Associations between AI-Assisted Tumor Amphiregulin and Epiregulin IHC and Outcomes from Anti-EGFR Therapy in the Routine Management of Metastatic Colorectal Cancer.

PURPOSE: High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in a retrospective analysis of clinical trial data. Here, AREG/EREG IHC was analyzed in a cohort of patients who received anti-EGFR therapy as part of routine care, including key clinical contexts not investigated in the previous analysis. EXPERIMENTAL DESIGN: Patients who received panitumumab or cetuximab ± chemotherapy for treatment of RAS wild-type mCRC at eight UK cancer centers were eligible. Archival formalin-fixed paraffin-embedded tumor tissue was analyzed for AREG and EREG IHC in six regional laboratories using previously developed artificial intelligence technologies. Primary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 494 of 541 patients (91.3%) had adequate tissue for analysis. A total of 45 were excluded after central extended RAS testing, leaving 449 patients in the primary analysis population. After adjustment for additional prognostic factors, high AREG/EREG expression (n = 360; 80.2%) was associated with significantly prolonged PFS [median: 8.5 vs. 4.4 months; HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.02] and OS [median: 16.4 vs. 8.9 months; HR, 0.66 95% CI, 0.50-0.86; P = 0.002]. The significant OS benefit was maintained among patients with right primary tumor location (PTL), those receiving cetuximab or panitumumab, those with an oxaliplatin- or irinotecan-based chemotherapy backbone, and those with tumor tissue obtained by biopsy or surgical resection. CONCLUSIONS: High tumor AREG/EREG expression was associated with superior survival outcomes from anti-EGFR therapy in mCRC, including in right PTL disease. AREG/EREG IHC assessment could aid therapeutic decisions in routine practice. See related commentary by Randon and Pietrantonio, p. 4021.

Living with Congenital Aortic Stenosis: Exercise Restriction, Patterns of Adherence, and Quality of Life.

Modern consensus panel guidelines recommend restriction from most organized sports for patients with moderate or severe aortic stenosis (AS). However, there is little published data on how frequently physicians deviate from guidelines, how well patients adhere to exercise restrictions, or the effect of restriction on patient-reported quality of life. In this study, we surveyed 93 subjects with AS and their cardiologists regarding participation in organized sports, physical activity, weightlifting, and exercise restriction. Subjects completed the pediatric quality of life inventory (PedsQL) and the pediatric cardiac quality of life inventory (PCQLI). We found that subjects with severe AS (n = 3) were commonly, but not universally, restricted from organized sports (n = 2, 66%). Subjects with moderate AS (n = 40) were rarely restricted from organized sports (n = 6, 17%). No physician-specific characteristics were associated with increased likelihood of recommending exercise restriction. Subjects were more likely to be restricted if they were older (16 years vs. 13 years, p 0.02) and had moderate versus mild AS (p 0.013). PCQLI scores for teens and young adults with AS (age 13-25) were lower than a comparison group of patients with mild congenital heart disease. For all age groups, the PedsQL social functioning score was lower for subjects with exercise restriction (p 0.052). In summary, cardiologists apply consensus guidelines leniently when restricting patients with moderate/severe AS from organized sports and weightlifting. Patients with AS routinely adhere to exercise restriction recommendations. Children and young adults with AS and exercise restriction have lower QOL scores in the social functioning domain.

Cardiovascular intensive care unit variables inform need for feeding tube utilization in infants with hypoplastic left heart syndrome.

OBJECTIVE: Feeding strategies in infants with hypoplastic left heart syndrome (HLHS) following stage 1 palliation (S1P) include feeding tube utilization (FTU). Timely identification of infants who will fail oral feeding could mitigate morbidity in this vulnerable population. We aimed to develop a novel clinical risk prediction score for FTU. METHODS: This was a retrospective study of infants with HLHS admitted to the Boston Children's Hospital cardiovascular intensive care unit for S1P from 2009 to 2019. Infants discharged with feeding tubes were compared with those on full oral feeds. Variables from early (birth to surgery), mid (postsurgery to cardiovascular intensive care unit transfer), and late (inpatient transfer to discharge) hospitalization were analyzed in univariate and multivariable models. RESULTS: Of 180 infants, 66 (36.7%) discharged with a feeding tube. In univariate analyses, presence of a genetic disorder (early variable, odds ratio, 3.25; P = .014) and nearly all mid and late variables were associated with FTU. In the mid multivariable model, abnormal head imaging, ventilation duration, and vocal cord dysfunction were independent predictors of FTU (c-statistic 0.87). Addition of late variables minimally improved the model (c-statistic 0.91). A risk score (the HV2 score) for FTU was developed based on the mid multivariable model with high specificity (93%). CONCLUSIONS: Abnormal head imaging, duration of ventilation, and presence of vocal cord dysfunction were associated with FTU in infants with HLHS following S1P. The predictive HV2 risk score supports routine perioperative head imaging and vocal cord evaluation. Future application of the HV2 score may improve nutritional morbidity and hospital length of stay in this population.

