Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19.

BACKGROUND: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood. METHODS: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models. RESULTS: Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P < .001), and a steeper rate of decline through the first 5 days (P < .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale. CONCLUSIONS: Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed. CLINICAL TRIALS REGISTRATION: NCT04501978.

Channel impeller design for centrifugal blood pump in hybrid pediatric total artificial heart: Modeling, magnet integration, and hydraulic experiments.

BACKGROUND: The purpose of this research is to address ongoing device shortfalls for pediatric patients by developing a novel pediatric hybrid total artificial heart (TAH). The valveless magnetically-levitated MCS device (Dragon Heart) has only two moving parts, integrates an axial and centrifugal blood pump into a single device, and will occupy a compact footprint within the chest for the pediatric patient population. METHODS: Prior work on the Dragon Heart focused on the development of pump designs to achieve hemodynamic requirements. The impeller of these pumps was shaft-driven and thus could not be integrated for testing. The presented research leverages an existing magnetically levitated axial flow pump and focuses on centrifugal pump development. Using the axial pump diameter as a geometric constraint, a shaftless, magnetically supported centrifugal pump was designed for placement circumferentially around the axial pump domain. The new design process included the computational analysis of more than 50 potential centrifugal impeller geometries. The resulting centrifugal pump designs were prototyped and tested for levitation and no-load rotation, followed by in vitro testing using a blood analog. To meet physiologic demands, target performance goals were pressure rises exceeding 90 mm Hg for flow rates of 1-5 L/min with operating speeds of less than 5000 RPM. RESULTS: Three puck-shaped, channel impellers for the centrifugal blood pump were selected based on achieving performance and space requirements for magnetic integration. A quasi-steady flow analysis revealed that the impeller rotational position led to a pulsatile component in the pressure generation. After prototyping, the centrifugal prototypes (3, 4, and 5 channeled designs) demonstrated levitation and no-load rotation. Hydraulic experiments established pressure generation capabilities beyond target requirements. The pressure-flow performance of the prototypes followed expected trends with a dependence on rotational speed. Pulsatile blood flow was observed without pump-speed modulation due to rotating channel passage frequency. CONCLUSION: The results are promising in the advancement of this pediatric TAH. The channeled impeller design creates pressure-flow curves that are decoupled from the flow rate, a benefit that could reduce the required controller inputs and improve treatment of hypertensive patients.

Technology landscape of pediatric mechanical circulatory support devices: A systematic review 2010-2021.

BACKGROUND: Mechanical circulatory support (MCS) devices, such as ventricular assist devices (VADs) and total artificial hearts (TAHs), have become a vital therapeutic option in the treatment of end-stage heart failure for adult patients. Such therapeutic options continue to be limited for pediatric patients. Clinicians initially adapted or scaled existing adult devices for pediatric patients; however, these adult devices are not designed to support the anatomical structure and varying flow capacities required for this population and are generally operated "off-design," which risks complications such as hemolysis and thrombosis. Devices designed specifically for the pediatric population which seek to address these shortcomings are now emerging and gaining FDA approval. METHODS: To analyze the competitive landscape of pediatric MCS devices, we conducted a systematic literature review. Approximately 27 devices were studied in detail: 8 were established or previously approved designs, and 19 were under development (11 VADs, 5 Fontan assist devices, and 3 TAHs). RESULTS: Despite significant progress, there is still no pediatric pump technology that satisfies the unique and distinct design constraints and requirements to support pediatric patients, including the wide range of patient sizes, increased cardiovascular demand with growth, and anatomic and physiologic heterogeneity of congenital heart disease. CONCLUSIONS: Forward-thinking design solutions are required to overcome these challenges and to ensure the translation of new therapeutic MCS devices for pediatric patients.

Challenges of prenatal diagnosis of fetal hypoplastic aortic arch and predication of the need for intervention.

