Open Field Exercise Testing in Pediatric Congenital Heart Disease Patients: A Subsumption of Cardiovascular Parameters.

Heart failure is a common phenomenon in congenital heart disease patients. Cardiopulmonary exercise testing is used for a reliable assessment of heart failure but is still challenging, especially for young children. Implementing mobile cardiopulmonary exercise testing (CPET) can close that diagnostic gap. While average values for healthy children have already been published, this study aims to describe typical ranges of cardiovascular performance parameters of young children with congenital heart disease performing an 8-min running cardiopulmonary exercise test. Children aged 4-8 years with common congenital heart defects after corrective surgery (Tetralogy of Fallot; transposition of the great arteries and univentricular hearts after palliation) were included. The outdoor running protocol consisted of slow walking, slow jogging, fast jogging, and maximum speed running. Each exercise was performed for 2 min, except the last, in which children were instructed to keep up maximal speed as long as possible. A total of 78 children (45 male/33 female, mean age 6,24) with congenital heart disease participated in the study, of which 97% completed the CPET successfully. A detailed description of participating patients, including data on cardiac function and subjective fitness levels, is given to help physicians use this method to classify their patients. This study presents a typical range for cardiovascular performance parameters in a population of 4-8-year-old children with congenital heart disease tested in a newly developed outdoor running protocol for CPET.

Development of an AI based automated analysis of pediatric Apple Watch iECGs.

Introduction: The Apple Watch valuably records event-based electrocardiograms (iECG) in children, as shown in recent studies by Paech et al. In contrast to adults, though, the automatic heart rhythm classification of the Apple Watch did not provide satisfactory results in children. Therefore, ECG analysis is limited to interpretation by a pediatric cardiologist. To surmount this difficulty, an artificial intelligence (AI) based algorithm for the automatic interpretation of pediatric Apple Watch iECGs was developed in this study. Methods: A first AI-based algorithm was designed and trained based on prerecorded and manually classified i.e., labeled iECGs. Afterward the algorithm was evaluated in a prospectively recruited cohort of children at the Leipzig Heart Center. iECG evaluation by the algorithm was compared to the 12-lead-ECG evaluation by a pediatric cardiologist (gold standard). The outcomes were then used to calculate the sensitivity and specificity of the Apple Software and the self-developed AI. Results: The main features of the newly developed AI algorithm and the rapid development cycle are presented. Forty-eight pediatric patients were enrolled in this study. The AI reached a specificity of 96.7% and a sensitivity of 66.7% for classifying a normal sinus rhythm. Conclusion: The current study presents a first AI-based algorithm for the automatic heart rhythm classification of pediatric iECGs, and therefore provides the basis for further development of the AI-based iECG analysis in children as soon as more training data are available. More training in the AI algorithm is inevitable to enable the AI-based iECG analysis to work as a medical tool in complex patients.

Into the Blue: First in Man Data on Diving Physiology in Fontan Patients.

Swimming and diving are popular recreational activities. As congenital heart disease, especially patients with univentricular hearts after Fontan palliation are thought to have reduced physiologic capacities for compensation of submersion-associated physiologic demands, current guidelines put restraints on this group of patients. Although these restrictions on doctoral advice place a significant burden on affected patients, it is especially interesting that these guideline recommendations are merely based on physiologic assumptions, i.e., expert consensus. A recent study by Paech et al. presented the first in vivo data on the effects of immersion in Fontan patients, stating no major adverse events in their study group as well as comparable physiologic adaption as reported in the literature for healthy people. Yet, submersion was not reflected in this study, and the current study therefore aimed to conduct a first study for the evaluation of the effects of submersion and apnea diving in Fontan patients. A control group of healthy adults as well as patients recruited from the Heart Center Leipzig, Department of pediatric cardiology underwent a standardized diving protocol including a static as well as dynamic apnea phase. Physiologic data were recorded. This study presents the first structured data on diving physiology in Fontan patients compared to healthy probands. There were no adverse events. The physiologic response to diving seems to be comparable between healthy probands and Fontan patients. Although, healthy probands did reach a much better performance, the basic mechanisms of physiologic adaption seem comparable.

Accuracy of the Apple Watch Oxygen Saturation Measurement in Adults and Children with Congenital Heart Disease.

