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Surveillance imaging at 45 to 90 days after transcatheter left atrial appendage occlusion device implantation with transesophageal echocardiography (TEE) or cardiac computed tomography (CT) is recommended to assess device position and the presence of device-related complications such as device-related thrombus (DRT) or peridevice leak. Detection of DRT is associated with a significantly increased risk of a stroke or systemic embolization event within 6 months of detection. Nonetheless, there is significant variability in detection of DRT as a result of timing, frequency, and imaging modality used for surveillance. The process of DRT formation vs benign device endothelization is not known. Here we highlight the spectrum of imaging findings seen on TEE and CT and emphasize the need for unified definitions and standardized reporting of imaging findings., Competing Interests: Dr Alkhouli has served on Advisory board for Boston Scientific and Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: A subset of individuals with major depressive disorder (MDD) have a high burden of cardiovascular risk factors and cerebral small-vessel disease, implicating vascular disease in the development of depression. Cross-sectional studies demonstrate a link between endothelial dysfunction and MDD, but the prospective association between peripheral endothelial dysfunction (PED) and an incident diagnosis of MDD is unknown., Methods and Results: Patients undergoing a baseline assessment of cardiovascular risk were evaluated for PED using reactive hyperemia-peripheral arterial tonometry (≤1.8 consistent with PED). Patient medical records were reviewed to identify those who underwent a formal clinical evaluation of MDD after the index PED evaluation. The frequency of PED was compared in those with and without MDD. Logistic regression analyses were performed to assess the association between baseline PED and incident MDD. Between January 2006 and December 2020, 1614 patients underwent testing for PED. Four hundred eighty-four (30.1%) patients underwent a formal evaluation for MDD after (0-15 years) the index procedure (mean±SD age, 52.8±13.8 years; 65.2% women). Of these, 157 (32.4%) had PED and 108 (31.0%) were diagnosed with MDD. Individuals with MDD had a higher frequency of PED (40.2% versus 30.2%; P =0.034) compared with those without MDD. In multivariable analyses, PED was significantly associated with MDD (odds ratio, 2.3 [95% CI, 1.4-3.8]; P <0.001)., Conclusions: PED is significantly associated with incident MDD. Thus, PED may be a useful marker to identify individuals at increased risk of depression who may benefit from more frequent and earlier management strategies.

Objective: To evaluate the diagnostic performance of the previously recommended baseline high-sensitivity cardiac troponin T (hs-cTnT) thresholds of 52 and 100 ng/L in identifying patients at high risk of acute myocardial infarction (AMI)., Patients and Methods: This study compared the positive predictive value (PPV) for index AMI of these high-risk hs-cTnT thresholds in adult patients in the emergency department undergoing hs-cTnT measurement., Results: The adjudicated MAyo Southwest Wisconsin 5th Gen Troponin T ImplementatiON cohort included 2053 patients, with 157 (7.6%) who received a diagnosis of AMI. The hs-cTnT concentrations of greater than 52 and greater than 100 ng/L resulted in PPVs of 41% (95% CI, 35%-48%) and 57% (95% CI, 48%-66%). In patients with chest discomfort, hs-cTnT concentrations greater than 52 ng/L resulted in a PPV of 66% (95% CI, 56%-76%) and hs-cTnT concentrations greater than 100 ng/L resulted in a PPV of 77% (95% CI, 65%-87%). The CV Data Mart Biomarker cohort included 143,709 patients, and 3003 (2.1%) received a diagnosis of AMI. Baseline hs-cTnT concentrations greater than 52 and greater than 100 ng/L resulted in PPVs of 12% (95% CI, 11%-12%) and 17% (95% CI, 17%-19%), respectively. In patients with chest pain and hs-cTnT concentrations greater than 52 ng/L, the PPV for MI was 17% (95% CI, 15%-18%) and in those with concentrations greater than 100 ng/L, only 22% (95% CI, 19%-25%)., Conclusion: In unselected patients undergoing hs-cTnT measurement, the hs-cTnT thresholds of greater than 52 and greater than 100 ng/L provide suboptimal performance for identifying high-risk patients. In patients with chest discomfort, an hs-cTnT concentration of greater than 100 ng/L, but not the European Society of Cardiology-recommended threshold of greater than 52 ng/L, provides an acceptable performance but should be used only with other clinical features., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

The management of pulmonary embolus and intracardiac masses is rapidly evolving with the availability of transcatheter aspiration devices. We describe the utility of a transcatheter aspiration device in management of a patient with pulmonary embolus and a right atrial mass in transit after spinal surgery where a topical hemostatic agent was used to control intraoperative bleeding., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Loneliness and social isolation are associated with poor health outcomes such as an increased risk of cardiovascular diseases., Objectives: The authors aimed to explore the association between social isolation with biological aging which was determined by artificial intelligence-enabled electrocardiography (AI-ECG) as well as the risk of all-cause mortality., Methods: The study included adults aged ≥18 years seen at Mayo Clinic from 2019 to 2022 who respond to a survey for social isolation assessment and had a 12-lead ECG within 1 year of completing the questionnaire. Biological age was determined from ECGs using a previously developed and validated convolutional neural network (AI-ECG age). Age-Gap was defined as AI-ECG age minus chronological age, where positive values reflect an older-than-expected age. The status of social isolation was measured by the previously validated multiple-choice questions based on Social Network Index (SNI) with score ranges between 0 (most isolated) and 4 (least isolated)., Results: A total of 280,324 subjects were included (chronological age 59.8 ± 16.4 years, 50.9% female). The mean Age-Gap was -0.2 ± 9.16 years. A higher SNI was associated with a lower Age-Gap (β of SNI = 4 was -0.11; 95% CI: -0.22 to -0.01; P  < 0.001, adjusted to covariates). Cox proportional hazard analysis revealed the association between social connection and all-cause mortality (HR for SNI = 4, 0.47; 95% CI: 0.43-0.5; P  < 0.001)., Conclusions: Social isolation is associated with accelerating biological aging and all-cause mortality independent of conventional cardiovascular risk factors. This observation underscores the need to address social connection as a health care determinant., Competing Interests: Drs Friedman, Lopez-Jimenez, and Attia are coinvestigators of the AI-ECG age algorithm, which has been licensed to Alumana, Mayo Clinic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Cardiovascular disease is often a disease of aging. Considerable advances in our understanding of the biological mechanisms of aging have been made; yet, cardiovascular disease remains the leading cause of death in the United States urging a continued search for novel risk factors to target for preventing and treating disease. Mental stress (MS) is emerging as an important risk factor, and while progress has been made in understanding the link between MS and cardiovascular disease, the precise mechanisms of a putative causal relationship require greater clarification. In the current review, we (1) summarize our current understanding of the pathological effects of MS on vascular health; (2) describe important aspects of the pathobiology of vascular aging including inflammation, oxidative stress, mitochondrial dysfunction as well as novel processes such as genomic instability, epigenetic alterations, and nutrient signal pathways; (3) highlight similarities in the downstream biologic effects of aging and MS on vascular health with an emphasis on cellular and molecular processes that could be used to develop novel prognostic markers and treatment strategies for cardiovascular disease; (4) discuss lifestyle and pharmacological methods that target indicators of aging whose role could be translated into approaches managing the effects of MS; and (5) outline important future steps that should be considered in this area of research including the need for prospective clinical trials and for creating greater collaboration between preclinical aging researchers and clinical investigators managing MS., Competing Interests: Disclosures None.