Prenatal diagnosis of hypoplastic aortic arch and coarctation of aorta is still challenging and remains one of the most difficult cardiac defects to diagnose. The results reveal a significant improvement of prenatal diagnosis of hypoplastic arch and coarctation of aorta. The data also shows the significant overlapping of fetal aortic isthmus z score between the infants who need the arch procedure and those who do not.

Invited commentary for: Essential role of cardiac computed tomography for surgical decision making in children with total anomalous pulmonary venous connection and single ventricle.

Thousands of neonates are born each year with complex congenital heart defects, such as total anomalous pulmonary venous connection combined with single ventricle physiology. This dual diagnosis with significant vessel and ventricular complexity requires alternative additional imaging to fully visualize the anatomical challenge and devise the appropriate treatment strategy for the patient.

Invited commentary: Total anomalous pulmonary venous connection remains a challenging pediatric disease.

Cervantes-Salazar and colleagues report the long-term surgical outcomes of 414 patients with total anomalous pulmonary venous connection (TAPVC) from January 2003 to June 2019. With an overall survival rate of 87.2% from 2003 to 2019, the authors found that an increased mortality risk was associated with infracardiac TAPVC, pulmonary venous obstruction, and postoperative mechanical ventilation. Their comprehensive study with a large sample size of varying age groups, and patients with late referrals for surgery, provide valuable insight into TAPVC surgical outcomes. Improved survival for these patients continues to be a major goal of clinical teams striving to transform treatment paradigms. The promising result of the study reported by Cervantes-Salazar and colleagues gives our field hope for a better future for these patients.

Novel hybrid total artificial heart with integrated oxygenator.

There continues to be an unmet therapeutic need for an alternative treatment strategy for respiratory distress and lung disease. We are developing a portable cardiopulmonary support system that integrates an implantable oxygenator with a hybrid, dual-support, continuous-flow total artificial heart (TAH). The TAH has a centrifugal flow pump that is rotating about an axial flow pump. By attaching the hollow fiber bundle of the oxygenator to the base of the TAH, we establish a new cardiopulmonary support technology that permits a patient to be ambulatory during usage. In this study, we investigated the design and improvement of the blood flow pathway from the inflow-to-outflow of four oxygenators using a mathematical model and computational fluid dynamics (CFD). Pressure loss and gas transport through diffusion were examined to assess oxygenator design. The oxygenator designs led to a resistance-driven pressure loss range of less than 35 mmHg for flow rates of 1-7 L/min. All of the designs met requirements. The configuration having an outside-to-inside blood flow direction was found to have higher oxygen transport. Based on this advantageous flow direction, two designs (Model 1 and 3) were then integrated with the axial-flow impeller of the TAH for simulation. Flow rates of 1-7 L/min and speeds of 10,000-16,000 RPM were analyzed. Blood damage studies were performed, and Model 1 demonstrated the lowest potential for hemolysis. Future work will focus on developing and testing a physical prototype for integration into the new cardiopulmonary assist system.

Covid-19 related oncologist's concerns about breast cancer treatment delays and physician well-being (the CROWN study).

PURPOSE: To examine how treatment delays brought on by the COVID-19 pandemic impacted the physical and emotional well-being of physicians treating these patients. METHODS: A cross-sectional survey of physician breast specialists was posted from April 23rd to June 11th, 2020 on membership list serves and social media platforms of the National Accreditation Program for Breast Centers and the American Society of Breast Surgeons. Physician well-being was measured using 6 COVID-19 burnout emotions and the 4-item PROMIS short form for anxiety and sleep disturbance. We examined associations between treatment delays and physician well-being, adjusting for demographic factors, COVID-19 testing and ten COVID-19 pandemic concerns. RESULTS: 870 physicians completed the survey, 61% were surgeons. The mean age of physicians was 52 and 548 (63.9%) were female. 669 (79.4%) reported some delay in patient care as a result of the COVID-19 pandemic. 384 (44.1%) and 529 (60.8%) of physicians scored outside normal limits for anxiety and sleep disturbance, respectively. After adjusting for demographic factors and COVID-19 testing, mean anxiety and COVID-19 burnout scores were significantly higher among physicians whose patients experienced either delays in surgery, adjuvant chemotherapy, radiation, breast imaging or specialty consultation. A multivariable model adjusting for ten physician COVID-19 concerns and delays showed that "delays will impact my emotional well-being" was the strongest concern associated with anxiety, sleep disturbance and COVID-19 burnout factors. CONCLUSIONS: Breast cancer treatment delays during the initial surge of the COVID-19 pandemic in the United States were associated with a negative impact on physician emotional wellness.

