ATF4 and mTOR regulate metabolic reprogramming in TGF-ß-treated lung fibroblasts.

Idiopathic pulmonary fibrosis is a fatal disease characterized by the TGF-ß-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive replacement of healthy lung with scar tissue. We and others have shown that fibroblast activation is supported by metabolic reprogramming, including the upregulation of the de novo synthesis of glycine, the most abundant amino acid found in collagen protein. How fibroblast metabolic reprogramming is regulated downstream of TGF-ß is incompletely understood. We and others have shown that TGF-ß-mediated activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and downstream upregulation of Activating Transcription Factor 4 (ATF4) promote increased expression of the enzymes required for de novo glycine synthesis; however, whether mTOR and ATF4 regulate other metabolic pathways in lung fibroblasts has not been explored. Here, we used RNA sequencing to determine how both ATF4 and mTOR regulate gene expression in human lung fibroblasts following TGF-ß. We found that ATF4 primarily regulates enzymes and transporters involved in amino acid homeostasis as well as aminoacyl-tRNA synthetases. mTOR inhibition resulted not only in the loss of ATF4 target gene expression, but also in the reduced expression of glycolytic enzymes and mitochondrial electron transport chain subunits. Analysis of TGF-ß-induced changes in cellular metabolite levels confirmed that ATF4 regulates amino acid homeostasis in lung fibroblasts while mTOR also regulates glycolytic and TCA cycle metabolites. We further analyzed publicly available single cell RNAseq data sets and found increased expression of ATF4 and mTOR metabolic targets in pathologic fibroblast populations from the lungs of IPF patients. Our results provide insight into the mechanisms of metabolic reprogramming in lung fibroblasts and highlight novel ATF4 and mTOR-dependent pathways that may be targeted to inhibit fibrotic processes.

Simultaneous stent implantation for pulmonary artery bifurcation stenosis in infants.

OBJECTIVES: Pulmonary artery (PA) bifurcation stenosis often requires simultaneous stent placement, which may be technically challenging. Limited data exist regarding this practice in infants. We aim to report the procedural outcomes and safety of bifurcation stent placement in infants. METHODS: We performed a single-center retrospective review of infants younger than 12 months who underwent simultaneous stent placement for PA bifurcation stenosis from January 1, 2001 through December 31, 2019. RESULTS: Seventeen infants underwent simultaneous PA bifurcation stent placement. The median age was 6.4 months (1.1-10.1 months), and weight was 5.8 kg (3-10.6 kg). Nine (52.9%) patients had had prior PA intervention. Most stents were placed in central PAs (28, 82.4%), followed by lobar branches (6, 17.6%). All patients received pre-mounted stents. The peak gradient across each branch decreased from 47.4 ± 16 to 18.7 ± 13 mm Hg (P less than .0001). The right ventricle to systemic systolic pressure ratio decreased from systemic (1.0 ± 0.3) to just over half systemic (0.58 ± 0.2) (P = .0001). The minimum vessel diameter increased from 3.6 ± 1.5 to 6.0 ± 1.9 mm (P less than .0001). There were 4 (23.5%) patients with high severity adverse events. There were no procedure-related deaths. The median follow-up period was 83.8 months (5.3 months-19.4 years). All patients had subsequent PA re-intervention at a median time of 8.1 months (2.9 months-8.8 years), and median time to re-operation was 19.1 months (2.9 months-7.5 years). CONCLUSIONS: Simultaneous PA stent placement is an effective strategy for relief of bifurcation stenosis in infants. Future transcatheter interventions are necessary to account for patient growth, but may delay the need for re-operation.

Impacto de retroalimentación integral (debriefing) frente al modelo de enseñanza tradicional en la mejora de la calidad en estudios de ultrasonido obstétrico / Impact of comprehensive feedback (debriefing) vs traditional teaching model on quality improvement in obstetric ultrasound studies