Spontaneous coronary artery dissection (SCAD) is an epicardial coronary artery dissection not associated with atherosclerosis or trauma, and is not iatrogenic. The pathogenesis of SCAD is not fully understood, and the association of coronary artery anomalies and SCAD is not known. We present a case of a 64-year-old woman presenting with non-ST-elevation myocardial infarction (NSTEMI) due to have multivessel SCAD in the setting of anomalous origin of the coronary arteries with all three coronary arteries - right coronary artery (RCA), left anterior descending artery (LAD), and left circumflex artery (LCx) originating from the right sinus of Valsalva., Learning Points: Spontaneous coronary artery dissection (SCAD) and coronary artery anomaly can arise where all three arteries originate from the right coronary cusp;There are possible associations between SCAD and coronary artery anomalies;Treatment and management of multivessel SCAD with a coronary artery anomaly where all three arteries arise from the right sinus of Valsalva., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests., (© EFIM 2023.)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: The outcomes of catheter ablation for atrial fibrillation in adults with congenital heart disease are not well described., Methods: In a retrospective study of adult patients with congenital heart disease who underwent catheter ablation for atrial fibrillation between 2000 and 2020 at Mayo Clinic, procedural characteristics and outcomes were collected. The primary outcomes were atrial arrhythmia (AA) recurrence following a 3-month blanking period and repeat ablation. An arrhythmia clinical severity score was assessed pre- and post-ablation based on the duration of arrhythmia episodes, symptoms, cardioversion frequency, and antiarrhythmic drug use., Results: One hundred forty-five patients (age, 57±12 years; 28% female; 63% paroxysmal atrial fibrillation) underwent 198 ablations with a median follow-up of 26 months (interquartile range, 14-69). One hundred ten, 26, and 9 patients had simple, moderate, and complex congenital heart disease, respectively. All patients underwent pulmonary vein isolation, and non-pulmonary vein targets were ablated in 79 (54%). AA recurrence at 12 months was 37% (95% CI, 29%-45%). On univariate analysis, increasing left atrial volume index was associated with higher odds of AA recurrence (odds ratio, 1.03 [1.00-1.06] per 1 mL/m 2 increment; P =0.05). Noninducibility of atrial flutter was predictive of decreased odds of AA recurrence (odds ratio, 0.43 [0.21-0.90]; P =0.03). A second ablation was performed in 43 patients after a median of 20 (interquartile range, 8-37) months. Arrhythmia clinical severity scores improved following ablation, reflecting a decrease in symptoms, cardioversions, and antiarrhythmic drugs., Conclusions: Catheter ablation of atrial fibrillation is feasible and effective in patients with adult congenital heart disease and reduces symptoms. Recurrence of AA frequently requires repeat ablation., Competing Interests: Disclosures Dr Madhavan receives research funding from Boston Scientific, BMS/Pfizer, and Convatec, Inc; speaker honorarium from Biosense Webster; and she is on the steering committee of CERTITUDE Registry, Biotronik, Inc. Dr Asirvatham receives speaking/honoraria from Abbott, Biosense Webster, Biotronik, Boston Scientific, Medtronic, and Zoll. All other authors have no conflicts to disclose.

Competing Interests: Conflict of interest: None declared.

Obesity remains a major public health problem, affecting almost half of adults in the United States. Increased risk of cardiovascular disease (CVD) and CVD mortality are major obesity-related complications, and management guidelines now recommend weight loss as a key strategy for the primary prevention of CVD in patients with overweight or obesity. The recently demonstrated efficacy of some pharmacologic therapies for chronic weight management may encourage health care professionals to recognize obesity as a treatable serious chronic disease and motivate patients to re-engage with weight loss when previous attempts have been ineffective or unsustainable. This review article summarizes the benefits and challenges associated with lifestyle changes, bariatric surgery, and historical pharmacologic interventions in the treatment of obesity, and focuses on the current evidence for the efficacy and safety of the newer glucagon-like peptide-1 receptor agonist medications in the management of obesity and potential reduction of CVD risk. We conclude that the available evidence demonstrates glucagon-like peptide-1 receptor agonists should be strongly considered in clinical practice for the treatment of obesity and reduction of CVD risk in people with type 2 diabetes. If ongoing research proves glucagon-like peptide-1 receptor agonists to be effective in reducing the risk of CVD onset in patients with obesity, irrespective of type 2 diabetes status, it will herald a new treatment paradigm in this setting, and now is the time for health care professionals to better recognize the benefits of these agents.

Transapical puncture for transcatheter treatment of mitral-paravalvular leak (PVL) is associated with increased risks even when the apical tract is closed with vascular plugs. A novel technique that leverages back wall support from the right or left atrium can be used to facilitate transcatheter closure of mitral PVL through an antegrade approach. ( Level of Difficulty: Advanced. )., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Spontaneous coronary artery dissection of the septal arteries is rare and may be overlooked on coronary angiogram. Additionally, dedicated intracoronary imaging may not be feasible due to artery size. Cardiac magnetic resonance imaging has an emerging role in diagnosis, which is critical because management changes significantly if spontaneous coronary artery dissection is diagnosed. ( Level of Difficulty: Beginner. )., Competing Interests: Dr Tweet is supported by funding from the National Institutes of Health (1K23HL155506-01A1). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Whole-Body Electromyostimulation (WB-EMS) is a training technology that enables simultaneous stimulation of all the main muscle groups with a specific impulse intensity for each electrode. The corresponding time-efficiency and joint-friendliness of WB-EMS may be particularly attractive for people unable or unmotivated to conduct (intense) conventional training protocols. However, due to the enormous metabolic and musculoskeletal impact of WB-EMS, particular attention must be paid to the application of this technology. In the past, several scientific and newspaper articles reported severe adverse effects of WB-EMS. To increase the safety of commercial non-medical WB-EMS application, recommendations "for safe and effective whole-body electromyostimulation" were launched in 2016. However, new developments and trends require an update of these recommendations to incorporate more international expertise with demonstrated experience in the application of WB-EMS. The new version of these consensus-based recommendations has been structured into 1) "general aspects of WB-EMS", 2) "preparation for training", recommendations for the 3) "WB-EMS application" itself and 4) "safety aspects during and after training". Key topics particularly addressed are 1) consistent and close supervision of WB-EMS application, 2) mandatory qualification of WB-EMS trainers, 3) anamnesis and corresponding consideration of contraindications prior to WB-EMS, 4) the participant's proper preparation for the session, 5) careful preparation of the WB-EMS novice, 6) appropriate regeneration periods between WB-EMS sessions and 7) continuous interaction between trainer and participant at a close physical distance. In summary, we are convinced that the present guideline will contribute to greater safety and effectiveness in the area of non-medical commercial WB-EMS application., 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 © 2023 Kemmler, Fröhlich, Ludwig, Eifler, von Stengel, Willert, Teschler, Weissenfels, Kleinöder, Micke, Wirtz, Zinner, Filipovic, Wegener, Berger, Evangelista, D’Ottavio, Sara, Lerman, Perez de Arrilucea Le Floc’h, Carle-Calo, Guitierrez and Amaro-Gahete.)