As new customer health devices have been spread throughout the consumer market in recent years, it now needs to be evaluated if they also fulfill the requirements of clinical use. The Apple Watch Series 6 provides a new health feature with its oxygen saturation measurement. The aim of this prospective, investigator-initiated, single-arm study was to compare transcutaneous oxygen saturation measurements using the Apple Watch 6 with the conventional method of pulse oximetry in patients with congenital heart disease. Patients of any age presenting at the Leipzig Heart Center, Department for pediatric cardiology, were included. After obtaining informed consent, the routine oxygen saturation measurement with the pulse oximeter was taken and simultaneously three measurements with the Apple Watch. A total of 508 patients were enrolled. Comparing children and adults in terms of measurement success shows a statistically significant difference with a higher proportion of unsuccessful measurements in children, but no difference concerning correct versus incorrect Apple Watch measurements. Noticeable, strapping on the watch properly around the patient's wrists significantly improved the measurements compared to a watch only laid on. The study demonstrated that oxygen saturation measurement with the Apple Watch 6 is not yet up to the medical standard of pulse oximetry, too large a proportion of the measurements remain either unsuccessful or incorrect. While a high proportion of unsuccessful measurements in children can be attributed to movement, the cause in adults usually remains unclear. Further influencing factors on a correct, or successful measurement could not be found.

Accuracy of the Apple Watch iECG in Children With and Without Congenital Heart Disease.

The development of smart technologies paves the way for new diagnostic modalities. The Apple Watch provides an FDA approved iECG function for users from 22 years of age. Yet, there are currently no data on the accuracy of the Apple Watch iECG in children. While arrhythmias are a frequent phenomenon in children, especially those with congenital heart disease, the increasing spread of smart watches provides the possibility to use a smart watch as mobile event recorder in case of suspected arrhythmia. This may help to provide valuable information to the treating physician, without having the patient to come to the hospital. Necessary treatment adjustments might be provided without timely delay. The aim of this study was therefore to evaluate the agreement of measured values of rate, interval, and amplitude with those obtained by a diagnostic quality ECG recording to an Apple Watch iECG in children with and without congenital heart disease. In this prospective, single-arm study, consecutive patients aged 0-16 years presenting to the Heart Center Leipzig, Department for pediatric cardiology were included. After obtaining informed consent from participants' parents, a 12-lead ECG and an iECG using an Apple Watch were performed. Cardiac rhythm was classified, amplitudes and timing intervals were measured and analyzed in iECG and 12-lead ECG for comparability. These measurements were performed blinded to the patients' history by two experienced pediatric cardiologists. Patient demographic data, medical and cardiac history were assessed. 215 children between 0 and 16 years were enrolled. Comparison of amplitudes and timing intervals between ECG and iECG showed excellent correlation (K > 0.7, p < 0.01) in all parameters except for the p-waves. Automatic rhythm classification was inferior to manual interpretation of ECG / iECG, while iECG interpretation was reliable in 94.86% of cases. The study demonstrates equal quality of the Apple Watch derived iECG compared to a lead I in 12-lead ECG in children of all age groups and independent from cardiac anatomy.

The Fontan and the Sea: First-in-Man Data on Swimming and Diving Physiology in Fontan Patients.

While swimming represents a popular recreational activity, the immersion of the human body into the water requires a complex physiologic adaption of the whole cardiopulmonary and circulatory system. While this sport is regarded as beneficial, especially in cardiovascular patients, current guidelines hypothesized a possible hazardous effect of swimming and especially diving in patients with univentricular hearts after Fontan palliation. Yet, actual data to underline or contradict these assumptions are lacking. Therefore, this study aimed to conduct a first feasibility study for the evaluation of these effects on Fontan physiology and elucidate the gap of evidence currently preventing patients after Fontan palliation from being restricted from swimming or diving on doctoral advice. Patients recruited from the Heart Center Leipzig, Department of pediatric cardiology, underwent spiroergometry treadmill testing followed by a spiroergometry swimming stress test in a counter current pool. Physiologic data were recorded. A short apnea diving test was performed. The current study found similar physiologic reactions comparing treadmill and swimming exercise stress testing. Heart rate response and oxygen uptake were comparable on land and in the water. This study presents the first-in-man data on swimming and diving in Fontan patients. In this small study cohort of three Fontan patients, there were no adverse events triggered by swimming and breath-hold diving seen. Basically, the physiologic response to exercise was comparable on land and in the water.

