Survival and Freedom From Reinterventions in Patients With Repaired Tetralogy of Fallot: Up to 42-Year Follow-Up of 917 Patients.

Background To evaluate long-term outcome of tetralogy of Fallot repair analyzing an unbiased country-wide surgically treated population with tetralogy of Fallot. Methods and Results Retrospective analysis of consecutive patients aged <18 years who underwent tetralogy of Fallot repair at a single nationwide pediatric cardiac center. Death from any cause and need for surgical or catheter reintervention were the study end points. Cox regression analysis was used to identify related risk factors. A total of 917 patients (male, 56.3%) were analyzed. Staged repair was performed in 16.9%. Early mortality (24/917, 2.62% patients) was confined to the early surgical eras. Late mortality was 4.5% (40/893 patients). Survival probability was 95.1%, 93.8% and 91.9% at 10, 20 and 30 years after repair, respectively. Early surgical era (P=0.013) and surgical/catheter reinterventions (P<0.001) were multivariable predictors of late death. A total of 487 reinterventions were performed after initial repair in 253/917 patients (27.6%), with pulmonary artery revalvulation (196/917 patients, 21.4%) being most frequent. Probability of freedom from first reintervention was 89.0%, 73.3%, and 55.1% at 10, 20, and 30 years after primary repair, respectively. Transannular repair was associated with the need for pulmonary artery revalvulation (P<0.001). Patients who underwent staged repair were more likely to need reinterventions on pulmonary arteries (P<0.001). Conclusions In an unbiased nationwide cohort, tetralogy of Fallot repair carried a favorable survival of >90% at 30 years. Each reintervention significantly incrementally increased the risk of mortality. Type of initial repair predicted the need for specific surgical or catheter reinterventions.

Baseline reticular basement membrane morphology is related to subsequent spirometry deterioration in pediatric chronic airway inflammation: a follow-up study.

Reticular basement membrane (RBM) thickening may occur in children with allergic bronchial asthma (BA), cystic fibrosis (CF), and primary ciliary dyskinesia (PCD). Its functional consequences remain unknown. We investigated the relationship between baseline RBM thickness and subsequent spirometry. In our cohort follow-up study, patients aged 3-18 yr with BA, CF, and PCD and controls underwent baseline lung clearance index (LCI) measurement, spirometry, and endobronchial biopsy sampling. Total RBM and collagen IV-positive layer thickness were measured. Trends in forced vital capacity (FVC), forced expired volume in 1 s (FEV1), and FEV1/FVC were analyzed during follow-up, and their relationship to baseline characteristics was studied using univariate analysis and multiple regression models. Complete baseline data were available in 19 patients with BA, 30 patients with CF, 25 patients with PCD, and 19 controls. The RBM was thicker in patients with BA (6.33 ± 1.22 µm), CF (5.60 ± 1.39 µm), and PCD (6.50 ± 1.87 µm) than in controls (3.29 ± 0.55 µm) (all P < 0.001). The LCI was higher in patients with CF (15.32 ± 4.58, P < 0.001) and PCD (10.97 ± 2.46, P = 0.002) than in controls (7.44 ± 0.43). The median follow-up times were 3.6, 4.8, 5.7, and 1.9 years in patients with BA, CF, PCD, and controls, respectively. The z-scores of FEV1 and FEV1/FVC deteriorated significantly in all groups except in controls. In patients with CF and PCD, trends in FEV1 z-scores correlated with baseline LCI and RBM; in BA, it correlated with collagen IV. In multiple regression models, RBM morphology and ventilation inhomogeneity could predict up to 84.4% of variability in spirometry trends. In conclusion, baseline LCI value and RBM morphology may predict trends in subsequent spirometry.NEW & NOTEWORTHY This paper deals with the relationship between reticular basement membrane (RBM) morphology at baseline and follow-up spirometry in children with asthma, cystic fibrosis, and primary ciliary dyskinesia. For the first time, to our knowledge, the possibility to predict subsequent lung function development using selected baseline characteristics (reticular basement membrane morphology from endobronchial biopsy and ventilation inhomogeneity from nitrogen multiple breath washout test) is proposed. Corresponding predictive models are presented.

