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EZH2 coding mutation (EZH2 MUT ), resulting in loss-of-function, is an independent predictor of overall survival in MDS. EZH2 function can be altered by other mechanisms including copy number changes, and mutations in other genes and non-coding regions of EZH2. Assessment of EZH2 protein can identify alterations of EZH2 function missed by mutation assessment alone. Precise evaluation of EZH2 function and gene-protein correlation in clinical MDS cohorts is important in the context of upcoming targeted therapies aimed to restore EZH2 function. In this study, we evaluated the clinicopathologic characteristics of newly diagnosed MDS patients with EZH2 MUT and correlated the findings with protein expression using immunohistochemistry. There were 40 (~6%) EZH2 MUT MDS [33 men, seven women; median age 74 years (range, 55-90)]. EZH2 mutations spanned the entire coding region. Majority had dominant EZH2 clone [median VAF, 30% (1-92)], frequently co-occurring with co-dominant TET2 (38%) and sub-clonal ASXL1 (55%) and RUNX1 (43%) mutations. EZH2 MUT MDS showed frequent loss-of-expression compared to EZH2 WT (69% vs. 27%, p = 0.001). Interestingly, NINE (23%) EZH2 WT MDS also showed loss-of-expression. EZH2 MUT and loss-of-expression significantly associated with male predominance and chr(7) loss. Further, only EZH2 loss-of-expression patients showed significantly lower platelet counts, a trend for higher BM blast% and R-IPSS scores. Over a 14-month median follow-up, both EZH2 MUT (p = 0.027) and loss-of-expression (p = 0.0063) correlated with poor survival, independent of R-IPSS, age and gender. When analyzed together, loss-of-expression showed a stronger correlation than mutation (p = 0.061 vs. p = 0.43). In conclusion, immunohistochemical assessment of EZH2 protein, alongside mutation, is important for prognostic workup of MDS., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Hypertension is a risk factor for end organ damage and death and is more common in persons with HIV compared to the general population. Several mechanisms have been studied in the pathogenesis of hypertension. Current evidence suggests that the epithelial sodium channel (ENaC) plays a key role in regulating blood pressure through the transport of sodium and water across membranes in the kidney tubules, resulting in retention of sodium and water and an altered fluid balance. However, there is scarcity of information that elucidates the role of ENaC in HIV as it relates to increasing the risk for development or pathogenesis of hypertension. This review summarized the evidence to date implicating a potential role for altered ENaC activity in contributing to hypertension in patients with HIV., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mutengo, Masenga, Mwesigwa, Patel and Kirabo.)

Objectives: To investigate the gene mutational profile of urachal carcinoma in correlation with its clinicopathologic features., Methods: We analyzed genetic mutations in 30 cases of urachal carcinoma by next-generation sequencing (NGS) test. Histologic slides and clinical data were reviewed., Results: The patients included 21 men and 9 women, with a mean age of 53 years (range, 24-75 years). The urachal carcinomas included mucinous (11), enteric (10), signet ring cell (8), and high-grade neuroendocrine (1) subtypes. Targeted NGS analysis demonstrated genetic mutations in all the urachal tumors (mean, 2; range, 1-4). TP53 was the most mutated gene (25), followed by KRAS (9) and GNAS (8) genes. TP53 mutations were more common in the signet ring cell subtype (7/8), and GNAS mutations were present only in the mucinous (5/11) and signet ring cell subtypes (3/8) but not in the enteric subtype (0/10). KRAS mutations were significantly associated with cancer stage IV (P = .02) and younger patient age (P = .046). Furthermore, the presence of KRAS mutations in urachal carcinoma portended a poorer overall survival (P = .006)., Conclusions: Urachal carcinoma demonstrates frequent gene mutations that are associated with distinct clinicopathologic features. Gene mutation may underlie the development and progression of this aggressive disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The development of clonally related hematologic neoplasms in the setting of primary mediastinal germ cell tumors (PMGCTs) has been recognized previously and is associated with a dismal prognosis. However, the presentation of hematologic neoplasms as chronic myelomonocytic leukemia (CMML) and hemophagocytic lymphohistiocytosis (HLH) has been rarely reported. Here we report two patients with PMGCTs and hematologic neoplasms. The PMGCT was composed mostly of yolk sac tumor whereas the hematologic neoplasms had morphologic features that resembled CMML and HLH. The hematologic neoplasms from both patients harbored isochromosome 12p [i(12p)] and TP53 mutations, supporting a clonal relationship between these tumors. This association represents a unique clinical syndrome that likely contributes to the poor clinical outcome of these patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Medical complications of eating disorders in males are understudied compared to females, as is the case of vitamin D deficiency. The aim of this study was to assess vitamin D levels among male and female adolescents and young adults hospitalized for medical complications of eating disorders., Methods: We retrospectively reviewed electronic medical records of patients aged 9-25 years (N = 565) admitted to the University of California, San Francisco Eating Disorders Program for medical instability, between May 2012 and August 2020. Serum vitamin D (25-hydroxy) level was assessed at admission as was history of prior calcium, vitamin D, or multivitamin supplementation. Linear regression was used to assess factors associated with vitamin D levels., Results: A total of 93 males and 472 females met eligibility criteria (age 15.5 ± 2.8, 58.8% anorexia nervosa; admission body mass index 17.6 ± 2.91). Among male participants, 44.1% had 25-hydroxyvitamin D levels < 30 ng/mL, 18.3% had 25-hydroxyvitamin D levels < 20 ng/mL, and 8.6% had 25-hydroxyvitamin D levels < 12 ng/mL. There were no significant differences in 25-hydroxyvitamin D levels in males compared to females, except that a lower proportion (1.9%) of female participants had 25-hydroxyvitamin D levels < 12 ng/mL (p = 0.001). Only 3.2% of males reported calcium or vitamin D-specific supplementation prior to hospital admission, while 8.6% reported taking multivitamins. White race, prior calcium/vitamin D supplementation, and higher calcium levels were associated with higher vitamin D levels on admission., Conclusions: Nearly half of patients admitted to the hospital for malnutrition secondary to eating disorders presented with low 25-hydroxyvitamin D levels; males were more likely than females to have severe vitamin D deficiency. These findings support vitamin D assessment as part of the routine medical/nutritional evaluation for hospitalized eating disorder patients, with particular attention on male populations., (© 2022. The Author(s).)

