBCL-NOS, EBV positivity was associated with a shorter OS outcome within patients >50 years (5-year OS, 53% [95% CI, 38.2-74] vs 60.8% [95% CI, 55.4-69.3], P = .038), but not in younger patients.

Pathogenic variants in TPM2 have been associated with a variable clinical spectrum, including congenital myopathies and distal arthrogryposis, all but one with dominant inheritance. We report the second case of recessively inherited TPM2-related Escobar variant of multiple pterygium syndrome and congenital myopathy in a patient from a consanguineous family. Ultra-structural examination of the biopsy revealed few cores/mini-cores and sparse nemaline rods. We found a novel homozygous intronic sequence variant, c.564–2A>C in TPM2. This variant is predicted to abolish the consensus acceptor splice site for exon 6b of TPM2 gene. Parents of the proband, both healthy adults with no clinical features, were heterozygous for the variant. Here we establish a homozygous intronic variant in TPM2 as the likely cause of Escobar variant of multiple pterygium syndrome and congenital myopathy, with sparse nemaline rods.

Mucolipidosis type IV is a rare autosomal recessive lysosomal storage disorder caused by bi-allelic pathogenic variants in the gene MCOLN1. This encodes for mucolipin-1 (ML1), an endo-lysosomal transmembrane Ca++ channel involved in vesicular trafficking. Although experimental models suggest that defects in mucolipin-1 can cause muscular dystrophy, putatively due to defective lysosomal-mediated sarcolemma repair, the role of mucolipin-1 in human muscle is still poorly deciphered. Elevation of creatine kinase (CK) had been reported in a few cases in the past but comprehensive descriptions of muscle pathology are lacking. Here we report a 7-year-old boy who underwent muscle biopsy due to persistently elevated CK levels (780-15,000 UI/L). Muscle pathology revealed features of a lysosomal storage myopathy with mild regenerative changes. Next generation sequencing confirmed homozygous nonsense variants in MCOLN1. This is a comprehensive pathological description of ML1-related myopathy, supporting the role of mucolipin-1 in muscle homoeostasis.

Disease course of feeding difficulties in spinal muscular atrophy type 2 is not well documented. Disease-modifying therapies rapidly change the trajectory of motor function and survival in spinal muscular atrophy, but effects on co-morbidities like bulbar function are unknown. We analysed data concerning feeding problems and their standard of care treatment in 146 patients with spinal muscular atrophy type 2. Data were collected from two separate cohorts: one single-centre retrospective chart review study from the United Kingdom (London), and one prospective questionnaire-based multicentre study from Italy. Cumulatively feeding difficulties were present in 88 patients (60%) in these 2 cohorts. Median age at onset of problems was 6.5years (range 0-16.5 years). Eighty-two patients (60%) showed periods of underweight according to age adjusted body mass index, and thirty-six patients (25%) showed malnourishment with a significant drop on their weight curves. Enteral feeding was indicated in 23 out of 72 patients in the UK cohort (32%) because of weight loss, oropharyngeal dysphagia or aspiration. Gastrostomy and its placement was generally well tolerated, uncomplicated in 96%, never reversed and performed without Nissen fundoplication in 66% of patients. After gastrostomy chest infections improved in 80% and nutritional status (e.g., Body Mass Index) in 84% of patients. These results show that feeding difficulties are a common problem in spinal muscular atrophy type 2. Treatment strategies should be tailor-made on the symptoms and needs of the individual patient.

Differential diagnosis of wide complex tachycardia in patients taking anti-arrhythmic can be challenging. Conventional ECG diagnostic criteria are poorly specific and should be applied with caution. Patients who develop life-threatening arrhythmias after flecainide infusion should be screened for Brugada Syndrome, especially if concomitant sinus node dysfunction is present. (Level of Difficulty: Intermediate.), Central Illustration

Objective To describe clinical features and disease progression of Selenoprotein N‐related myopathy in a large multicenter cohort of patients. Methods Cross‐sectional multicenter data analysis of 60 patients (53 families) with Selenoprotein N‐related myopathy and single‐center retrospective longitudinal analysis of 25 patients (21 families) over a median period of 5.3 years. Results The majority of patients (46/60, 77%) presented before age 2 years with hypotonia, poor head/neck control, and developmental delay. At last assessment (median age 14 years; range 2.5 to 36 years), 10/60 patients had minimal or no ambulation. Ventilatory support was initiated in 50/60 patients at a mean Forced Vital Capacity (FVC) of 38% and at a median age of 13 years. Forty‐five/60 patients developed scoliosis (at median age 12.1 years) and 18 had scoliosis surgery at a median age of 13.6 years. Five children needed nasogastric feeds and/or gastrostomy. Longitudinal data analysis on 25 patients showed progressive decline of Hammersmith functional motor scores (estimated annual change −0.55 point), time to walk 10 meter, time standing from sitting, and from lying. Sixteen patients had weights

Objective To characterize natural history of Laminin‐α2 related muscular dystrophies (LAMA2‐RD) to help anticipating complications and identifying reliable outcome measures for clinical trial design and powering. Methods We conducted a retrospective, single‐center, cross‐sectional and longitudinal study on 46 LAMA2‐RD pediatric patients (37 families). Patients were seen at the Dubowitz Neuromuscular Centre, London between 1985 and 2019. Data were collected by case note reviews. Time‐to‐event analysis was performed to estimate median age at complications occurrence. Results Forty two patients had complete deficiency of Laminin‐α2 (CD) and four had partial deficiency (PD). Median age at first and last assessment was 2 years and 12.1 years, respectively. Median follow‐up length was 7.8 years (range 0‐18 years). Seven CD patients died at median age 12 years. One CD and two PD subjects achieved independent ambulation. We observed a linear increase in elbow flexor contractures in CD subjects. Thirty‐two CD and one PD patient developed scoliosis, nine underwent spinal surgery. Twenty‐two CD required nocturnal noninvasive ventilation (median age 11.7 years). CD subjects showed a 2.9% linear annual decline in forced vital capacity % predicted. Nineteen CD and one PD patient required gastrostomy insertion for failure to thrive and/or unsafe swallow (median age 10.9 years). Four CD patients had partial seizures. Mild left cardiac ventricular dysfunction and rhythm disturbances were identified in seven CD patients. Interpretation This retrospective longitudinal study provides long‐term natural history of LAMA2‐RD. This will help management and identification of key milestones of disease progression that could be considered for future therapeutic intervention.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.