Integrated long-term multifunctional pediatric mechanical circulatory assist device.

There continues to be limited, viable ventricular assist device technology options to support the dysfunctional states of pediatric heart failure. To address this need, we are developing a magnetically suspended, versatile pumping technology that uniquely integrates two blood pumps in a series configuration within a single device housing. This device enables operational switching from the usage of one pump to another as needed for clinical management or to support growth and development of the pediatric patient. Here, we present the initial design where we conducted a virtual fit study, the Taguchi Design Optimization Method, iterative design to develop pump geometries. Computational tools were used to estimate the pressure generation, capacity delivery, hydraulic efficiency, fluid stress levels, exposure time to stresses, blood damage index, and fluid forces on the impellers. Prototypes of the pumps were tested in a flow loop using a water-glycerin solution. Both designs demonstrated the capability to generate target pressures and flows. Blood damage estimations were below threshold levels and achieved design requirements; however, maximum scalar stress levels were above the target limit. Radial and axial forces were less than 1 N and 10 N, respectively. The performance data trends for physical prototypes correlated with theoretical expectations. The centrifugal prototype was able to generate slightly higher pressure rises than numerical predictions. In contrast, the axial prototype outperformed the computational studies. Experimental data were both repeatable and reproducible. The findings from this research are promising, and development will continue.

The newly emerging field of pediatric engineering: Innovation for our next generation.

Neonates, infants, and children have unique physiology and body surface areas that dramatically change during growth and development, and the substantial diversity of complicated pediatric illnesses and rare childhood diseases are distinct from the adult sphere. Unfortunately, medical innovation is generally constrained to retrofitting adult treatment strategies for this heterogeneous population. This conventional, but limited, approach ignores the dynamic biopsychosocial, growth, and developmental complexities that abound, as one progresses through this life cycle from newborn onward toward early adulthood. Forward-thinking solutions are essential to advance the state-of-the-art to address the challenges and unmet clinical needs that are uniquely presented by the pediatric population, and it has become obvious that newly trained engineers are essential for success. These unmet clinical needs and the necessity of new technical skills and expertise give rise to the emergence of an entirely new field of engineering and applied science: Pediatric Engineering. The field of Pediatric Engineering flips conventional wisdom that adult therapies can simply be scaled or successfully modified for children. It commandeers design to suit the specific needs of the child, while anticipating the dynamic growth and development into adulthood. We are growing a new pipeline of educated scientists and engineers who will have developed a unique toolbox of skills that they can use to tackle unmet clinical needs in global pediatric healthcare for years to come.

Invited commentary: A prospective randomized trial on parents' disease knowledge and quality of life. Shall WeChat about telehealth?

WeChat and access to wireless communication may offer a continuum of care following medical and surgical intervention. This cardiac surgery research study evaluates the process of parental education and social support following pediatric cardiac surgery utilizing standard of care compared to telehealth.

Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic. the COVID-19 pandemic breast cancer consortium.