Measurable residual disease (MRD) is highly prognostic for relapse and overall survival (OS) in acute lymphoblastic leukemia (ALL), although many patients with apparent "MRD negativity" by standard assays still relapse. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay in 74 adults with ALL undergoing frontline therapy. Among remission samples that were MRD negative by multiparameter flow cytometry (MFC), 46% were MRD+ by the NGS assay. After 1 cycle of induction chemotherapy, MRD negativity by MFC at a sensitivity of 1 × 10-4 and NGS at a sensitivity of 1 × 10-6 was achieved in 66% and 23% of patients, respectively. The 5-year cumulative incidence of relapse (CIR) among patients who achieved MRD negativity by MFC at complete remission (CR) was 29%; in contrast, no patients who achieved early MRD negativity by NGS relapsed, and their 5-year OS was 90%. NGS MRD negativity at CR was associated with significantly decreased risk of relapse compared with MRD positivity (5-year CIR, 0% vs 45%, respectively; P = .04). Among patients who were MRD negative by MFC, detection of low levels of MRD by NGS identified patients who still had a significant risk of relapse (5-year CIR, 39%). Early assessment of MRD using a highly sensitive NGS assay adds clinically relevant prognostic information to standard MFC-based approaches and can identify patients with ALL undergoing frontline therapy who have a very low risk of relapse and excellent long-term survival., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Adolescents are particularly vulnerable to health misinformation and are at risk for suboptimal adherence to protective health behaviors in the COVID-19 pandemic. Guided by factors consistent with the theories of planned behavior and rumor transmission, this study sought to analyze the impact of multiple information sources, including social media, television media, internet and parental counseling, on masking behaviors in adolescents. Responses from the December 2020 COVID-19 survey, representing 4,106 U.S. adolescents ages 12-14 from the Adolescent Brain Cognitive Development Study (ABCD) were analyzed. The majority of parents (61.1%) reported counseling their children on the importance of wearing masks all the time in the past week. A minority of adolescents reported more than one hour of daily exposure to COVID-19 related information on social media (9.1%), the internet (4.3%) and television (10.2%). In unadjusted and adjusted models, greater frequency of parental counseling and exposure to COVID-19 television or social media were associated with 'always masking' behaviors. Our findings provide support for the importance of parent counseling and suggest that socialmedia and television may overall support rather than dissuade protective COVID-19 health behaviors in adolescents., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Aims: Many cardiac pacemakers and defibrillators are not approved by regulators for magnetic resonance imaging (MRI). Even following generator exchange to an approved magnetic resonance (MR)-conditional model, many systems remain classified 'non-MR conditional' due to the leads. This classification makes patient access to MRI challenging, but there is no evidence of increased clinical risk. We compared the effect of MRI on non-MR conditional and MR-conditional pacemaker and defibrillator leads., Methods and Results: Patients undergoing clinical 1.5T MRI with pacemakers and defibrillators in three centres over 5 years were included. Magnetic resonance imaging protocols were similar for MR-conditional and non-MR conditional systems. Devices were interrogated pre- and immediately post-scan, and at follow-up, and adverse clinical events recorded. Lead parameter changes peri-scan were stratified by MR-conditional labelling. A total of 1148 MRI examinations were performed in 970 patients (54% non-MR conditional systems, 39% defibrillators, 15% pacing-dependent) with 2268 leads. There were no lead-related adverse clinical events, and no clinically significant immediate or late lead parameter changes following MRI in either MR-conditional or non-MR conditional leads. Small reductions in atrial and right ventricular sensed amplitudes and impedances were similar between groups, with no difference in the proportion of leads with parameter changes greater than pre-defined thresholds (7.1%, 95% confidence interval: 6.1-8.3)., Conclusions: There was no increased risk of MRI in patients with non-MR conditional pacemaker or defibrillator leads when following recommended protocols. Standardizing MR conditions for all leads would significantly improve access to MRI by enabling patients to be scanned in non-specialist centres, with no discernible incremental risk., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions., (© 2022. The Author(s).)

Purpose of Review: This review focuses on studies implicating forebrain neural pathways and neuromodulator systems, particularly, the nitric oxide system within the paraventricular nucleus of the hypothalamus in regulating neurohumoral drive, autonomic pathways, and fluid balance., Recent Findings: Accumulating evidence from animals with experimental models of hypertension and heart failure as well as humans with hypertension suggests that alterations in central neural pathways, particularly, within the PVN neuromodulated by neuronal nitric oxide, are involved in regulating sympathetic outflow particularly to the kidney resulting in alterations in fluid balance commonly observed in hypertension and heart failure states. The characteristics of the hypertensive and heart failure states include alterations in neuronal nitric oxide within the PVN to cause an increase in renal sympathetic nerve activity to result in sodium and fluid retention in these diseases. A comprehensive understanding of these mechanisms will enhance our ability to treat hypertensive and heart failure conditions and their cardiovascular complications more efficiently., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Acute decompensated aortic stenosis (ADAS) is common and associated with poor outcomes. Myocardial remodeling and function, including a novel echo staging classification (0 to 4, representing increasing degrees of cardiac damage/dysfunction), impact outcomes in stable aortic stenosis. However, this has not been assessed in patients with ADAS. This study aims to evaluate the impact of the myocardium, echo staging classification, and clinical parameters on mortality in ADAS. ADAS was defined as an acute deterioration in symptoms (New York Heart Association 4, Canadian Cardiovascular Society 3/4, or syncope) that warranted admission to the hospital and urgent aortic valve replacement. Using a retrospective observational study design, 292 consecutive patients with ADAS who underwent transcatheter aortic valve implantation (TAVI) were identified and included in this study. Echocardiographic and clinical characteristics were evaluated using regression analysis. The outcome was all-cause mortality after TAVI. At 1 year after TAVI, advanced echo staging (>2) independently predicted mortality (hazards ratio: 1.85, 95% confidence interval: 1.01 to 3.39; p = 0.045). At a follow-up of 2.4 ± 1.4 years, myocardial, valvular, and clinical parameters did not predict mortality, except for frailty (hazards ratio: 2.31, 95% confidence interval: 1.38 to 3.85; p = 0.001). In patients with ADAS, short-term mortality after TAVI is influenced by more advanced cardiac damage/dysfunction based on the echo staging classification, whereas mid-term mortality is driven by frailty rather than echo staging classification., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

The maintenance of cardiovascular homeostasis is highly dependent on tightly controlled interactions between the heart and the kidneys. Therefore, it is not surprising that a dysfunction in one organ affects the other. This interlinking relationship is aptly demonstrated in the cardiorenal syndrome. The characteristics of the cardiorenal syndrome state include alterations in neurohumoral drive, autonomic reflexes, and fluid balance. The evidence suggests that several factors contribute to these alterations. These may include peripheral and central nervous system abnormalities. However, accumulating evidence from animals with experimental models of congestive heart failure and renal dysfunction as well as humans with the cardiorenal syndrome suggests that alterations in neural pathways, from and to the kidneys and the heart, including the central nervous system are involved in regulating sympathetic outflow and may be critically important in the alterations in neurohumoral drive, autonomic reflexes, and fluid balance commonly observed in the cardiorenal syndrome. This review focuses on studies implicating neural pathways, particularly the afferent and efferent signals from the heart and the kidneys integrating at the level of the paraventricular nucleus in the hypothalamus to alter neurohumoral drive, autonomic pathways, and fluid balance. Further, it explores the potential mechanisms of action for the known beneficial use of various medications or potential novel therapeutic manipulations for the treatment of the cardiorenal syndrome. A comprehensive understanding of these mechanisms will enhance our ability to treat cardiorenal conditions and their cardiovascular complications more efficaciously and thoroughly.

The outbreak of the novel coronavirus pandemic (COVID-19) has resulted in dramatic changes to the conduct of surgery both from a patient management perspective and in protecting healthcare providers. The current study reports on the status of COVID-19 infections in patients presenting for cardiac surgery with cardiopulmonary bypass (CPB) on circuit complications. A tracking process for monitoring the presence of COVID-19 in adult cardiac surgery patients was integrated into a case documentation system across United States hospitals where out-sourced perfusion services were provided. Assessment included infection status, testing technique employed, surgery status and CPB complications. Records from 5612 adult patients who underwent cardiac surgery between November 1, 2020 and January 18, 2021 from 176 hospitals were reviewed. A sub-cohort of coronary artery bypass graft patients (3283) was compared using a mixed effect binary logistic regression analysis. 4297 patients had negative test results (76.6%) while 49 (0.9%) tested positive for COVID-19, and unknown or no results were reported in 693 (12.4%) and 573 (10.2%) respectively. Coagulation complications were reported at 0.2% in the negative test results group versus 4.1% in the positive test result group (p < 0.001). Oxygenator gas exchange complications were 0.2% in the negative test results group versus 2.0% in the positive test results group (p = 0.088). Coronary artery bypass graft patients with a positive test had significantly higher risk for any CPB complication (p = 0.003) [OR 10.38, CI 2.18-49.53] then negative test patients [OR 0.01, CI 0.00-0.20]. The present study has shown that patients undergoing cardiac surgery with CPB who test positive for COVID-19 have higher CPB complication rate than those who test negative.