Virtual surgical planning (VSP) and three-dimensional (3D) printing have become a standard of care at our institution, transforming the surgical care of complex patients. Patient-specific, anatomic models and surgical guides are clinically used to improve multidisciplinary communication, presurgical planning, intraoperative guidance, and the patient informed consent. Recent innovations have allowed both VSP and 3D printing to become more accessible to various sized hospital systems. Insourcing such work has several advantages including quicker turnaround times and increased innovation through collaborative multidisciplinary teams. Centralizing 3D printing programs at the point-of-care provides a greater cost-efficient investment for institutions. The following article will detail capital equipment needs, institutional structure, operational personnel, and other considerations necessary in the establishment of a POC manufacturing program., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Circulating tumor DNA (ctDNA), the tumor-derived cell-free DNA fragments in the bloodstream carrying tumor-specific genetic and epigenetic alterations, represents an emerging novel tool for minimal residual disease (MRD) assessment in patients with resected colorectal cancer (CRC). For many decades, precise risk-stratification following curative-intent colorectal surgery has remained an enduring challenge. The current risk stratification strategy relies on clinicopathologic characteristics of the tumors that lacks precision and results in over-and undertreatment in a significant proportion of patients. Consequently, a biomarker that can reliably identify patients harboring MRD would be of critical importance in refining patient selection for adjuvant therapy. Several prospective cohort studies have provided compelling data suggesting that ctDNA could be a robust biomarker for MRD that outperforms all existing clinicopathologic criteria. Numerous clinical trials are currently underway to validate the ctDNA-guided MRD assessment and adjuvant treatment strategies. Once validated, the ctDNA technology will likely transform the adjuvant therapy paradigm of colorectal cancer, supporting ctDNA-guided treatment escalation and de-escalation. The current article presents a comprehensive overview of the published studies supporting the utility of ctDNA for MRD assessment in patients with CRC. We also discuss ongoing ctDNA-guided adjuvant clinical trials that will likely shape future adjuvant therapy strategies for patients with CRC.

Background: There are good data to support using a single high-sensitivity cardiac troponin T (hs-cTnT) below the limit of detection of 5 ng/L to exclude acute myocardial infarction. Per the US Food and Drug Administration, hs-cTnT can only report to the limit of quantitation of 6 ng/L, a threshold for which there are limited data. Our goal was to determine whether a single hs-cTnT below the limit of quantitation of 6 ng/L is a safe strategy to identify patients at low risk for acute myocardial injury and infarction., Methods: The efficacy (proportion identified as low risk based on baseline hs-cTnT<6 ng/L) of identifying low-risk patients was examined in a multicenter (n=22 sites) US cohort study of emergency department patients undergoing at least 1 hs-cTnT (CV Data Mart Biomarker cohort). We then determined the performance of a single hs-cTnT<6 ng/L (biomarker alone) to exclude acute myocardial injury (subsequent hs-cTnT >99th percentile in those with an initial hs-cTnT<6 ng/L). The clinically intended rule-out strategy combining a nonischemic ECG with a baseline hs-cTnT<6 ng/L was subsequently tested in an adjudicated cohort in which the diagnostic performance for ruling out acute myocardial infarction and safety (myocardial infarction or death at 30 days) were evaluated., Results: A total of 85 610 patients were evaluated in the CV Data Mart Biomarker cohort, among which 24 646 (29%) had a baseline hs-cTnT<6 ng/L. Women were more likely than men to have hs-cTnT<6 ng/L (38% versus 20%, P <0.0001). Among 11 962 patients with baseline hs-cTnT<6 ng/L and serial measurements, only 1.2% developed acute myocardial injury, resulting in a negative predictive value of 98.8% (95% CI, 98.6-99.0) and sensitivity of 99.6% (95% CI, 99.5-99.6). In the adjudicated cohort, a nonischemic ECG with hs-cTnT<6 ng/L identified 33% of patients (610/1849) as low risk and resulted in a negative predictive value and sensitivity of 100% and a 30-day rate of 0.2% for myocardial infarction or death., Conclusions: A single hs-cTnT below the limit of quantitation of 6 ng/L is a safe and rapid method to identify a substantial number of patients at very low risk for acute myocardial injury and infarction.

Background: Uncompensated vestibular hypofunction can result in symptoms of dizziness, imbalance, and/or oscillopsia, gaze and gait instability, and impaired navigation and spatial orientation; thus, may negatively impact an individual's quality of life, ability to perform activities of daily living, drive, and work. It is estimated that one-third of adults in the United States have vestibular dysfunction and the incidence increases with age. There is strong evidence supporting vestibular physical therapy for reducing symptoms, improving gaze and postural stability, and improving function in individuals with vestibular hypofunction. The purpose of this revised clinical practice guideline is to improve quality of care and outcomes for individuals with acute, subacute, and chronic unilateral and bilateral vestibular hypofunction by providing evidence-based recommendations regarding appropriate exercises., Methods: These guidelines are a revision of the 2016 guidelines and involved a systematic review of the literature published since 2015 through June 2020 across 6 databases. Article types included meta-analyses, systematic reviews, randomized controlled trials, cohort studies, case-control series, and case series for human subjects, published in English. Sixty-seven articles were identified as relevant to this clinical practice guideline and critically appraised for level of evidence., Results: Based on strong evidence, clinicians should offer vestibular rehabilitation to adults with unilateral and bilateral vestibular hypofunction who present with impairments, activity limitations, and participation restrictions related to the vestibular deficit. Based on strong evidence and a preponderance of harm over benefit, clinicians should not include voluntary saccadic or smooth-pursuit eye movements in isolation (ie, without head movement) to promote gaze stability. Based on moderate to strong evidence, clinicians may offer specific exercise techniques to target identified activity limitations and participation restrictions, including virtual reality or augmented sensory feedback. Based on strong evidence and in consideration of patient preference, clinicians should offer supervised vestibular rehabilitation. Based on moderate to weak evidence, clinicians may prescribe weekly clinic visits plus a home exercise program of gaze stabilization exercises consisting of a minimum of: (1) 3 times per day for a total of at least 12 minutes daily for individuals with acute/subacute unilateral vestibular hypofunction; (2) 3 to 5 times per day for a total of at least 20 minutes daily for 4 to 6 weeks for individuals with chronic unilateral vestibular hypofunction; (3) 3 to 5 times per day for a total of 20 to 40 minutes daily for approximately 5 to 7 weeks for individuals with bilateral vestibular hypofunction. Based on moderate evidence, clinicians may prescribe static and dynamic balance exercises for a minimum of 20 minutes daily for at least 4 to 6 weeks for individuals with chronic unilateral vestibular hypofunction and, based on expert opinion, for a minimum of 6 to 9 weeks for individuals with bilateral vestibular hypofunction. Based on moderate evidence, clinicians may use achievement of primary goals, resolution of symptoms, normalized balance and vestibular function, or plateau in progress as reasons for stopping therapy. Based on moderate to strong evidence, clinicians may evaluate factors, including time from onset of symptoms, comorbidities, cognitive function, and use of medication that could modify rehabilitation outcomes., Discussion: Recent evidence supports the original recommendations from the 2016 guidelines. There is strong evidence that vestibular physical therapy provides a clear and substantial benefit to individuals with unilateral and bilateral vestibular hypofunction., Limitations: The focus of the guideline was on peripheral vestibular hypofunction; thus, the recommendations of the guideline may not apply to individuals with central vestibular disorders. One criterion for study inclusion was that vestibular hypofunction was determined based on objective vestibular function tests. This guideline may not apply to individuals who report symptoms of dizziness, imbalance, and/or oscillopsia without a diagnosis of vestibular hypofunction., Disclaimer: These recommendations are intended as a guide to optimize rehabilitation outcomes for individuals undergoing vestibular physical therapy. The contents of this guideline were developed with support from the American Physical Therapy Association and the Academy of Neurologic Physical Therapy using a rigorous review process. The authors declared no conflict of interest and maintained editorial independence.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A369)., Competing Interests: All members of the Guideline Development Group and Advisory Board completed conflict of interest forms, which included information about grant funding, royalties, device/company shares, legal assistance, patents, device consultant/advocacy, publications, presentations, and clinical practice related to the Clinical Practice Guideline (CPG) topic. Forms were submitted to the Academy of Neurologic Physical Therapy (ANPT) Evidence-Based Documents Committee, who monitored and managed any identified perceived conflicts of interest. All recommendations were written as a group per standard CPG methodology. Therefore, no one individual made all the decisions. These recommendations are intended as a guide to optimize rehabilitation outcomes for individuals undergoing vestibular physical therapy. The contents of this guideline were developed with support from the American Physical Therapy Association and the Academy of Neurologic Physical Therapy using a rigorous review process. The authors declared no conflict of interest and maintained editorial independence., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Academy of Neurologic Physical Therapy, APTA.)

