Pediatric Cardiology Fellowship Standards for Training in Exercise Medicine and Curriculum Outline.

Over the past 2 decades, fundamentals of exercise medicine, including clinical exercise testing, assessment and promotion of physical activity, exercise prescription, and supervised exercise training/rehabilitation programming have demonstrated considerable clinical value in the management of children and adolescents with congenital and acquired heart disease. Although the principles of exercise medicine have become an integral component in pediatric cardiology, there are no standardized training recommendations for exercise physiology during pediatric cardiology fellowship at this time. Thus, the Pediatric Cardiology Exercise Medicine Curriculum Committee (PCEMCC) was formed to establish core and advanced exercise physiology training recommendations for pediatric cardiology trainees. The PCEMCC includes a diverse group of pediatric cardiologists, exercise physiologists, and fellowship program directors. The expert consensus training recommendations are by no means a mandate and are summarized herein, including suggestions for achieving the minimum knowledge and training needed for general pediatric cardiology practice.

Women, Younger Clinicians', and Caregivers' Experiences of Burnout and Well-being During COVID-19 in a US Healthcare System.

BACKGROUND: The COVID-19 pandemic brought rapid changes to the work and personal lives of clinicians. OBJECTIVE: To assess clinician burnout and well-being during the COVID-19 pandemic and guide healthcare system improvement efforts. DESIGN: A survey asking about clinician burnout, well-being, and work experiences. PARTICIPANTS: Surveys distributed to 8141 clinicians from June to August 2020 in 9 medical groups and 17 hospitals at Sutter Health, a large healthcare system in Northern California. MAIN MEASURES: Burnout was the primary outcome, and other indicators of well-being and work experience were also measured. Descriptive statistics and multivariate logistic regression analyses were performed. All statistical inferences were based on weighted estimates adjusting for response bias. KEY RESULTS: A total of 3176 clinicians (39.0%) responded to the survey. Weighted results showed 29.2% reported burnout, and burnout was more common among women than among men (39.0% vs. 22.7%, p<0.01). In multivariate models, being a woman was associated with increased odds of reporting burnout (OR=2.19, 95% CI: 1.51-3.17) and being 55+ years old with lower odds (OR=0.54, 95% CI: 0.34-0.87). More women than men reported that childcare/caregiving was impacting work (32.9% vs. 19.0%, p<0.01). Even after controlling for age and gender, clinicians who reported childcare/caregiving responsibilities impacted their work had substantially higher odds of reporting burnout (OR=2.19, 95% CI: 1.54-3.11). Other factors associated with higher burnout included worrying about safety at work, being given additional work tasks, concern about losing one's job, and working in emergency medicine or radiology. Protective factors included believing one's concerns will be acted upon and feeling highly valued. CONCLUSIONS: This large survey found the pandemic disproportionally impacted women, younger clinicians, and those whose caregiving responsibilities impacted their work. These results highlight the need for a holistic and targeted strategy for improving clinician well-being that addresses the needs of women, younger clinicians, and those with caregiving responsibilities.

A multiplex real-time PCR assay for routine diagnosis of bacterial vaginosis.

A semi-quantitative multiplex PCR assay for the diagnosis of bacterial vaginosis (BV) was evaluated in a prospective study in a population of Dutch women with complaints of abnormal vaginal discharge. The PCR targets Gardnerella vaginalis, Atopobium vaginae, Megasphaera phylotype 1, Lactobacillus crispatus and Lactobacillus iners. Together with a short questionnaire, a vaginal swab for PCR and vaginal smear for microscopy were taken by their general practitioner or gynaecologist. Data from 151 women (median age 32) were available. Nugent Score (NS) was used to classify the samples and 83 samples were classified as normal (NS 0-3), 13 as intermediate (NS 4-6), and 55 as bacterial vaginosis (NS 7-10). In women with a NS of 7-10, PCR detected Gardnerella vaginalis, Atopobium vaginae and Megasphaera phylotype 1 in respectively, 96 %, 87 % and 60 %, whereas in women with a NS of 1-3 these species were detected in 27 %, 6 % and 2 % (P <0.001). A ratio of Lactobacillus crispatus over Lactobacillus iners of <1 (as calculated from the quantification cycle value (Cq)) was present in women with a NS of 7-10 in 66 % versus 33 % in women with a NS of 1-3 (P <0.001). The BV-PCR displayed a sensitivity of 92 % and specificity of 96 % with a positive predictive value of 94 % and a negative predictive value of 95 %. The Lactobacillus-index improved the correct classification of samples where only one of the other bacterial species was detected. Compared to the Nugent Score this multiplex qPCR offers a convenient tool for performing observer independent diagnosis of BV.

