An isolated mid-anterolateral wall true ventricular aneurysm due to coronary artery disease.

Aneurysms following a myocardial infarction usually involve the apical wall segments. We present a case of a rare isolated mid-anterolateral wall aneurysm due to occlusion of a diagonal branch. We review the echocardiographic criteria for diagnosing a left ventricular (LV) aneurysm and discuss how to differentiate one from a more critical pseudoaneurysm. We demonstrate the utility of using ultrasound enhancing contrast and review imaging protocols for ruling out associated LV thrombus.

Adverse impact of a high CD4/CD8 ratio in the allograft may be overcome by methotrexate- but not mycophenolate- or post-transplant cyclophosphamide-based graft versus host disease prophylaxis.

INTRODUCTION: A high CD4/CD8 T cell ratio in hematopoietic stem cell transplant (HSCT) allografts was observed to predict graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) but has not been comparatively examined in settings of various GVHD-prophylaxis regimens. METHODS: This retrospective monocentric study included all consecutive HSCT performed with peripheral blood stem cells between January 2000 and June 2021. The impact of the graft CD4/CD8 ratio was analyzed in three cohorts with different GVHD-prophylaxis platforms. RESULTS: In the cyclosporine/mycophenolate-mofetil (CSA/MMF) cohort (n = 294, HLA-matched HSCT), a high (>75th percentile) CD4/CD8 ratio was associated with increased overall mortality (HR: 1.56; p = .01), increased NRM (HR: 1.85; p = .01) and GVHD-associated mortality (HR: 2.13; p = .005). In the post-transplant cyclophosphamide (PTCy)/tacrolimus/MMF cohort (n = 113, haploidentical-related or mismatched-unrelated HSCT), a high CD4/CD8 ratio was associated with increased overall mortality (HR 2.07; p = .04) and aGVHD3-4 (HR: 2.24; p = .02). By contrast, in the CSA/methotrexate (CSA/MTX) cohort (n = 185, HLA-matched HSCT) the CD4/CD8 ratio had no significant impact on any of the investigated endpoints. CONCLUSION: A high CD4/CD8 ratio in the allograft has an adverse impact on GVHD and survival in CSA/MMF- and PTCy-based HSCT, while MTX-based prophylaxis may largely alleviate this important risk factor.

Growth Differentiation Factor-15 Predicts Mortality and Heart Failure Exacerbation But Not Ventricular Arrhythmias in Patients With Cardiomyopathy.

Background Heart failure (HF) has been increasing in prevalence, and a need exists for biomarkers with improved predictive and prognostic ability. GDF-15 (growth differentiation factor-15) is a novel biomarker associated with HF mortality, but no serial studies of GDF-15 have been conducted. This study aimed to investigate the association between GDF-15 levels over time and the occurrence of ventricular arrhythmias, HF hospitalizations, and all-cause mortality. Methods and Results We used a retrospective case-control design to analyze 148 patients with ischemic and nonischemic cardiomyopathies and primary prevention implantable cardioverter-defibrillator (ICD) from the PROSe-ICD (Prospective Observational Study of the ICD in Sudden Cardiac Death Prevention) cohort. Patients had blood drawn every 6 months and after each appropriate ICD therapy and were followed for a median follow-up of 4.6 years, between 2005 to 2019. We compared serum GDF-15 levels within ±90 days of an event among those with a ventricular tachycardia/fibrillation event requiring ICD therapies and those hospitalized for decompensated HF. A comparator/control group comprised patients with GDF-15 levels available during 2-year follow-up periods without events. Median follow-up was 4.6 years in the 148 patients studied (mean age 58±12, 27% women). The HF cohort had greater median GDF-15 values within 90 days (1797 pg/mL) and 30 days (2039 pg/mL) compared with the control group (1062 pg/mL, both P<0.0001). No difference was found between the ventricular tachycardia/fibrillation subgroup within 90 days (1173 pg/mL, P=0.60) or 30 days (1173 pg/mL, P=0.78) and the control group. GDF-15 was also significantly predictive of mortality (hazard ratio, 3.17 [95% CI, 2.33-4.30]). Conclusions GDF-15 levels are associated with HF hospitalization and mortality but not ventricular arrhythmic events.

A retrospective comparison of albumin versus mannitol priming fluid with relation to postoperative atrial fibrillation.