Introducción: El debriefing es una técnica que permite mejorar los resultados en el proceso de aprendizaje a través de un proceso de reflexión y retroalimentación. El objetivo del estudio es comparar la efectividad del debriefing frente al modelo tradicional de enseñanza para mejorar el cumplimiento de calidad en ultrasonido obstétrico. Sujetos y métodos: Se evaluaron los resultados del control de calidad de 45 médicos recién egresados de diplomados de ultrasonido durante tres meses. Los médicos fueron divididos en dos grupos para llevar a cabo la retroalimentación de áreas de oportunidad: el grupo de control sólo recibió educación a través del modelo tradicional y el grupo de intervención recibió retroalimentación con metodología de debriefing. Resultados: Al comparar, ambos métodos mostraron ser efectivos para la mejora global del cumplimiento de calidad (42,9% el tradicional; p = 0,0083; 75% el de debriefing; p = 0,0002). El grupo de debriefing fue significativamente mejor en los rubros de calidad global (el 56,7 frente al 38,1%; p = 0,009 frente a p = 0,0432) y error de medición (el 88,1 frente al 68,7%, con significancia estadística; p = 0,349). Conclusión: Ambas técnicas de retroalimentación tuvieron un impacto positivo para la mejora del cumplimiento de la calidad en estudios de ultrasonido obstétrico, y la técnica de debriefing mostró ventajas significativas sobre el modelo deenseñanza tradicional en la retroalimentación de las áreas de oportunidad detectadas.(AU)

Introduction: Debriefing is a technique to improve learning outcomes through a process of reflection and feedback. The aim of the study is to compare the effectiveness of debriefing vs. the traditional teaching model to improve quality compliance in obstetric ultrasound. Subjects and methods: Forty-five recent graduates of ultrasound diploma courses were evaluated during three months of quality control. The physicians were divided into two groups to carry out feedback on areas of opportunity: the control group only received education through the traditional model and the intervention group, which received feedback with debriefing methodology. Results: When compared, both methods were shown to be effective for the overall improvement of quality compliance (42.9% traditional, p = 0.0083, 75% debriefing, p = 0.0002). The debriefing group was significantly better in the areas of overall quality (56.7% vs. 38.1%, p = 0.0090 vs. p = 0.0432), measurement error (88.1% vs. 68.7%, with statistical significance p = 0.349). Conclusion: Both feedback techniques offered positive results for the improvement of quality compliance in obstetric ultrasound studies, with the debriefing technique showing significant advantages over the traditional teaching model in the feedback of detected areas of opportunity.(AU)

Abnormal bolus reflux on impedance-pH testing independently predicts 3-year pulmonary outcome and mortality in pulmonary fibrosis.

BACKGROUND AND AIM: Gastroesophageal reflux has been associated with idiopathic pulmonary fibrosis (IPF), although the directionality of the relationship has been debated. Data on the value of objective reflux measures in predicting IPF disease progression and mortality remain limited. We aimed to evaluate the association between multichannel intraluminal impedance and pH testing (MII-pH) and 3-year pulmonary outcomes in IPF patients. METHODS: This was a retrospective cohort study of adults with IPF who underwent pre-lung transplant MII-pH off acid suppression at a tertiary center. Patients were followed for 3 years after MII-pH for poor pulmonary outcomes (hospitalization for respiratory exacerbation or death). A secondary analysis was performed using mortality as outcome of interest. Time-to-event analyses using Kaplan-Meier and Cox regression were performed to evaluate associations between MII-pH and poor outcomes. RESULTS: One hundred twenty-four subjects (mean age = 61.7 ± 8 years, 62% male) were included. Increased bolus exposure time (BET) on MII-pH was associated with decreased time to poor pulmonary outcomes and death (log-ranked P-value = 0.017 and 0.031, respectively). On multivariable Cox regression analyses controlling for potential confounders including age, sex, smoking history, body mass index, proton pump inhibitor use, baseline pulmonary function, and anti-fibrotic therapy, increased BET was an independent predictor for poor pulmonary outcomes [hazard ratio 3.18 (95% confidence interval: 1.25-8.09), P = 0.015] and mortality [hazard ratio 11.3 (95% confidence interval: 1.37-63.9), P = 0.025] over 3 years. CONCLUSIONS: Increased BET on MII-pH is an independent predictor of poor pulmonary outcomes and mortality over 3 years in IPF patients. These findings also support a role for gastroesophageal reflux in IPF disease progression and the potential impact of routine reflux testing and treatment.

Outcomes and Risk Factors of Interventions for Pediatric Post-operative Pulmonary Vein Stenosis.