Denileukin diftitox in combination with rituximab for previously untreated follicular B-cell non-Hodgkin's lymphoma.

Follicular lymphoma exhibits intratumoral infiltration by non-malignant T lymphocytes, including CD4+CD25+ regulatory T (T(reg)) cells. We combined denileukin diftitox with rituximab in previously untreated, advanced-stage follicular lymphoma patients anticipating that denileukin diftitox would deplete CD25+ T(reg) cells while rituximab would deplete malignant B cells. Patients received rituximab 375 mg/m(2) weekly for 4 weeks and denileukin diftitox 18 mcg/kg/day for 5 days every 3 weeks for 4 cycles; neither agent was given as maintenance therapy. Between August 2008 and March 2010, 24 patients were enrolled. One patient died before treatment was given and was not included in the analysis. Eleven of 23 patients (48%; 95% confidence interval (CI): 27-69%) responded; 2 (9%) had complete responses and 9 (39%) had partial responses. The progression-free rate at 2 years was 55% (95%CI: 37-82%). Thirteen patients (57%) experienced grade ≥3 adverse events and one patient (4%) died. In correlative studies, soluble CD25 and the number of CD25+ T cells decreased after treatment; however, there was a compensatory increase in IL-15 and IP-10. We conclude that although the addition of denileukin diftitox to rituximab decreased the number of CD25+ T cells, denileukin diftitox contributed to the toxicity of the combination without an improvement in response rate or time to progression.

[Oncologic outcomes after radical prostatectomy: French validation of the D'Amico risk group classification]. / Résultats carcinologiques après prostatectomie totale pour cancer: validation française de la classification de D'Amico.

PURPOSE: To validate the D'Amico risk group classification in French consecutive series and to analyse recurrence risk factor after radical prostatectomy (RP) for prostate cancer. MATERIAL: We retrospectively analyzed data collected from 10/2000 to 05/2009 for 730 consecutive patients who underwent RP for clinically localized or locally advanced prostate cancer (cT1-cT3) in our institution. Biochemical recurrence (BCR) was defined by prostate-specific antigen (PSA) of greater than 0.1 ng/ml, with rising PSA at two consecutive dosages. Postoperative survival was estimated using the Kaplan-Meier method after D'Amico's group stratification. The accuracy of the model was evaluated using the Harrell's concordance index. The impact on outcomes of preoperative PSA and pathological features was evaluated using a monovariate and multivariate Cox analysis. RESULTS: Median follow-up was 30 months [interquartile range: 13-51]. The overall 3-year and 5-year probability of freedom from BCR was 85% (95% Confidence Interval (CI), 81-88%) and 78% (95% CI, 74-83%), respectively. For low, intermediate, and high-risk group, the 5-year freedom from BCR was 92% (95% CI, 88-97%), 73% (95% CI, 65-81%) and 44% (95% CI, 28-59%), respectively (p<0.001). Harrell's concordance index was 0.71. Surgical margins were positive in 31% of all cases. In a multivariate analysis, preoperative PSA, pathological tumor stage, Gleason score and surgical margins status predicted BCR after RP. CONCLUSIONS: We externally validated the ability of the D'Amico's risk group stratification to predict disease progression following RP in European patients. Preoperative PSA, pathological stage, Gleason score and surgical margins status predicted BCR after RP in our series through a multivariate analysis.

Enhanced degradation of tryptophan in patients on hemodialysis.

BACKGROUND: Hemodialysis patients often present with increased concentrations of tryptophan catabolites perhaps related to an enhanced activity of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) that is inducible by pro-inflammatory stimuli. The often chronic inflammation and immune activation status in dialysis patients may accelerate tryptophan degradation, which could influence patients' psychological performance. PATIENTS AND METHODS: In this study, plasma concentrations of kynurenine and tryptophan were determined by HPLC in 75 dialysis patients, aged 65.3 ± 15.0 years. Forty patients were female, 35 male; 21 (28%) had diabetes mellitus Type 1 or 2 and 32 (43%) suffered from sleep disturbances and/or depression. Their dialysis vintage was 4.26 ± 4.72 years. HPLC results were compared to concentrations obtained from 40 healthy blood donors, to immune activation marker neopterin, and to psychological test results based on INTERMED scores. RESULTS: Compared to those in healthy controls, tryptophan concentrations were decreased in patients. Neopterin, kynurenine and the kynurenine to tryptophan ratio (kyn/trp, an index of tryptophan degradation) were increased in patients (all p < 0.01). Kyn/trp correlated with neopterin concentrations (rs = 0.393, p < 0.01). INTERMED scores were 21.0 + 8.4 and slightly higher in females (U = -1.831, p < 0.07); they correlated with tryptophan concentrations (rs = -0.227, p < 0.05) but with no other parameter studied. Data point to a possible relationship between tryptophan metabolic disturbances and psychologic presentation of patients, although only a rather weak relationship was found. CONCLUSION: We conclude that tryptophan degradation is increased in dialysis patients. The association with increased neopterin concentrations indicates activated IDO.