NOTCH1 is one of the most frequently mutated genes in chronic lymphocytic leukemia and has emerged as a marker of poor prognosis. In addition to coding NOTCH1 mutations involving exon 34, non-coding NOTCH1 mutations involving the 3' UTR have been described in a limited number of chronic lymphocytic leukemia (CLL) patients and were associated with adverse outcomes. In this study, 1574 CLL patients were assessed using targeted sequencing with a 29 gene panel and the results were correlated with prognostic characteristics. NOTCH1 mutations were detected in 252 (16%) patients, including both coding (220/252, 14%), non-coding (24/252, 1.5%) and a mixture of coding and non-coding (8/252, 0.5%) NOTCH1 mutations. NOTCH1 mutations were more commonly seen in patients with unmutated IGHV, ZAP70 positivity and CD38 positivity. Mixed NOTCH1 mutations were also more commonly seen in patients with unmutated IGHV and ZAP70. There was no association between mixed NOTCH1 mutations and CD38 expression in this cohort. The most common cytogenetic alteration detected in patients with coding and mixed NOTCH1 mutations was trisomy 12, whereas del13q was the most common cytogenetic alteration detected in patients with non-coding NOTCH1 mutation. The most common gene mutations co-occurring with coding NOTCH1 mutations were: TP53 (23.2%), SF3B1 (16.4%) and SPEN (10%). The most common gene mutations co-occurring with non-coding NOTCH1 mutations were: SF3B1 11(34.4%), ATM 4(12.5%) and TP53 4(12.5%). CLL patients with clonal coding and non-coding NOTCH1 mutations had a significantly shorter time-to-first treatment than patients with wild type NOTCH1 (4.3 vs 10.0 years and 0.9 vs 10.0 years respectively, p < 0.05). Similarly, CLL patients with subclonal coding NOTCH1 mutations had a significantly shorter time-to-first treatment than patients with wild type NOTCH1 (5.6 vs 10.0 years, p < 0.05). CLL patients with subclonal non-coding NOTCH1 mutations also had a shorter time-to-first treatment than patients with wild type NOTCH1 mutations, however, the difference was not significant (5.1 vs 10.0 years, p = 0.15). These data confirm that both coding and non-coding NOTCH1 mutations carry adverse prognostic impact and need to be included in sequencing assays performed for the prognostic workup of CLL patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Many THA simulation models rely on a limited set of preoperative static radiographs to replicate sagittal pelvic tilt during functional positions and to recommend an implant orientation that minimizes the risk of prosthetic impingement. However, possible random changes in pelvic or lower extremity angular motions and the effect of coronal and axial pelvic tilt are not included in these preoperative models., Questions/purposes: (1) Can prosthetic impingement occur if the pelvic tilt or lower extremity alignment randomly varies up to ± 5° from what is measured on a single preoperative static radiographic image? (2) Do changes in coronal and axial pelvic tilt or lower extremity alignment angles have a similar effect on the risk of prosthetic impingement?, Methods: A de-identified pelvis and lower-body CT image of a male patient without previous THA or lower extremity surgery was used to import the pelvis, femur, and tibia into a verified MATLAB computer model. The motions of standing, pivoting, sitting, sit-to-stand, squatting, and bending forward were simulated. THA implant components included a full hemispherical acetabular cup without an elevated rim, polyethylene liner without an elevated rim, femoral head (diameter: 28 mm, 32 mm, 36 mm, or 40 mm), and a triple-taper cementless stem with three different neck shaft angles (127°, 132°, or 135°) with a trapezoidal neck were used in this model. A static model (cup anatomical abduction 40°, cup anatomical anteversion 20°, stem anatomical anteversion 10°) with a predefined range of sagittal pelvic tilt and hip alignment (0° coronal or axial tilt, without random ± 5° change) was used to simulate each motion. We then randomly varied pelvic tilt in three different pelvic planes and hip alignments (flexion, extension, abduction, adduction, rotation) up to ± 5° and assessed the same motions without changing the implant's anatomical orientation. Prosthetic impingement as the endpoint was defined as mechanical abutment between the prosthetic neck and polyethylene liner. Multiple logistic regression was used to investigate the effect of variation in pelvic tilt and hip alignment (predictors) on prosthetic impingement (primary outcome)., Results: The static-based model without the random variation did not result in any prosthetic impingement under any conditions. However, with up to ± 5° of random variation in the pelvic tilt and hip alignment angles, prosthetic impingement occurred in pivoting (18 possible combinations), sit-to-stand (106 possible combinations), and squatting (one possible combination) when a 28-mm or a 32-mm head was used. Variation in sagittal tilt (odds ratio 4.09 [95% CI 3.11 to 5.37]; p < 0.001), axial tilt (OR 3.87 [95% CI 2.96 to 5.07]; p < 0.001), and coronal tilt (OR 2.39 [95% CI 2.03 to 2.83]; p < 0.001) affected the risk of prosthetic impingement. Variation in hip flexion had a strong impact on the risk of prosthetic impingement (OR 4.11 [95% CI 3.38 to 4.99]; p < 0.001)., Conclusion: The combined effect of 2° to 3° of change in multiple pelvic tilt or hip alignment angles relative to what is measured on a single static radiographic image can result in prosthetic impingement. Relying on a few preoperative static radiographic images to minimize the risk of prosthetic impingement, without including femoral implant orientation, axial and coronal pelvic tilt, and random angular variation in pelvis and lower extremity alignment, may not be adequate and may fail to predict prosthetic impingement-free ROM., Clinical Relevance: Determining a safe zone for THA implant positioning with respect to impingement may require a dynamic computer simulation model to fully capture the range of possible impingement conditions. Future work should concentrate on devising simple and easily available methods for dynamic motion analysis instead of using a few static radiographs for preoperative planning., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2022 by the Association of Bone and Joint Surgeons.)

The prevalence, incidence, and characteristics of bacterial infections in patients infected with severe acute respiratory syndrome coronavirus 2 are not well understood and have been raised as an important knowledge gap. Therefore, our study focused on the most common opportunistic infections/secondary infections/superinfections in coronavirus disease 2019 (COVID-19) patients. This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Eligible studies were identified using PubMed/Medline since inception to June 25, 2021. Studies meeting the inclusion criteria were selected. Statistical analysis was conducted in Review Manager 5.4.1. A random-effect model was used when heterogeneity was seen to pool the studies, and the result was reported as inverse variance and the corresponding 95% confidence interval. We screened 701 articles comprising 22 cohort studies which were included for analysis. The pooled prevalence of opportunistic infections/secondary infections/superinfections was 16% in COVID-19 patients. The highest prevalence of secondary infections was observed among viruses at 33%, followed by bacteria at 16%, fungi at 6%, and 25% among the miscellaneous group/wrong outcome. Opportunistic infections are more prevalent in critically ill patients. The isolated pathogens included Epstein-Barr virus, Pseudomonas aeruginosa , Escherichia coli , Acinetobacter baumannii , Hemophilus influenza , and invasive pulmonary aspergillosis. Large-scale studies are required to better identify opportunistic/secondary/superinfections in COVID-19 patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Kurra et al.)

The incidence and prevalence of valvular heart disease (VHD) is increasing and has been described as the next cardiac epidemic. Advances in imaging and therapeutics have revolutionized how we assess and treat patients with VHD. Although echocardiography continues to be the first-line imaging modality to assess the severity and the effects of VHD, advances in cardiac computed tomography (CT) now provide novel insights into VHD. Transcatheter valvular interventions rely heavily on CT guidance for procedural planning, predicting and detecting complications, and monitoring prosthesis. This review focuses on the current role and future prospects of CT in the assessment of aortic and mitral valves for transcatheter interventions, prosthetic valve complications such as thrombosis and endocarditis, and assessment of the myocardium., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Patel, Vandermolen, Herrey, Cheasty, Menezes, Moon, Pugliese and Treibel.)