Purpose: The histone-methyl transferase EZH2, catalytic subunit of the PRC2 complex involved in transcriptional regulation, is mutated in approximately 25% of germinal center B-cell lymphomas. Aberrant proliferative dependency on EZH2 activity can be targeted by the orally available EZH2 inhibitor tazemetostat (EPZ-6438). We report the results of the phase Ib tazemetostat plus R-CHOP combination (NCT02889523), in patients 60 to 80 years of age with newly diagnosed diffuse large B-cell lymphoma. Patients and Methods: The primary objective of this dose-escalation study was to evaluate the safety of the combination and to determine the recommended phase II dose (RP2D) of tazemetostat. Results: A total of 17 patients were enrolled. During C1 and C2, two dose-limiting toxicities were observed: one grade 3 constipation at 400 mg and one grade 5 pulmonary infection at 800 mg. Grade 3 or more toxicities observed in more than 10% of the patients were constipation (24%), nausea (12%), and hypokalemia (12%). Grade 3 to 4 hematologic adverse events were recorded in 8 patients (47%): neutropenia (47%), leukopenia (29%), anemia (18%), and thrombocytopenia (12%). The tazemetostat RP2D was 800 mg. No organ-oriented toxicity increased with tazemetostat dosage escalation (severity and incidence). At 800 mg, AUC and Cmax of tazemetostat were similar compared with the single-agent study (E7438-G000-101). Conclusions: The RP2D of tazemetostat combined with R-CHOP is 800 mg twice a day. The association presents safety and PK comparable with R-CHOP alone. Preliminary efficacy data are encouraging and further investigations in phase II trial are warranted.

Mantle cell lymphoma has a dismal prognosis at relapse or in the refractory setting. Among therapies, mTor pathway targeting by temsirolimus has been the first strategy approved for relapse in Europe. While its efficacy in monotherapy has long been demonstrated, its use remains limited. In the T3 phase Ib clinical trial, we investigated the recommended dose of temsirolimus in association with R-CHOP (R-CHOP-T), or high-dose cytarabine plus rituximab (R-DHA-T), or fludarabine, cyclophosphamide plus rituximab (R-FC-T). From November 11, 2011 to February 26, 2015, forty-one patients were enrolled. Patients presented with high MIPI (47.5%) at relapse and a median number of treatments of 1 (1–3). Patients were treated by R-CHOP-T (n = 10), R-FC-T (n = 14), or R-DHA-T (n = 17) according to the choice of local investigators. The maximum tolerated dose (MTD) was 15 mg in the R-CHOP-T arm and has not been determined in other treatment arms because of toxicities. All patients experienced ≥ Grade 3 adverse events, mainly thrombocytopenia (76%). Twenty-six patients discontinued prematurely the treatment, mostly for toxicity (n = 12) and progression of the disease (n = 8). Of note, 6 patients of the R-DHA-T arm reached complete remission (35%). Temsirolimus with immuno-chemotherapy is associated with a high rate of toxicities. Determination of MTD could only be achieved for R-CHOP-T arm. Associations between temsirolimus and other targeted therapies may be warranted for R/R MCL patients.

Background Literature regarding congenital subependymal giant cell astrocytomas (SEGA) is limited, and suggests they are at risk of rapid growth and complications. We sought to characterise the growth patterns of congenital SEGA. The second part of the study was an exploratory analysis of congenital SEGA as a possible biomarker for poor neurological outcome. Methods This single-centre case series describes ten patients with TSC who had SEGA diagnosed before 12 months. SEGA diameter and volumetric growth were analysed using serial MRIs. Neurological outcomes were compared to a genotype-matched group. Results All children with congenital SEGA had a TSC2 mutation. Patients were followed for 1-8.7 years, during which median SEGA growth rate was 1.1 mm/yr in diameter or 150 mm3/yr volumetrically. SEGA with volume > 500 mm3 had a significantly higher growth rate compared with smaller SEGA (462 mm3/yr vs. 42 mm3/yr, p = 0.0095). Children with congenital SEGA had a high prevalence of severe epilepsy, developmental disability and autism spectrum disorder. Conclusion Congenital SEGA can follow a relatively benign course with a lower growth rate compared with published literature. Frequent neuroimaging surveillance is recommended for congenital SEGA with volumes exceeding 500 mm3. Impact Congenital SEGA occur in 9.2% of paediatric patients with tuberous sclerosis complex.There are few published cases of congenital SEGA to date. This case series of ten patients adds our experience seen in a tertiary referral hospital over 10 years.Congenital SEGA can follow a relatively benign course with a lower growth rate compared with published literature.Congenital SEGA with volume exceeding 500 mm3 had a significantly higher growth rate compared with smaller SEGA and should have more frequent neuroimaging surveillance.

Gray zone lymphoma (GZL), a B-cell lymphoma with features intermediate between large B-cell lymphoma (LBCL) and classic Hodgkin lymphoma (cHL), is a rare and poorly defined entity. Alongside GZL, a subset of Epstein-Barr virus (EBV)–positive diffuse large B-cell lymphoma (DLBCL) has been described with polymorphic/GZL-like morphology (polymorphic-EBV-L). To fill the important gap in our understanding of the pathogenic process underlying these entities, we performed a gene expression study of a large international cohort of GZL and polymorphic-EBV-L, combined with cHL and primary mediastinal large B-cell lymphoma (PMBCL) cases. In an unsupervised principal component analysis, GZL cases presented with intermediate scores in a spectrum between cHL and PMBCL, whereas polymorphic-EBV-L clustered distinctly. The main biological pathways underlying the GZL spectrum were related to cell cycle, reflecting tumor cell content, and extracellular matrix signatures related to the cellular tumor microenvironment. Differential expression analysis and phenotypic characterization of the tumor microenvironment highlighted the predominance of regulatory macrophages in GZL compared with cHL and PMBCL. Two distinct subtypes of GZL were distinguishable that were phenotypically reminiscent of PMBCL and DLBCL, and we observed an association of PMBCL-type GZL with clinical presentation in the “thymic” anatomic niche. In summary, gene expression profiling (GEP) enabled us to add precision to the GZL spectrum, describe the biological distinction compared with polymorphic-EBV-L, and distinguish cases with and without thymic involvement as 2 subgroups of GZL, namely PMBCL-like and DLBCL-like GZL.

Composite and sequential lymphomas involving both classical Hodgkin lymphoma (CHL) and primary mediastinal B-cell lymphoma (PMBCL) are rare phenomena. Beyond the relevant biological interest raised by these cases, treatments and outcome data are poorly covered in the recent literature. This retrospective analysis describes the pathological and clinical characteristics of 10 composite and 15 sequential cases included after a central pathological review. At diagnosis, 70% of the composite lymphomas presented a disseminated and extranodal disease. Among the 15 sequential lymphomas, 12 were CHL at first occurrence and three were PMBCL. Based on their clinical evolution, these sequential lymphomas could be divided into early (i.e., diagnosis of second lymphoma within a year) and late [(i.e., a second lymphoma occurrence occurring after a long period of complete remission]). All composite cases were alive in complete remission after a median follow-up of 34 months. If the early sequential lymphoma presented a particularly poor outcome with a median overall survival shorter than one year, the late cases were efficiently salvaged. Further molecular studies are needed to describe the underlying biology of these rare diseases, possibly representing the extreme of tumour cell plasticity found in grey-zone lymphoma.

Ventricular arrhythmias are an important cause of morbidity and mortality and come in a variety of forms, from single premature ventricular complexes to sustained ventricular tachycardia and fibrillation. Rapid developments have taken place over the past decade in our understanding of these arrhythmias and in our ability to diagnose and treat them. The field of catheter ablation has progressed with the development of new methods and tools, and with the publication of large clinical trials. Therefore, global cardiac electrophysiology professional societies undertook to outline recommendations and best practices for these procedures in a document that will update and replace the 2009 EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias. An expert writing group, after reviewing and discussing the literature, including a systematic review and meta-analysis published in conjunction with this document, and drawing on their own experience, drafted and voted on recommendations and summarized current knowledge and practice in the field. Each recommendation is presented in knowledge byte format and is accompanied by supportive text and references. Further sections provide a practical synopsis of the various techniques and of the specific ventricular arrhythmia sites and substrates encountered in the electrophysiology lab. The purpose of this document is to help electrophysiologists around the world to appropriately select patients for catheter ablation, to perform procedures in a safe and efficacious manner, and to provide follow-up and adjunctive care in order to obtain the best possible outcomes for patients with ventricular arrhythmias.