Structural Integrity and Cellular Viability of Cryopreserved Allograft Heart Valves in Right Ventricular Outflow Tract Reconstruction: Correlation of Histopathological Changes with Donor Characteristics and Preservation Times

Abstract Introduction: Cryopreserved allograft heart valves (CAHV) show longer event-free survival compared to other types of protheses. However, all patients develop early and/or late allograft failure. Negative predictors are clinical, and there is a lack of evidence whether they correspond with the microscopic structure of CAHV. We assessed histopathological signs of structural degeneration, degree of cellular preservation, and presence of antigen-presenting cells (APC) in CAHV and correlated the changes with donor clinical characteristics, cryopreservation times, and CAHV types and diameters. Methods: Fifty-seven CAHV (48 pulmonary, nine aortic) used for transplantation between November/2017 and May/2019 were included. Donor variables were age, gender, blood group, height, weight, and body surface area (BSA). Types and diameters of CAHV, cold ischemia time, period from decontamination to cryopreservation, and cryopreservation time were recorded. During surgery, arterial wall (n=56) and valvar cusp (n=20) samples were obtained from the CAHV and subjected to microscopy. Microscopic structure was assessed using basic staining methods and immunohistochemistry (IHC). Results: Most of the samples showed signs of degeneration, usually of mild degree, and markedly reduced cellular preservation, more pronounced in aortic CAHV, correlating with arterial APC counts in both basic staining and IHC. There was also a correlation between the degree of degeneration of arterial samples and age, height, weight, and BSA of the donors. These findings were independent of preservation times. Conclusion: CAHV show markedly reduced cellular preservation negatively correlating with the numbers of APC. More preserved CAHV may be therefore prone to stronger immune rejection.

Repeatability of lung clearance index in infants with cystic fibrosis and recurrent wheeze.

OBJECTIVES: To describe the short- and medium-term repeatability of lung clearance index at 2.5% (LCI2.5 ) in infants and calculate the number of patients needed to enroll in a study (N) using LCI2.5 as a primary outcome. METHODS: An 8-month follow-up observational study was employed for assessing short-term [coefficient of repeatability (CR) and intraclass correlation (ICC)] and medium-term repeatability (Bland-Altman method) of LCI2.5 in infants with cystic fibrosis (CF) or recurrent wheeze (RW) measured by the nitrogen multiple-breath washout test (N2 -MBW). Using these variability data, the N to reach 90% test power at the level of statistical significance (0.05) was calculated. RESULTS: Forty infants with CF and 21 with RW were enrolled. Initial N2 -MBW testing was successful in 33 and 17 patients, respectively. Follow-up data were available for 23 and 11 infants, respectively. Short-term repeatability of LCI2.5 was high (CR = 1.10 and 1.04 in CF and RW patients, respectively; ICC = 0.88 and 0.83 in CF and RW patients, respectively). The between-subject standard deviation was <13% of the actual LCI2.5 value. In clinically stable patients, LCI2.5 did not significantly change during the 8-month follow-up. Mean LCI2.5 change was -0.08 (1% of baseline) in CF and -0.05 (0.6%) in RW, with 95% limits of agreement being (-1.70; 1.53) in CF and (-1.51; 1.40) in RW patients. N = 23 infants if both intragroup differences of LCI2.5 and minimal difference to be detected would be 2.0. CONCLUSION: N2 -MBW may be a reproducible tool with reasonable test power to detect differences in infant studies.

Structural Integrity and Cellular Viability of Cryopreserved Allograft Heart Valves in Right Ventricular Outflow Tract Reconstruction: Correlation of Histopathological Changes with Donor Characteristics and Preservation Times.