The role of WT1 protein in hematopoiesis and leukemogenesisis incompletely elucidated. WT1 overexpression is common in acute myeloid leukemia (AML); however, WT1 mutations occur in only about 10% of cases, with increasing incidence in the setting of relapse. In this study, we investigated the clinical and molecular characteristics of WT1 mutations in NPM1-mutated AML, to enhance our understanding of the biology and potential therapeutic implications of WT1 mutations. Our study cohort included 67 patients with NPM1 mutated AML and a median follow-up of 13.7 months. WT1 mutations were identified in 7% (n = 5) of patients at the time of initial diagnosis. WT1 mutant clones were presumed to be present as co-dominant clones in 3/5 and in subclonal populations in 2/5 cases based on variant allelic frequency (VAF) when compared with NPM1 mutation VAF. All WT1 mutations became undetectable at time of MRD-negative (NPM1-wild type) remission. None of these patients experienced relapse at the time of last follow-up (median, 15 months; range, 4.5-20.2 months). A total of 15/67 (22%) patients relapsed; among these patient, four (27%) relapsed with WT1 mutant AML. Three of four patients had undergone allogeneic hematopoietic stem cell transplantation (HSCT). None of these patients had detectable WT1 mutations at the time of initial diagnosis. WT1 mutations were presumed clonal in two cases and subclonal in the other two cases, based on VAF. Our results indicate that WT1 mutations contribute to relapse in NPM1 mutated AML, especially in the setting of HSCT. These findings suggest that emerging WT1 mutations may serve as a conduit for relapse in NPM1-mutated AML, and that sequential molecular profiling to evaluate potential emergent WT1 mutations during surveillance and particularly at relapse likely has prognostic value in patients with NPM1 mutated AML., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Induction with ibrutinib and rituximab provides an opportunity to minimise chemotherapy exposure, because upfront use of these targeted therapies could result in remission without chemotherapy and allow for consolidation with only four cycles of chemotherapy instead of the conventional eight. We aimed to determine the activity and safety of ibrutinib-rituximab induction followed by shortened chemoimmunotherapy (four cycles) with rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) alternating with methotrexate-cytarabine in previously untreated patients with mantle cell lymphoma., Methods: We did a single-centre, single-arm, phase 2 trial in previously untreated patients with mantle cell lymphoma. Eligible patients were aged 65 years or younger and had serum bilirubin of less than 1·5 mg/dL, creatinine clearance of 30 mL/min or more, Eastern Cooperative Oncology Group performance status of 2 or less, and cardiac ejection fraction 50% or more by echocardiogram. Patients received 12 cycles of ibrutinib-rituximab induction (part A; oral ibrutinib 560 mg daily and intravenous rituximab 375 mg/m 2 weekly for the first 4 weeks and then on day 1 of cycles 3-12). As soon as patients had a complete response, four cycles of R-HCVAD alternating with methotrexate-cytarabine (part B) were administered. If they did not have a complete response or had a partial response, patients received two cycles of R-HCVAD alternating with methotrexate-cytarabine followed by reassessment, up to a total of eight cycles. Patients were taken off study if they had stable disease or progression during R-HCVAD. The primary outcome was the overall response rate after part A. The analyses were conducted on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT02427620., Findings: 131 patients were enrolled between June 12, 2015, and Dec 6, 2018. The median age was 56 years (IQR 49-60). 58 (50%) of 117 patients had high Ki-67 (≥30%). 129 (98%, 95% CI 95-100) of 131 patients had an overall response in part A. The most common grade 3-4 adverse events were lymphocytopenia (19 [14%] of 131), skin rash (16 [12%]), thrombocytopenia (12 [9%]), infections (11 [8%]), and fatigue (ten [8%]) in part A and lymphocytopenia (96 [73%]), leukocytopenia (42 [32%]), thrombocytopenia (40 [30%]), and neutropenia (26 [20%]) in part B. There was one on-study death, which was not deemed to be treatment-related., Interpretation: Induction with ibrutinib-rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimisation of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma., Funding: Pharmacyclics, Janssen., Competing Interests: Declaration of interests MLW reports consultancy for InnoCare, Loxo Oncology, Juno, Oncternal, CStone, AstraZeneca, Janssen, VelosBio, Pharmacyclics, Genentech, and Bayer Healthcare; research funding from Pharmacyclics, Janssen, AstraZeneca, Celgene, Loxo Oncology, Kite Pharma, Juno, BioInvent, VelosBio, Acerta Pharma, Oncternal, Verastem, Molecular Templates, Lilly, and Innocare; and honoraria from Janssen, Acerta Pharma, OMI, Physicians Education Resources, Dava Oncology, CAHON, Hebei Cancer Prevention Federation, Clinical Care Options, Mumbai Hematology Group, Anticancer Association, and Newbridge Pharmaceuticals. PJ reports consultancy for Incyte, Eli Lilly, Aptitude Health, and Kite Pharma; research funding from Kite and AstraZeneca; and honoraria from Aptitude Health. FV reports research funding and support from National Cancer Institute, CRISP Therapeutics, and Geron Corporation; and honoraria from i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and Society of Hematology Oncology. CRF has consulted for Abbvie, Bayer, BeiGene, Celgene, Denovo Biopharma, Epizyme, Genentech–Roche, Gilead, Karyopharm, MEI Pharmaceuticals, Pharmacyclics–Janssen, and Spectrum in the past 3 years; and reports research funding in the past 12 months from Abbvie, Acerta, Celgene, Gilead, Genentech–Roche, Janssen Pharmaceutical, Millennium–Takeda, Pharmacyclics, TG Therapeutics, Burroughs Wellcome Fund, CPRIT, Eastern Cooperative Oncology Group, National Cancer Institute, and V Foundation. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Acute promyelocytic leukemia (APL) is characterized by the chromosomal translocation t (15;17) and the resulting gene PML-RARA, used for measurable residual disease (MRD) monitoring. Despite highly effective therapy for APL, MRD monitoring practices are not fully established. We aimed to assess the value of MRD monitoring by RT-qPCR in patients with APL treated with ATRA and arsenic trioxide +/- GO. We reviewed 223 patients with APL treated with this regimen. RT-qPCR for PML-RARA was measured every 3 months, and at 12, 18, and 24 months after therapy. Seven patients relapsed. Time to relapse was 7.9-12.4 months in 6 patients, and one patient relapsed after 79.5 months. These data show that MRD monitoring may be important for the detection of relapse in patients treated with this regimen within one year after completing therapy, however, since late molecular relapse is rare, our data suggest a low value of MRD monitoring beyond that first year.