The COVID-19 pandemic presents clinicians a unique set of challenges in managing breast cancer (BC) patients. As hospital resources and staff become more limited during the COVID-19 pandemic, it becomes critically important to define which BC patients require more urgent care and which patients can wait for treatment until the pandemic is over. In this Special Communication, we use expert opinion of representatives from multiple cancer care organizations to categorize BC patients into priority levels (A, B, C) for urgency of care across all specialties. Additionally, we provide treatment recommendations for each of these patient scenarios. Priority A patients have conditions that are immediately life threatening or symptomatic requiring urgent treatment. Priority B patients have conditions that do not require immediate treatment but should start treatment before the pandemic is over. Priority C patients have conditions that can be safely deferred until the pandemic is over. The implementation of these recommendations for patient triage, which are based on the highest level available evidence, must be adapted to current availability of hospital resources and severity of the COVID-19 pandemic in each region of the country. Additionally, the risk of disease progression and worse outcomes for patients need to be weighed against the risk of patient and staff exposure to SARS CoV-2 (virus associated with the COVID-19 pandemic). Physicians should use these recommendations to prioritize care for their BC patients and adapt treatment recommendations to the local context at their hospital.

Fluid-structure interaction analysis of a collapsible axial flow blood pump impeller and protective cage for Fontan patients.

Limited donor organs and alternative therapies have led to a growing interest in the use of blood pumps as a treatment strategy for patients with single functional ventricle. The present study examines the use of collapsible and flexible impeller, cage, and diffuser designs of an axial blood pump for Fontan patients. Using one-way fluid-structure interaction (FSI) studies, the impact of blade deformation on blood damage and pump performance was investigated for flexible impellers. We evaluated biocompatible materials, including Nitinol, Bionate 80A polyurethane, and silicone for flow rates between 2.0-4.0 L/min and rotational speeds of 3000-9000 rpm. The level of deformation experienced by a cage and diffuser made of surgical stainless steel (control), Nitinol, and Bionate 80A polyurethane was also predicted using one-way FSI. The fluid pressure on the surface of the impeller, cage, and diffuser was determined using computational fluid dynamics (CFD), and then, the surface pressure was exported and used to investigate the impeller, cage, and diffuser deformation using finite element analysis. Finally, deformed impeller geometries were imported into the CFD software to determine the implication of deformation on pressure generation, blood damage index, and fluid streamlines. It was found that rotational speed, and not flow rate, is the largest determinant of impeller deformation, occurring at the blade trailing edges. The models predicted the maximum impeller deformation for Nitinol to be 40 nm, Bionate 80A polyurethane to be 106 µm, and silicone to be 2.8 mm, all occurring at 9000 rpm. The effects of silicone deformation on performance were significant, particularly at speeds above 5000 rpm where a decrease in pressure generation of more than 10% was observed. Despite this loss, the pressure generation at 5000 rpm exceeded the level required to alleviate Fontan complications. A blood damage estimation was performed and levels remained low. The effect of significant impeller deformation on blood damage was inconsistent and requires additional investigation. Cage and diffuser geometries made of steel and Nitinol deformed minimally but Bionate 80A experienced unacceptable levels of deformation, particularly in the free-flow case without a spinning impeller. These results support the continued evaluation of a flexible, pitch-adjusting, axial-flow, mechanical assist device as a clinical therapeutic option for patients with dysfunctional Fontan physiology.

Fontan procedure: Early outcomes of 87 consecutive patients in a tertiary care center.

Al Absi and colleagues report their early results of the Fontan procedure in 87 consecutive patients between August 2008 and July 2017 in a tertiary care hospital. The use of the intra/extracardiac fenestration is a promising modification because it is unlikely to be occluded by surrounding tissue and may be associated with decreased pleural effusions, length of hospital stay, and incidence of postoperative arrhythmias.

Efficient approach to superior vena cava baffle stenosis following the Mustard procedure: Expanding the role of a mechanical rotating dilator sheath for lead extraction.