BACKGROUND AND AIM OF THE STUDY: Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery which can result in increased mortality and increased healthcare costs. During Hurricane Maria (2017), a nationwide shortage of mannitol occurred, and our institution switched to the utilization of albumin as a priming fluid solution. We observed decreased rates of POAF during that time and began alternating albumin and mannitol priming fluid solutions. We hypothesized this observation may be from altered perinexal conduction from albumin utilization. METHODS: A retrospective chart review of all patients from January 2020 through December 2020 who underwent cardiac surgery was performed, to determine if albumin was associated with reduced POAF rates. Two hundred and thirteen patients were identified and 4 were excluded. Two hundred and nine patients (110 albumin priming fluid and 99 mannitol priming fluid) were included in our final analysis. RESULTS: Analysis was performed for all patients with POAF and in patients with new-onset AF (without a history of prior AF) after surgery. POAF rates showed no statistically significant difference between cohorts. For all patients, POAF occurred in 43% of the albumin subgroup and 47% of the mannitol subgroup (p = .53) and for patients with new-onset AF, POAF occurred in 35% of the albumin subgroup versus 42% of the mannitol subgroup (p = .36). Logistic regression revealed that age, ejection fraction and cardiopulmonary bypass time was associated with POAF, in our cohort. CONCLUSIONS: The use of albumin compared to mannitol as priming fluid solutions was not associated with statistically significant reductions in POAF rate, in our population.

Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children.

Children have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and a substantially lower risk for developing severe coronavirus disease 2019 compared with adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n = 18) and age-matched SARS-CoV-2-positive (n = 24) children and corresponding samples from adults (n = 44), covering an age range of 4 weeks to 77 years. Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than in adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)+ cytotoxic T cells and a CD8+ T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults.

Prevalence of heart disease in patients with mitochondrial abnormalities on skeletal muscle biopsy.

OBJECTIVE: Mitochondrial DNA mutations are associated with an increased risk of heart disease. Whether an increased prevalence of cardiovascular disease is present in patients presenting with mitochondrial abnormalities on skeletal muscle biopsy remains unknown. This study was designed to determine the prevalence of cardiac conduction disease and structural heart disease in patients presenting with mitochondrial abnormalities on skeletal muscle biopsy. METHODS: This is a retrospective cohort study of 103 patients with mitochondrial abnormalities on skeletal muscle biopsy who were referred for evaluation of muscle weakness at a single tertiary care referral center from 2012 to 2018. Of these patients, 59 (57.3%) had an electrocardiogram available and were evaluated for the presence of conduction disease. An echocardiogram was available in 43 patients (42%) who were evaluated for the presence of structural heart disease. The prevalence of cardiac disease was compared to control cohort populations (Framingham and the Atherosclerosis Risk in Communities, ARIC cohorts). RESULTS: Mitochondrial abnormalities associated with cardiac conduction disease (defined as QRS duration ≥ 120 msec) were present in 8.9%, versus 2.0% (p < 0.001) in the Framingham population and 2.6% (p = 0.003) in the ARIC cohort. LV systolic dysfunction (LVEF ≤ 50%) was present in 11.6%, versus 3.6% (p < 0.01) in the Framingham and 3% (p < 0.01) in the ARIC populations. Left ventricular hypertrophy was present in 28.6%, versus 13.6% (p < 0.02) in the Framingham and 10.4% (p < 0.001) in the ARIC populations. INTERPRETATION: Given the increased prevalence of cardiovascular disease, patients with mitochondrial abnormalities on skeletal muscle biopsy should undergo routine cardiac screening with physical exam, electrocardiography, and cardiac imaging.

101 Dothideomycetes genomes: A test case for predicting lifestyles and emergence of pathogens.

Dothideomycetes is the largest class of kingdom Fungi and comprises an incredible diversity of lifestyles, many of which have evolved multiple times. Plant pathogens represent a major ecological niche of the class Dothideomycetes and they are known to infect most major food crops and feedstocks for biomass and biofuel production. Studying the ecology and evolution of Dothideomycetes has significant implications for our fundamental understanding of fungal evolution, their adaptation to stress and host specificity, and practical implications with regard to the effects of climate change and on the food, feed, and livestock elements of the agro-economy. In this study, we present the first large-scale, whole-genome comparison of 101 Dothideomycetes introducing 55 newly sequenced species. The availability of whole-genome data produced a high-confidence phylogeny leading to reclassification of 25 organisms, provided a clearer picture of the relationships among the various families, and indicated that pathogenicity evolved multiple times within this class. We also identified gene family expansions and contractions across the Dothideomycetes phylogeny linked to ecological niches providing insights into genome evolution and adaptation across this group. Using machine-learning methods we classified fungi into lifestyle classes with >95 % accuracy and identified a small number of gene families that positively correlated with these distinctions. This can become a valuable tool for genome-based prediction of species lifestyle, especially for rarely seen and poorly studied species.

