Toxoplasma gondii rhoptry discharge factor 3 is essential for invasion and microtubule-associated vesicle biogenesis.

Rhoptries are specialized secretory organelles conserved across the Apicomplexa phylum, essential for host cell invasion and critical for subverting of host cellular and immune functions. They contain proteins and membranous materials injected directly into the host cells, participating in parasitophorous vacuole formation. Toxoplasma gondii tachyzoites harbor 8 to 12 rhoptries, 2 of which are docked to an apical vesicle (AV), a central element associated with a rhoptry secretory apparatus prior to injection into the host cell. This parasite is also equipped with 5 to 6 microtubule-associated vesicles, presumably serving as AV replenishment for iterative rhoptry discharge. Here, we characterized a rhoptry protein, rhoptry discharge factor 3 (RDF3), crucial for rhoptry discharge and invasion. RDF3 enters the secretory pathway, localizing near the AV and associated with the rhoptry bulb. Upon invasion, RDF3 dynamically delocalizes, suggesting a critical role at the time of rhoptry discharge. Cryo-electron tomography analysis of RDF3-depleted parasites reveals irregularity in microtubule-associated vesicles morphology, presumably impacting on their preparedness to function as an AV. Our findings suggest that RDF3 is priming the microtubule-associated vesicles for rhoptry discharge by a mechanism distinct from the rhoptry secretory apparatus contribution.

2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy" provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy. METHODS: A comprehensive literature search was conducted from September 14, 2022, to November 22, 2022, encompassing studies, reviews, and other evidence on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through May 23, 2023, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Hypertrophic cardiomyopathy remains a common genetic heart disease reported in populations globally. Recommendations from the "2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy" have been updated with new evidence to guide clinicians.

Compliance with U.S. Government Nutrition Advice and Concurrent Obesity Trends Using Nurses' Health Study Data, 1980-2011.

BACKGROUND: Beginning in 1977, the U.S. Government began formally issuing dietary advice, a main objective of which was to reduce and prevent the prevalence of obesity in the American population. Concurrently, the Harvard School of Public Health began conducting dietary intake surveys and collecting body mass index (BMI) (kg/m2) data on female nurses in the Nurses' Health Study I (NHSI) and II (NHSII). OBJECTIVES: We aimed to assess whether compliance with the nutrition guidance from the U.S. Government to restrict dietary intake regarding total fat, saturated fat, and cholesterol was meaningfully associated with the prevalence of obesity. METHODS: We analyzed nutrition survey data from 1980 to 2011, grouping the sample into "compliers," those who complied with guidance on the intake of total fat, saturated fat, and cholesterol, and "noncompliers," those who did not. We then compared the means, medians, and distributions of BMI for compliers and noncompliers over the period for both the full survey population and an age-controlled sample. Finally, we plotted raw NHS data to examine respondents' Fat Proportion intake of energy and concurrent BMI. RESULTS: The mean and median BMI for both compliers and noncompliers increased throughout the sample period, and the BMI distributions shifted toward obese and severely obese overall and for an age-controlled subset compared with the 1980 NHSI and 1990 NHSII baselines. Compliers had slightly lower mean BMI increases than noncompliers but saw a relatively higher increase in the growth of the prevalence of those with BMI >30. We also found no linear relationship between Fat Proportion of energy intake and concurrent BMI. CONCLUSIONS: Guidance from the U.S. Government to limit fat, saturated fat, and cholesterol consumption was widely adopted by American female nurses during the study period. Our results show that compliance with this guidance had little if any effect in mitigating population-wide BMI increases during our study period.

Advances in pediatric gliomas: from molecular characterization to personalized treatments.

Pediatric gliomas, consisting of both pediatric low-grade (pLGG) and high-grade gliomas (pHGG), are the most frequently occurring brain tumors in children. Over the last decade, several milestone advancements in treatments have been achieved as a result of stronger understanding of the molecular biology behind these tumors. This review provides an overview of pLGG and pHGG highlighting their clinical presentation, molecular characteristics, and latest advancements in therapeutic treatments.  Conclusion: The increasing understanding of the molecular biology characterizing pediatric low and high grade gliomas has revolutionized treatment options for these patients, especially in pLGG. The implementation of next generation sequencing techniques for these tumors is crucial in obtaining less toxic and more efficacious treatments. What is Known: • Pediatric Gliomas are the most common brain tumour in children. They are responsible for significant morbidity and mortality in this population. What is New: • Over the last two decades, there has been a significant increase in our global understanding of the molecular background of pediatric low and high grade gliomas. • The implementation of next generation sequencing techniques for these tumors is crucial in obtaining less toxic and more efficacious treatments, with the ultimate goal of improving both the survival and the quality of life of these patients.