Pulmonary vein stenosis (PVS) in children is a challenging condition with poor outcomes. Post-operative stenosis can occur after repair of anomalous pulmonary venous return (APVR) or stenosis within native veins. There is limited data on the outcomes of post-operative PVS. Our objective was to review our experience and assess surgical and transcatheter outcomes. Single-center retrospective study was performed including patients < 18 years who developed restenosis after baseline pulmonary vein surgery that required additional intervention(s) from 1/2005 to 1/2020. Non-invasive imaging, catheterization and surgical data were reviewed. We identified 46 patients with post-operative PVS with 11 (23.9%) patient deaths. Median age at index procedure was 7.2 months (range 1 month-10 years), and median follow-up was 10.8 months (range 1 day-13 years). Index procedure was surgical in 36 (78.3%) and transcatheter in 10 (21.7%). Twenty-three (50%) patients developed vein atresia. Mortality was not associated with number of affected veins, vein atresia, or procedure type. Single ventricle physiology, complex congenital heart disease (CCHD), and genetic disorders were associated with mortality. Survival rate was higher in APVR patients (p = 0.03). Patients with three or more interventions had a higher survival rate compared to patients with 1-2 interventions (p = 0.02). Male gender, necrotizing enterocolitis, and diffuse hypoplasia were associated with vein atresia. In post-operative PVS, mortality is associated with CCHD, single ventricle physiology, and genetic disorders. Vein atresia is associated with male gender, necrotizing enterocolitis, and diffuse hypoplasia. Multiple repeated interventions may offer a patient survival benefit; however, larger prospective studies are necessary to elucidate this relationship further.

Effect of different quilting techniques on seroma formation after breast surgery: retrospective study.

BACKGROUND: Quilting, a technique in which skin flaps are sutured to the underlying muscle, reduces seroma after mastectomy and/or axillary lymph node dissection. The aim of this study was to assess the effect of different quilting techniques on the formation of clinically significant seroma. METHODS: This was a retrospective study including patients undergoing mastectomy and/or axillary lymph node dissection. Four breast surgeons applied the quilting technique based on their own discretion. Technique 1 was performed using Stratafix in 5-7 rows placed at 2-3 cm distance. Technique 2 was performed using Vicryl 2-0 in 4-8 rows placed at 1.5-2 cm distance. Technique 3 was performed using Vicryl 0/1 in 3 rows placed at 3-4 cm distance. Technique 4 was performed using Vicryl 0 in 4-5 rows placed at 1.5 cm distance. The primary outcome was clinically significant seroma. RESULTS: A total of 445 patients were included. Clinically significant seroma incidence was 4.1 per cent (six of 147) for technique 1, which was significantly lower than that for the other techniques (25.0 per cent (29 of 116), 29.4 per cent (32 of 109), and 33 per cent (24 of 73) for techniques 2, 3, and 4 (P < 0.001) respectively). The duration of surgery was not significantly longer for technique 1 compared with the other three techniques. The length of hospital stay, number of additional visits to the outpatient clinic, and reoperations did not differ significantly between the four techniques. CONCLUSION: Quilting using Stratafix and placing 5-7 rows with 2-3 cm distance between the stitches associates with low clinically significant seroma incidence without adverse effects.

Safety and Short-Term Outcomes for Infants < 2.5 kg Undergoing PDA Device Closure: A C3PO Registry Study.

To evaluate short-term procedural outcomes and safety for infants < 2.5 kg who underwent catheterization with intended patent ductus arteriosus (PDA) device closure in a multi-center registry, as performance of this procedure becomes widespread. A multi-center retrospective review was performed using data from the Congenital Cardiac Catheterization Project on Outcomes (C3PO) registry. Data were collected for all intended cases of PDA closure in infants < 2.5 kg from April 2019 to December 2020 at 13 participating sites. Successful device closure was defined as device placement at the conclusion of the catheterization. Procedural outcomes and adverse events (AE) were described, and associations between patient characteristics, procedural outcomes and AEs were analyzed. During the study period, 300 cases were performed with a median weight of 1.0 kg (range 0.7-2.4). Successful device closure was achieved in 98.7% of cases with a 1.7% incidence of level 4/5 AEs, including one periprocedural mortality. Neither failed device placement nor adverse events were significantly associated with patient age, weight or institutional volume. Higher incidence of adverse events associated with patients who had non-cardiac problems (p = 0.017) and cases with multiple devices attempted (p = 0.064). Transcatheter PDA closure in small infants can be performed with excellent short-term outcomes and safety across institutions with variable case volume.

CD24+CD44+CD54+EpCAM+ gastric cancer stem cells predict tumor progression and metastasis: clinical and experimental evidence.