Disproportionate Negative Career Impact of the COVID-19 Pandemic on Female Pediatric Cardiologists in the Northeast United States.

The COVID-19 pandemic has had a dramatic impact on practicing physicians, with effects in clinical practice, academic pursuits, research endeavors, and personal lives. Women in medicine have been uniquely impacted. We examined the impact of the pandemic on the careers of pediatric cardiologists in the Northeast with an anonymous online survey. Participants reported demographic data, information on work hours, administrative burden, career satisfaction, academic productivity, and burnout. We approached 490 cardiologists and received 127 completed surveys (response rate 26%; 49% female). Among all respondents, 72% reported increased burnout, 43% reported decreased career satisfaction, and 57% reported decreased academic productivity. In multivariable ordinal regression analysis, when compared to male physicians, females were 2.4 times more likely to report decreased overall career satisfaction (p = 0.027), 2.6 times more likely to report decreased academic productivity (p = 0.028), and 2.6 times more likely to report increased feelings of burnout "to a large degree" (p = 0.022). Among all respondents, decreased career satisfaction was independently associated with increased household responsibility (OR = 4.4, p = 0.001). Increased administrative burden was independently associated with decreased academic productivity (OR = 2.6, p = 0.038). Open-ended responses highlighted loss of community due to remote work and blurring of the boundaries between work and home. Conversely, respondents appreciated flexibility to work remotely. In conclusion, the majority of pediatric cardiologists in the Northeast experienced negative career impacts due to the COVID-19 pandemic. Important gender differences emerged, with female physicians disproportionately reporting increased burnout, decreased career satisfaction, and decreased academic productivity.

Isometric Exercise Increases the Diameter of the Ascending Aorta in Youth with Bicuspid Aortic Valves.

Central arterial pressure rises to much higher levels during heavy isometric exercise compared to other forms of exercise. For this reason, patients with bicuspid aortic valves (BAV) are often restricted from heavy isometric exercise. Although this approach may be theoretically appealing, no data exist regarding the efficacy of this activity restriction.Patients between 12 and 21 years old with isolated BAV were enrolled if they had a previous echocardiogram at least 2 years prior to the current clinic visit. Patients were excluded if they had additional congenital heart disease, a diagnosed syndrome, or had undergone a procedure involving the aortic valve or ascending aorta. Patients completed a questionnaire regarding frequency and intensity of isometric exercise during the 3-month period prior to the visit. We compared aortic dimensions (Z-score), aortic stenosis, and aortic insufficiency between an echocardiogram performed as part of the current visit and one obtained 2-5 years previously using paired t tests and multivariable regression controlling for age, gender, degree of aortic stenosis, and the presence of isometric exercise. In this sample of 50 adolescents with isolated bicuspid aortic valve, 30 (60%) subjects did not participate in any isometric exercise. Over an average of 2.9 years (SD 0.9 years), we did not find a significant difference between changes in the Z-score diameters of the aortic root (0.9 vs 0.9, p = 0.913) and ascending aorta Z-score (2.9 vs 2.9, p = 0.757), between subjects engaging and not engaging in isometric exercise. Further, we did not find that changes in valve function (i.e., aortic stenosis and aortic insufficiency) differed between the two groups.In this sample of adolescents with isolated bicuspid aortic valve, there was no medium-term increase in aortic dilation or worsening valve function in those who engaged in isometric exercise versus those who refrained from isometric exercise.

Transformational Leadership Meets Innovative Strategy: How Nurse Leaders and Clinical Nurses Redesigned Bedside Handover to Improve Nursing Practice.