Introduction: Social media platforms are constantly evolving and expanding to new populations, exposing their users to various topics and serving as an informal educational resource. Medical ideas and topics are freely discussed online, making understanding of what is present on these platforms of particular importance to the practicing medical professional. In the field of otolaryngology, the public social media portrayal of sinus surgery has not been previously reported., Methods: Social media posts using keywords related to sinus surgery on Facebook, Instagram, and TikTok were qualitatively analyzed and categorized based on media type, author, subject, timing, depiction, and popularity., Results: The total number of posts included in final analysis was 1798, with a majority stemming from Instagram (68.5%), then Facebook (20.2%) and finally TikTok (11.3%). The most common type of media analyzed was images (69.0%) and patients were more often authors of posts (45.1%) as compared to physicians (34.8%). The subjects of the posts were nearly equally reassurance regarding surgery (41.3%) and educational or informational posts (38.8%) and were most commonly timed in the postoperative period (41.3%). Sinus surgery was depicted in a positive fashion most frequently (56.6%), notably compared against the negative portrayal at 3.2%. Negative posts most commonly cited postoperative pain or bleeding., Conclusions: Most social media posts analyzed in this multi-platform study depicted sinus surgery in a positive fashion. Patients tended to post in the postoperative or perioperative period, whereas physicians tender to post intraoperative educational posts. Negative posts were most commonly centered around postoperative pain. Cautious interpretation of these results could be used for improving patient care and outreach in the digital age., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Spontaneous bacterial peritonitis (SBP) is a bacterial infection associated with a high mortality rate in cirrhotic patients. The gold standard for the detection of SBP is a manual cell count from ascitic fluid; however, alternative screening methods are under investigation. In particular, leukocyte esterase reagent strips (LERS) has been studied as an alternative method to detect SBP with a low cost and instant turnaround time. Therefore, this study aims to evaluate the performance of LERS in the detection of SBP., Methods: A literature search was performed for studies evaluating LERS for the detection of SBP on PubMed, Embase, Scopus, Cochrane, and clinical trial registries. Summary sensitivity, specificity, log diagnostic odds ratio (LDOR), and the area under the summary receiver operating curve (AUC) were calculated according to the respective manufacturer., Results: In total, 31 studies were evaluated. The summary sensitivity of Aution Sticks, Combur, Multistix, Periscreen reagent strips was 0.962 (95% confidence interval [CI] 0.926, 0.998), 0.892 (95% CI 0.846, 0.938), 0.806 (95% CI 0.738, 0.874), and 0.939 (95% CI 0.900, 0.979), respectively. The summary specificity of Aution Sticks, Combur, Multistix, and Periscreen reagent strips was 0.940 (95% CI 0.904, 0.976), 0.922 (95% CI 0.874, 0.970), 0.974 (95% CI 0.962, 0.985), and 0.672 (95% CI 0.381, 0.963), respectively., Conclusion: LERS appears to have a notable overall performance for the detection of SBP. LERS appeared to be an acceptable alternative to diagnose SBP in facilities without ability to perform cell count. However, there were significant differences in performance between each manufacturer., (© 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The global COVID-19 pandemic has highlighted the need for rapid, accurate and accessible nucleic acid tests to enable timely identification of infected individuals. We optimized a sample-to-answer nucleic acid test for SARS-CoV-2 that provides results in <1 hour using inexpensive and readily available reagents. The test workflow includes a simple lysis and viral inactivation protocol followed by direct isothermal amplification of viral RNA using RT-LAMP. The assay was validated using two different instruments, a portable isothermal fluorimeter and a standard thermocycler. Results of the RT-LAMP assay were compared to traditional RT-qPCR for nasopharyngeal swabs, nasal swabs, and saliva collected from a cohort of patients hospitalized due to COVID-19. For all three sample types, positive agreement with RT-LAMP performed using the isothermal fluorimeter was 100% for samples with Ct <30 and 69-91% for samples with Ct <40. Following validation, the test was successfully scaled to test the saliva of up to 400 asymptomatic individuals per day as part of the campus surveillance program at Rice University. Successful development, validation, and scaling of this sample-to-answer, extraction-free real-time RT-LAMP test for SARS-CoV-2 adds a highly adaptable tool to efforts to control the COVID-19 pandemic, and can inform test development strategies for future infectious disease threats., Competing Interests: The authors have declared that no competing interests exist.

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with myelofibrosis (MF). Bone marrow (BM) morphologic evaluation of myelofibrosis following allo-HSCT is known to be challenging in this context because resolution of morphologic changes is a gradual process., Patients and Methods: We compared BM samples of patients with myelofibrosis who underwent first allo-HSCT and achieved molecular remission by day 100 with BM samples of patients who continued to have persistent molecular evidence of disease following allo-HSCT., Results: The study group included 29 patients: 17 primary MF, 7 post-polycythemia vera (PV) MF, and 5 post-essential thrombocythemia (ET) MF. In this cohort there were 18 JAK2 p.V617F, 8 CALR; 1 MPL, and 2 patients had concurrent JAK2 p.V617F and MPL mutations. The control group included 5 patients with primary MF, one with post-PV MF, one with post-ET MF (5 JAK2 p.V617F; 2 CALR). Following allo-HSCT, both groups showed reduction in BM cellularity and number of megakaryocytes. The study cohort also less commonly had dense megakaryocyte clusters and endosteal located megakaryocytes and showed less fibrosis. There was no statistical difference in BM cellularity, presence of erythroid islands, degree of osteosclerosis, or megakaryocyte number, size, nuclear lobation, presence of clusters or intrasinusoidal location., Conclusions: Following allo-HSCT at 100 days, morphologic evaluation of BM in patients with MF cannot reliably predict persistence versus clearance of molecular evidence of MF. Disappearance of BM MF, dense megakaryocyte clusters, and endosteal localization of megakaryocytes are suggestive of disease response., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The Supreme healing-targeted drug-eluting stent (DES) is designed to promote endothelial healing to reduce stent-related adverse events. This may be particularly relevant among complex lesions that have a higher rate of adverse events. We sought to compare 1-year outcomes of percutaneous coronary intervention in complex lesions between the Supreme DES and contemporary durable-polymer, everolimus-eluting stents (DP-EES)., Methods: PIONEER III was a multicenter, prospective, single-blind clinical trial, randomizing 1629 patients with either an acute or chronic coronary syndrome in a 2:1 ratio to the Supreme DES or DP-EES. Complex lesions (American College of Cardiology/American Heart Association type B2/C) were found in 1137 patients. Outcomes were also compared for specific parameters of lesion complexity: severe calcification, long length (>20 ​mm), and severe tortuosity. The primary end point was target lesion failure at 1 ​year., Results: At 1 ​year, there was no difference in target lesion failure between the Supreme DES and DP-EES: (5.7% vs 5.6%; hazard ratio 1.00, 95% confidence interval 0.59-1.68, P = .99). Similarly, there were no differences in the secondary end points of lesion success (99.7% vs 99.4%, P = .41), device success (97.0% vs 98.5%, P = .14), target vessel failure (6.5% vs 7.4%, P = .50), major adverse cardiac events (7.8% vs 8.5%, P = .64), or stent thrombosis (0.7% vs 1.1%, P = .48). A trend was observed toward a higher rate of target lesion revascularization with the Supreme DES (2.5% vs 0.9%, P = .06)., Conclusions: This study suggests that the Supreme DES is as effective and safe at 1 ​year compared with the standard DP-EES across a broad spectrum of lesion complexity., (Crown Copyright © 2021 Published by Elsevier Inc. on behalf of the Society for Cardiovascular Angiography and Interventions Foundation.)

Although transcatheter aortic valve implantation (TAVI) has revolutionised the landscape of treatment for aortic stenosis, there exists a cohort of patients where TAVI is deemed futile. Among the pivotal high-risk trials, one-third to half of patients either died or received no symptomatic benefit from the procedure at 1 year. Futility of TAVI results in the unnecessary exposure of risk for patients and inefficient resource utilisation for healthcare services. Several cardiac and extra-cardiac conditions and frailty increase the risk of mortality despite TAVI. Among the survivors, these comorbidities can inhibit improvements in symptoms and quality of life. However, certain conditions are reversible with TAVI (e.g. functional mitral regurgitation), attenuating the risk and improving outcomes. Quantification of disease severity, identification of reversible factors and a systematic evaluation of frailty can substantially improve risk stratification and outcomes. This review examines the contribution of pre-existing comorbidities towards futility in TAVI and suggests a systematic approach to guide patient evaluation., Competing Interests: Disclosure: KPP and PRS are supported by a clinical research training fellowship from the British Heart Foundation. KPP has received a project grant from Edwards Lifesciences. TAT is supported by a BHF Intermediate Research Fellowship (FS/19/35/34374). JCM is directly and indirectly supported by the UCLH NIHR Biomedical Research Centre and Biomedical Research Unit at UCLH and Barts, respectively. MM has received grants and personal fees from Edwards Lifesciences, and personal fees from Abbott Vascular., (Copyright © 2022, Radcliffe Cardiology.)