[Sporadic upper urinary tract urothelial cell carcinomas: identification of interaction between toxic carcinogens and individuals genetic susceptibility]. / Tumeurs des voies excrétrices urinaires supérieures sporadiques: identification de l'interaction entre l'exposition aux carcinogènes environnementaux et la susceptibilité génétique des individus.

Upper urinary tract urothelial cell carcinomas (UUT UCC) are rare sporadic tumors. Recent epidemiologic and molecular data have shown a singular susceptibility of UUT UCCs for specific risk factors. The main exogenic factors involved in UUT UCCs carcinogenesis remain tobacco and occupational exposure (aromatic amines, polycyclic hydrocarbures and chlored solvents). Enzymatic variants of detoxification system may be responsible of carcinogenesis with these toxics. Tumors induced by phenacetine consumption are decreasing since it was banned in the 1970s. Also, acid aristolochic exposure (Balkan nephropathy, Chinese Herb nephropathy) has been demonstrated to specifically induce UUT UCCs. Familial genic polymorphism of detoxification system would explain geographic distribution in endemic areas. In Taiwan, chronic arsenic exposition would constitute the main risk factor of UUT UCC. However, theses mechanisms of carcinogenesis remain unclear. The knowledge of UUT UCC development mechanisms implying toxic detoxification systems is still incomplete. To date, there is a growing body of evidence supporting that the interaction between individual genetic susceptibilities and environmental toxic exposure is a key to explain carcinogenesis in the majority of sporadic UUT UCC occurrence.

In vivo turnover study demonstrates diminished clearance of lipoprotein(a) in hemodialysis patients.

Lipoprotein(a) (Lp(a)) consists of a low-density lipoprotein-like particle and a covalently linked highly glycosylated protein, called apolipoprotein(a) (apo(a)). Lp(a) derives from the liver but its catabolism is still poorly understood. Plasma concentrations of this highly atherogenic lipoprotein are elevated in hemodialysis (HD) patients, suggesting the kidney to be involved in Lp(a) catabolism. We therefore compared the in vivo turnover rates of both protein components from Lp(a) (i.e. apo(a) and apoB) determined by stable-isotope technology in seven HD patients with those of nine healthy controls. The fractional catabolic rate (FCR) of Lp(a)-apo(a) was significantly lower in HD patients compared with controls (0.164+/-0.114 vs 0.246+/-0.067 days(-1), P=0.042). The same was true for the FCR of Lp(a)-apoB (0.129+/-0.097 vs 0.299+/-0.142 days(-1), P=0.005). This resulted in a much longer residence time of 8.9 days for Lp(a)-apo(a) and 12.9 days for Lp(a)-apoB in HD patients compared with controls (4.4 and 3.9 days, respectively). The production rates of apo(a) and apoB from Lp(a) did not differ significantly between patients and controls and were even lower for patients when compared with controls with similar Lp(a) plasma concentrations. This in vivo turnover study is a further crucial step in understanding the mechanism of Lp(a) catabolism: the loss of renal function in HD patients causes elevated Lp(a) plasma levels because of decreased clearance but not increased production of Lp(a). The prolonged retention time of Lp(a) in HD patients might importantly contribute to the high risk of atherosclerosis in these patients.

Development of a fluorescence-based assay for screening of modulators of human organic anion transporter 1B3 (OATP1B3).