2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

Aim This executive summary of the hypertrophic cardiomyopathy clinical practice guideline provides recommendations and algorithms for clinicians to diagnose and manage hypertrophic cardiomyopathy in adult and pediatric patients as well as supporting documentation to encourage their use. Methods A comprehensive literature search was conducted from January 1, 2010, to April 30, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Structure Many recommendations from the earlier hypertrophic cardiomyopathy guidelines have been updated with new evidence or a better understanding of earlier evidence. This summary operationalizes the recommendations from the full guideline and presents a combination of diagnostic work-up, genetic and family screening, risk stratification approaches, lifestyle modifications, surgical and catheter interventions, and medications that constitute components of guideline directed medical therapy. For both guideline-directed medical therapy and other recommended drug treatment regimens, the reader is advised to follow dosing, contraindications and drug-drug interactions based on product insert materials.

Atrial fibrillation in hypertrophic cardiomyopathy: prevalence, clinical impact, and management.

Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiomyopathy characterized by left ventricular hypertrophy and spectrum of clinical manifestation. Atrial fibrillation (AF) is a common sustained arrhythmia in HCM patients and is primarily related to left atrial dilatation and remodeling. There are several clinical, electrocardiographic (ECG), and echocardiographic (ECHO) features that have been associated with development of AF in HCM patients; strongest predictors are left atrial size, age, and heart failure class. AF can lead to progressive functional decline, worsening heart failure and increased risk for systemic thromboembolism. The management of AF in HCM patient focuses on symptom alleviation (managed with rate and/or rhythm control methods) and prevention of complications such as thromboembolism (prevented with anticoagulation). Finally, recent evidence suggests that early rhythm control strategy may result in more favorable short- and long-term outcomes.

At High Levels, Constitutively Activated STAT3 Induces Apoptosis of Chronic Lymphocytic Leukemia Cells.

In chronic lymphocytic leukemia (CLL), the increment in PBLs is slower than the expected increment calculated from the cells' proliferation rate, suggesting that cellular proliferation and apoptosis are concurrent. Exploring this phenomenon, we found overexpression of caspase-3, higher cleaved poly (ADP-ribose) polymerase levels (p < 0.007), and a higher apoptosis rate in cells from patients with high counts compared with cells from patients with low counts. Although we previously found that STAT3 protects CLL cells from apoptosis, STAT3 levels were significantly higher in cells from patients with high counts than in cells from patients with low counts. Furthermore, overexpression of STAT3 did not protect the cells. Rather, it upregulated caspase-3 and induced apoptosis. Remarkably, putative STAT3 binding sites were identified in the caspase-3 promoter, and a luciferase assay, chromatin immunoprecipitation, and an EMSA revealed that STAT3 activated caspase-3 However, caspase-3 levels increased only when STAT3 levels were sufficiently high. Using chromatin immunoprecipitation and EMSA, we found that STAT3 binds with low affinity to the caspase-3 promoter, suggesting that at high levels, STAT3 activates proapoptotic mechanisms and induces apoptosis in CLL cells.

Impact of Annual Hospital Volume on Outcomes after Left Ventricular Assist Device (LVAD) Implantation in the Contemporary Era.