Objective: The coexistence of wild-type transthyretin cardiac amyloidosis (ATTR) is common in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). However, the impact of ATTR and AS on the resultant AS-ATTR is unclear and poses diagnostic and management challenges. We therefore used a multicohort approach to evaluate myocardial structure, function, stress and damage by assessing age-related, afterload-related and amyloid-related remodelling on the resultant AS-ATTR phenotype., Methods: We compared four samples (n=583): 359 patients with AS, 107 with ATTR (97% Perugini grade 2), 36 with AS-ATTR (92% Perugini grade 2) and 81 age-matched and ethnicity-matched controls. 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy was used to diagnose amyloidosis (Perugini grade 1 was excluded). The primary end-point was NT-pro Brain Natriuretic Peptide (BNP) and secondary end-points related to myocardial structure, function and damage., Results: Compared with older age controls, the three disease cohorts had greater cardiac remodelling, worse function and elevated NT-proBNP/high-sensitivity Troponin-T (hsTnT). NT-proBNP was higher in AS-ATTR (2844 (1745, 4635) ng/dL) compared with AS (1294 (1077, 1554)ng/dL; p=0.002) and not significantly different to ATTR (3272 (2552, 4197) ng/dL; p=0.63). Diastology, hsTnT and prevalence of carpal tunnel syndrome were statistically similar between AS-ATTR and ATTR and higher than AS. The left ventricular mass indexed in AS-ATTR was lower than ATTR (139 (112, 167) vs 180 (167, 194) g; p=0.013) and non-significantly different to AS (120 (109, 130) g; p=0.179)., Conclusions: The AS-ATTR phenotype likely reflects an early stage of amyloid infiltration, but the combined insult resembles ATTR. Even after treatment of AS, ATTR-specific therapy is therefore likely to be beneficial., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Permanent pacemaker (PPM) implantation is a common complication of transcatheter aortic valve implantation (TAVI). The optimum timing of PPM implantation is still unclear as conduction abnormalities evolve and a balance needs to be struck between conservative delays in the hope of conduction recovery and overutilization of pacing. This study aimed to assess the safety and efficacy of early PPM implantation, without an observation period, among TAVI patients., Methods: This is a retrospective, observational study of 1398 TAVI patients. Clinical and pacing data were collected at baseline, 30 days and at a median of 15 (4-21) months post-TAVI. Study endpoints included PPM-related complications, pacing utilization and hospital length of stay., Results: One hundred five patients (8.2%) required a PPM, of which 13 were implanted pre and 92 post-TAVI. Seventy-six percent required pacing for either second- or third-degree heart block. Time to implantation for post-TAVI PPM was 1 (0-3) day. Six patients experienced a pacing-related complication- lead displacement (n = 3), hematoma (n = 2), and device infection (n = 1). Pacing utilization defined as pacing >10% of the time or a pacing requirement at the time of the pacing check was demonstrated in 83% of patients. Multivariate analysis revealed complete heart block (CHB) was the only independent predictor of pacing utilization. Hospital length of stay for the post-TAVI PPM group was longer than the group without PPM (4 [2-8] vs. 3 [2-4] days; p < .001)., Conclusions: Early PPM implantation in TAVI patients is safe and majority of patients require pacing in the short and mid-term., (© 2021 Wiley Periodicals LLC.)

Hairy cell leukemia variant (HCLv) responds poorly to purine analogue monotherapy. Rituximab concurrent with cladribine (CDAR) improves response rates, but long-term outcomes are unknown. We report final results of a phase 2 study of CDAR for patients with HCLv. Twenty patients with 0 to 1 prior courses of cladribine and/or rituximab, including 8 who were previously untreated, received cladribine 0.15 mg/kg on days 1 to 5 with 8 weekly rituximab doses of 375 mg/m2 beginning day 1. Patients received a second rituximab course ≥6 months after cladribine, if and when minimal residual disease (MRD) was detected in blood. The complete remission (CR) rate from CDAR was 95% (95% confidence interval, 75-100). Sixteen (80%) of 20 patients (95% confidence interval, 56-94) became MRD negative according to bone marrow at 6 months. The median duration of MRD-negative CR was 70.1 months, and 7 of 16 are still MRD negative up to 120 months. With a median follow-up of 69.7 months, 11 patients received delayed rituximab, and the 5-year progression-free survival (PFS) and overall survival (OS) were 63.3% and 73.9%, respectively. Five patients with TP53 mutations had shorter PFS (median, 36.4 months vs unreached; P = .0024) and OS (median, 52.4 months vs unreached; P = .032). MRD-negative CR at 6 months was significantly associated with longer PFS (unreached vs 17.4 months; P < .0001) and OS (unreached vs 38.2 months; P < .0001). Lack of MRD in blood at 6 months was also predictive of longer PFS and OS (P < .0001). After progression following CDAR, median OS was 29.7 months. CDAR is effective in HCLv, with better outcomes in patients who achieve MRD-negative CR. This trial is registered at www.clinicaltrials.gov as #NCT00923013., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Competing Interests: The authors declare no conflict of interest.

Background: Recent clinical studies demonstrate that SGLT2 (sodium-glucose cotransporter 2) inhibitors ameliorate heart failure (HF). The present study was conducted to assess the expression and function of renal SGLT2 and the influence of enhanced renal sympathetic tone in HF., Methods: Four weeks after coronary artery ligation surgery to induce HF, surgical bilateral renal denervation (RDN) was performed in rats. Four groups of rats (Sham-operated control [Sham], Sham+RDN, HF and HF+RDN; n=6/group) were used. Immunohistochemistry and Western blot analysis were performed to evaluate the renal SGLT2 expression. One week after RDN (5 weeks after induction of HF), intravenous injection of SGLT2 inhibitor dapagliflozin were performed to assess renal excretory responses. In vitro, human embryonic kidney cells were used to investigate the fractionation of SGLT2 after norepinephrine treatment., Results: In rats with HF, (1) SGLT2 expression in the proximal tubule of the kidney was increased; (2) the response of increases in urine flow, sodium excretion, and glucose excretion to dapagliflozin were greater; and (3) RDN attenuated renal SGLT2 expression and normalized renal functional responses to dapagliflozin. In vitro, norepinephrine promoted translocation of SGLT2 to the cell membrane., Conclusions: These results indicate that the enhanced tonic renal sympathetic nerve activation in HF increases the expression and functional activity of renal SGLT2. Potentiated trafficking of SGLT2 to cell surface in renal proximal tubules mediated by norepinephrine may contribute to this functional activation of SGLT2 in HF. These findings provide critical insight into the underlying mechanisms for the beneficial effects of SGLT2 inhibitors on HF reported in the clinical studies.

Breast implant anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm arising around textured breast implants that was recognized recently as a distinct entity by the World Health Organization. Rarely, other types of lymphoma have been reported in patients with breast implants, raising the possibility of a pathogenetic relationship between breast implants and other types of lymphoma. We report eight cases of Epstein-Barr virus (EBV)-positive large B-cell lymphoma associated with breast implants. One of these cases was invasive, and the other seven neoplasms were noninvasive and showed morphologic overlap with breast implant ALCL. All eight cases expressed B-cell markers, had a non-germinal center B-cell immunophenotype, and were EBV+ with a latency type III pattern of infection. We compared the noninvasive EBV+ large B-cell lymphoma cases with a cohort of breast implant ALCL cases matched for clinical and pathologic stage. The EBV+ large B-cell lymphoma cases more frequently showed a thicker capsule, and more often were associated with calcification and prominent lymphoid aggregates outside of the capsule. The EBV+ B-cell lymphoma cells were more often arranged within necrotic fibrinoid material in a layered pattern. We believe that this case series highlights many morphologic similarities between EBV+ large B-cell lymphoma and breast implant ALCL. The data presented suggest a pathogenetic role for breast implants (as well as EBV) in the pathogenesis of EBV+ large B-cell lymphoma. We also provide some histologic findings useful for distinguishing EBV+ large B-cell lymphoma from breast implant ALCL in this clinical setting., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Aims: In computer simulations, the shape of the range of motion (ROM) of a stem with a cylindrical neck design will be a perfect cone. However, many modern stems have rectangular/oval-shaped necks. We hypothesized that the rectangular/oval stem neck will affect the shape of the ROM and the prosthetic impingement., Methods: Total hip arthroplasty (THA) motion while standing and sitting was simulated using a MATLAB model (one stem with a cylindrical neck and one stem with a rectangular neck). The primary predictor was the geometry of the neck (cylindrical vs rectangular) and the main outcome was the shape of ROM based on the prosthetic impingement between the neck and the liner. The secondary outcome was the difference in the ROM provided by each neck geometry and the effect of the pelvic tilt on this ROM. Multiple regression was used to analyze the data., Results: The stem with a rectangular neck has increased internal and external rotation with a quatrefoil cross-section compared to a cone in a cylindrical neck. Modification of the cup orientation and pelvic tilt affected the direction of projection of the cone or quatrefoil shape. The mean increase in internal rotation with a rectangular neck was 3.4° (0° to 7.9°; p < 0.001); for external rotation, it was 2.8° (0.5° to 7.8°; p < 0.001)., Conclusion: Our study shows the importance of attention to femoral implant design for the assessment of prosthetic impingement. Any universal mathematical model or computer simulation that ignores each stem's unique neck geometry will provide inaccurate predictions of prosthetic impingement. Cite this article: Bone Joint Res  2021;10(12):780-789.