The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein syntaxin-5 (Stx5) is essential for Golgi transport. In humans, the STX5 mRNA encodes two protein isoforms, Stx5 Long (Stx5L) from the first starting methionine and Stx5 Short (Stx5S) from an alternative starting methionine at position 55. In this study, we identify a human disorder caused by a single missense substitution in the second starting methionine (p.M55V), resulting in complete loss of the short isoform. Patients suffer from an early fatal multisystem disease, including severe liver disease, skeletal abnormalities and abnormal glycosylation. Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking. Measurements of cognate binding SNAREs, based on biotin-synchronizable forms of Stx5 (the RUSH system) and Förster resonance energy transfer (FRET), revealed that the short isoform of Stx5 is essential for intra-Golgi transport. Alternative starting codons of Stx5 are thus linked to human disease, demonstrating that the site of translation initiation is an important new layer of regulating protein trafficking., (© 2021. The Author(s).)

Background Anxiety disorders are the most prevalent mental disorders and are an emerging risk factor for coronary artery disease and its complications. We determine the relationship between having a clinical diagnosis of an anxiety disorder and coronary endothelial dysfunction (CED) using invasive coronary reactivity testing across both sexes. Methods and Results Patients presenting with chest pain and nonobstructive coronary artery disease (stenosis <40%) at coronary angiography underwent an invasive assessment of CED. Patients were categorized as having a clinical diagnosis of an anxiety disorder at the time of coronary angiography by chart review. The frequency of CED was compared between patients with versus without an anxiety disorder and after stratifying patients by sex. Between 1992 and 2020, 1974 patients (mean age, 51.3 years; 66.2% women) underwent invasive coronary reactivity testing, of which 550 (27.9%) had a documented anxiety disorder at the time of angiography. There was a significantly higher proportion of patients with any type of CED in those with an anxiety disorder in all patients (343 [62.7%] versus 790 [56.4%]; P =0.011) that persisted in women but not in men. After adjusting for covariables, anxiety was significantly associated with any CED among all patients (odds ratio [95% CI], 1.36 [1.10-1.68]; P =0.004), and after stratifying by sex in women but not in men. Conclusions Anxiety disorders are significantly associated with CED in women presenting with chest pain and nonobstructive coronary artery disease. Thus, CED may represent a mechanism underpinning the association between anxiety disorders and coronary artery disease and its complications, highlighting the role of anxiety as a potential therapeutic target to prevent cardiovascular events.