Correction: Role of growth arrest-specific gene 6-mer axis in multiple myeloma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Novel FHL1 Mutation Associated With Hypertrophic Cardiomyopathy, Sudden Cardiac Death, and Myopathy.

A 24-year-old man with muscle cramps and a family history of sudden death presented with palpitations. Electrocardiography showed signs of left ventricular hypertrophy and nonsustained ventricular tachycardia, and imaging studies confirmed hypertrophic cardiomyopathy. Genetic testing revealed a novel FHL1 mutation associated with Emery-Dreifuss muscular dystrophy. An implantable cardioverter-defibrillator was placed. (Level of Difficulty: Advanced.).

Contemporary results after repair of partial and transitional atrioventricular septal defects.

OBJECTIVE: The exact incidence and risk factors for reoperation in partial and transitional atrioventricular septal defects are unclear. The goal of this study was to assess risk factors for left atrioventricular valve and left ventricular outflow tract reoperation in partial and transitional atrioventricular septal defects. METHODS: All patients undergoing partial and transitional atrioventricular septal defects repair between 1995 and 2017 were reviewed. Patients were classified as infants (<1 year), toddlers (1-3 years), children (3-17 years), and adults (≥18 years). Survival and reoperation were assessed using log-rank test and Cox models for univariate and multivariable analyses, respectively. RESULTS: Overall, 265 patients underwent partial and transitional atrioventricular septal defects repair (partial: 177 [67%]). Median age was 2 years. The cohort included 73 infants (28%), 85 toddlers (32%), 94 children (35%), and 13 adults (5%). Trisomy 21 was present in 76 patients (29%), and in 216 patients (83%), the zone of apposition was completely closed. Perioperative mortality was 0.8%. Complete heart block did not develop in any patients. Ten-year survival and freedom from reoperation were 98% and 81%, respectively. On multivariable analysis, trisomy 21 (hazard ratio [HR], 0.16) and older age compared with infants (toddlers: HR, 0.35; children: HR, 0.25) were protective for any reoperation, whereas heterotaxy (HR, 3.43) was a risk factor. For left atrioventricular valve reoperation, toddlers (HR, 0.35), children (HR, 0.25), and trisomy 21 (HR, 0.16) remained protective, whereas left atrioventricular valve anomaly was a risk factor (HR, 2.61). Likewise, for left ventricular outflow tract reoperation, toddlers (HR, 0.24) and children (HR, 0.06) were protective. CONCLUSIONS: Mortality after partial and transitional atrioventricular septal defects repair is minimal, yet reoperation for left atrioventricular valve disease and left ventricular outflow tract obstruction remains significant. Patients requiring repair during infancy are at higher risk of reoperation.

Prognostic implications of abnormalities of chromosome 13 and the presence of multiple cytogenetic high-risk abnormalities in newly diagnosed multiple myeloma.

Fluorescence in situ hybridization evaluation is essential for initial risk stratification in multiple myeloma. While the presence of specific cytogenetic high-risk abnormalities (HRA) is known to confer a poor prognosis, less is known about the cumulative effect of multiple HRA. We studied 1181 patients with newly diagnosed multiple myeloma who received novel agents as first-line therapy. High-risk abnormalities were defined as t(4;14), t(14;16), t(14;20) and del(17p). There were 884 patients (75%) without any HRA and 297 patients (25%) with HRA, including 262 (22%) with one HRA and 35 (3%) with two HRA. The presence of one HRA (versus zero, hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.32-2.05, p<0.001) and the presence of two HRA (versus zero, HR 3.15, 95% CI 2.00-4.96, p<0.001) were of prognostic significance after adjusting for other prognostic factors. Abnormalities of chromosome 13 were of prognostic significance independent of the established HRA: Monosomy 13 (HR 1.27, 95% CI 1.04-1.56, P=0.022) and del(13q) (HR 0.48, 95% CI 0.28-0.81, P=0.006) with opposite effects. Patients with HRA experienced worse overall survival suggesting a cumulative adverse effect of multiple HRA. Abnormalities of chromosome 13 were of prognostic significance after adjusting for other prognostic factors.