Case series of idiopathic membranous nephropathy with long-term beneficial effects of ACTH peptide 1-24.

BACKGROUND: In patients with idiopathic membranous nephropathy (IMN), immunosuppressive therapy is usually considered when severe nephrotic syndrome or risk for progressive renal failure exist. Recently, several studies showing beneficial effects of synthetic adrenocorticotropic hormone (ACTH) under such circumstances have been published. The objective of the present case series was to evaluate long-term ACTH effects on proteinuria and renal function. METHODS: Four patients with biopsy-proven membranous nephropathy and nephrotic syndrome were enrolled (median age 50 years (range 38 - 61), median GFR 39.5 ml/min (range 20 - 62), median proteinuria 9.6 g/d (range 6.0 - 20.0). Prior immunosuppressive treatment regimens included steroids, cyclosporine A, cyclophosphamide, mycophenolate mofetil or azathioprine. The patients received a synthetic ACTH analogue intramuscularly for a median duration of 8 months (range 3 - 24). ACTH dosage was adjusted according to side effects between 0.25 and 2.25 mg/week. Follow-up lasted between 24 and 82 months after therapy initiation. RESULTS: All 4 patients exhibited partial (n = 2) or complete (n = 2) remissions of their nephrotic syndrome within the first year. After discontinuation of ACTH therapy, proteinuria remained low in 3 of 4 cases, whereas 1 patient exhibited undulating proteinuria. Glomerular function (as assessed by glomerular filtration rate, GFR) was maintained in all patients. Side effects were minor and included weight gain, elevated blood pressure and hyperglycemia. CONCLUSION: In all 4 cases with IMN, ACTH treatment induced a lasting disease remission with relatively few side effects.

HIV-related stigma, service utilization, and status disclosure among truck drivers crossing the Southern borders in Brazil.

HIV-related stigma and discrimination (S&D) have been shown to impede prevention, care and treatment. Yet, few quantitative studies have tested the associations between stigma, service utilization and status disclosure, especially in countries with concentrated HIV epidemics. Surveys, administered to a random sample of 1,775 truck drivers crossing Southern borders in Brazil, included items on multiple conceptual domains of S&D, such as fear of casual contact and blame towards people living with HIV/AIDS. Pearson's chi-square tests and logistic regression were used to examine correlations. Less stigma (both individual items and grouped as a scale) was significantly correlated with VCT use (p

Lack of effect of rifalazil on ethinyl estradiol pharmacokinetics in healthy postmenopausal women.

Rifalazil, a second-generation rifamycin, is being evaluated for the treatment of sexually transmitted disease and gastrointestinal infections. We determined whether rifalazil influences CYP3A4 metabolism by studying the effect of a single oral, 25 mg dose of rifalazil administered to healthy postmenopausal women, on the steady-state pharmacokinetics (PK) of ethinyl estradiol (EE) during administration of Ortho-Novum 1/35 (EE/NET). Noncompartmental PK and sequential statistical analyses were performed to establish if and when subjects achieved steady-state EE plasma concentrations and to determine whether this steady state was altered by rifalazil administration. The geometric mean ratios for the difference between EE alone and following rifalazil for EE Cmax, AUC(0-24) and Cmin were 105.9, 104.4 and 105.0, respectively. The 90% confidence intervals for each ratio fell within 80 - 125% of the reference treatment indicating no significant difference in the PK of EE before or after rifalazil administration. The posterior probabilities for the true treatment differences of Cmax or AUC(0-24) being less than 20% were > 99.99% in both cases. Based on the results of this study, there is no CYP3A4-metabolic interaction between a single oral, 25 mg dose of rifalazil and EE for either induction or inhibition. Consequently, there is minimal threat of contraceptive failure when single doses of rifalazil are administered with EE/NET. A single dose of rifalazil 25 mg was well tolerated when administered concomitantly with a combination oral contraceptive (EE/NET) by healthy postmenopausal females.

Effect of food on the pharmacokinetics of rifalazil, a novel antibacterial, in healthy male volunteers.