BACKGROUND: Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. Specific and thorough identification of cancer cell subsets with higher tumorigenicity and chemoresistance, such as cancer stem cells (CSCs), could lead to the development of new and promising therapeutic targets. For better CSC identification, a complete or extended surface marker phenotype is needed to provide increased specificity for new cell targeting approaches. Our goal is to identify and characterize a putative extended phenotype for CSCs derived from patients with GC before treatment, as well as to evaluate its clinical value. In addition, we aim to ensure that cells with this phenotype have stemness and self-renewal capabilities. METHODS: This is a cohort study including 127 treatment-naïve patients with GC who attended the Instituto Nacional de Cancerología. Multiparametric flow cytometry analysis was performed to determine the extended phenotype of cells derived from gastric biopsies. The tumorigenic capability of cells identified in patients was assessed in a zebrafish model. RESULTS: CD24+CD44+CD54+EpCAM+ cells were present in all treatment-naïve patients included, with a median abundance of 1.16% (0.57-1.89%). The percentage of CD24+CD44+CD54+EpCAM+ cells was categorized as high or low using 1.19% as the cutoff for the CD24+CD44+CD54+EpCAM+ cell subset. Additionally, a higher TNM stage correlated with a higher percentage of CD24+CD44+CD54+EpCAM+ cells (Rho coefficient 0.369; p < 0.0001). We also demonstrated that a higher percentage of CD24+CD44+CD54+EpCAM+ cells was positively associated with metastasis. The metastatic potential of these cells was confirmed in a zebrafish model. Ultimately, under our conditions, we conclude that CD24+CD44+CD54+EpCAM+ cells are true gastric cancer stem cells (GCSCs). CONCLUSION: The CD24+CD44+CD54+EpCAM+ cells present in tissue samples from patients are true GCSCs. This extended phenotype results in better and more specific characterization of these highly tumorigenic cells. The relative quantification of CD24+CD44+CD54+EpCAM+ cells has potential clinical value, as these cells are associated with metastatic disease, making their presence an additional prognostic marker and possibly a target for the design of new antineoplastic treatments in the era of precision oncology. Overall, the extended CD24+CD44+CD54+EpCAM+ phenotype of GCSCs could support their isolation for the study of their stemness mechanisms, leading to the identification of better molecular targets for the development of both new therapeutic approaches such as oncoimmunotherapy and new diagnostic and clinical prognostic strategies for GC.

[Gallbladder torsion]. / Torsie van de galblaas.

BACKGROUND: Gallbladder torsion or gallbladder volvulus is a rare condition of the hepatobiliary system, defined as a rotation of the gallbladder along its long axis causing an interruption of the vascular and biliary flow. It clinically mimics acute cholecystitis which makes accurate preoperative diagnosis challenging. CASE DESCRIPTION: We present the case of an 81-year-old woman with a three day history of upper-right quadrant pain, nausea, vomiting and no evidence of cholelithiasis on imaging. Emergency cholecystectomy was performed, intraoperative findings included a necrotic gallbladder with complete torsion. After the secondary diagnosis of gallbladder torsion, the clinical and radiologic findings were reviewed retrospectively. CONCLUSION: The acute onset of abdominal pain without clear progression over time should initially be the trigger for differential diagnostic consideration of gallbladder torsion. This combined with the previously described risk factors and radiological characteristics could result in successful pre-operative diagnosis of gallbladder torsion.

Intermittent hypoxia inhibits epinephrine-induced transcriptional changes in human aortic endothelial cells.

Obstructive sleep apnea (OSA) is an independent risk factor for cardiovascular disease. While intermittent hypoxia (IH) and catecholamine release play an important role in this increased risk, the mechanisms are incompletely understood. We have recently reported that IH causes endothelial cell (EC) activation, an early phenomenon in the development of cardiovascular disease, via IH-induced catecholamine release. Here, we investigated the effects of IH and epinephrine on gene expression in human aortic ECs using RNA-sequencing. We found a significant overlap between IH and epinephrine-induced differentially expressed genes (DEGs) including enrichment in leukocyte migration, cytokine-cytokine receptor interaction, cell adhesion and angiogenesis. Epinephrine caused higher number of DEGs compared to IH. Interestingly, IH when combined with epinephrine had an inhibitory effect on epinephrine-induced gene expression. Combination of IH and epinephrine induced MT1G (Metallothionein 1G), which has been shown to be highly expressed in ECs from parts of aorta (i.e., aortic arch) where atherosclerosis is more likely to occur. In conclusion, epinephrine has a greater effect than IH on EC gene expression in terms of number of genes and their expression level. IH inhibited the epinephrine-induced transcriptional response. Further investigation of the interaction between IH and epinephrine is needed to better understand how OSA causes cardiovascular disease.