The organic anion transporting protein 1B3 (OATP1B3), formerly termed OATP8, is responsible for uptake and subsequent elimination of multiple amphipathic drugs by the liver. In silico methods for the prediction of transport rates for drugs and drug-like molecules might provide an important tool in drug development. Most prediction methods however require a large training set of in vitro experimental data in order to yield reliable results. To obtain these data, we have developed a fluorescence-based assay that allows screening a relatively high number of substances for their transporter affinity. HEK293 cells overexpressing OATP1B3 (HEK-OATP8) [Y. Cui, J. Konig, D. Keppler, Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2, Mol. Pharmacol. 60 (2001) 934-943.] were tested for transport of Fluo-3. Fluo-3 uptake could be seen in a concentration-dependent manner. Uptake can be inhibited completely by the addition of the known OATP1B3-inhibitor rifampicin proving that Fluo-3 is transported by OATP1B3. To verify the suitability of the system to identify modulators of OATP1B3, we tested known substrates for competitively inhibiting the Fluo-3 transport by giving them simultaneously with a 2muM Fluo-3-solution to the cells. The transport of Fluo-3 was decreased by all test substrates in a concentration dependent manner.

Hybrid pediatric cardiac surgery.

Minimally invasive strategies can be expanded by combining standard surgical and interventional techniques. We performed a longitudinal prospective study of all pediatric patients who have undergone hybrid cardiac surgery at the University of Chicago Children's Hospital. Hybrid cardiac surgery was defined as combined catheter-based and surgical interventions in either one setting or in a planned sequential fashion within 24 hours. Between June 2000 and June 2003, 25 patients were treated with hybrid approaches. Seventeen patients with muscular ventricular septal defects (mVSDs) (mean age, 4 months; range, 2 weeks-4 years) underwent either sequential Amplatzer device closure in the catheterization laboratory followed by surgical completion (group 1A, n = 9) or one-stage intraoperative off-pump device closure (group IB, n = 8) with subsequent repair of any concomitant heart lesions. Eight patients with branch pulmonary artery (PA) stenoses (group 2) underwent intraoperative PA stenting or stent balloon dilatation along with concomitant surgical procedures. All patients survived hospitalization. Complications from the hybrid approach were mostly confined to groups 1A and 2. At a mean follow-up of 18 months, 2 group 1A patients died suddenly several months after discharge. All other patients are doing well. Hybrid pediatric cardiac surgery performed in tandem by surgeons and cardiologists is safe and effective in reducing or eliminating cardiopulmonary bypass. Patients with mVSDs who are small, have poor vascular access, or have concomitant cardiac lesions are currently treated in one setting with the perventricular approach.

Multicenter experience with perventricular device closure of muscular ventricular septal defects.

Hybrid procedures are becoming increasingly important, especially in the management of congenital heart lesions for which there are no ideal surgical or interventional options. This report describes a multicenter experience with perventricular muscular venticular septal defect (VSD) device closure. Three groups of patients (n = 12) were identified: infants with isolated muscular VSDs (n = 2), neonates with aortic coarctation and muscular VSDs (n = 3) or patients with muscular VSDs and other complex cardiac lesions (n = 2), and patients with muscular VSDs and pulmonary artery bands (n = 5). Via a sternotomy or a subxyphoid approach, the right ventricle (RV) free wall was punctured under transesophageal echocardiography guidance. A guidewire was introduced across the largest defect. A short delivery sheath was positioned in the left ventricle cavity. An Amplatzer muscular VSD occluding device was deployed across the VSD. Cardiopulmonary bypass was needed only for repair of concomitant lesions, such as double-outlet right ventricle, aortic coarctation, or pulmonary artery band removal. No complications were encountered using this technique. Discharge echocardiograms showed either mild or no significant shunting across the ventricular septum. At a median follow-up of 12 months, all patients were asymptomatic and 2 patients had mild residual ventricular level shunts. Perventricular closure of muscular VSDs is safe and effective for a variety of patients with muscular VSDs.

Echocardiographic guidance of transcatheter closure of atrial septal defects: is intracardiac echocardiography better than transesophageal echocardiography?

Transcatheter closure of atrial septal defects is an established practice. The imaging method best suited for guidance of this procedure is under debate. This review highlights the areas of disagreement and presents available evidence supporting the contention that intracardiac echocardiography is at least as good, if not a superior imaging method to guide the procedure. Points of discussion include comparisons of imaging capability, complications or discomfort, and the relative costs of these procedures. It is concluded that intracardiac echocardiography is the superior imaging method.

[Diagnostic image (197). A man who suddenly collapsed]. / Diagnose in beeld (197). Een plotseling gecollabeerde man.

A 40-year-old man suffered a witnessed collapse with brief loss of consciousness, due to electrical injury.

Immediate and six-month results of the profile of the Amplatzer septal occluder as assessed by transesophageal echocardiography.