Rifalazil is a new antibiotic structurally related to rifampin but devoid of the metabolic liabilities typically associated with the rifamycin class of antibiotics. A randomized, 3-way crossover study in healthy male volunteers (n = 12) investigated the safety and pharmacokinetics of a single 25-mg oral rifalazil dose administered under a standard breakfast containing fat as 30% of calories, a high-fat breakfast containing fat as 60% of calories, and an overnight fast of 10 hours with a 21- to 28-day washout between doses. Systemic exposure to rifalazil based on Cmax, AUC(0-Tlast), and AUC(0-infinity) was increased progressively as the fat content of the test breakfast was increased from 30% to 60% compared with fasting. The confidence intervals for both fat-containing breakfasts are outside the limits of 80% to 125% allowed for food effect bioequivalence based on Cmax, AUC(0-Tlast), and AUC(0-infinity). This food effect may be a result of increased fractional absorption with increasing dietary fat content. Another striking finding was the large reduction of the pharmacokinetic intersubject variability after rifalazil administration with food. Rifalazil was safe and well tolerated under fed and fasted conditions.

Combined application of MH and TEM for conditioning treatment simultaneously triggers two protective functions against induction of chromatid aberrations in Vicia faba root tip meristem cells.

Conditioning pre-exposure of Vicia faba root tip meristem cells to triethylenemelamine (TEM) does not trigger an adaptive response to maleic hydrazide (MH) and vice versa. Since TEM conditioning treatment can induce protective effects (as evident from the yield of metaphases with chromatid aberrations) against TEM challenging treatment and MH conditioning can trigger an adaptive response to MH challenging treatment, two different protective functions are apparently triggered in dependence on the agent used for conditioning pre-exposure. When a mixture of TEM and MH is being used for conditioning treatment, adaptive responses to both TEM and MH can simultaneously be induced and significantly reduce the yield of metaphases with chromatid aberrations observed after challenge treatment with TEM or MH.

Inhibition of protein synthesis by cycloheximide does not prevent adaptive responses triggered by heavy metal salts in Vicia faba.

Copper sulfate, lead nitrate, and cadmium nitrate conditioning treatments of Vicia faba root tip meristem cells result in adaptive responses to triethylenemelamine (TEM)- and maleic hydrazide (MH)-induced genotoxic effects, i.e., they significantly reduce the yield of metaphases with chromatid aberrations. Contrary to adaptive responses triggered by low clastogen concentrations or heat shock, protective effects induced by heavy metals cannot be prevented by inhibition of protein synthesis and last for a much longer time span (up to at least 48 h). These and other data support the conclusion that the cells can react to the impact of external factors by various inducible functions which eventually protect their DNA from damage.

Low temperature between conditioning and challenge treatment prevents the 'adaptive response' of Vicia faba root tip meristem cells.

When the temperature during intertreatment time (2 h) between conditioning and challenge treatment of Vicia faba root tip meristems with either triethylenemelamine or maleic hydrazide was reduced from 24 degrees C to 12 degrees C no adaptive response occurred any more. The yield of metaphases with chromatid aberrations under these circumstances was similar to that observed after challenge treatment alone, i.e., no reduction occurred. This indicates that the metabolic state of the cells is of critical importance for the presence or absence of adaptive responses.

Involvement of phytochelatins in NiCl2-triggered protection against induction of chromatid aberrations by TEM and MH in Vicia faba root tip meristems?

Conditioning treatment of Vicia faba root tip meristem cells with NiCl2 prior to challenge treatment with triethylenemelamine (TEM) or maleic hydrazide (MH) triggered protective functions against both these clastogens, i.e., resulted in a significantly reduced yield of metaphases with chromatid aberrations. Protection was prevented by pretreatment with buthionine sulfoximine (BSI), an inhibitor of the synthesis of plant phytochelatins (PCs), indicating that the NiCl2-triggered PC synthesis may be involved in the protective functions induced by NiCl2 conditioning treatment. BSI (instead of NiCl2) conditioning treatment triggered protection against MH but not against TEM.

Heat shock protection against induction of chromatid aberrations is dependent on the time span between heat shock and clastogen treatment of Vicia faba root tip meristem cells.