Background: Limited data exist on high-sensitivity cardiac troponin (hs-cTn) for risk-stratification in COVID-19., Methods: We conducted a multicenter, retrospective, observational, US-based study of COVID-19 patients undergoing hs-cTnT. Outcomes included short-term mortality (in-hospital and 30-days post-discharge) and a composite of major adverse events, including respiratory failure requiring mechanical ventilation, cardiac arrest, and shock within the index presentation and/or mortality during the index hospitalization or within 30-days post-discharge., Results: Among 367 COVID-19 patients undergoing hs-cTnT, myocardial injury was identified in 46%. They had a higher risk for mortality (20% vs 12%, P < 0.0001; unadjusted HR 4.44, 95% CI 2.13-9.25, P < 0.001) and major adverse events (35% vs. 11%, P < 0.0001; unadjusted OR 4.29, 95% CI 2.50-7.40, P < 0.0001). Myocardial injury was associated with major adverse events (adjusted OR 3.84, 95% CI 2.00-7.36, P < 0.0001) but not mortality. Baseline (adjusted OR 1.003, 95% CI 1.00-1.007, P = 0.047) and maximum (adjusted OR 1.005, 95% CI 1.001-1.009, P = 0.0012) hs-cTnT were independent predictors of major adverse events. Most (95%) increases were due to myocardial injury, with 5% (n = 8) classified as type 1 or 2 myocardial infarction. A single hs-cTnT <6 ng/L identified 26% of patients without mortality, with a 94.9% (95% CI 87.5-98.6) negative predictive value and 93.1% sensitivity (95% CI 83.3-98.1) for major adverse events in those presenting to the ED., Conclusions: Myocardial injury is frequent and prognostic in COVID-19. While most hs-cTnT increases are modest and due to myocardial injury, they have important prognostic implications. A single hs-cTnT <6 ng/L at presentation may facilitate the identification of patients with a favorable prognosis., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Limited U.S. data exist regarding high-sensitivity cardiac troponin (cTn) implementation., Objectives: This study sought to evaluate the impact of high-sensitivity cardiac troponin T (cTnT) implementation., Methods: Observational U.S. cohort study of emergency department (ED) patients undergoing measurement of cTnT during the transition from 4th (pre-implementation March 12, 2018, to September 11, 2018) to 5th generation (Gen) cTnT (post-implementation September 12, 2018, to March 11, 2019). Diagnoses were adjudicated following the Fourth Universal Definition of Myocardial Infarction (MI). Resources evaluated included length of stay, hospitalizations, and cardiac testing., Results: In this study, 3,536 unique patients were evaluated, including 2,069 and 2,491 ED encounters pre- and post-implementation. Compared with 4th Gen cTnT, encounters with ≥1 cTnT >99th percentile increased using 5th Gen cTnT (15% vs. 47%; p < 0.0001). Acute MI (3.3% vs. 8.1%; p < 0.0001) and myocardial injury (11% vs. 38%; p < 0.0001) increased. Although type 1 MIs increased (1.7% vs. 2.9%; p = 0.0097), the overall MI increase was largely due to more type 2 MIs (1.6% vs. 5.2%; p < 0.0001). Women were less likely than men to have MI using 4th Gen cTnT (2.3% vs. 4.4%; p = 0.008) but not 5th Gen cTnT (7.7% vs. 8.5%; p = 0.46). Overall length of stay and stress testing were reduced, and angiography was increased (all p < 0.05). Among those without cTnT increases, there were more ED discharges and a reduction in length of stay, echocardiography, and stress tests (all p < 0.05)., Conclusions: High-sensitivity cTnT implementation resulted in a marked increase in myocardial injury and MI, particularly in women and patients with type 2 MI. Despite this, except for angiography, overall resource use did not increase. Among those without cTnT increases, there were more ED discharges and fewer cardiac tests., Competing Interests: Funding Support and Author Disclosures This publication was made possible in part by the Mayo Clinic CTSA through grant UL1TR002377 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health. Dr. Jaffe has consulted or presently consults for most of the major diagnostics companies, including Beckman, Abbott, Siemens, ET Healthcare, Roche, Radiometer, Sphingotec, Amgen, and Novartis. Dr. Sandoval has previously served on the Advisory Boards for Roche Diagnostics and Abbott Diagnostics without personal compensation; and has also been a speaker without personal financial compensation for Abbott Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the association of voice analysis with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection., Patients and Methods: A vocal biomarker, a unitless scalar with a value between 0 and 1, was developed based on 434 voice samples. The biomarker training was followed by a prospective, multicenter, observational study. All subjects were tested for SARS-CoV-2, had their voice recorded to a smartphone application, and gave their informed consent to participate in the study. The association of SARS-CoV-2 infection with the vocal biomarker was evaluated., Results: The final study population included 80 subjects with a median age of 29 [range, 23 to 36] years, of whom 68% were men. Forty patients were positive for SARS-CoV-2. Infected patients were 12 times more likely to report at least one symptom (odds ratio, 11.8; P <.001). The vocal biomarker was significantly higher among infected patients (OR, 0.11; 95% CI, 0.06 to 0.17 vs OR, 0.19; 95% CI, 0.12 to 0.3; P =.001). The area under the receiver operating characteristic curve evaluating the association of the vocal biomarker with SARS-CoV-2 status was 72%. With a biomarker threshold of 0.115, the results translated to a sensitivity and specificity of 85% (95% CI, 70% to 94%) and 53% (95% CI, 36% to 69%), respectively. When added to a self-reported symptom classifier, the area under the curve significantly improved from 0.775 to 0.85., Conclusion: Voice analysis is associated with SARS-CoV-2 status and holds the potential to improve the accuracy of self-reported symptom-based screening tools. This pilot study suggests a possible role for vocal biomarkers in screening for SARS-CoV-2-infected subjects., (© 2021 The Authors.)

Background: Adoption of the Digital Imaging and Communications in Medicine (DICOM) standard for whole slide images (WSIs) has been slow, despite significant time and effort by standards curators. One reason for the lack of adoption is that there are few tools which exist that can meet the requirements of WSIs, given an evolving ecosystem of best practices for implementation. Eventually, vendors will conform to the specification to ensure enterprise interoperability, but what about archived slides? Millions of slides have been scanned in various proprietary formats, many with examples of rare histologies. Our hypothesis is that if users and developers had access to easy to use tools for migrating proprietary formats to the open DICOM standard, then more tools would be developed as DICOM first implementations., Methods: The technology we present here is dicom&#95;wsi, a Python based toolkit for converting any slide capable of being read by the OpenSlide library into DICOM conformant and validated implementations. Moreover, additional postprocessing such as background removal, digital transformations (e.g., ink removal), and annotation storage are also described. dicom&#95;wsi is a free and open source implementation that anyone can use or modify to meet their specific purposes., Results: We compare the output of dicom&#95;wsi to two other existing implementations of WSI to DICOM converters and also validate the images using DICOM capable image viewers., Conclusion: dicom&#95;wsi represents the first step in a long process of DICOM adoption for WSI. It is the first open source implementation released in the developer friendly Python programming language and can be freely downloaded at ., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Pathology Informatics.)

A congenital disorder of glycosylation due to biallelic mutations in B4GALT1 has been previously reported in only three patients with two different mutations. Through homozygosity mapping followed by segregation analysis in an extended pedigree, we identified three additional patients homozygous for a novel mutation in B4GALT1, expanding the phenotypic spectrum of the disease. The patients showed a uniform clinical presentation with intellectual disability, marked pancytopenia requiring chronic management, and novel features including pulmonary hypertension and nephrotic syndrome. Notably, affected individuals exhibited a moderate elevation of Man3GlcNAc4Fuc1 on serum N-glycan analysis, yet two of the patients had a normal pattern of transferrin glycosylation in repeated analysis. The novel mutation is the third disease-causing variant described in B4GALT1, and the first one within its transmembrane domain., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Emerging data suggest that noninvasive voice biomarker analysis is associated with coronary artery disease. We recently showed that a vocal biomarker was associated with hospitalization and heart failure in patients with heart failure. We evaluate the association between a vocal biomarker and invasively measured indices of pulmonary hypertension (PH). Patients were referred for an invasive cardiac hemodynamic study between January 2017 and December 2018, and had their voices recorded on three separate occasions to their smartphone prior to each study. A pre-established vocal biomarker was determined based on each individual recording. The intra-class correlation co-efficient between the separate voice recording biomarker values for each individual participant was 0.829 (95% CI 0.740-0.889) implying very good agreement between values. Thus, the mean biomarker was calculated for each patient. Patients were divided into two groups: high pulmonary arterial pressure (PAP) defined as ≥ 35 mmHg (moderate or greater PH), versus lower PAP. Eighty three patients, mean age 61.6 ± 15.1 years, 37 (44.6%) male, were included. Patients with a high mean PAP (≥ 35 mmHg) had on average significantly higher values of the mean voice biomarker compared to those with a lower mean PAP (0.74 ± 0.85 vs. 0.40 ± 0.88 p = 0.046). Multivariate logistic regression showed that an increase in the mean voice biomarker by 1 unit was associated with a high PAP, odds ratio 2.31, 95% CI 1.05-5.07, p = 0.038. This study shows a relationship between a noninvasive vocal biomarker and an invasively derived hemodynamic index related to PH obtained during clinically indicated cardiac catheterization. These results may have important practical clinical implications for telemedicine and remote monitoring of patients with heart failure and PH., Competing Interests: Dr. Elad Maor serves as a consultant for Beyond Verbal Communications. This author receives no salary for this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The remaining authors have nothing to disclose.