Transcatheter Closure of Atrial and Ventricular Septal Defects: JACC Focus Seminar.

The field of congenital interventional cardiology has experienced tremendous growth in recent years. Beginning with the development of early devices for transcatheter closure of septal defects in the 1970s and 1980s, such technologies have evolved to become a mainstay of treatment for many atrial septal defects (ASDs) and ventricular septal defects (VSDs). Percutaneous device closure is now the preferred approach for the majority of secundum ASDs. It is also a viable treatment option for selected VSDs, though limitations still exist. In this review, the authors describe the current state of transcatheter closure of ASDs and VSDs in children and adults, including patient selection, procedural approach, and outcomes. Potential areas for future evolution and innovation are also discussed.

Transcatheter Cardiac Interventions in the Newborn: JACC Focus Seminar.

For neonates with critical congenital heart disease requiring intervention, transcatheter approaches for many conditions have been established over the past decades. These interventions may serve to stabilize or palliate to surgical next steps or effectively primarily treat the condition. Many transcatheter interventions have evidence-based records of effectiveness and safety, which have led to widespread acceptance as first-line therapies. Other techniques continue to innovatively push the envelope and challenge the optimal strategies for high-risk neonates with right ventricular outflow tract obstruction or ductal-dependent pulmonary blood flow. In this review, the most commonly performed neonatal transcatheter interventions will be described to illustrate the current state of the field and highlight areas of future opportunity.

Cardiac Magnetic Resonance to Predict Coronary Artery Compression in Transcatheter Pulmonary Valve Implantation Into Conduits.

OBJECTIVES: The aim of this study was to evaluate the accuracy of cardiac magnetic resonance (CMR) in predicting coronary artery (CA) compression during transcatheter pulmonary valve implantation (TPVi). BACKGROUND: TPVi is a widely available option to treat dysfunctional right ventricle (RV)-to-pulmonary artery (PA) conduits, but CA compression is an absolute contraindication. CMR can evaluate coronary anatomy, but its utility in predicting CA compression is not well established. METHODS: After Institutional Review Board approval was obtained, all patients at 9 centers with attempted TPVi in RV-PA conduits and recent CMR (≤12 months) were analyzed. A core laboratory reviewed all CMR studies for the shortest orthogonal distance from a CA to the conduit, the shortest distance from a CA to the most stenotic area of the conduit, and subjective assessment of CA compression risk. RESULTS: Among 231 patients, TPVi was successful in 198 (86%); in 24 (10%), balloon testing precluded implantation (documented CA compression or high risk). Distance to the RV-PA conduit ≤2.1 mm (area under the curve [AUC]: 0.70) and distance to most stenotic area ≤13.1 mm (AUC: 0.69) predicted CA compression. Subjective assessment had the highest AUC (0.78), with 96% negative predictive value. Both distances and qualitative assessment remained independently associated with CA compression when controlling for abnormal coronary anatomy or degree of conduit calcification. CONCLUSIONS: CMR can help predict the risk for CA compression during TPVi in RV-PA conduits but cannot completely exclude CA compression. CMR may assist in patient selection and counseling families prior to TPVi, although balloon testing remains essential.

The cross talk between gastric cancer stem cells and the immune microenvironment: a tumor-promoting factor.

Cross talk between cancer cells and the immune system is determinant for cancer progression. Emerging evidence demonstrates that GC characteristics such as metastasis, treatment resistance, and disease recurrence are associated with a tumor subpopulation called gastric cancer stem cells (GCSCs). However, the specific interaction between GCSCs and the immune microenvironment is still under investigation. Although immune evasion has been well described for cancer stem cells (CSCs), recent studies show that GCSCs can also regulate the immune system and even benefit from it. This review will provide an overview of bidirectional interactions between CSCs and immune cells in GC, compiling relevant data about how CSCs can induce leukocyte reprogramming, resulting in pro-tumoral immune cells that orchestrate promotion of metastasis, chemoresistance, tumorigenicity, and even increase in number of cancer cells with stem properties. Some immune cells studied are tumor-associated macrophages (TAMs), neutrophils, Th17 and T regulatory (Treg) cells, mesenchymal stem cells (MSCs), and cancer-associated fibroblasts (CAFs), as well as the signaling pathways involved in these pro-tumoral activities. Conversely, although there are cytotoxic leukocytes that can potentially eliminate GCSCs, we describe mechanisms for immune evasion in GCSCs and their clinical implications. Furthermore, we describe current available immunotherapy targeting GCSC-related markers as possible treatment for GC, discussing how the CSC-modified immune microenvironment can mitigate or inactivate these immunotherapies, limiting their effectiveness. Finally, we summarize key concepts and relevant evidence to understand the cross talk between GCSCs and the immune microenvironment as an important process for effective design of therapies against GCSCs that improve the outcome of patients with GC.