In 2000, the Institute of Medicine (IOM) published To Err Is Human: Building a Safer Health System, highlighting medical errors resulting from failure in perception, assumption, and communication. The handover process is a high-risk activity prone to the communication vulnerabilities described in the IOM report. The handover project started as a 3-month pilot with plans to expand to the entire facility. The handover education had 4 elements: questionnaire, presentation, video, and simulation. Compliance with the new process was measured using audits completed by the unit managers. Sixty-four registered nurses on 2 acute units were educated by nurse champions. After a successful implementation, the surge of COVID-19 patients in spring of 2020 required us to adjust expectations regarding bedside handover. As the number of hospitalized COVID patients began to decrease, we reinvigorated the project and re-established the expectation that handover be performed at the bedside. A post-questionnaire was completed after implementation and revealed more favorable responses toward bedside handover. We also saw improvements in our patient satisfaction scores (Hospital Consumer Assessment of Healthcare Providers and Systems [HCAHPS]). With direct observation and a checklist, we were able to return to the practice of bedside handover following the surge of COVID-19 patients. As a direct result of the bedside RN involvement, we created and implemented a handover process that prioritized nursing needs and concerns. Our implementation of this evidence-based practice enhanced patient experience and improved safety. Through education, observational audits, and use of a checklist, we were able to re-establish the expectation and practice of handover being completed at the bedside.

Weaning Dexmedetomidine in Non-ICU Areas: An Implementation Effort.

OBJECTIVES: To develop and implement clinical practice guidelines for safely weaning dexmedetomidine infusions in non-ICU areas. DESIGN: Development, implementation, and analysis of effectiveness of clinical practice guidelines. SETTING: Quaternary care academic free-standing pediatric hospital. PATIENTS: Children, otherwise medically ready for transfer to non-ICU areas, who were undergoing a planned wean of a dexmedetomidine infusion. INTERVENTIONS: Subject matter experts developed evidence-based guidelines for weaning dexmedetomidine in patients whose critical phase of illness had resolved. MEASUREMENTS AND MAIN RESULTS: Searches identified no prospective studies of dexmedetomidine weaning. We identified two retrospective reviews of withdrawal symptoms and one on the use of clonidine. There were case studies on withdrawal symptoms. Guidelines were piloted on a cohort of 24 patients while in the ICU. The guidelines were then implemented in non-ICU areas for patients undergoing dexmedetomidine weaning after ICU transfer. Over a 2-year period (October 1, 2018, to September 30, 2020), 63 patients (1 mo to 18 yr old) successfully weaned dexmedetomidine in non-ICU areas. The median time to discontinuation of dexmedetomidine after transfer to non-ICU areas was 5.8 days (interquartile range, 4.75-15 d). Fifty-eight percent (n = 41) of all patients were considered high risk for dexmedetomidine withdrawal based on the dose, duration of exposure, and the risk of experiencing physiologic detriment with more than mild withdrawal. Twenty-nine patients (46%) exhibited no signs or symptoms of withdrawal while weaning per guidelines. For those with signs and symptoms of withdrawal, the most common were tachycardia (n = 26, 40%), agitation (n = 9, 14%), and hypertension (n = 9, 11%). CONCLUSIONS: Weaning dexmedetomidine in non-ICU areas is feasible and can be accomplished safely even among pediatric patients at high risk for withdrawal using standardized weaning guidelines. At our institution, implementation was associated with reduced ICU length of stay for patients recovering from critical illness.

Graves' disease in a five-month-old boy with an unusual treatment course.

OBJECTIVES: Graves' disease (GD) is rare in children under age five years. Antithyroid drugs are typically first-line therapy but carry the risks of agranulocytosis and liver dysfunction. CASE PRESENTATION: A male infant with multiple congenital anomalies, left ventricular hypertrophy, and neurologic dysfunction developed GD at five months of life. The presence of chronic hepatitis complicated medical management. Potassium iodide was effective temporarily, but urgent thyroidectomy was required at nine months of age. Postoperatively, the patient developed a thyroid function pattern consistent with impaired pituitary sensitivity to thyroid hormone (TH) that responded to the addition of liothyronine. Exome sequencing revealed a heterozygous de novo duplication of the ATAD3 gene cluster, suggesting a possible mitochondrial disorder. CONCLUSIONS: This case describes the youngest child to date to be diagnosed with endogenous GD and to successfully undergo definitive treatment with thyroidectomy. An underlying defect in mitochondrial function is suspected, suggesting a potential novel pathophysiologic link to early-onset thyroid autoimmunity. Additionally, this case illustrated the development of impaired pituitary sensitivity to TH following thyrotoxicosis of postnatal onset, which may contribute to our understanding of hypothalamic-pituitary-thyroid (HPT) axis development.