Hypertrophic osteoarthropathy in a young adult male from Berber, Sudan (2nd-3rd century CE).

Hypertrophic osteoarthropathy (HOA) is a pathological condition characterised by extensive periosteal new bone formation (NBF) on the diaphyses of the long bones, metacarpal and metatarsal bones. In modern clinical contexts, the secondary form of the disease is common and most often occurs secondary to intra-thoracic cancer and other forms of chronic pulmonary disease. Paleopathological evidence for HOA on the other hand has only occasionally been reported. Here we report a young adult male from the Meriotic cemetery at Berber in Sudan (2nd-3rd century CE) displaying widespread NBF on the diaphyses of the upper and lower limb bones, metacarpal and metatarsal bones, as well as the pelvis and scapulae. While several pathological conditions have to be considered as differential diagnostic options for NBF in the post-cranial skeleton, HOA is the most likely diagnosis, based on the distribution of the changes observed in this individual, as well as their macroscopic and radiographic characteristics. A chronic pulmonary condition as indicated by NBF on the visceral side of the ribs may represent the underlying cause for the HOA. This individual represents the first paleopathological case of HOA reported from an archaeological site in Africa.

Optimization of design and production strategies for novel adeno-associated viral display peptide libraries.

Libraries displaying random peptides on the surface of adeno-associated virus (AAV) are powerful tools for the generation of target-specific gene therapy vectors. However, for unknown reasons the success rate of AAV library screenings is variable and the influence of the production procedure has not been thoroughly evaluated. During library screenings, the capsid variants with the most favorable tropism are enriched over several selection rounds on a target of choice and identified by subsequent sequencing of the encapsidated viral genomes encoding the library capsids with targeting peptide insertions. Thus, a high capsid-genome correlation is crucial to obtain the correct information about the selected capsid variants. Producing AAV libraries by a two-step protocol with pseudotyped library transfer shuttles has been proposed as one way to ensure such a correlation. Here we show that AAV2 libraries produced by such a protocol via transfer shuttles display an unexpected additional bias in the amino-acid composition which confers increased heparin affinity and thus similarity to wildtype AAV2 tropism. This bias may fundamentally impair the intended use of AAV libraries, discouraging the use of transfer shuttles for the production of AAV libraries in the future.

High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group.

To investigate safety and efficacy of high-dose chemotherapy followed by autologous stem cell transplantation (HCT-ASCT) in relapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL), we conducted a single-arm multicentre study for immunocompetent patients (<66 years) with PCNSL failing high-dose methotrexate)-based chemotherapy. Induction consisted of two courses of rituximab (375 mg/m2), high-dose cytarabine (2 × 3 g/m2) and thiotepa (40 mg/m2) with collection of stem cells in between. Conditioning for HCT-ASCT consisted of rituximab 375 mg/m2, carmustine 400 mg/m2 and thiotepa (4 × 5 mg/kg). Patients commenced HCT-ASCT irrespective of response after induction. Patients not achieving complete remission (CR) after HCT-ASCT received whole-brain radiotherapy. Primary end point was CR after HCT-ASCT. We enrolled 39 patients; median age and Karnofsky performance score are 57 years and 90%, respectively. About 28 patients had relapsed and 8 refractory disease. About 22 patients responded to induction and 32 patients commenced HCT-ASCT. About 22 patients (56.4%) achieved CR after HCT-ASCT. Respective 2-year progression-free survival (PFS) and overall survival (OS) rates were 46.0% (median PFS 12.4 months) and 56.4%; median OS not reached. We recorded four treatment-related deaths. Thiotepa-based HCT-ASCT is an effective treatment option in eligible patients with r/r PCNSL. Comparative studies are needed to further scrutinise the role of HCT-ASCT in the salvage setting.

Mutational landscape reflects the biological continuum of plasma cell dyscrasias.