INTRODUCTION: There are few data in the literature regarding impact of annual hospital volume on outcomes such as mortality and length of stay (LOS) post-LVAD implantation. METHODS: We queried the nationwide inpatient sample from 2008 to 2011 using International Classification of Diseases, 9th Revision procedure code 37.66. We included patients ≥18 years without primary diagnosis of orthotopic heart transplant. Annual volume of LVAD implantation was computed for each hospital. Multivariable hierarchical mixed effect logistic regression models were used to determine predictors of in-hospital mortality and LOS. RESULTS: There were 1749 LVAD implants from 2008 to 2011; patients had a mean age of 55.4 years, and 23% were female. In-hospital mortality decreased from 20.9% in the first tertile (1-22 LVADs/y) to 13.7% in the third tertile (≥35 LVADs/y) of hospital volume. Median LOS decreased from 34 days in the first tertile to 28 days in third tertile of hospital volume. The adjusted odds ratios of the highest tertile of hospital volume in predicting in-hospital mortality and LOS were 0.41 (0.26-0.64, P < .001) and 0.41 (0.23-0.73, P = .003), respectively. Restricted cubic spline analysis showed that a volume threshold of >20 LVADs/year was associated with favorable mortality rates of <10%. CONCLUSIONS: High annual LVAD volume is associated with significantly decreased in-hospital mortality and LOS after LVAD implantation. Center experience is an important determinant of optimal patient outcomes.

Resting qualitative and quantitative myocardial contrast echocardiography to predict cardiac events in patients with acute myocardial infarction and percutaneous revascularization.

Successful restoration of patency of the infarct-related artery is important in management of acute ST-segment elevation myocardial infarction (STEMI); however, it does not necessarily translate into the restoration of perfusion at the tissue level. In this study, we evaluate the prognostic role of qualitative and quantitative myocardial contrast echocardiography (MCE) in predicting cardiac events (after adjustment for cardiovascular risk factors) in STEMI patients undergoing reperfusion. Bedside resting real-time MCE using continuous infusion of diluted contrast agent (Definity) was performed within a median of 21.4 h from revascularization in STEMI. Myocardial perfusion on qualitative MCE was graded 1 = homogenous; 2 = partial/patchy; and 3 = absent. Perfusion score index (PSI) was calculated by adding the perfusion score in all segments divided by the total number of evaluable segments. Quantitative perfusion parameters [A, dB; ß, sec(-1); and Aß] were analyzed using a 17-segment model. Patients were followed for cardiac events including death; nonfatal myocardial infarction (MI); hospitalization for cardiac symptoms; coronary revascularization; or heart failure. Thirty-seven reperfused STEMI patients with a mean age of 64 years (range, 40-86 years) were enrolled and followed for a median of 1.4 years. Cardiac events occurred in 22 patients. Patients with cardiac events had a higher perfusion score index (PSI), and lower A, ß and Aß parameters compared to patients without events [1.84 ± 0.36 vs 1.39 ± 0.17 for PSI, P < 0.001; 0.57 ± 0.24 vs 0.85 ± 0.30 for A, P = 0.03; 0.34 ± 0.15 vs. 0.53 ± 0.17 for ß, P = 0.002; and 0.21 ± 0.12 vs. 0.49 ± 0.32, for Aß, P = 0.003; respectively]. A PSI value of 1.58 provided an area under the curve (AUC) of 0.873, while ß of 0.423 and Aß of 0.323 provided an AUC of 0.858 and 0.842, respectively. PSI and Aß were independent predictors of cardiac events with an adjusted hazard ratio of 3.41 (1.19-12.27); and 4.19 (1.3-19.09), respectively. No contrast-related side effects were reported. Evaluation of perfusion in reperfused STEMI patients by qualitative and quantitative MCE (myocardial blood flow, Aß) provides independent prediction of cardiac events.

Paradoxical embolism interrupted.

A 41 year-old African-American male presented with syncope preceded by shortness of breath at outside facility and transferred to us for management of extensive pulmonary embolism with unstable vital signs. Electrocardiogram showed sinus tachycardia with S1Q3T3 pattern. A transthoracic echocardiogram revealed a freely mobile strand like mass in the left atrium. A transoesophageal echocardiogram showed a very large freely mobile thrombus extending from a patent foramen ovale in to the left atrium. He underwent emergent surgery for the extraction of clot followed by thromboembolectomy from both pulmonary arteries. He made a remarkable recovery and was discharged after seven days of hospital stay.

Durability, reliability, viability: 48 year-survival of a Starr-Edwards mitral valve.