Ventricular arrhythmias are an important cause of morbidity and mortality and come in a variety of forms, from single premature ventricular complexes to sustained ventricular tachycardia and fibrillation. Rapid developments have taken place over the past decade in our understanding of these arrhythmias and in our ability to diagnose and treat them. The field of catheter ablation has progressed with the development of new methods and tools, and with the publication of large clinical trials. Therefore, global cardiac electrophysiology professional societies undertook to outline recommendations and best practices for these procedures in a document that will update and replace the 2009 EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias. An expert writing group, after reviewing and discussing the literature, including a systematic review and meta-analysis published in conjunction with this document, and drawing on their own experience, drafted and voted on recommendations and summarized current knowledge and practice in the field. Each recommendation is presented in knowledge byte format and is accompanied by supportive text and references. Further sections provide a practical synopsis of the various techniques and of the specific ventricular arrhythmia sites and substrates encountered in the electrophysiology lab. The purpose of this document is to help electrophysiologists around the world to appropriately select patients for catheter ablation, to perform procedures in a safe and efficacious manner, and to provide follow-up and adjunctive care in order to obtain the best possible outcomes for patients with ventricular arrhythmias. Electronic supplementary material The online version of this article (10.1007/s10840-019-00664-2) contains supplementary material, which is available to authorized users.

Background: Primary refractory (PREF) follicular lymphoma (FL) has a completely different clinical course from that of FL that responds to front-line treatments. In addition to having poor responses to salvage therapies, it seems that patients with PREF are at increased risk of histological transformation (HT). The Aristotle consortium presented the opportunity of investigating the risk of HT in a very large series of cases. Thus, we investigated the risk of HT in patients with PREF FL compared with that of responding patients or in stable disease and ultimately their outcome. Methods: Six thousand three hundred thirty-nine patients from the Aristotle database were included in the analysis. These patients had a histologically confirmed grade 1, 2 or 3a FL diagnosed between 1997 and 2013. The primary end-points were the cumulative incidence (CI) of HT at the first progression or relapse and the survival after transformation. Findings.: The 5-year CI of HT among patients with PREF was 34% (95% confidence interval (CI): 27–43), whilst it was 7.1% (95% CI: 6.0–8.5) in the group of patients with partial response (PR) or stable disease (SD) (PR + SD) and 3.5% (95% CI: 3.0–4.2) in the group of patients achieving complete response (CR). The 5-year survival after relapse (SAR) was 33% (95% CI: 28–39) for the PREF group, 57% (95% CI 54–61) in patients with PR, 51% (95% CI 43–58) in the SD group after first-line therapy and 63% (95% CI: 66–72) in patients with CR after initial treatment (p-value

TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient's fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. Several authors of this study are members of the European Reference Network for Neuromuscular disease, Project ID No 739543. This study was supported by the AFM (grant 21644 to AR), the framework of the NME-GPS project by the European Regional Development Fund (AR/US/AS), the support by the Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, the Regierende Bürgermeister von Berlin-inkl. Wissenschaft und Forschung, and the Bundesministerium für Bildung und Forschung (AH and AS), the European Research Council (RH), the Wellcome Investigator Award (109915/Z/15/Z to RH), the Medical Research Council UK (MR/N025431/1 to RH), the Newton Fund (MR/N027302/1 to RH), the Lily Foundation (RH) and the Evelyn Trust (RH). This research was supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1 and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care

Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a rare subtype of lymphoma, clinically and biologically distinct from diffuse large B-cell lymphoma (DLBCL) that shows overlapping ...

Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3–6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.

International audience; Purpose High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype-phenotype correlations in this cohort. Methods We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenicTTNvariants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families). Results Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final threeTTNexons (362-364). Conclusion Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.

Funding Acknowledgements Type of funding sources: None. Background/Introduction: Atrial fibrillation (AF) carries a thrombotic risk related to left atrial blood stasis. Many risk scores, such as the CHA2DS2-VASc score, have been developed to guide physicians in initiating anticoagulant therapy. However, the risk prediction with these models is modest at best (C-statistic = 0.6). The presence of mitral regurgitation (MR) has been shown to reduce thrombotic risk in patients with rheumatic AF. In nonrheumatic AF, direct evidence of a lower thrombotic risk in patients with MR is still controversial. Purpose The current study assessed the effect of MR on thrombotic risk in nonrheumatic AF patients. Methods The prevalence of atrial thrombosis, defined as the presence of left atrial appendage thrombus (LAAT) and/or left atrial spontaneous echo contrast (LASEC) grade >2, was determined in 686 consecutive nonrheumatic AF patients without (adequate) anticoagulation scheduled for transoesophageal echocardiography before electrical cardioversion and was related to the severity of MR adjusted for the CHA2DS2-VASc score. The independent predictors of atrial thrombosis were assessed by stepwise multiple logistic regression analysis. Results A total of 103 (15%) patients had severe MR, 210 (31%) had moderate MR, and 373 (54%) had no-mild MR; the median CHA2DS2-VASc score was 3.0 (IQR 2.0-4.0). Atrial thrombosis (LAAT and/or LASEC grade >2) was observed in 118 patients (17%). The prevalence of atrial thrombosis decreased with increasing MR severity: 19.9% versus 15.2% versus 11.6% for no-mild, moderate, and severe MR, respectively (p for trend = 0.03) (Figure 1). Patients with moderate and severe MR had a lower risk of atrial thrombosis than patients with no-mild MR, with adjusted odds ratios (ORs) of 0.51 (95% CI 0.31-0.84) and 0.24 (95% CI 0.11-0.49), respectively. The other independent predictors of atrial thrombosis were: the CHA2DS2-VASc score with an adjusted OR of 1.25 (95% CI 1.10-1.42), poor left ventricular ejection fraction (LVEF, 37 ml/m²) with an adjusted OR of 1.90 (95% CI 1.19-3.03) (Figure 1, upper right corner). The C-statistic of the regression model increased significantly (p = 0.0003) from 0.62 to 0.75 by adding MR grade, LVEF, and LAVI to the univariate CHA2DS2-VASc score model. The protective effect of MR was present across all levels of the CHA2DS2-VASc score and the presence of moderate-severe MR in patients with an intermediate CHA2DS2-VASc score (2-3) lowered the atrial thrombotic risk to the level of patients with a low CHA2DS2-VASc score (0-1). Conclusion Our data show that the presence of MR attenuated the atrial thrombotic risk by more than 50% in patients with nonrheumatic AF, independent of the CHA2DS2-VASc risk score. Moderate to severe MR can therefore be considered a new risk modifier of the CHA2DS2-VASc score, which might help refine the indication of anticoagulants in AF patients. Abstract Figure 1. Thrombotic risk per MR grade.