Background: The use of essential oils is growing in the United States, but clinician attitudes, experience, and beliefs regarding their use have not previously been studied., Methods: One hundred five of 106 clinician attendees (99.1%) of an integrative medicine continuing education conference were surveyed using an audience response system to obtain baseline information. Response frequencies of each item were reported. Nonparametric correlations were assessed comparing the statement "In the last 12 months, I have used essential oils for myself and/or my family" with the other agree/disagree statements using Spearman's rho., Results: A majority of participants personally used integrative medicine approaches other than aromatherapy (92.6%) and recommended them clinically (96.8%). Most had personally used essential oils (61%) and wished to offer essential oil recommendations or therapies to their patients (74.0%). Only 21.9% felt confident in their ability to counsel patients on safe use. Personal use of essential oils was highly correlated with confidence in the ability to counsel patients on safe use (Spearman coefficient 0.376, P = 0.000)., Conclusions: This study indicates that clinicians interested in integrative medicine desire to provide aromatherapy recommendations, but do not feel confident in their ability to do so.

Background: Patients with type 2 diabetes mellitus are at an increased risk of adverse cardiovascular events compared to those without diabetes. The timing, relative to disease onset, and degree of glycemic control that reduces the risk of adverse cardiovascular events remains uncertain. Coronary microvascular dysfunction is prevalent in patients with type 2 diabetes mellitus and is linked to adverse cardiovascular events. We assessed the association between endothelial-dependent and endothelial-independent coronary microvascular dysfunction and glycemic control in patients presenting with chest pain and nonobstructive coronary disease at angiography., Methods: Patients presenting with chest pain and found to have non-obstructive CAD (stenosis < 40%) at angiography underwent an invasive assessment of endothelial-independent and endothelial -dependent microvascular function. Endothelial-independent microvascular function was assessed by comparing the coronary flow velocity, measured using a Doppler guidewire, in response to intracoronary infusion of adenosine to calculate the coronary flow reserve ratio in response to adenosine (CFRAdn Ratio). A CFRAdn Ratio ≤ 2.5 was considered abnormal. Endothelial-dependent microvascular function was assessed by measuring the percent change in coronary blood flow in response to intracoronary infusions of acetylcholine (%ΔCBFAch), and microvascular endothelial dysfunction defined as a %ΔCBFAch of ≤ 50%. Patients were classified by normal versus abnormal CFRAdn Ratio and %ΔCBFAch. Measurements of HbA1c and fasting serum glucose were obtained prior to catheterization and compared between groups., Results: Between 1993 and 2012, 1469 patients (mean age 50.4 years, 35% male) underwent coronary angiography and invasive testing for coronary microvascular dysfunction, of which 129 (8.8%) had type 2 diabetes. Fifty-one (39.5%) had an abnormal %ΔCBFAch and 49 (38.0%) had an abnormal CFRAdn Ratio. Conventional cardiovascular risk factors and cardiovascular or diabetic medication use did not vary significantly between groups. Females with an abnormal CFRAdn Ratio or abnormal %ΔCBFAch had a significantly higher HbA1c compared to patients with a normal CFRAdn Ratio or %ΔCBFAch respectively: HbA1c % (standard deviation) 7.4 (2.1) vs. 6.5 (1.1), p = 0.035 and 7.3 (1.9) vs. 6.4 (1.2), p = 0.022, respectively. Female patients with an abnormal CFRAdn Ratio had significantly higher fasting serum glucose concentrations compared to those with a normal CFRAdn Ratio: fasting serum glucose mg/dL (standard deviation) 144.4 (55.6) vs. 121.9 (28.1), p = 0.035. This was not observed in men. Amongst female diabetics, a higher HbA1c was significantly associated with any coronary microvascular dysfunction both in a univariate and multivariate analysis: odds ratio (95% confidence interval) 1.69 (1.01-2.86) p = 0.049; and a fasting serum glucose > 140 mg/dL was significantly associated with an abnormal CFRAdn Ratio, 4.28 (1.43-12.81)., Conclusion: Poor glycemic control is associated with coronary microvascular dysfunction amongst female diabetics presenting with chest pain and non-obstructive CAD. These findings highlight the importance of sex specific risk stratification models and treatment strategies when managing cardiovascular risk amongst diabetics. Further studies are required to identify additional risk prevention tools and therapies targeting microvascular dysfunction as an integrated index of cardiovascular risk.

Whole-slide images (WSIs) are a rich new source of biomedical imaging data. The use of automated systems to classify and segment WSIs has recently come to forefront of the pathology research community. While digital slides have obvious educational and clinical uses, their most exciting potential lies in the application of quantitative computational tools to automate search tasks, assist in classic diagnostic classification tasks, and improve prognosis and theranostics. An essential step in enabling these advancements is to apply advances in machine learning and artificial intelligence from other fields to previously inaccessible pathology datasets, thereby enabling the application of new technologies to solve persistent diagnostic challenges in pathology. Here, we applied convolutional neural networks to differentiate between two forms of melanocytic lesions (Spitz and conventional). Classification accuracy at the patch level was 99.0%-2% when applied to WSI. Importantly, when the model was trained without careful image curation by a pathologist, the training took significantly longer and had lower overall performance. These results highlight the utility of augmented human intelligence in digital pathology applications, and the critical role pathologists will play in the evolution of computational pathology algorithms., Competing Interests: There are no conflicts of interest.

Fluoropyrimidines such as 5-fluorouracil (5-FU) form the foundation of a wide variety of chemotherapy regimens. 5-FU is in fact the third most commonly used chemotherapeutic agent in the treatment of solid malignancies across the world. As with all chemotherapy, balancing the potential benefits of therapy against the risks of drug-related toxicity is crucial when clinicians and patients make shared decisions about treatment. 5-FU is the second most common chemotherapeutic drug associated with cardiotoxicity after anthracyclines, which can manifest as chest pain, acute coronary syndrome/myocardial infarction or death. Nevertheless a widespread appreciation of 5-FU-related cardiotoxicity and its implications is lacking amongst clinicians. In this review, we outline the incidence, possible risk factors, and likely pathophysiological mechanisms that may account for 5-FU-related cardiotoxicity and also highlight potential management strategies for this poorly understood clinical entity., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Background: The surgical Apgar score (SAS) is a 10-point scale using the lowest heart rate, lowest mean arterial pressure, and estimated blood loss (EBL) during surgery to predict postoperative outcomes. The SAS has not yet been validated in liver transplantation patients, because typical blood loss usually exceeds the highest EBL category. Our primary aim was to develop a modified SAS for liver transplant (SAS-LT) by replacing the EBL parameter with volume of red cells transfused. We hypothesized that the SAS-LT would predict death or severe complication within 30 days of transplant with similar accuracy to current scoring systems., Methods: A retrospective cohort of consecutive liver transplantations from July 2007 to November 2013 was used to develop the SAS-LT. The predictive ability of SAS-LT for early postoperative outcomes was compared with Model for End-stage Liver Disease, Sequential Organ Failure Assessment, and Acute Physiology and Chronic Health Evaluation III scores using multivariable logistic regression and receiver operating characteristic analysis., Results: Of 628 transplants, death or serious perioperative morbidity occurred in 105 (16.7%). The SAS-LT (receiver operating characteristic area under the curve [AUC], 0.57) had similar predictive ability to Acute Physiology and Chronic Health Evaluation III, model for end-stage liver disease, and Sequential Organ Failure Assessment scores (0.57, 0.56, and 0.61, respectively).Seventy-nine (12.6%) patients were discharged from the ICU in 24 hours or less. These patients' SAS-LT scores were significantly higher than those with a longer stay (7.0 vs 6.2, P < 0.01). The AUC on multivariable modeling remained predictive of early ICU discharge (AUC, 0.67)., Conclusions: The SAS-LT utilized simple intraoperative metrics to predict early morbidity and mortality after liver transplant with similar accuracy to other scoring systems at an earlier postoperative time point., Competing Interests: The authors declare no conflicts of interest in this work.