Catheter closure of secundum atrial septal defect (ASD) using the Amplatzer septal occluder (ASO) is a potential alternative for open surgical repair. However, the large profile of the device obtained immediately after closure continues to raise some concerns regarding its long-term safety. To evaluate the changes in the profile of the device after being deployed, transesophageal echocardiography was performed in 70 patients (17 men and 53 women) who underwent catheter closure of ASDs immediately after and at 6-month follow-up. The median age at closure was 16 years (range 1.9 to 75) and the median size of the ASD as assessed by transesophageal echocardiography was 14 mm (range 3 to 25). The thickness (profile) of the device was assessed in the 4-chamber, short- and long-axis views of the interatrial septum, and measured at its middle and at the junction of the waist with the disc at its 2 ends. Seventy-three devices were deployed in the 70 patients. The median size of the device was 19 mm (range 8 to 34). Complete closure was achieved in 81.4% and 91.4% immediately after and at 6-months follow-up, respectively. The thickness of the device at its middle decreased from 12.2 +/- 4.3, 12.2 +/- 3.7, and 12.5 +/- 4.3 mm in the 4-chamber, short- and long-axis views to 6.5 +/- 2.0, 6.3 +/- 1.9, and 6.5 +/- 2.2 mm, respectively. The thickness of the device at its superior, inferior, anterior, and posterior edges also decreased by 41.8% +/- 14.0% to 43.7% +/- 9.8%. The changes in the thickness were related to device size. Larger devices were thicker after being deployed. We conclude that the thickness of the ASO decreases by 42% to 48% within 6 months after deployment, resulting in a lower profile.

A rule-based categorization deficit in Alzheimer's disease?

This study examined the categorization processes that Alzheimer's disease (AD) patients use during assessments of semantic memory. Rule-based categorization involves the careful, analytic processing of strict criteria to determine category membership, particularly for items from graded categories with ambiguous category membership; similarity-based categorization requires an overall comparison of a test stimulus with a prototype or remembered exemplar of the category and is relatively effective for the rapid categorization of items with unambiguous category membership. To assess these processes in AD, patients were asked to decide the category membership of test stimuli for categories with poorly defined or fuzzy boundaries (e.g., VEGETABLE) and for categories with well-defined boundaries (e.g., FEMALE) and then to judge the representativeness of the test stimulus for its chosen category. A subgroup of AD patients demonstrated a typical pattern of impaired semantic memory compared to healthy control subjects; that is, difficulty deciding the category membership of test items from fuzzy categories. Among these patients, we found no deficit in category membership decisions about items taken from well-defined categories. We also found that AD patients and healthy controls do not differ in their representativeness judgments of items within a correctly judged category. These findings are most consistent with the hypothesis that rule-based categorization difficulty limits semantic memory in AD.

Transcatheter closure of atrial septal defects and patent foramen ovale under intracardiac echocardiographic guidance: feasibility and comparison with transesophageal echocardiography.

Transesophageal echocardiography (TEE) has been employed successfully for guiding transcatheter device closure of secundum atrial septal defect (ASD) and patent foramen ovale (PFO). However, the use of TEE for device closure requires general anesthesia. Intracardiac echocardiography (ICE) can provide similar anatomical views that might replace the use of TEE for device closure. Eleven patients (eight female/three male) with secundum ASD and PFO associated with strokes underwent attempts at transcatheter closure of their defects under sequential TEE and ICE guidance (six patients) and under ICE alone (five patients). The ages of the patients ranged from 6.6 to 74.7 yr, and their weights ranged from 23 to 124.5 kg. The sizes of the defects, as measured by TEE (six patients), ranged from 3 to 27 mm and, as measured by ICE (11 patients), from 3 to 27 mm. The balloon-stretched diameter of the ASD, as measured by TEE (six patients), ranged from 16 to 38 mm and, as measured by ICE (11 patients), from 16 to 35 mm. Both techniques correlated well for the measured two-dimensional diameter and for the balloon-stretched diameter (r = 0.97 and 0.98, respectively). Both TEE and ICE provided similar views of the defects and the various stages of device deployment. Owing to the proximity of the left atrium to the esophagus, however, the images obtained by ICE were more helpful and informative than those obtained by TEE. All patients experienced successful device placement (six patients under both TEE and ICE; five patients under ICE guidance alone); complete closure of the defects was effected in nine patients, whereas two patients had small residual shunts. There were no complications. We conclude that ICE provides unique images of the atrial communications and measurements similar to those obtained by TEE. ICE potentially could replace TEE as a guiding imaging tool for ASD and PFO device closure, thus eliminating the need for general anesthesia.