The mutational landscape of gray zone lymphoma (GZL) has not yet been established, and differences from related entities are largely unknown. Here, we studied coding sequence mutations of 50 Epstein-Barr virus (EBV)-negative GZLs and 20 polymorphic EBV+ diffuse large B-cell lymphoma (DLBCL) not otherwise specified (poly-EBV-L) in comparison with classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), and DLBCL. Exomes of 21 GZL and 7 poly-EBV-L cases, along with paired constitutional DNA, were analyzed as a discovery cohort, followed by targeted sequencing of 217 genes in an extension cohort of 29 GZL and 13 poly-EBV-L cases. GZL cases with thymic niche involvement (anterior mediastinal mass) exhibited a mutation profile closely resembling cHL and PMBCL, with SOCS1 (45%), B2M (45%), TNFAIP3 (35%), GNA13 (35%), LRRN3 (32%), and NFKBIA (29%) being the most recurrently mutated genes. In contrast, GZL cases without thymic niche involvement (n = 18) had a significantly distinct pattern that was enriched in mutations related to apoptosis defects (TP53 [39%], BCL2 [28%], BIRC6 [22%]) and depleted in GNA13, XPO1, or NF-κB signaling pathway mutations (TNFAIP3, NFKBIE, IKBKB, NFKBIA). They also exhibited more BCL2/BCL6 rearrangements compared with thymic GZL. Poly-EBV-L cases presented a distinct mutational profile, including STAT3 mutations and a significantly lower coding mutation load in comparison with EBV− GZL. Our study highlights characteristic mutational patterns in GZL associated with presentation in the thymic niche, suggesting a common cell of origin and disease evolution overlapping with related anterior mediastinal lymphomas.

Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype–phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the Janus kinase-signal transducer and activator of transcription and nuclear factor κB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, and PDCD1LG2). Our analyses highlight the interferon response factor (IRF) pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, and IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB, and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL compared with diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relation between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic evaluation and therapeutic decision-making.

Objective: The present study aims to identify the long-term effects of atrial fibrillation (AF) on atrial remodelling and on the progression of mitral/tricuspid valve regurgitation (MR/TR). Methods: The severity of MR/TR was assessed by the colour jet area and by multi-integrative approach at baseline and after a period of 65 +/- 10 months in 37 patients with permanent AF, in 80 patients with non-permanent AF (of whom 43 were treated with ablation) and in 53 control patients with sinus rhythm. Results: At baseline, AF patients had larger MR jet areas than control patients. At follow up, progression of MR, expressed as delta MR jet area, was 0.05 +/- 1.3 cm(2) in the control group, 0.73 +/- 2.1 cm(2) in the non-permanent AF group and 1.95 +/- 3.6 cm(2) in the permanent AF group (p = .001). Severe MR at follow up was observed in 0%, 2.5%, 8%, respectively. There was a significant positive correlation between progression of MR and increase of left atrium volume (r = 0.31, p < .001). After adjustment for baseline clinical and echocardiographic parameters, permanent AF remained independently associated with the progression of MR. Although rhythm control was better with AF ablation than with medical treatment only, the MR evolution was similar. Comparable findings, albeit less pronounced, were observed for the association between of AF and TR progression. Conclusions: The presence of longstanding AF is associated with a significant progression of MR/TR mainly due to atrial remodelling. Our data showed a beneficial effect of sustained rhythm control, either medically or by ablation, on MR/TR progression.

Gray-zone lymphoma (GZL) with features intermediate between classic Hodgkin lymphoma (cHL) and large B-cell lymphoma (LBCL) was introduced as a provisional entity into the World Health Organization classification in 2008. However, as diagnostic criteria are imprecise, reliable identification of GZL cases remains challenging. Here, we describe the histopathologic features of 139 GZL cases from a retrospective Lymphoma Study Association (LYSA) study with the goal to improve classification accuracy. Inclusion criteria were based on literature review and an expert consensus opinion of the LYSA hematopathologist panel. We observed 86 cases with a morphology more closely related to cHL, but with an LBCL immunophenotype based on strong and homogenous B-cell marker expression (CD20 and/or CD79a, OCT2, BOB1, PAX5) on all tumor cells (cHL-like GZL). Fifty-three cases were morphologically more closely related to LBCL but harbored a cHL immunophenotype (LBCL-like GZL). Importantly, we observed a continuous morphologic and immunophenotypic spectrum within these 2 GZL categories. The majority of cases presented genetic immune escape features with CD274/PDCD1LG2 and/or CIITA structural variants by fluorescence in situ hybridization. Patients without mediastinal involvement at diagnosis (17%) were older than those with mediastinal tumors (median: 56 vs. 39 y). Cases associated with Epstein-Barr virus (24%) presented with similar patient characteristics and outcome as Epstein-Barr virus negative cases. In summary, we provide refined diagnostic criteria that contribute to a more precise pathologic and clinical characterization of GZL within a broad spectrum from cHL-like to LBCL-like disease.

Follicular lymphoma (FL) is a common indolent lymphoma in which clinical and biological heterogeneity is increasingly recognized.[1][1] Although median survival for newly diagnosed FL patients may be as high as 18 years,[2][2] a significant subset of patients is at risk of adverse outcomes. In

The prevalence of obesity continues to rise in the United States at a disparaging rate. Although previous studies have attempted to identify the influence obesity has on short-term outcomes following elective spine surgery, few studies have assessed the impact on discharge disposition following anterior cervical discectomy and fusion (ACDF) for cervical spondylotic myelopathy (CSM). The aim of this study was to determine whether obesity impacts the hospital management, cost, and discharge disposition after elective ACDF for adult CSM.The National Inpatient Sample database was queried using the International Classification of Diseases, 10th revision, Clinical Modification, coding system to identify all (≥18 years) patients with a primary diagnosis of CSM undergoing an elective ACDF for the years 2016 and 2017. Discharge weights were used to estimate national demographics, Elixhauser comorbidities, complications, length of stay, total cost of admission, and discharge disposition.There were 17,385 patients included in the study, of whom 3035 (17.4%) had obesity (no obesity: 14,350; obesity: 3035). The cohort with obesity had a significantly greater proportion of patients with 3 or more comorbidities compared with the cohort with no obesity (no obesity: 28.1% vs. obesity: 43.5%, P0.001). The overall complication rates were greater in the cohort with obesity (no obesity: 10.3% vs. obesity: 14.3%, P = 0.003). On average, the cohort with obesity incurred a total cost of admission $1154 greater than the cost of the cohort with no obesity (no obesity: $19,732 ± 11,605 vs. obesity: $20,886 ± 10,883, P = 0.034) and a significantly greater proportion of nonroutine discharges (no obesity: 16.6% vs. obesity: 24.2%, P0.001). In multivariate regression analysis, obesity, age, race, health care coverage, hospital bed size, region, comorbidity, and complication rates all were independently associated with nonroutine discharge disposition.Our study demonstrates that obesity is an independent predictor for nonroutine discharge disposition following elective anterior cervical discectomy and fusion for cervical spondylotic myelopathy.