A partial differential equation-constrained optimization approach is presented for reconstructing mechanical properties (e.g., elastic moduli). The proposed method is based on the minimization of an error in constitutive equations functional augmented with a least squares data misfit term referred to as MECE for "modified error in constitutive equations." The main theme of this paper is to demonstrate several key strengths of the proposed method on experimental data. In addition, some illustrative examples are provided where the proposed method is compared with a common shear wave elastography (SWE) approach. To this end, both synthetic data, generated with transient finite element simulations, as well as ultrasonically tracked displacement data from an acoustic radiation force (ARF) experiment are used in a standard elasticity phantom. The results indicate that the MECE approach can produce accurate shear modulus reconstructions with significantly less bias than SWE.

Introduction: Many providers report lack of confidence in managing patients with chronic pain. Thus, the primary aim of this study was to investigate the associations of provider confidence in managing chronic pain with their practice behaviors and demographics., Materials and Methods: The primary outcome measure was the results of the Opioid Therapy Provider Survey, which was administered to clinicians attending a pain-focused continuing medical education conference. Nonparametric correlations were assessed using Spearman's rho., Results: Of the respondents, 55.0% were women, 92.8% were white, and 56.5% were physicians. Primary care providers accounted for 56.5% of the total respondents. The majority of respondents (60.8%) did not feel confident managing patients with chronic pain. Provider confidence in managing chronic pain was positively correlated with 1) following an opioid therapy protocol ( P =0.001), 2) the perceived ability to identify patients at risk for opioid misuse ( P =0.006), and 3) using a consistent practice-based approach to improve their comfort level with prescribing opioids ( P <0.001). Provider confidence was negatively correlated with the perception that treating pain patients was a "problem in my practice" ( P =0.005)., Conclusion: In this study, the majority of providers did not feel confident managing chronic pain. However, provider confidence was associated with a protocolized and consistent practice-based approach toward managing opioids and the perceived ability to identify patients at risk for opioid misuse. Future studies should investigate whether provider confidence is associated with measurable competence in managing chronic pain and explore approaches to enhance appropriate levels of confidence in caring for patients with chronic pain., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Anatomic pathology laboratory workflow consists of 3 major specimen handling processes. Among the workflow are preanalytic, analytic, and postanalytic phases that contain multistep subprocesses with great impact on patient care. A worldwide representation of experts came together to create a system of metrics, as a basis for laboratories worldwide, to help them evaluate and improve specimen handling to reduce patient safety risk., Method: Members of the Initiative for Anatomic Pathology Laboratory Patient Safety (IAPLPS) pooled their extensive expertise to generate a list of metrics highlighting processes with high and low risk for adverse patient outcomes., Results: : Our group developed a universal, comprehensive list of 47 metrics for patient specimen handling in the anatomic pathology laboratory. Steps within the specimen workflow sequence are categorized as high or low risk. In general, steps associated with the potential for specimen misidentification correspond to the high-risk grouping and merit greater focus within quality management systems. Primarily workflow measures related to operational efficiency can be considered low risk., Conclusion: Our group intends to advance the widespread use of these metrics in anatomic pathology laboratories to reduce patient safety risk and improve patient care with development of best practices and interlaboratory error reporting programs., (© American Society for Clinical Pathology 2017.)

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of renal failure. Here we identify miR-17 as a target for the treatment of ADPKD. We report that miR-17 is induced in kidney cysts of mouse and human ADPKD. Genetic deletion of the miR-17∼92 cluster inhibits cyst proliferation and PKD progression in four orthologous, including two long-lived, mouse models of ADPKD. Anti-miR-17 treatment attenuates cyst growth in short-term and long-term PKD mouse models. miR-17 inhibition also suppresses proliferation and cyst growth of primary ADPKD cysts cultures derived from multiple human donors. Mechanistically, c-Myc upregulates miR-17∼92 in cystic kidneys, which in turn aggravates cyst growth by inhibiting oxidative phosphorylation and stimulating proliferation through direct repression of Pparα. Thus, miR-17 family is a promising drug target for ADPKD, and miR-17-mediated inhibition of mitochondrial metabolism represents a potential new mechanism for ADPKD progression.

Background: Recent studies show that microRNA-145 (miRNA-145) might be an attractive tumor biomarker of considerable prognostic value, but little is known about their relationship with acute myocardial infarction (AMI). This study investigated the correlation between the level of miR-145 and AMI., Methods: One-hundred patients were divided into three groups: no coronary artery disease (CAD) group, non-ST segment elevation myocardial infarction group, and ST segment elevation myocardial infarction group. The plasma levels of miR-145 were quantified using real-time quantitative polymerase chain reaction. Logarithmic transformation of miRNA-145 levels (Ln&#95;miRNA-145) was used for statistical analysis due to the skewed data distribution., Results: Plasma levels of miR-145 were significantly lower in patients with AMI compared to patients in the non-CAD group (-6.38 ± 0.11 vs. -4.47 ± 0.17, P< 0.0001). Compared to those without heart failure, the levels of miR-145 were significantly lower in patients with heart failure (-6.91 ± 0.20 vs. -5.35 ± 0.13, P< 0.0001). We also found that the lower plasma levels of miRNA-145 significantly correlated with increased serum levels of B-type natriuretic peptide (Spearman ρ= -0.60, P< 0.0001), troponin T (Spearman ρ= -0.62, P< 0.0001), and decreased ejection fraction (Spearman ρ= 0.65, P< 0.0001). In a multivariable linear regression analysis, AMI and heart failure were independently associated with lower Ln&#95;miRNA-145 (estimate -0.99, standard error [SE] 0.28; P= 0.001 and estimate -0.62, SE 0.21; P= 0.004)., Conclusions: Our results suggest that decreased plasma levels of miR-145 are associated with AMI. Circulating miR-145 may be useful in prognosticating cardiac function and the risk of developing heart failure., Competing Interests: There are no conflicts of interest.