We report a case of 67 year-old female with a 48-year survival of a Starr-Edwards valve at mitral position. The patient underwent Starr-Edwards mitral valve replacement at age of 19 years for mitral stenosis secondary to severe rheumatic valve disease. The patient had experienced a progressive decline in her functional status with increasing dyspnoea on exertion over a two-week period to eventual development of severe shortness of breath at rest prior to hospitalisation. Transoesophageal echocardiogram revealed severe para-prosthetic and intravalvular mitral valve regurgitation. The patient underwent explantation of Starr-Edwards valve and replacement with a mechanical prosthesis. Our case details the longest reported survival of a Starr-Edwards prosthetic valve at mitral area.

Shared decision making for participation in elite athletes with cardiovascular conditions. Where are we now?

Sudden Cardiac Death is a leading medical cause of death in athletes of all ages. Recently there has been a shift from an authoritarian approach to that of using a Shared Decision Making (SDM) model in eligibility decisions of athletes with cardiovascular decisions. SDM in elite athletics can be complex and collaboration amongst the athlete, family, physicians, athletic trainers, and institutional stakeholders is critical. SDM acknowledges the complexities of a collaboration between sports cardiologists bringing disease and sport-specific expertise, and team physicians, in complementary fashion to integrate medical knowledge, clinical uncertainty, athlete and family values, and institutional philosophies and risk tolerance.

Exercise After Acute Myocarditis: When and How to Return to Sports.

Myocarditis is an inflammatory disease of the myocardium secondary to infectious and noninfectious insults. The most feared consequence of myocarditis is sudden cardiac death owing to electrical instability and arrhythmia. Typical presenting symptoms include chest pain, dyspnea, palpitations and/or heart failure. Diagnosis is usually made with history, electrocardiogram, biomarkers, echocardiogram, and cardiac MRI (CMR). Application of the Lake Louise criteria to CMR results can help identify cases of myocarditis. Treatment is usually supportive with medical therapy, and patients are recommended to abstain from exercise for 3 to 6 months. Exercise restrictions may be lifted after normalization on follow-up testing.

Retrospective Review of Complications and Revision Rates Between Isolated Talonavicular vs Talonavicular and Subtalar (Double) Arthrodesis vs Triple Arthrodesis.

Background: Hindfoot fusion procedures are common for the treatment of end-stage arthritis or deformity. Surgical treatments for these conditions include talonavicular joint (single) arthrodesis, talonavicular and subtalar (double) arthrodesis, or talonavicular, subtalar, and calcaneocuboid (triple) arthrodesis. This study evaluated the complication rate, revision surgery rate, and hardware removal rate for those treated with either single, double, or triple arthrodesis. Methods: A retrospective review was conducted for patients who underwent single (Current Procedural Terminology [CPT] code 28740), double (CPT 28725 and 28740), or triple (CPT 28715) arthrodesis to treat hindfoot arthritis/deformity (International Classification of Diseases, Ninth Revision [ICD-9] code: 734, International Classification of Diseases, Tenth Revision [ICD-10] codes: M76821, M76822, and M76829) from 2005 to 2022 using the South Carolina Revenue and Fiscal Affairs databank. Data collected included demographics, comorbidities, procedure data, and postoperative outcomes within 1 year of principal surgery. Student t test, chi-squared test, and multivariable logistic regression analysis were utilized during data analysis. Results: A total of 433 patients were identified, with 248 undergoing single arthrodesis, 67 undergoing double arthrodesis, and 118 undergoing triple arthrodesis. There was no significant difference between single, double, and triple arthrodesis in the rate of complications, hardware removals, revision surgeries, or 30-day readmission when controlling for confounding variables. However, a decrease in Charlson Comorbidity Index (CCI) was found to be predictive of an increase in the revision surgery rate (OR = 0.46, 95% CI 0.22-0.85, P = .02). Conclusion: We found no difference in the rate of complications, hardware removals, or revision surgeries in those undergoing single, double, or triple arthrodesis. Surprisingly we found that a lower Charlson Comorbidity Index, indicating a healthier patient had a significant relationship with a higher rate of revision surgery. Further study including radiographic indications for surgery or the impact of overall health status on revision surgery rates may further elucidate the other components of this relationship. Level of Evidence: Level III, cohort study.