Mutations in the sarcomeric protein titin, encoded byTTN, are emerging as a common cause of myopathies. The diagnosis of aTTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence ofTTNvariants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis ofTTN-related myopathies and the pathogenicity ascertainment ofTTNmissense variants. We identified 30 patients with a primaryTTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missenseTTNvariant, or homozygous for oneTTNmissense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizingTTNmissense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.

Laminopaties; Distròfia muscular; Múscul estriat Laminopatías; Distrofia muscular; Músculo estriado Laminopathies; Muscular dystrophy; Striated muscle Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0–2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8–4.0) and age of ambulation loss (median: 7 years, range: 1.2–38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype–phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations. This work was supported by the AFM-Telethon, the Institut National de la Santé et de la Recherche Médicale (INSERM) and Sorbonne Université (R.B.Y., G.B.), intramural funds of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (C.G.B.), Cure-CMD (A.R., G.B., R.B.Y.), The Andres Marcio Fondation (G.B., R.B.Y). and the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular and the Fashion Industries Guild Endowed Fellowship for the Undiagnosed Diseases Program (T.M.P).

The current study assessed the effect of mitral regurgitation (MR) on thrombotic risk in nonrheumatic atrial fibrillation (AF). AF carries a thrombotic risk related to left atrial blood stasis. The prevalence of atrial thrombosis, defined as the presence of left atrial appendage thrombus and/or left atrial spontaneous echo contrast grade >2, was determined in 686 consecutive nonrheumatic AF patients without (adequate) anticoagulation scheduled for transesophageal echocardiography before electrical cardioversion and was related to the severity of MR adjusted for the CHA2DS2-VASc score. A total of 103 (15%) patients had severe MR, 210 (31%) had moderate MR, and 373 (54%) had no-mild MR; the median CHA2DS2-VASc score was 3.0 (interquartile range 2.0 to 4.0). Atrial thrombosis was observed in 118 patients (17%). The prevalence of atrial thrombosis decreased with increasing MR severity: 19.9% versus 15.2% versus 11.6% for no-mild, moderate, and severe MR, respectively (p value for trend = 0.03). Patients with moderate and severe MR had a lower risk of atrial thrombosis than patients with no-mild MR, with adjusted odds ratios of 0.51 (95% confidence interval 0.31 to 0.84) and 0.24 (95% confidence interval 0.11 to 0.49), respectively. The protective effect of MR was present across all levels of the CHA2DS2-VASc risk score and the presence of moderate-severe MR in patients with an intermediate CHA2DS2-VASc score (2 to 3) lowered the atrial thrombotic risk to the level of patients with a low CHA2DS2-VASc score (0 to 1). In conclusion, our data show that the presence of MR attenuated the atrial thrombotic risk by more than 50% in patients with nonrheumatic AF.

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Aims To develop quality indicators (QIs) that may be used to evaluate the quality of care and outcomes for adults with atrial fibrillation (AF). Methods and results We followed the ESC methodology for QI development. This methodology involved (i) the identification of the domains of AF care for the diagnosis and management of AF (by a group of experts including members of the ESC Clinical Practice Guidelines Task Force for AF); (ii) the construction of candidate QIs (including a systematic review of the literature); and (iii) the selection of the final set of QIs (using a modified Delphi method). Six domains of care for the diagnosis and management of AF were identified: (i) Patient assessment (baseline and follow-up), (ii) Anticoagulation therapy, (iii) Rate control strategy, (iv) Rhythm control strategy, (v) Risk factor management, and (vi) Outcomes measures, including patient-reported outcome measures (PROMs). In total, 17 main and 17 secondary QIs, which covered all six domains of care for the diagnosis and management of AF, were selected. The outcome domain included measures on the consequences and treatment of AF, as well as PROMs. Conclusion This document defines six domains of AF care (patient assessment, anticoagulation, rate control, rhythm control, risk factor management, and outcomes), and provides 17 main and 17 secondary QIs for the diagnosis and management of AF. It is anticipated that implementation of these QIs will improve the quality of AF care.

Knowledge about the quality of care delivered to children with autism spectrum disorders (ASD) in relation to that recommended by clinical practice guidelines (CPGs) is limited. ASD care quality indicators were developed from CPGs and validated by experts, then used to assess the quality of care delivered by general practitioners (GPs) and pediatricians in Australia. Data were retrospectively collected from the medical records of 228 children (≤ 15 years) with ASD for 2012–2013.Overall quality of care was high, but with considerable variation among indicators, and between GPs and pediatricians—e.g., GPs were less likely to complete the assessment care bundle (61%; 95% CI 21–92). Findings highlight potential areas for improvement in the need for standardized criteria for diagnosis. Refereed/Peer-reviewed

Mutations in the LAMA2 gene affect the production of the α2 subunit of laminin-211 (= merosin) and result in either partial or complete laminin-211 deficiency. Complete merosin deficiency is typically associated with a more severe congenital muscular dystrophy (CMD), clinically manifested by hypotonia and weakness at birth, the development of contractures of large joints, and progressive respiratory involvement. Muscle atrophy and severe weakness typically prevent independent ambulation. Partial merosin deficiency is mostly manifested by later onset limb-girdle weakness and joint contractures so that independent ambulation is typically achieved. Collectively, complete and partial merosin deficiency is referred to as LAMA2-related dystrophies (LAMA2-RDs) and represents one of the most common forms of congenital muscular dystrophies worldwide. LAMA2-RDs are classically characterized by both central and peripheral nervous system involvement with abnormal appearing white matter (WM) on brain MRI and dystrophic appearing muscle on muscle biopsy as well as creatine kinase (CK) levels commonly elevated to >1,000 IU/L. Next-generation sequencing (NGS) has greatly improved diagnostic abilities for LAMA2-RD, and the majority of patients with merosin deficiency carry recessive pathogenic variants in the LAMA2 gene. The existence of multiple animal models for LAMA2-RDs has helped to advance our understanding of laminin-211 and has been instrumental in preclinical research progress and translation to clinical trials. The first clinical trial for the LAMA2-RDs was a phase 1 pharmacokinetic and safety study of the anti-apoptotic compound omigapil, based on preclinical studies performed in the dyW/dyW and dy2J/dy2J mouse models. This phase 1 study enabled the collection of pulmonary and motor outcome measures and also provided the opportunity for investigating exploratory outcome measures including muscle ultrasound, muscle MRI and serum, and urine biomarker collection. Natural history studies, including a five-year prospective natural history and comparative outcome measures study in patients with LAMA2-RD, have helped to better delineate the natural history and identify viable outcome measures. Plans for further clinical trials for LAMA2-RDs are presently in progress, highlighting the necessity of identifying adequate, disease-relevant biomarkers, capable of reflecting potential therapeutic changes, in addition to refining the clinical outcome measures and time-to-event trajectory analysis of affected patients.

Follicular lymphoma (FL) accounts for about 20% of all non-Hodgkin lymphoma (NHL) and is the most common indolent form. The disease is characterized by an extremely heterogeneous clinical course dr...