Background: Cardiac troponin I (cTnI) and cardiac troponin T (cTnT) determinations are fixtures in clinical practice and research. Cardiac troponin testing has been the standard of practice for the diagnosis of acute myocardial infarction (AMI), early rule-out, risk stratification, and outcomes assessment in patients presenting with acute coronary syndrome (ACS) and non-ACS myocardial injury. We recognize from reading the literature over the past several years how poorly understood the analytical characteristics are for cTnI and cTnT assays by laboratorians, clinicians, and scientists who use these assays., Content: The purposes of this mini-review are (a) to define limit of blank, limit of detection, limit of quantification, and imprecision, (b) overview the analytical characteristics of the existing cardiac troponin assays, (c) recommend approaches to define a healthy (normal) reference population for determining the 99th percentile and the appropriate statistic to use for this calculation, (d) clarify how an assay becomes designated as "high sensitivity," and (e) provide guidance on determining delta (Δ) change values., Summary: This review raises important educational information regarding cTnI and cTnT assays, their 99th percentile upper reference limits (URL) differentiated by sex, and specifically addresses high-sensitivity (hs)-assays used to measure low concentrations. Recommendations are made to help clarify the nomenclature and analytical and clinical characteristics to define hs-assays. The review also identifies challenges for the evolving implementation of hs-assays into clinical practice. It is hoped that with the introduction of these concepts, laboratorians, clinicians and researchers can develop a more unified view of how these assays should be used worldwide., (© 2016 American Association for Clinical Chemistry.)

A 45-year-old man was admitted for investigation of a symmetric lower limb rash associated with recurrent fever for two weeks following a hiking trip in Italy and Greece. He was treated for sepsis secondary to lower limb cellulitis with no clinical improvement and subsequently diagnosed with Streptococcus gallolyticus endocarditis mediating an infectious vasculitis.

A 63 year old female was admitted for investigation of worsening renal insufficiency. During hospitalization she developed persistent immune thrombocytopenia refractory to supportive or immunosuppressive treatment. She was diagnosed with Mycobacterium chimaera prosthetic valve endocarditis and thrombocytopenia resolved with anti-mycobacterial therapy.

Background: The study compared downstream coronary and conduit disease progression in the left anterior descending coronary artery treated with coronary artery bypass grafting using the left internal mammary artery (LIMA) versus percutaneous coronary intervention with bare metal stent (BMS) or drug eluting stent (DES)., Methods and Results: A total of 12 301 consecutive patients underwent isolated primary coronary revascularization, of which 2386 met our inclusion criteria (Percutaneous coronary intervention, n=1450; coronary artery bypass grafting, n=936). Propensity score analysis matched 628 patients, of which 468 were treated to the left anterior descending with coronary artery bypass grafting with LIMA (n=314), percutaneous coronary intervention with BMS (n=94), and DES (n=60). Coronary angiograms were analyzed by quantitative coronary angiography (QCA; n=433). Cumulative downstream coronary and conduit disease progression were estimated by Kaplan-Meier method and effect of treatment type by Cox proportional hazard models. Patients treated with LIMA had significantly lower risk of downstream coronary disease progression at follow-up angiogram compared with BMS and DES (hazard ratio [HR] [95% CI], 0.34; [0.20-0.59]; P=0.0002; and HR [95% CI], 0.39; [0.20-0.79]; P=0.01, respectively). LIMA was associated with a lower risk of conduit disease progression compared to BMS and DES (HR [95% CI], 0.18; [0.12-0.28]; P<0.001; and HR [95% CI], 0.27; [0.16-0.46]; P<0.001, respectively). BMS was associated with higher HR for downstream coronary and conduit disease progression compared with DES, but the difference did not reach statistical significance (HR [95% CI], 1.13; [0.57-2.36]; P=0.73; and HR [95% CI], 1.46; [0.88-2.50]; P=0.14, respectively)., Conclusions: LIMA grafting to left anterior descending is associated with significantly lower risk of downstream coronary and conduit disease progression compared to percutaneous coronary intervention with BMS and DES., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Objectives: Percutaneous coronary intervention (PCI) for acute coronary syndromes frequently fails to restore myocardial perfusion despite establishing epicardial vessel patency. Endothelin-1 (ET-1) is a potent vasoconstrictor, and its expression is increased in atherosclerosis and after PCI. In this study, we aim to define the role of endothelin in regulating coronary microvascular blood flow and myocardial perfusion following PCI in patients with non-ST elevation acute coronary syndromes (NSTACS), by assessing whether adjunctive therapy with a selective endothelin A (ETA) receptor antagonist acutely improves postprocedural coronary microvascular blood flow., Methods: In a randomised, double-blinded, placebo-controlled trial, 23 NSTACS patients were enrolled to receive an intracoronary infusion of placebo (n=11) or BQ-123 (n=12) immediately before PCI. Post-PCI coronary microvascular blood flow and myocardial perfusion were assessed by measuring Doppler-derived average peak velocity (APV), and cardiac biomarker levels were quantified., Results: Compared with the placebo group, APV was significantly higher in the drug group immediately after PCI (30 (20, 37) vs 19 (9, 26) cm/s; p=0.03). Hyperaemic APV, measured post-adenosine administration, was higher in the BQ-123 group, but the difference did not achieve statistical significance (56 (48, 72) vs 46 (34, 64) cm/s; p=0.090). Maximum coronary flow reserve postprocedure was not different between the two groups (2.1 (1.6, 2.3) vs 2.5 (1.8, 3.0)). Per cent change in creatine kinase isoenzyme MB from the time of PCI to 8 and 16 hours post-PCI was significantly lower in the drug group compared with the placebo group (-17 (-26, -10) vs 26 (-15, 134); p=0.02 and -17 (-38, 14) vs 107 (2, 446); p=0.007, respectively)., Conclusions: Endothelin is a mediator of microvascular dysfunction during PCI in NSTACS, and adjunctive selective ETA antagonist may augment myocardial perfusion during PCI., Trial Registration Number: NCT00586820; Results.

The V-ATPase is the main regulator of intra-organellar acidification. Assembly of this complex has extensively been studied in yeast, while limited knowledge exists for man. We identified 11 male patients with hemizygous missense mutations in ATP6AP1, encoding accessory protein Ac45 of the V-ATPase. Homology detection at the level of sequence profiles indicated Ac45 as the long-sought human homologue of yeast V-ATPase assembly factor Voa1. Processed wild-type Ac45, but not its disease mutants, restored V-ATPase-dependent growth in Voa1 mutant yeast. Patients display an immunodeficiency phenotype associated with hypogammaglobulinemia, hepatopathy and a spectrum of neurocognitive abnormalities. Ac45 in human brain is present as the common, processed ∼40-kDa form, while liver shows a 62-kDa intact protein, and B-cells a 50-kDa isoform. Our work unmasks Ac45 as the functional ortholog of yeast V-ATPase assembly factor Voa1 and reveals a novel link of tissue-specific V-ATPase assembly with immunoglobulin production and cognitive function.