We subjected 90 patients covering a biological spectrum of plasma cell dyscrasias (monoclonal gammopathy of undetermined significance (MGUS), amyloid light-chain (AL) amyloidosis and multiple myeloma) to next-generation sequencing (NGS) gene panel analysis on unsorted bone marrow. A total of 64 different mutations in 8 genes were identified in this cohort. NRAS (28.1%), KRAS (21.3%), TP53 (19.5%), BRAF (19.1%) and CCND1 (8.9%) were the most commonly mutated genes in all patients. Patients with non-myeloma plasma cell dyscrasias showed a significantly lower mutational load than myeloma patients (0.91±0.30 vs 2.07±0.29 mutations per case, P=0.008). KRAS and NRAS exon 3 mutations were significantly associated with the myeloma cohort compared with non-myeloma plasma cell dyscrasias (odds ratio (OR) 9.87, 95% confidence interval (CI) 1.07-90.72, P=0.043 and OR 7.03, 95% CI 1.49-33.26, P=0.014). NRAS exon 3 and TP53 exon 6 mutations were significantly associated with del17p cytogenetics (OR 0.12, 95% CI 0.02-0.87, P=0.036 and OR 0.05, 95% CI 0.01-0.54, P=0.013). Our data show that the mutational landscape reflects the biological continuum of plasma cell dyscrasias from a low-complexity mutational pattern in MGUS and AL amyloidosis to a high-complexity pattern in multiple myeloma. Our targeted NGS approach allows resource-efficient, sensitive and scalable mutation analysis for prognostic, predictive or therapeutic purposes.

High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study).

To investigate immuno-chemotherapy for elderly immuno-competent patients (⩾65 years) with newly diagnosed primary central nervous system lymphoma, we conducted a multicentre single-arm trial. One cycle consisted of rituximab (375 mg/m2, days 1, 15, 29), high-dose methotrexate (3 g/m2 days 2, 16, 30), procarbazine (60 mg/m2 days 2-11) and lomustine (110 mg/m2, day 2)-R-MPL protocol. Owing to infectious complications, we omitted lomustine during the study and consecutive patients were treated with the R-MP protocol. Three cycles were scheduled and repeated on day 43. Subsequently, patients commenced 4 weekly maintenance treatment with procarbazine (100 mg for 5 days). Primary end point was complete remission (CR) after 3 cycles. We included 107 patients (69 treated with R-MPL and 38 with R-MP). In all, 38/107 patients achieved CR (35.5%) and 15 (14.0%) achieved partial remission. R-MP was associated with a lower CR rate (31.6%) compared with R-MPL (37.7%), but respective 2-year progression-free survival (All 37.3%; R-MP 34.9%; R-MPL 38.8%) and overall survival (All 47.0%; R-MP 47.7%; R-MPL 46.0%) rates were similar. R-MP was associated with less ⩾grade 3 toxicities compared with R-MPL (71.1% vs 87.0%). R-MP is more feasible while still associated with similar efficacy compared with R-MPL and warrants further improvement in future studies.

Oesophageal lichen planus: the efficacy of topical steroid-based therapies.

BACKGROUND: Oesophageal lichen planus is an idiopathic inflammatory disorder characterized by significant oesophageal stricturing. Oesophageal lichen planus is a rare, difficult to diagnose, and likely an under recognized disease. As a result, there is no standardized approach to therapy and treatment strategies vary. AIM: To examine the utility of topical steroid therapy (fluticasone or budesonide) in the management of oesophageal lichen planus. METHODS: A retrospective chart review was conducted of patients diagnosed with oesophageal lichen planus who underwent baseline and follow up endoscopy pre and post topical steroid therapy between 1995 and 2016 at Mayo Clinic, Rochester MN. Average time between upper GI endoscopy was 3.2 months (0.7-11.7). Swallowed steroid preparations included fluticasone 880 µg twice daily or budesonide 3 mg twice daily. Patients were reviewed for symptomatic response to therapy using the Dakkak-Bennett dysphagia score (0-4, no dysphagia to total aphagia). Pre- and post-endoscopic findings were assessed. Additional baseline demographic, endoscopic, and histologic data were also obtained. RESULTS: We identified 40 patients who met the inclusion criteria. A significant reduction in median dysphagia score from 1 (0-4) to 0 (0-3) after steroid therapy (P < 0.001) was noted. 62% of patients reported resolution of their dysphagia after receiving topical corticosteroids. 72.5% had an endoscopic response to steroid therapy. CONCLUSION: Topical swallowed budesonide or fluticasone appear to effective treatment for oesophageal lichen planus.