INTRODUCTION: In adult congenital patients with transposition of the great arteries originally treated with the Mustard (atrial switch) procedure, the most common reason for re-intervention is baffle stenosis. This may be exacerbated by permanent transvenous pacemaker lead placement across the baffle. CASE REPORT: A 47-year-old female status post Mustard procedure performed at 15 months old presented with a high-grade stenosis of the superior vena cava (SVC) baffle from the SVC to the left atrium, with a nonfunctional permanent pacemaker lead passing through the baffle. A mechanical rotating dilator sheath was used for attempted lead extraction, relieving the baffle stenosis almost completely as a secondary effect, before the placement of a 10 × 27 mm Visipro balloon-expandable stent in the SVC baffle. CONCLUSIONS: Use of the mechanical rotating dilator sheath is an evolving treatment strategy in adult congenital heart disease to minimize the risk of bleeding, trauma to surrounding structures, and death. Its ability to fully alleviate baffle stenosis even when full lead extraction is not feasible or is associated with significant procedural risk, further demonstrates its expanded role in this patient population. A multidisciplinary approach and great diligence must be employed to avoid potential complications.

Left innominate vein creation using left internal jugular vein tunneled to right internal jugular vein.

BACKGROUND: Left innominate vein occlusion is a known complication of pacemaker and central venous catheter placement. For dialysis-dependent patients with an arteriovenous fistula (AVF), this can prevent successful hemodialysis and may require surgical intervention. CASE REPORT: An 8-month-old male was diagnosed with hemolytic uremic syndrome and became dialysis-dependent at 11 months of age. After multiple vascular access and peritoneal dialysis complications, the patient had construction of a brachiobasalic AVF in his left arm at 13 years old. While waiting for the AVF to mature, an attempt to remove a previously placed left subclavian vein port-a-cath was unsuccessful and a follow-up imaging revealed that the vessel had become occluded. The fistula remained patent, but due to arm swelling and venous obstruction, his fistula was not accessible. Multiple attempts to percutaneously cross the left innominate vein were unsuccessful and the patient was referred for surgical intervention. At 15 years old, the patient was taken to the operating room for transposition of the left internal jugular vein (LIJ) to the right internal jugular vein (RIJ). The LIJ was transected under the mandible and anastomosed to the RIJ. Subsequently the patient underwent VWING insertion rather than venous transposition for constant site dialysis. Although he has required frequent transcatheter dilation of the LIJ-RIJ anastomosis, the patient was successfully dialyzed using this fistula for 5 years. The patient received a cadaveric renal transplant at 5 years 20 days. CONCLUSIONS: In cases of left innominate vein stenosis, transposing the LIJ can create a new left innominate vein that can alleviate venous hypertension and preserve fistula function. This procedure avoids sternotomy and only requires one anastomosis.

Pharmacokinetics of cefazolin delivery via the cardiopulmonary bypass circuit priming solution in infants and children.

OBJECTIVES: Our aim was to describe the pharmacokinetics of cefazolin in paediatric patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) who received cefazolin for peri-operative surgical prophylaxis in addition to having cefazolin added to the CPB circuit priming solution. Secondary aims were to determine the pharmacodynamic exposure associated with the addition of cefazolin to the CPB priming solution and to assess whether a target cefazolin concentration range for the CPB priming solution could be identified. METHODS: A multicentre, prospective, open-label pharmacokinetic study was carried out in children from birth to 16 years of age undergoing cardiac surgery. RESULTS: Forty-one patients met the inclusion criteria and accounted for 492 samples for analysis. Cefazolin concentrations were best described by a one-compartment model with weight as a covariate on the volume of distribution (Vd) with allometric scaling. The mean ± standard deviation (SD) total body CL for the birth-6 month cohort was 0.009 ± 0.006 mL/min/kg with a mean ± SD Vd of 0.59 ± 0.26 L/kg, the mean ± SD total body CL for the 7 month-3 year cohort was 0.01 ± 0.005 mL/min/kg with a mean ± SD Vd of 0.79 ± 0.15 L/kg, and the mean ± SD total body CL for the 4-16 year cohort was 0.007 ± 0.004 mL/min/kg with a mean ± SD Vd of 3.4 ± 0.94 L/kg. The median cefazolin loss in the CPB circuit ranged from 78% to 95% and the median patient cefazolin concentration after CPB circuit detachment ranged from 92 to 197 mg/L. CONCLUSIONS: These data demonstrate that mixing cefazolin in the CPB circuit priming solution was effective in maintaining cefazolin serum concentrations during surgery. If this practice is utilized, re-dosing of cefazolin during the CPB run and upon CPB circuit detachment is most probably not needed. Larger pharmacokinetic studies are warranted.