Performing an urgent neonatal cardiac intervention safely during the COVID-19 pandemic.

The current pandemic has driven the medical community to adapt quickly to unprecedented challenges. Among these challenges is the need to minimize staff exposure to COVID-19 during neonatal cardiac procedures. In this report, we describe measures we have taken to protect health care workers while ensuring successful outcomes. These measures include wearing appropriate personal protective equipment, physical distancing, designating separate delivery and transport teams, and limiting the number of providers in direct contact with any patient who is infected or whose infection status is unknown. LEARNING OBJECTIVES: 1.To understand specific challenges caused by the COVID-19 pandemic for patients with congenital heart disease needing urgent neonatal intervention.2.To recognize measures that can be taken to minimize health care workers' exposures to the virus during high-risk neonatal cardiac procedures.3.To review the management of neonates with d-transposition of the great arteries and inadequate mixing.

A phase 2 trial of buparlisib in patients with platinum-resistant metastatic urothelial carcinoma.

BACKGROUND: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway frequently is activated in patients with urothelial carcinoma (UC). In the current study, the authors performed a phase 2 study evaluating the efficacy of the pan-isoform class I PI3K inhibitor buparlisib in patients with platinum-refractory metastatic UC. METHODS: Two cohorts were recruited: an initial genetically unselected cohort and a subsequent expansion cohort of patients with PI3K/Akt/mTOR pathway-altered tumors. The primary endpoint was the 2-month progression-free survival rate. A rate of ≥80% was considered promising using a Simon 2-stage minimax design. Secondary endpoints included safety and correlation of markers of PI3K pathway activation with outcome. RESULTS: Six of 13 evaluable patients within the initial cohort demonstrated stable disease and 1 demonstrated a partial response, which was below the cutoff of 9 patients required to proceed to stage 2. Three of the patients with stable disease and the patient with a partial response harbored somatic TSC1 alterations. Four patients subsequently were recruited onto an expansion cohort: 3 patients with TSC1 alterations and 1 patient with a PIK3CA-activating mutation. No patient achieved disease control at 8 weeks and accrual was halted. Of the 19 patients evaluable for toxicity, 17 demonstrated treatment-related toxicities, 2 of whom had to discontinue therapy. CONCLUSIONS: Buparlisib was found to demonstrate modest activity in patients with metastatic UC whose tumors harbored TSC1 loss of function alterations; however, this was not a robust predictor of response to buparlisib. The pattern of genetic coalterations likely influences drug sensitivity. Given the modest clinical activity and substantial toxicity of buparlisib, future trials of PI3K inhibitors in patients with UC should focus on isoform-selective PI3K inhibitors in genomically selected patients. LAY SUMMARY: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway frequently is upregulated in patients with metastatic urothelial carcinoma (UC). This trial explored buparlisib, an inhibitor of the pathway, in patients with heavily pretreated metastatic UC. Although the drug was found to have modest efficacy, with 6 patients experiencing stable disease and 1 patient achieving a partial response at 8 weeks on therapy, significant side effects also were observed. Patients with specific genetic alterations responded to treatment. Further studies of PI3K pathway inhibition are warranted using newer agents that have superior toxicity profiles and are more selective inhibitors of the pathway.

Neonates With Complex Cardiac Malformation and Congenital Diaphragmatic Hernia Born to SARS-CoV-2 Positive Women-A Single Center Experience.