Variation of the time span between heat shock (hs) and clastogen treatment of V. faba root tip meristems showed that hs protection is a very quick response (effective after less than 10 min) and lasting for up to 240 min in the case of induction of chromatid aberrations by maleic hydrazide (MH). Analogous protective responses are significantly slower and shorter when TEM is used for aberration induction. This, together with absence of 'clastogenic cross-adaptation' to these agents and differential effects of benzamide (BA, an inhibitor of poly-ADP-ribosylation) pretreatment before hs on hs protection, suggests that hs before clastogen treatment triggers at least 2 clastogen-specific, protective functions which eventually result in protection against these 2 clastogens.

Effects of novobiocin on heat shock protection against chromatid aberration induction by triethylenemelamine (TEM) and maleic hydrazide (MH) in Vicia faba.

Heat shock (10 min 40 degrees C) prior to challenge treatment with triethylenemelamine (TEM) or maleic hydrazide (MH) significantly reduced the frequency of induced chromatid aberrations in Vicia faba main root meristems. Novobiocin treatment before heat shock did not prevent heat shock protection against both clastogens; novobiocin application after heat shock prevented protective effects. These results and those obtained earlier for heat shock protection against X-ray challenge are used to discuss possible causes underlying the protective effects triggered by heat shock.

Induction of chromatid aberrations by TEM and maleic hydrazide is differently affected by pretreatment of Vicia faba root-tip meristems with methyl iodide.

Treatment of Vicia faba main root meristems with methyl iodide (MeI) 2 h before challenge treatment with triethylene melamine (TEM) significantly reduced the yield of metaphases with chromatid aberrations, i.e., resulted in clastogenic adaptation. Combined treatment with MeI and TEM increased the aberration yield; MeI treatment alone (10(-3) M, 0.5 h) was without clastogenic effect. No protective effects were observed after MeI pretreatment and challenge treatment by maleic hydrazide (MH). The data obtained in V. faba are compared to those previously reported for E. coli.

Effects of ethidium bromide and nalidixic acid pretreatment on the induction of chromatid aberrations by TEM and maleic hydrazide in Vicia faba main root meristems.

Pretreatment of Vicia faba main root meristems with ethidium bromide (EB) or nalidixic acid (NA) significantly reduced the yield of metaphases with chromatid aberrations induced by maleic hydrazide (MH), i.e., triggered clastogenic adaptation to MH. No such protection occurred when the alkylating agent triethylenemelamine (TEM) was used for challenge treatment. The differential response of pretreated cells to MH on the one hand (protection) and to TEM (no protection) on the other supports the conclusion that clastogenic adaptation is due to different inducible (repair?) functions, which eventually exert protection against clastogenic impacts.

On the toleration of duplications and deletions by the Vicia faba genome.

From eight pairs of crosses between differently reconstructed diploid karyotypes of Vicia faba, the progeny after selfing of plants heterozygous for both parental chromosome reconstructions were inspected for occurrence and transmission of duplications and deletions of defined chromosome segments, comprising together about one third of the metaphase genome length. The duplications and deletions studied involved either one or more chromosome segments of the respective karyotype (0.8%-9.1% of the metaphase length). They arose during meiosis in double heterozygotes by crossing over between partially homologous chromosomes or by mis-segregation from multivalents. While most duplications, provided they were not accompanied by deletions and in dependence on the segment involved, were viable and transmissible, even in homozygous state, deletions had lethal effects on gametes of both sexes.

Effects of benzamide pretreatment on clastogenic adaptation of Vicia faba root-tip meristem cells to triethylenemelamine (TEM) and maleic hydrazide (MH).

Clastogenic adaptation to TEM or MH no longer occurred when benzamide, an inhibitor of nuclear ADP-ribosyltransferase (ADPRT), was applied prior to the low dose (conditioning) treatment which triggers this phenomenon. This may be indicative that inducible processes connected with ribosylation reactions are involved in the protective effects exerted by clastogenic adaptation. No increase by benzamide pretreatment was observed in the yield of metaphases with TEM- or MH-induced chromatid aberrations after conditioning and challenge treatment, respectively. High benzamide concentrations (1 h, 5 X 10(-3) M) exerted protective effects against TEM challenging but not against MH.