The pathogenesis of hypertension has been linked to excessive levels of reactive oxygen species (ROS), particularly superoxide (O 2 •- ), in multiple tissues and organ systems. Overexpression of superoxide dismutase (SOD) to scavenge O 2 •- has been shown to decrease blood pressure in hypertensive animals. We have previously shown that MnTnBuOE-2-PyP 5+ (BuOE), a manganese porphyrin SOD mimic currently in clinical trials as a normal tissue protector for cancer patients undergoing radiation therapy, can scavenge O 2 •- and acutely decrease normotensive blood pressures. Herein, we hypothesized that BuOE decreases hypertensive blood pressures. Using angiotensin II (AngII)-hypertensive mice, we demonstrate that BuOE administered both intraperitoneally and intravenously (IV) acutely decreases elevated blood pressure. Further investigation using renal sympathetic nerve recordings in spontaneously hypertensive rats (SHRs) reveals that immediately following IV injection of BuOE, blood pressure and renal sympathetic nerve activity (RSNA) decrease. BuOE also induces dose-dependent vasodilation of femoral arteries from AngII-hypertensive mice, a response that is mediated, at least in part, by nitric oxide, as demonstrated by ex vivo video myography. We confirmed this vasodilation in vivo using doppler imaging of the superior mesenteric artery in AngII-hypertensive mice. Together, these data demonstrate that BuOE acutely decreases RSNA and induces vasodilation, which likely contribute to its ability to rapidly decrease hypertensive blood pressure., Competing Interests: Disclosures The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Oberley-Deegan is a consultant with BioMimetix Pharmaceutical, Inc. and holds equities in BioMimetix Pharmaceutical, Inc. There are no other conflicts of interest reported by the authors.

Aims: Hypertension increases the risk of heart disease. Hallmark features of hypertensive heart disease is sympathoexcitation and cardiac mitochondrial abnormality. However, the molecular mechanisms for specifically neurally mediated mitochondrial abnormality and subsequent cardiac dysfunction are unclear. We hypothesized that enhanced sympatho-excitation to the heart elicits cardiac miR-18a-5p/HIF-1α and mitochondrial unfolded protein response (UPR mt ) signaling that lead to mitochondrial abnormalities and consequent pathological cardiac remodeling. Methods and Results: Using a model of neurogenic hypertension (NG-HTN), induced by intracerebroventricular (ICV) infusion of Ang II (NG-HTN; 20 ng/min, 14 days, 0.5 μl/h, or Saline; Control, 0.9%) through osmotic mini-pumps in Sprague-Dawley rats (250-300 g), we attempted to identify a link between sympathoexcitation (norepinephrine; NE), miRNA and HIF-1α signaling and UPR mt to produce mitochondrial abnormalities resulting in cardiomyopathy. Cardiac remodeling, mitochondrial abnormality, and miRNA/HIF-1α signaling were assessed using histology, immunocytochemistry, electron microscopy, Western blotting or RT-qPCR. NG-HTN demonstrated increased sympatho-excitation with concomitant reduction in UPR mt , miRNA-18a-5p and increased level of HIF-1α in the heart. Our in silico analysis indicated that miR-18a-5p targets HIF-1α. Direct effects of NE on miRNA/HIF-1α signaling and mitochondrial abnormality examined using H9c2 rat cardiomyocytes showed NE reduces miR-18a-5p but increases HIF-1α. Electron microscopy revealed cardiac mitochondrial abnormality in NG-HTN, linked with hypertrophic cardiomyopathy and fibrosis. Mitochondrial unfolded protein response was decreased in NG-HTN indicating mitochondrial proteinopathy and proteotoxic stress, associated with increased mito-ROS and decreased mitochondrial membrane potential (ΔΨm), and oxidative phosphorylation. Further, there was reduced cardiac mitochondrial biogenesis and fusion, but increased mitochondrial fission, coupled with mitochondrial impaired TIM-TOM transport and UPR mt . Direct effects of NE on H9c2 rat cardiomyocytes also showed cardiomyocyte hypertrophy, increased mitochondrial ROS generation, and UPR mt corroborating the in vivo data. Conclusion: In conclusion, enhanced sympatho-excitation suppress miR-18a-5p/HIF-1α signaling and increased mitochondrial stress proteotoxicity, decreased UPR mt leading to decreased mitochondrial dynamics/OXPHOS/ΔΨm and ROS generation. Taken together, these results suggest that ROS induced mitochondrial transition pore opening activates pro-hypertrophy/fibrosis/inflammatory factors that induce pathological cardiac hypertrophy and fibrosis commonly observed in NG-HTN., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nandi, Katsurada, Mahata and Patel.)

Tourniquets are widely used to stop extremity hemorrhage, but their use and subsequent release can result in nerve damage and degeneration, leading to neurological deficits. Increasing evidence has suggested a pivotal role of inflammation in nerve damage and abnormal mechanoreception. In this study, we investigated the therapeutic effects of masitinib (Mas), an anti-neuroinflammatory drug, on the mechanoreception of sensory neurons in a mouse model of tourniquet-induced hind paw ischemia-reperfusion (tourniquet/IR). C57BL/6 mice were subjected to 3 h of ischemia by placing a rubber band at the ankle joint and evaluated for subsequent reperfusion injury on day 1, 3, 7, 14, and 28 based on the experiments. Treatment with Mas (28 mg/kg/day, i.p.) began on the day of IR induction and lasted for 1, 3, 7, 14, or 28 days. Tourniquet/IR caused sensory nerve denervation in the skin of paw pads and abolished the hind paw mechanoreception to mechanical stimulation during the first 3 days of reperfusion. Sensory nerves gradually reinnervated in the skin of paw pads and allodynia began to appear on day 7. The maximum reaction occurred on day 14 and was maintained throughout the study period. Treatment with Mas mitigated nerve damage and improved hind paw mechanoreception to mechanical stimulation by decreasing the production of reactive oxygen species (ROS) during the early stages of tourniquet/IR. Mas also alleviated allodynia and decreased inflammatory cytokines (IL-1β and TNFα) in the skin of paw pads from days 7-28. Our data suggest that treatment with Mas significantly ameliorated paw numbness and allodynia in mouse hind paw tourniquet/IR., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background The gut-derived hormone GLP-1 (glucagon-like peptide-1) exerts beneficial effects against established risk factors for chronic kidney disease. GLP-1 influences renal function by stimulating diuresis and natriuresis and thus lowering arterial blood pressure. The role of the sympathetic nervous system has been implicated as an important link between obesity with elevated arterial pressure and chronic kidney disease. The primary aim of this study was to determine the contribution of renal sympathetic nerves on intrapelvic GLP-1-mediated diuresis and natriuresis in high-fat diet (HFD)-induced obese rats. Methods and Results Obesity was induced in rats by HFD for 12 weeks, followed by either surgical bilateral renal denervation or chronic subcutaneous endopeptidase neprilysin inhibition by sacubitril for a week. Diuretic and natriuretic responses to intrapelvic administration of the GLP-1R (GLP-1 receptor) agonist exendin-4 were monitored in anesthetized control and HFD rats. Renal GLP-1R expression and neprilysin expression and activity were measured. The effects of norepinephrine on the expression of GLP-1R and neprilysin in kidney epithelial LLC-PK1 cells were also examined. We found that diuretic and natriuretic responses to exendin-4 were significantly reduced in the HFD obese rats compared with the control rats (cumulative urine flow at 40 minutes, 387±32 versus 650±65 µL/gkw; cumulative sodium excretion at 40 minutes, 42±5 versus 75±10 µEq/gkw, P <0.05). These responses in the HFD rats were restored after ablation of renal nerves (cumulative urine flow at 40 minutes, 625±62 versus 387±32 µL/gkw; cumulative sodium excretion at 40 minutes, 70±9 versus 42±5 µEq/gkw, P <0.05). Renal denervation induced significant reductions in arterial pressure and heart rate responses to intrapelvic GLP-1 in the HFD rats. Renal denervation also significantly increased the GLP-1R expression and reduced neprilysin expression and activity in renal tissues from the HFD rats. Chronic subcutaneous neprilysin inhibition by sacubitril increased GLP-1-induced diuretic and natriuretic effects in the HFD rats. Finally, exposure of the renal epithelial cells to norepinephrine in vitro led to downregulation of GLP-1R expression but upregulation of neprilysin expression and activity. Conclusions These results suggest that renal sympathetic nerve activation contributes to the blunted diuretic and natriuretic effects of GLP-1 in HFD obese rats. This study provides significant novel insight into the potential renal nerve-neprilysin-GLP-1 pathway involved in renal dysfunction during obesity that leads to hypertension.