The aim of this study was to investigate whether race is an independent predictor of extended length of stay (LOS) after elective anterior cervical discectomy and fusion (ACDF) for cervical spondylotic myelopathy (CSM).A retrospective cohort study was performed using the National Inpatient Sample database from 2016 to 2017. All adult patients undergoing ACDF for CSM were identified using the International Classification of Diseases, Tenth Revision, Clinical Modification coding system.A total of 15,400 patients were identified, of whom 13,250 (86.0%) were Caucasian (C) and 2150 (14.0%) were African American (AA). The C cohort tended to be older, whereas the AA cohort had 2 times as many patients in the 0-25th income quartile. The prevalence of comorbidities was greater in the AA cohort. Intraoperative fusion levels were similar between the cohorts, whereas the AA cohort had a higher rate of cerebrospinal fluid leak/dural tear. In relation to the number of complications, the C cohort had a lower rate compared with the AA cohort (P = 0.006), including no complication (89.4% vs. 85.3%), 1 complication (9.9% vs. 12.8%), and1 complication (0.7% vs. 1.9%). The AA cohort experienced significantly longer hospital stays (C, 1.9 ± 2.3 days vs. AA, 2.7 ± 3.5; P0.001), greater proportion of extended LOS (C, 17.5% vs. AA, 29.1%; P0.001) and nonroutine discharges (C, 16.1% vs. AA, 28.6%; P0.001). AA race was a significant independent risk factor for extended LOS (odds ratio, 1.98; 95% confidence interval, 1.50-2.61; P0.001).Our study suggests that AA patients have a significantly higher risk of prolonged LOS after elective ACDF for CSM compared with C patients.

Purpose of Review Sex differences in clinical manifestations, electrophysiological properties and treatment of ventricular arrhythmias (VA) have been an area of research in the last years. In this review, we focus on sex differences in the catheter ablation of VA in patients with and without structural heart disease. Recent Findings Women have more frequently RVOT than LVOT PVC/VTs but intrafascicular re-entry occurs more frequently in men than in women. Sex-dependent differences in the autonomic nervous system, hormonal status and/or arrhythmogenic characteristics of the substrate may explain these differences. Women are severely underrepresented in studies of catheter ablation of VA in patients with structural heart disease. This may be explained by the fact that women have lower incidence of certain structural heart diseases (as coronary artery disease and ARVC) and lower susceptibility to ventricular arrhythmias and arrhythmic sudden cardiac death. Catheter ablation of VT in women with coronary artery disease may be associated with slightly higher VT recurrence and same complication rate as in male patients. In women with non-ischemic cardiomyopathy and ARVC catheter ablation are equally effective. In summary, all studies up to date reported that catheter ablation of idiopathic ventricular arrhythmias is equally effective with the same risk of complications in both sex groups. Women with structural heart disease show lower susceptibility to ventricular arrhythmias and arrhythmic sudden cardiac death. Catheter ablation of VT in ischemic heart disease is slightly less effective in women, but is equally effective in NICM and ARVC as in men.

Objective To assess General Practitioner (GP) and pediatrician adherence to clinical practice guidelines (CPGs) for diagnosis, treatment and management of attention deficit hyperactivity disorder (ADHD). Method Medical records for 306 children aged ≤15 years from 46 GP clinics and 20 pediatric practices in Australia were reviewed against 34 indicators derived from CPG recommendations. At indicator level, adherence was estimated as the percentage of indicators with ‘Yes’ or ‘No’ responses for adherence, which were scored ‘Yes’. This was done separately for GPs, pediatricians and overall; and weighted to adjust for sampling processes. Results Adherence with guidelines was high at 83.6% (95% CI: 77.7–88.5) with pediatricians (90.1%; 95% CI: 73.0–98.1) higher than GPs (68.3%; 95% CI: 46.0–85.8; p = 0.02). Appropriate assessment for children presenting with signs or symptoms of ADHD was undertaken with 95.2% adherence (95% CI: 76.6–99.9), however ongoing reviews for children with ADHD prescribed stimulant medication was markedly lower for both pediatricians (51.1%; 95% CI: 9.6–91.4) and GPs (18.7%; 95% CI: 4.1–45.5). Conclusion Adherence to CPGs for ADHD by pediatricians was generally high. Adherence by GPs was lower across most domains; timely recognition of medication side effects is a particular area for improvement.

ObjectiveTo evaluate the relationship between deficit in digit span and genotype in nonsense mutation (nm) Duchenne muscular dystrophy (DMD) (nmDMD).MethodsWe investigated the relationship between normalized digit-span forward (d-sf) and digit-span backward (d-sb) scores to the location of nmDMD mutations in 169 participants ≥5 to ≤20 years who participated in a phase 2b clinical trial. Because alternative promoters are found upstream of DMD exons 30, 45, and 63, we correlated d-sf and d-sb to the specific nmDMD mutation location.ResultsParticipants with nm downstream of exon 30, downstream of exon 45, and downstream of exon 63 had significantly lower normalized d-sf scores (p < 0.0001). Participants with nm downstream of exon 45 in addition had significantly lower normalized d-sb score (p < 0.04). There was no significant difference in the normalized d-sb score in participants with mutations upstream or downstream of DMD exon 30 or upstream or downstream of DMD exon 63.ConclusionOur data provide evidence that specific cognitive deficits correlate to genotype in individuals with nmDMD, highlighting the critical role of brain-specific dystrophin isoforms in the neurobiological manifestations of this disease.Clinicaltrials.gov identifierNCT02090959.

Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma and is notorious for its clinical heterogeneity. Patient outcomes can be predicted by cell-of-origin (COO) classification, demonstrating that the underlying transcriptional signature of malignant B-cells informs biological behavior in the context of standard combination chemotherapy regimens. In the current study, we used mass cytometry (CyTOF) to examine tumor phenotypes at the protein level with single cell resolution in a collection of 27 diagnostic DLBCL biopsy specimens from treatment naive patients. We found that malignant B-cells from each patient occupied unique regions in 37-dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Interestingly, variable MHC class II expression was found to be the greatest contributor to phenotypic diversity. Within individual tumors, a subset of cases showed multiple phenotypic subpopulations, and in one case, we were able to demonstrate direct correspondence between protein-level phenotypic subsets and DNA mutation-defined subclones. In summary, CyTOF analysis can resolve both intertumoral and intratumoral heterogeneity among primary samples and reveals that each case of DLBCL is unique and may be comprised of multiple, genetically distinct subclones. © 2019 International Society for Advancement of Cytometry.