BACKGROUND: Our understanding of the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pregnancies and perinatal outcomes is limited. The clinical course of neonates born to women who acquired coronavirus disease 2019 (COVID-19) during their pregnancy has been previously described. However, the course of neonates born with complex congenital malformations during the COVID-19 pandemic is not known. METHODS: We report a case series of seven neonates with congenital heart and lung malformations born to women who tested positive for SARS-CoV-2 during their pregnancy at a single academic medical center in New York City. RESULTS: Six infants had congenital heart disease and one was diagnosed with congenital diaphragmatic hernia. In all seven infants, the clinical course was as expected for the congenital lesion. None of the seven exhibited symptoms generally associated with COVID-19. None of the infants in our case series tested positive by nasopharyngeal test for SARS-CoV-2 at 24 hours of life and at multiple points during their hospital course. CONCLUSIONS: In this case series, maternal infection with SARS-CoV-2 during pregnancy did not result in adverse outcomes in neonates with complex heart or lung malformations. Neither vertical nor horizontal transmission of SARS-CoV-2 was noted.

Non-Elective Pediatric Cardiac Catheterization During COVID-19 Pandemic: A New York Center Experience.

BACKGROUND: COVID-19 has led to major changes in hospital systems across the world. In an effort to reduce viral transmission, conserve resources, and in accordance with institutional and state mandates, all elective procedures and surgeries were postponed during the initial outbreak. Guidelines for case selection are limited and management for pediatric catheterization laboratories during this crisis is unprecedented. OBJECTIVES: To report the protocols and case selection of a high-volume pediatric cardiac catheterization laboratory in the epicenter of the novel coronavirus (COVID-19) pandemic. METHODS: All pediatric cardiac catheterization procedures from March 16, 2020 through May 10, 2020 were reviewed. Changes to case selection and periprocedural workflow are described. Data were collected on COVID-19 testing status and primary procedure type, and all procedures were classified by urgency. RESULTS: There were 52 catheterizations performed on 50 patients. Endomyocardial biopsies were the most common procedure (n = 27; 52%). Interventional and diagnostic procedures represented 27% (n = 14) and 21% (n = 11) of cases, respectively. Two emergent procedures (3.8%) were performed on patients with positive COVID-19 testing. Most cases were performed on patients with negative COVID-19 testing (n = 33; 94%). CONCLUSIONS: Adjusting to the COVID-19 pandemic in a high-volume pediatric cardiac catheterization laboratory can be safely and effectively managed by prioritizing emergent and urgent cases and modifying workflow operations. The experience of this center may assist other pediatric cardiac catheterization laboratories in adapting to similar practice changes as the pandemic continues to evolve.

Cardiac workup and monitoring in hospitalised children with COVID- 19.

Approximately, 1.7 million individuals in the United States have been infected with SARS-CoV-2, the virus responsible for the novel coronavirus disease-2019 (COVID-19). This has disproportionately impacted adults, but many children have been infected and hospitalised as well. To date, there is not much information published addressing the cardiac workup and monitoring of children with COVID-19. Here, we share the approach to the cardiac workup and monitoring utilised at a large congenital heart centre in New York City, the epicentre of the COVID-19 pandemic in the United States.

Percutaneous Impella RP use for refractory right heart failure in adolescents and young adults-A multicenter U.S. experience.

OBJECTIVE: To assess the outcomes of the use of the percutaneous Impella RP device (Abiomed, Danvers, MA) in adolescents and young adults. BACKGROUND: Results of the Impella RP device have been reported in adults, but a multicenter experience in adolescents and young adults has yet to be reported. METHODS: Patients ≤21 years of age who underwent implantation of an Impella RP device for refractory right heart failure from June, 2016 to April, 2018 at nine U.S. Centers were included. RESULTS: A total of 12 adolescents, median age of 18 (14-21) years and median weight 74.4 (49-112.4) kg underwent Impella RP implantation (INTERMACS Profile 1 in nine and Profile 2 in three patients. The central venous pressure decreased from 20 (16-35) to 12 (7-17) mmHg, (p = .001). One patient was concomitantly supported with an intra-aortic balloon pump (IABP) and the rest with a percutaneous/surgically placed left ventricular assist device. There was one adverse event related to the Impella RP device (thrombosis requiring explant). The support duration was 6.5 days (4.8 hr-18.4 days) and survival to hospital discharge was 83%. At a median follow-up of 11 months (5 days-2.5 years), 8 of 12 (67%) patients are alive. CONCLUSIONS: In this multicenter experience, the Impella RP device was found to be efficacious and safe when used in adolescents and young adults. Further studies are warranted to identify suitable young/pediatric candidates for Impella RP therapy for right heart failure.