New versatile dual-support pediatric heart pump.

Mechanical circulatory support (MCS) devices for pediatric patients continue to lag in development behind those for adults. There is no heart pump with the design innovation to support dysfunctional states of heart failure and the anatomic heterogeneity of cardiac defects in pediatric patients. To address this unmet need, we are developing a versatile MCS technology with 2 separate blood pumps under 1 housing, whereby a centrifugal pump rotates around an axial pump. In this study, we advanced the design with a new inducer for the axial pump component and flat inlet volute for the centrifugal pump component. We conducted computational modeling of the design iterations, built prototypes, and tested their performance. The axial pump component was able to generate pressure rises of 1-112 mm Hg for 2-5 L/min at 10 000-14 000 RPM, and the centrifugal pump component produced pressure rises of 1-184 mm Hg for 2-5 L/min at 1750-3000 RPM. Shear stresses and blood damage estimations were less than  490 Pa and 0.5%, respectively. Axial and radial forces were also estimated to be less than 5 N for the axially and radially centered impellers. Data sets were repeatable, and data trends followed theoretical expectations. The new designs for the axial and centrifugal pumps enabled us to reduce the height of the pump while maintaining performance expectations. These findings support the continued development of this new medical device for pediatric patients.

Oblique coronary artery prolongation in anomalous left coronary artery arising from the pulmonary artery: A case series.

BACKGROUND: Anomalous left coronary artery (LMCA) arising from the pulmonary artery (ALCAPA) is a life-threatening congenital birth defect. Prompt surgical correction by reimplantation of the LMCA into the aorta is the treatment of choice, however, unfavorable LCA location or length can make direct reimplantation difficult or even impossible without causing significant stretching or tension on the LMCA. This tension can lead to stenosis of the artery and coronary ischemia and must be avoided if possible. METHODS: A chart review from January 2010 to December 2018 of patients who had ALCAPA repair. Patients were excluded if direct reimplantation was possible. Herein, we describe four cases in which remote LMCA position necessitated the creation of a tubular prolongation of the LMCA. RESULTS: A generous coronary button from the pulmonary artery along with the oblique flap of aorta served as the prolongation of the left main coronary artery. This allowed for a tension-free anastomosis using native tissue with the ability to grow with the patient. The pulmonary artery and the aorta were then patched using pericardial tissue. All four patients had improvement in left ventricular function and degree of mitral regurgitation within weeks of surgery. No patient required extracorporeal membrane oxygenation support. Subsequent long-term angiographic follow-up has revealed excellent durability and patency of these coronary conduits. CONCLUSIONS: The variable nature of ALCAPA requires modification of the surgical approach on a patient by patient basis, and the above described technique adds an alternate and reliable long-term treatment option.

Mechanical Circulatory Support Devices for Pediatric Patients With Congenital Heart Disease.

The use of mechanical circulatory support (MCS) devices is a viable therapeutic treatment option for patients with congestive heart failure. Ventricular assist devices, cavopulmonary assist devices, and total artificial heart pumps continue to gain acceptance as viable treatment strategies for both adults and pediatric patients as bridge-to-transplant, bridge-to-recovery, and longer-term circulatory support alternatives. We present a review of the current and future MCS devices for patients having congenital heart disease (CHD) with biventricular or univentricular circulations. Several devices that are specifically designed for patients with complex CHD are in the development pipeline undergoing rigorous animal testing as readiness experiments in preparation for future clinical trials. These advances in the development of new blood pumps for patients with CHD will address a significant unmet clinical need, as well as generally improve innovation of the current state of the art in MCS technology.