Introduction/Purpose Patients with myotonic dystrophy (DM1) have an increased risk of cardiac conduction disease and ventricular tachycardia associated with sudden cardiac death. Whilst this is well-established in adults, there is little published data on cardiac abnormalities in paediatric patients. To our knowledge this is the largest described cohort of children with DM1. The aim of this study is to better understand the prevalence and type of cardiac abnormalities in paediatric patients with DM1. Methods We retrospectively studied consecutive patients referred to our paediatric quaternary institution between 31 December 2000 and 31 January 2019. The electronic patient record was reviewed for the presence of cardiac manifestations, including clinical assessment in clinic, echocardiogram, 12 lead ECG and 24-hour ECG. Results 60 children were identified with a diagnosis of DM1, 56 (93%) with the congenital form of the disease. The median age at diagnosis was 2.4 (IQR 1.2–24, n=52) months. 51 (85%) were under regular formal cardiac follow up. Cardiac symptoms (syncope, palpitations or chest pain) were present in 6 (10%). 12 lead ECGs were available in 50 (83%) and there was at least one echocardiogram performed in 57 (95%). There were 3 deaths (5%), 2 sudden and unexplained (aged 11 and 6.5 years old). 1 child (2%) underwent pacemaker implantation due to the presence of syncope and evidence of progressive conduction disease (Mobitz II AV block). During the period of follow-up, 37 (62%) patients had evidence of conduction disease on 12 lead ECG or Holter: 1st degree or higher AV block (35%, n=21), trifascicular block (6.7%, n=4), intraventricular conduction delay (32%, n=19), prolonged QTc (15%, n=9) and junctional rhythm (5% n=3). In addition to abnormalities of conduction, 27 (45%) patients had axis deviation and 12 (20%) abnormal repolarisation. Abnormalities were present in 8 (14%) of those with an echocardiogram. 2 (3.5%) had hypertrophic cardiomyopathy. Other abnormalities included bicuspid aortic valve, aortic root dilatation, dyskinetic septal motion, pericardial effusion, mitral valve thickening and perimembranous VSD. 24 (40%) patients had a signal averaged ECG of which 14 (58%) were positive in 1 or more vector. 3 (5%) patients had an exercise test with no arrhythmia or progression of conduction abnormalities. 1 patient had an invasive EP study showing a prolonged HV interval but no inducible ventricular tachycardia. Conclusions There appears to be a high incidence of cardiac involvement in children with DM1. Adverse events (death and pacemaker implantation) are represented in our cohort. More studies are required in order to establish how we might better identify those at risk of progression of conduction disease and ventricular arrhythmia. Regular and lifelong cardiac follow up is advisable but risk stratification and device implantation remains challenging.

Background While severe mitral regurgitation is a well-established risk factor for atrial fibrillation (AF), it is less known whether atrial fibrillation induces mitral/tricuspid valve regurgitation (MR/TR). The present study aims to identify the long-term effects of permanent or non-permanent AF on atrial remodelling and on the progression of MR/TR. Methods The severity of MR/TR was assessed at baseline and after a period of 65±10 months in 37 patients with permanent AF, in 80 patients with non-permanent AF (of whom 43 were treated with ablation) and in 53 control patients with persistent sinus rhythm. MR/TR was qualitatively assessed by the multi-integrative approach, and quantitatively by measurement of the colour jet area. Results At baseline, AF patients had larger MR jet areas than control patients. At follow up, progression of MR, expressed as delta MR jet area, was 0.05±1.3 cm2 in the control group, 0.73±2.1 cm2 in the non-permanent AF group and 1.95±3.6 cm2 in the permanent AF group (p=0.001). Severe MR at follow up was observed in 0%, 2.5%, 8%, respectively. After adjustment for baseline clinical and echocardiographic parameters, permanent AF remained independently associated with the progression of MR. There was a significant positive correlation between a progression of MR and an increase in left atrial volume index (r=0.31, p MR jet area Conclusions The presence of longstanding AF is associated with a significant progression of MR/TR mainly due to atrial remodelling. Our data showed a beneficial effect of sustained rhythm control, either medically or by ablation, on MR/TR progression.

In the rituximab era, one-third of diffuse large B-cell lymphoma patients experience relapse/refractory disease after first-line anthracycline-based immunochemotherapy. Optimal management remains an unmet medical need. The aim of this study was to report the outcomes of a cohort of refractory patients according to their patterns of refractoriness and the type of salvage option. We performed a retrospective analysis, which included 104 diffuse large B-cell lymphoma patients treated at Lyon Sud University Hospital (2002-2017) who presented with refractory disease. Refractoriness was defined as progressive/stable disease during first-line treatment (primary refractory, N = 47), a partial response after the end of first-line treatment that required subsequent treatment (residual disease, N = 19), or relapse within 1 year of diagnosis after an initial complete response (CR) (early relapse, N = 38). The 2-year overall survival (OS) rates for primary refractory, early relapse, and residual disease patients were 27%, 25%, and 52%, respectively, while the event-free survival rates for those groups were 13%, 13%, and 42%, respectively. In a univariate analysis, lactate dehydrogenase level, Ann Arbor stage, poor performance status, high age-adjusted International Prognostic Index score, and age > 65 years were associated with shorter OS. The use of rituximab and platinum-based chemo during the first salvage treatment was associated with prolonged OS. In a multivariate analysis, age (HR:2.06) and rituximab use (HR:0.54) were associated with OS. Among patients

BackgroundDefects in glycosylation of alpha-dystroglycan (α-DG) cause autosomal-recessive disorders with wide clinical and genetic heterogeneity, with phenotypes ranging from congenital muscular dystrophies to milder limb girdle muscular dystrophies. Patients show variable reduction of immunoreactivity to antibodies specific for glycoepitopes of α-DG on a muscle biopsy. Recessive mutations in 18 genes, including guanosine diphosphate mannose pyrophosphorylase B (GMPPB), have been reported to date. With no specific clinical and pathological handles, diagnosis requires parallel or sequential analysis of all known genes.MethodsWe describe clinical, genetic and biochemical findings of 21 patients withGMPPB-associated dystroglycanopathy.ResultsWe report eight novel mutations and further expand current knowledge on clinical and muscle MRI features of this condition. In addition, we report a consistent shift in the mobility of beta-dystroglycan (β-DG) on Western blot analysis of all patients analysed by this mean. This was only observed in patients with GMPPB in our large dystroglycanopathy cohort. We further demonstrate that this mobility shift in patients with GMPPB was due to abnormalN-linked glycosylation of β-DG.ConclusionsOur data demonstrate that a change in β-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect inGMPPB.

The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly progressive course. Pronounced weakness in axial and proximal muscle groups is a common feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects. Central core disease (CCD), multi-minicore disease (MmD), centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital myopathies to be reported, and they still represent the main diagnostic categories. However, these entities seem to belong to a much wider phenotypic spectrum. To date, congenital myopathies have been attributed to mutations in over 20 genes, which encode proteins implicated in skeletal muscle Ca 2+ homeostasis, excitation-contraction coupling, thin-thick filament assembly and interactions, and other mechanisms. RYR1 mutations are the most frequent genetic cause, and CCD and MmD are the most common subgroups. Next-generation sequencing has vastly improved mutation detection and has enabled the identification of novel genetic backgrounds. At present, management of congenital myopathies is largely supportive, although new therapeutic approaches are reaching the clinical trial stage.