INTRODUCTION: Cryopreserved allograft heart valves (CAHV) show longer event-free survival compared to other types of protheses. However, all patients develop early and/or late allograft failure. Negative predictors are clinical, and there is a lack of evidence whether they correspond with the microscopic structure of CAHV. We assessed histopathological signs of structural degeneration, degree of cellular preservation, and presence of antigen-presenting cells (APC) in CAHV and correlated the changes with donor clinical characteristics, cryopreservation times, and CAHV types and diameters. METHODS: Fifty-seven CAHV (48 pulmonary, nine aortic) used for transplantation between November/2017 and May/2019 were included. Donor variables were age, gender, blood group, height, weight, and body surface area (BSA). Types and diameters of CAHV, cold ischemia time, period from decontamination to cryopreservation, and cryopreservation time were recorded. During surgery, arterial wall (n=56) and valvar cusp (n=20) samples were obtained from the CAHV and subjected to microscopy. Microscopic structure was assessed using basic staining methods and immunohistochemistry (IHC). RESULTS: Most of the samples showed signs of degeneration, usually of mild degree, and markedly reduced cellular preservation, more pronounced in aortic CAHV, correlating with arterial APC counts in both basic staining and IHC. There was also a correlation between the degree of degeneration of arterial samples and age, height, weight, and BSA of the donors. These findings were independent of preservation times. CONCLUSION: CAHV show markedly reduced cellular preservation negatively correlating with the numbers of APC. More preserved CAHV may be therefore prone to stronger immune rejection.

Demographic and public health characteristics explain large part of variability in COVID-19 mortality across countries.

BACKGROUND: The numbers of coronavirus disease 2019 (COVID-19) deaths per million people differ widely across countries. Often, the causal effects of interventions taken by authorities are unjustifiably concluded based on the comparison of pure mortalities in countries where interventions consisting different strategies have been taken. Moreover, the possible effects of other factors are only rarely considered. METHODS: We used data from open databases (European Centre for Disease Prevention and Control, World Bank Open Data, The BCG World Atlas) and publications to develop a model that could largely explain the differences in cumulative mortality between countries using non-interventional (mostly socio-demographic) factors. RESULTS: Statistically significant associations with the logarithmic COVID-19 mortality were found with the following: proportion of people aged 80 years and above, population density, proportion of urban population, gross domestic product, number of hospital beds per population, average temperature in March and incidence of tuberculosis. The final model could explain 67% of the variability. This finding could also be interpreted as follows: less than a third of the variability in logarithmic mortality differences could be modified by diverse non-pharmaceutical interventions ranging from case isolation to comprehensive measures, constituting case isolation, social distancing of the entire population and closure of schools and borders. CONCLUSIONS: In particular countries, the number of people who will die from COVID-19 is largely given by factors that cannot be drastically changed as an immediate reaction to the pandemic and authorities should focus on modifiable variables, e.g. the number of hospital beds.

Cadmium contents of vertically and horizontally deposited winter precipitation in Central Europe: Spatial distribution and long-term trends.

Cadmium (Cd) and its forms has recently been a focus of attention due to its toxic effects on human health and the environment. We evaluated the atmospheric deposition of Cd during three consecutive winter seasons (2009-2011) at 10 mountain-top locations in the Czech Republic along the borders with Poland, Germany, Austria and Slovakia. Cadmium concentrations of soluble and insoluble forms in both horizontal (rime) and vertical (snow) deposition were determined using sector-field ICP-MS. Across the sites, 94% of the total winter Cd deposition occurred in the soluble (environmentally available) Cd form. Mean concentrations of soluble Cd in rime were six times higher than in snow (398 vs. 66 ng L-1). Vertical deposition contributed as much as 41% to the total winter Cd input. Between-site variability in Cd deposition was large, ranging between 13 and 108 µg m-2 winter-1. Overall, Cd concentrations in winter deposition did not reach the drinking water limits and did not pose a direct threat for human health. Long-term trends (1996-2017) in winter Cd deposition were evaluated at six GEOMON sites (a monitoring network of small forested catchments). Since 1996, Cd input in winter atmospheric deposition decreased by 73-93%. Simultaneously, we found declines in between-site variability in winter Cd inputs. The highest recent winter Cd inputs were found at sites located in the northeast of the country. A north-south pollution gradient, which has frequently been mentioned in the literature, was not observed, with both northwestern sites and southern sites being among those with the lowest Cd pollution. Backward trajectories of the HYSPLIT model for fresh snow samples identified Poland and Germany as major transboundary Cd pollution sources for the Czech Republic.

