The pulmonary valve in tetralogy of Fallot: Insights from a necroscopy series

\ua9 The Author(s), 2025. Published by Cambridge University Press.Background: Tetralogy of Fallot is the most common cyanotic congenital malformation of the heart. The right ventricular outflow tract is of great interest in this setting, but most of the focus on this feature has been on the size of the so-called pulmonary valvar "annulus". We aimed to characterise other aspects of the morphology of the pulmonary root in heart specimens with tetralogy of Fallot. Methods: We reviewed archived hearts with tetralogy of Fallot from four registries. The pulmonary root was examined with specific attention to the number of sinuses, the number of leaflets, presence of any fusion of leaflets, and the direction of the zone of apposition between the leaflets. Cluster analyses were then conducted to see if the features permitted segregation into groups. Results: We examined a total of 155 hearts. The pulmonary valve had two leaflets in 62%, three leaflets in 34%, and one leaflet in 3%. Irrespective of leaflet morphology, most hearts had two sinuses. Cluster analysis permitted segregation into three groups, with the direction of the zone of apposition being the most important feature for segregation. Conclusion: In two-thirds of our hearts with tetralogy of Fallot, the pulmonary valve had two leaflets. Most frequently there were three sinuses. In the setting of a valve with two sinuses, the zone of apposition between the leaflets pointing towards the aorta. Cluster analysis permitted statistically sound segregation of the heart and highlights the importance of delineating these features, specifically the leaflet and sinus morphology, with clinical imaging

Incidence and costs of injuries to children and adults in the United States

Background: Injuries are a leading cause of death and acquired disability, and result in significant medical spending. Prior estimates of injury-related cost have been limited by older data, for certain population, or specific mechanisms. Findings: This study estimated the incidence of hospital-treated nonfatal injuries in the United States (US) in 2013 and the related comprehensive costs. Injury-related emergency department (ED) visits and hospitalizations were identified using 2013 Healthcare Cost and Utilization Project (HCUP) data. Models estimated the costs of medical spending and lost future work due to injuries in 2013 U.S. dollars. A total of 31,038,072 nonfatal injury-related hospitalizations and ED visits were identified, representing 9.8 per 100 people. Hospital-treated nonfatal injuries cost an estimated $1.853 trillion, including$168 billion in medical spending, $223 billion in work losses, and$1.461 trillion in quality of life losses. Conclusions: Approximately one in 10 individuals in the US is treated in the hospital for injury each year, with high corresponding costs. These data support priority-setting to reduce the injury burden in the US

Assessing the criteria for definition of perimembranous ventricular septal defects in light of the search for consensus

BACKGROUND: Discussions continue as to whether ventricular septal defects are best categorized according to their right ventricular geography or their borders. This is especially true when considering the perimembranous defect. Our aim, therefore, was to establish the phenotypic feature of the perimembranous defect, and to establish the ease of distinguishing its geographical variants. // METHODS AND RESULTS: We assessed unrepaired isolated perimembranous ventricular defects from six historic archives, subcategorizing them using the ICD-11 coding system. We identified 365 defects, of which 94 (26%) were deemed to open centrally, 168 (46%) to open to the outlet, and 84 (23%) to the inlet of the right ventricle, with 19 (5%) being confluent. In all hearts, the unifying phenotypic feature was fibrous continuity between the leaflets of the mitral and tricuspid valves. This was often directly between the valves, but in all instances incorporated continuity through the atrioventricular portion of the membranous septum. In contrast, we observed fibrous continuity between the leaflets of the tricuspid and aortic valves in only 298 (82%) of the specimens. When found, discontinuity most commonly was seen in the outlet and central defects. There were no discrepancies between evaluators in distinguishing the borders, but there was occasional disagreement in determining the right ventricular geography of the defect. // CONCLUSIONS: The unifying feature of perimembranous defects, rather than being aortic-to-tricuspid valvar fibrous continuity, is fibrous continuity between the leaflets of the atrioventricular valves. While right ventricular geography is important in classification, it is the borders which are more objectively defined

A phase I study of afatinib combined with paclitaxel and bevacizumab in patients with advanced solid tumors

Purpose: The combination of afatinib, an irreversible ErbB family blocker, with paclitaxel and bevacizumab was assessed in patients with advanced solid tumors. / Methods: This phase I study used a 3 + 3 design to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel and bevacizumab. Safety, pharmacokinetics, and anti-tumor activity were also assessed. The starting dose was oral afatinib 40 mg once daily plus intravenous paclitaxel (fixed dose 80 mg/m2, Days 1, 8, and 15 of a 4-week cycle) and intravenous bevacizumab 5 mg/kg every 2 weeks. / Results: Twenty-nine patients were enroled. The afatinib dose was de-escalated to 30 mg and then 20 mg after 2/6 and 2/5 evaluable patients developed dose-limiting toxicities at 40 and 30 mg, respectively, when combined with paclitaxel and bevacizumab 5 mg/kg. The bevacizumab dose was subsequently escalated to 10 mg/kg, and MTD was defined as afatinib 20 mg plus paclitaxel 80 mg/m2 and bevacizumab 10 mg/kg. Frequent (any grade) treatment-related adverse events (AEs) included diarrhea (83%), rash/acne (83%), fatigue (79%), mucosal inflammation (59%), and nausea (59%). Based on overall safety, bevacizumab was amended to 7.5 mg/kg for the recommended phase II dose. Pharmacokinetic analyses suggested no relevant drug–drug interactions. Three (10%) confirmed partial responses were observed; 15 (52%) patients had stable disease. / Conclusions: The recommended phase II dose schedule was afatinib 20 mg/day with paclitaxel 80 mg/m2 (Days 1, 8, and 15 every 4 weeks) and bevacizumab 7.5 mg/kg every 2 weeks. At this dose schedule, AEs were manageable, and anti-tumor activity was observed

Fibro-Vascular Coupling in the Control of Cochlear Blood Flow

Transduction of sound in the cochlea is metabolically demanding. The lateral wall and hair cells are critically vulnerable to hypoxia, especially at high sound levels, and tight control over cochlear blood flow (CBF) is a physiological necessity. Yet despite the importance of CBF for hearing, consensus on what mechanisms are involved has not been obtained.We report on a local control mechanism for regulating inner ear blood flow involving fibrocyte signaling. Fibrocytes in the super-strial region are spatially distributed near pre-capillaries of the spiral ligament of the albino guinea pig cochlear lateral wall, as demonstrably shown in transmission electron microscope and confocal images. Immunohistochemical techniques reveal the inter-connected fibrocytes to be positive for Na+/K+ ATPase β1 and S100. The connected fibrocytes display more Ca(2+) signaling than other cells in the cochlear lateral wall as indicated by fluorescence of a Ca(2+) sensor, fluo-4. Elevation of Ca(2+) in fibrocytes, induced by photolytic uncaging of the divalent ion chelator o-nitrophenyl EGTA, results in propagation of a Ca(2+) signal to neighboring vascular cells and vasodilation in capillaries. Of more physiological significance, fibrocyte to vascular cell coupled signaling was found to mediate the sound stimulated increase in cochlear blood flow (CBF). Cyclooxygenase-1 (COX-1) was required for capillary dilation.The findings provide the first evidence that signaling between fibrocytes and vascular cells modulates CBF and is a key mechanism for meeting the cellular metabolic demand of increased sound activity