Excessive activation of the sympathetic nervous system is one of the pathophysiological hallmarks of hypertension and heart failure. Within the central nervous system, the paraventricular nucleus (PVN) of the hypothalamus and the rostral ventrolateral medulla in the brain stem play critical roles in the regulation of sympathetic outflow to peripheral organs. Information from the peripheral circulation, including serum concentrations of sodium and angiotensin II, is conveyed to the PVN via adjacent structures with a weak blood-brain barrier. In addition, signals from baroreceptors, chemoreceptors and cardiopulmonary receptors as well as afferent input via the renal nerves are all integrated at the level of the PVN. The brain renin-angiotensin system and the balance between nitric oxide and reactive oxygen species in these brain areas also determine the final sympathetic outflow. Additionally, brain inflammatory responses have been shown to modulate these processes. Renal denervation interrupts both the afferent inputs from the kidney to the PVN and the efferent outputs from the PVN to the kidney, resulting in the suppression of sympathetic outflow and eliciting beneficial effects on both hypertension and heart failure., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

The tourniquet or femoral artery ligation is widely used to stop extremity hemorrhage or create a bloodless operating field in the combat scenario and civilian setting. However, these procedures with subsequent reperfusion also induce ischemia-reperfusion (IR) injuries. To fully evaluate animal models of limb IR injuries, we compared tourniquet- and femoral artery ligation-induced IR injuries in the hindlimb of mice. In C57/BL6 mice, 3 h of unilateral hindlimb ischemia was induced by placement of a rubber band at the hip joint or a surgical ligation of the femoral artery. The tourniquet or femoral artery ligation was then released, allowing for 24 h of reperfusion. Compared to the femoral artery ligation/IR, the tourniquet/IR induced more severe skeletal muscle damage, including muscle necrosis and interruption of muscle fibers. There was no gastrocnemius muscle contraction in tourniquet/IR, while femoral artery ligation/IR markedly weakened gastrocnemius muscle contraction. Motor nerve terminals disappeared, and endplate potentials (EPPs) were undetectable in tourniquet/IR, whereas femoral artery ligation/IR only induced mild impairment of motor nerve terminals and decreased the amplitude of EPPs. Additionally, western blot data showed that proinflammatory cytokine levels (IL-1β and TNF-α) were higher in the tourniquet/IR than that in femoral artery ligation/IR. Moreover, tourniquet/IR caused significant tissue edema and dilation of lymphatic vessels in the hindlimb, compared to femoral artery ligation/IR. The above data demonstrated that tourniquet/IR-induced acute hindlimb injuries are more severe than those induced by femoral artery ligation/IR. This suggests that future investigators should determine which hindlimb IR model (tourniquet/IR or femoral artery ligation/IR) is optimal depending on the purpose of their study., Competing Interests: Declaration of Competing Interest No conflicts of interest are declared by the authors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Context.—: RNA-based next-generation sequencing (NGS) assays are being used with increasing frequency for comprehensive molecular profiling of solid tumors., Objective.—: To evaluate factors that might impact clinical assay performance., Design.—: A 4-month retrospective review of cases analyzed by a targeted RNA-based NGS assay to detect fusions was performed. RNA extraction was performed from formalin-fixed, paraffin-embedded tissue sections and/or cytology smears of 767 cases, including 493 in-house and 274 outside referral cases. The types of samples included 422 core needle biopsy specimens (55%), 268 resection specimens (35%), and 77 cytology samples (10%)., Results.—: Successful NGS fusion testing was achieved in 697 specimens (90.9%) and correlated positively with RNA yield (P < .001) and negatively with specimen necrosis (P = .002), decalcification (P < .001), and paraffin block age of more than 2 years (P = .001). Of the 697 cases that were successfully sequenced, 50 (7.2%) had clinically relevant fusions. The testing success rates and fusion detection rates were similar between core needle biopsy and cytology samples. In contrast, RNA fusion testing was often less successful using resection specimens (P = .007). Testing success was independent of the tumor percentage in the specimen, given that at least 20% tumor cellularity was present., Conclusions.—: The success of RNA-based NGS testing is multifactorial and is influenced by RNA quality and quantity. Identification of preanalytical factors affecting RNA quality and yield can improve NGS testing success rates.

Fluorescence in situ hybridization (FISH) is a confirmatory test to establish a diagnosis of inv(16)/t(16;16) AML. However, incidental findings and their clinical diagnostic implication have not been systemically studied. We studied 1629 CBFB FISH cases performed in our institution, 262 (16.1%), 1234 (75.7%), and 133 (8.2%) were reported as positive, normal, and abnormal, respectively. The last included CBFB copy number changes ( n = 120) and atypical findings such as 3'CBFB deletion ( n = 11), 5'CBFB deletion ( n = 1), and 5' CBFB gain ( n = 1). Correlating with CBFB-MYH11 RT-PCR results, totally 271 CBFB rearrangement cases were identified, including five with discrepancies between FISH and RT-PCR due to new partner genes ( n = 3), insertion ( n = 1), or rare CBFB-MYH11 variant ( n = 1) and eight with 3'CBFB deletion. All cases with atypical findings and/or discrepancies presented clinical diagnostic challenges. Correlating FISH signal patterns and karyotypes, additional chromosome 16 aberrations (AC16As) show impacts on the re-definition of a complex karyotype and prognostic prediction. The CBFB rearrangement but not all AC16As will be detected by NGS-based methods. Therefore, FISH testing is currently still needed to provide a quick and straightforward confirmatory inv(16)/t(16;16) AML diagnosis and additional information related to clinical management.

Background: Occipital condyle fractures (OCFs) have been reported in up to 4-16% of individuals suffering cervical spine trauma. The current management of OCF fractures relies on a rigid cervical collar for 6 weeks or longer. Here, we calculated the rate of acute and delayed surgical intervention (occipitocervical fusion) for patients with isolated OCF who were managed with a cervical collar over a 10-year period at a single institution., Methods: This was a retrospective analysis performed on all patients admitted to a Level 1 Trauma Center between 2008 and 2018 who suffered traumatic isolated OCF managed with an external rigid cervical orthosis. Radiographic imaging was reviewed by several board-certified neuroradiologists. Demographic and clinical data were collected including need for occipitocervical fusion within 12 months after trauma., Results: The incidence of isolated OCF was 4% (60/1536) for those patients admitted with cervical spine fractures. They averaged 49 years of age, and 58% were male falls accounted for the mechanism of injury in 47% of patients. Classification of OCF was most commonly classified in 47% as type I Anderson and Montesano fractures. Of the 60 patients who suffered isolated OCF that was managed with external cervical orthosis, 0% required occipitocervical fusion within 12 months posttrauma. About 90% were discharged, while the remaining 10% sustained traumatic brain/orthopedic injury that limited an accurate neurological assessment., Conclusion: Here, we documented a 4% incidence of isolated OCF in our cervical trauma population, a rate which is comparable to that found in the literature year. Most notably, we documented a 0% incidence for requiring delayed occipital-cervical fusions., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Surgical Neurology International.)