Keeping the team together: Transformation of an inpatient neurology service at an urban, multi-ethnic, safety net hospital in New York City during COVID-19.

The COVID-19 pandemic dramatically affected the operations of New York City hospitals during March and April of 2020. This article describes the transformation of a neurology division at a 450-bed tertiary care hospital in a multi-ethnic community in Brooklyn during this initial wave of COVID-19. In lieu of a mass redeployment of staff to internal medicine teams, we report a novel method for a neurology division to participate in a hospital's expansion of care for patients with COVID-19 while maintaining existing team structures and their inherent supervisory and interpersonal support mechanisms.

A Pediatric Cardiology Fellowship Boot Camp improves trainee confidence.

Introduction New paediatric cardiology trainees are required to rapidly assimilate knowledge and gain clinical skills to which they have limited or no exposure during residency. The Pediatric Cardiology Fellowship Boot Camp (PCBC) at Boston Children's Hospital was designed to provide incoming fellows with an intensive exposure to congenital cardiac pathology and a broad overview of major areas of paediatric cardiology practice. METHODS: The PCBC curriculum was designed by core faculty in cardiac pathology, echocardiography, electrophysiology, interventional cardiology, exercise physiology, and cardiac intensive care. Individual faculty contributed learning objectives, which were refined by fellowship directors and used to build a programme of didactics, hands-on/simulation-based activities, and self-guided learning opportunities. RESULTS: A total of 16 incoming fellows participated in the 4-week boot camp, with no concurrent clinical responsibilities, over 2 years. On the basis of pre- and post-PCBC surveys, 80% of trainees strongly agreed that they felt more prepared for clinical responsibilities, and a similar percentage felt that PCBC should be offered to future incoming fellows. Fellows showed significant increase in their confidence in all specific knowledge and skills related to the learning objectives. Fellows rated hands-on learning experiences and simulation-based exercises most highly. CONCLUSIONS: We describe a novel 4-week-long boot camp designed to expose incoming paediatric cardiology fellows to the broad spectrum of knowledge and skills required for the practice of paediatric cardiology. The experience increased trainee confidence and sense of preparedness to begin fellowship-related responsibilities. Given that highly interactive activities were rated most highly, boot camps in paediatric cardiology should strongly emphasise these elements.

Growth of the atrial septum after Amplatzer device closure of atrial septal defects in young children.

BACKGROUND: Trans-catheter closure of atrial septal defects (ASD) with the Amplatzer Septal Occluder (ASO) device is safe and effective, but concern over erosions has increased. Devices are placed in growing children but septal growth after ASOs is ill-defined. Understanding the device relationship to cardiac structures as a child grows may help us understand erosions. OBJECTIVE: To define (1) how preprocedural septal measurements change after ASO and (2) the effect of somatic growth on these dimensions. METHODS: Data were collected retrospectively. Echocardiograms were reviewed and rims measured prior to ASO, immediately after ASO, and at follow-up. Demographic, procedural and device data were collected. RESULTS: Thirty-three patients were enrolled; mean age 5.2 ± 3.2 years with 4.0 ± 2.2 years follow-up. All septal measurements decreased after ASO. Thirty-one of 33 devices (94%) contacted the aortic root after ASO; all remained in contact at follow-up with only the IVC rim growing significantly over time. Change in BSA predicted an asymmetric septal growth with increases in superior (P = 0.01) and IVC (P = 0.005) rims and no increase in aortic or AVV rims. No episodes of erosion occurred. CONCLUSIONS: ASDs in young children are not central in the septum, but proximate to the aorta. After ASO, the device remains in close proximity to the aorta. With somatic growth, the septum grows asymmetrically, and device position relative to the aorta is constant. Our study was not powered to detect rare serious adverse events such as erosion, but aortic rims were consistently zero and yet no events occurred.

Dreaming big dreams: the University of Alabama at Birmingham School of Medicine.

The University of Alabama School of Medicine has a rich legacy dating back almost 150 years to Antebellum Mobile and the original Medical College of Alabama. The school's success helped transform Birmingham from a city rooted in the steel industry to one of the U.S.'s major biomedical research centers. Today the school is an internationally acclaimed leader in research and education and serves as the anchor of the University of Alabama at Birmingham and the UAB Health System.