Follicular lymphoma (FL) is an indolent lymphoma of mature B-cells but may transform to a more aggressive histology, most commonly diffuse large B cell lymphoma. Recurrent mutations associated with transformation have been identified; however, biological predictors to guide initial therapy have remained elusive. We hypothesized that clonal heterogeneity and patient-specific immune responses would contribute to variable clinical outcomes and that understanding the complexity of the entire tumor "ecosystem" would allow more individualized matching of patients with specific therapies. In prior ASH meetings, we presented preliminary analyses of B and T cell-focused phenotypic profiling of 155 newly diagnosed pre-treatment FL biopsy samples at single cell resolution by mass cytometry (CyTOF). These prior analyses unexpectedly revealed two distinct evolutionary trajectories which were independently reflected in both B and T cell compartments. One trajectory expectedly involved germinal center B cells (GCB); however, the other was more related to naïve/memory B-cells (NMB). Interestingly, cluster co-occurrence analysis suggested that the GCB and NMB trajectories were mutually exclusive of another and tended not to be found within the same tumor despite their high prevalences (χ 2 = 29.8, DF=1, p=4.8e-8; χ 2 test). Clustering analysis based on relative abundances of T cell subsets revealed 4 distinct immune patterns: Group 1 was characterized by naive T cells; Group 2 by T follicular helper (Tfh) cells; Group 3 by CD4+ regulatory T (Treg) and CD8 effector memory cells (CD8EM); and Group 4 by a diverse complement of naive, memory, and differentiated effector subsets. We report here further analyses, now incorporating DNA mutational and clinical outcome information. Tumors were parsed into 3 types based on the phenotype of the majority (>50%) of tumor cells present in the diagnostic biopsy: Type A tumors dominated by GCB cells (28% of samples), type B tumors dominated by NMB cells (18% of samples), and type nonA/nonB tumors dominated by neither GCB nor NMB cells (54% of samples). Type A tumors were significantly enriched for mutations in EZH2, TNFRSF14, and MEF2B, while no significant mutational associations were seen in type B and nonA/nonB tumors. Type B was significantly associated with increased risk of transformation, and when combined with a measure of intratumoral phenotypic diversity ("Entropy"), we found that type B tumors with high (above median) Entropy, representing 8.5% of all cases, exhibited a hazard ratio (HR) of 5.9 for transformation risk in comparison to all others combined (log-rank p We also investigated survival outcomes using a sub-cohort of 108 patients who had received bendamustine + rituximab (BR) as their primary therapy. Despite the association of type B tumors with transformation risk, patients with type nonA/nonB tumors exhibited the poorest outcomes as measured by disease-specific survival (DSS; 5yr survival 78% vs 98% for all others combined, log-rank p=0.0241). Combining type nonA/nonB with high Entropy defined 20% of patients with significantly shorter DSS (HR 5.3, log-rank p=0.0019). In multivariate analysis, type nonA/nonB and high risk FLIPI score were significant (p=0.038 and 0.035, respectively), while high Entropy trended with inferior DSS (HR 2.8, 95% CI 0.76-10; p=0.123). Taken together, these data support that CyTOF-defined phenotypic subtypes of FL and intratumoral phenotypic diversity identify clinically significant subgroups at initial diagnosis and compare favorably against FLIPI score in predicting both risk of transformation and inferior DSS. Figure 1 Figure 1. Disclosures Freeman: Incyte: Honoraria; Seattle Genetics: Honoraria; Sanofi: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Amgen: Honoraria; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Teva: Research Funding; Abbvie: Honoraria; Roche: Research Funding. Sehn: Genmab: Consultancy; Novartis: Consultancy; Debiopharm: Consultancy. Savage: BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Seattle Genetics: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; Takeda: Other: Institutional clinical trial funding; Roche: Research Funding; Servier: Consultancy, Honoraria; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Craig: Bayer: Consultancy. Scott: Abbvie: Consultancy; AstraZeneca: Consultancy; Incyte: Consultancy; Celgene: Consultancy; NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. ; Rich/Genentech: Research Funding; Janssen: Consultancy, Research Funding. Steidl: Trillium Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy; Seattle Genetics: Consultancy; Curis Inc.: Consultancy; Bayer: Consultancy; Epizyme: Research Funding.

BackgroundT-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory domains (TIGIT), and costimulatory receptor CD226 competitively bind 2 ligands, CD155 and CD112, which are expressed by tumor cells and antigen-presenting cells in the tumor microenvironment.1 2 Dual TIGIT/programmed cell death protein-1 (PD-1) blockade increased tumor antigen-specific CD8+ T-cell expansion and function in vitro and promoted potent antitumor response in vivo.3 4 TIGIT/PD-1 dual blockade using a TIGIT monoclonal antibody (mAb) with intact Fc produced clinical responses in advanced cancer.5 SEA-TGT is an investigational, human, nonfucosylated mAb directed against TIGIT. SEA-TGT binds to TIGIT, blocking inhibitory checkpoint signals directed at T cells. SEA-TGT enhances binding to activating FcγRIIIa and decreases binding to inhibitory FcγRIIb; this depletes immunosuppressive regulatory T cells and amplifies naive and memory T cells, potentially augmenting PD-1 inhibition effects. Preclinically, at suboptimal doses, SEA-TGT plus anti-PD-1 mAbs had superior antitumor activity than either agent alone.6MethodsSafety and antitumor activity of SEA TGT in ~377 adults (≥18 years) will be evaluated in this phase 1, multicenter, open-label, dose-escalation/expansion study. Part A will assess the safety/tolerability of SEA TGT to determine maximum tolerated and recommended doses. Part B will assess the safety and antitumor activity of the recommended dose in disease-specific expansion cohorts. Part C will assess SEA-TGT plus sasanlimab in dose-expansion cohorts after an initial safety run-in. Patients with histologically/cytologically confirmed relapsed/refractory/progressive metastatic solid tumors including non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), gastric/gastroesophageal junction carcinoma, cutaneous melanoma, bladder, cervical, ovarian or triple-negative breast cancer, or selected lymphomas will be eligible for Parts A and B. Part C will enroll patients with histologically confirmed advanced NSCLC (high [tumor proportion score (TPS) ≥50%] and low [TPS=1–49%] PD ligand 1 [PD-L1] expression), cutaneous melanoma, and HNSCC without previous anti–PD-1/PD-L1 therapy exposure. SEA TGT will be administered on Day 1 of 21-day cycles.Laboratory abnormalities, adverse events, dose-limiting toxicities, and dose-level safety and activity are primary endpoints. Secondary endpoints are objective response (OR) and complete response (CR) rates, duration of OR/CR, progression-free survival, overall survival, pharmacokinetics (PK), and antidrug antibodies. Exploratory analysis will include pharmacodynamics (PD), PK/PD relationships, biomarkers, and resistance to SEA-TGT. This trial is recruiting in Europe and North America.Trial RegistrationNCT04254107ReferencesBlake SJ, Dougall WC, Miles JJ, et al. Molecular pathways: Targeting CD96 and TIGIT for cancer immunotherapy. Clin Cancer Res 2016;22(21):5183–5188.Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy. J ImmunoTher Cancer 2020;8:e000957.Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 2014;26(6):923–937.Chauvin JM, Pagliano O, Fourcade J, et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest 2015;125(5):2046–2058.Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase 2 study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol 2020;38(15 suppl):9503.Smith A, Zeng W, Lucas S, et al. Poster 1583. SEA-TGT is an empowered anti-TIGIT antibody that displays superior combinatorial activity with several therapeutic agents. Presented at: American Association for Cancer Research Annual Meeting; April 9–14, 2021; Virtual Meeting.Ethics ApprovalInstitutional review boards or independent ethics committees of participating sites approved the trial, which will be conducted in compliance with the Declaration of Helsinki and International Conference on Harmonisation Guidelines for Good Clinical Practice. All patients will provide written informed consent.