Personalized risk-based screening for diabetic retinopathy: A multivariate approach versus the use of stratification rules.

AIMS: To evaluate our proposed multivariate approach to identify patients who will develop sight-threatening diabetic retinopathy (STDR) within a 1-year screen interval, and explore the impact of simple stratification rules on prediction. MATERIALS AND METHODS: A 7-year dataset (2009-2016) from people with diabetes (PWD) was analysed using a novel multivariate longitudinal discriminant approach. Level of diabetic retinopathy, assessed from routine digital screening photographs of both eyes, was jointly modelled using clinical data collected over time. Simple stratification rules based on retinopathy level were also applied and compared with the multivariate discriminant approach. RESULTS: Data from 13 103 PWD (49 520 screening episodes) were analysed. The multivariate approach accurately predicted whether patients developed STDR or not within 1 year from the time of prediction in 84.0% of patients (95% confidence interval [CI] 80.4-89.7), compared with 56.7% (95% CI 55.5-58.0) and 79.7% (95% CI 78.8-80.6) achieved by the two stratification rules. While the stratification rules detected up to 95.2% (95% CI 92.2-97.6) of the STDR cases (sensitivity) only 55.6% (95% CI 54.5-56.7) of patients who did not develop STDR were correctly identified (specificity), compared with 85.4% (95% CI 80.4-89.7%) and 84.0% (95% CI 80.7-87.6%), respectively, achieved by the multivariate risk model. CONCLUSIONS: Accurate prediction of progression to STDR in PWD can be achieved using a multivariate risk model whilst also maintaining desirable specificity. While simple stratification rules can achieve good levels of sensitivity, the present study indicates that their lower specificity (high false-positive rate) would therefore necessitate a greater frequency of eye examinations.

Shout-It-Now: A Mobile HCT Model Employing Technology and Edutainment in South Africa.

BACKGROUND: Mobile HIV counseling and testing (HCT) has been effective in reaching men, women, and adolescents in South Africa. However, there is limited understanding of effective mobile HCT programs utilizing tools like technology and edutainment to increase HIV counseling and testing rates. The authors examine data from the Shout-It-Now (S-N) program that uses such tools in South Africa. METHODS: The S-N program utilizes various forms of technology and ongoing telephonic counseling within a 6-step program of HIV testing and linkage-to-care support, and program data were analyzed over an 18-month period. Data were analyzed from women, men, and adolescent program participants. Summative statistics was conducted on participant registration, HIV risk assessment, and HIV testing profiles. HIV prevalence were estimated along with the related 95% confidence intervals using the Clopper-Pearson method. RESULTS: Over an 18-month period, there were 72 220 program participants with high representation of men, women, and adolescents and 40% of the participants being men at each site. There were 3343 participants who tested HIV positive, and a higher proportion of women tested positive. DISCUSSION: Integrating technology, quality assurance measures, and edutainment with mobile HCT has the potential to increase the number of those who test within communities. Research is needed to understand the effectiveness of this model in facilitating regular testing and linkage to care.

Infliximab trough levels may predict sustained response to infliximab in patients with Crohn's disease.

BACKGROUND AND AIMS: Over 10% of Crohn's disease (CD) patients annually lose response to infliximab. Infliximab trough levels (TL), concomitant immunosuppressants and endoscopic healing were proposed as predictors of favourable infliximab outcome. We assessed infliximab TL measured after induction therapy as predictors of sustained clinical response. Furthermore, we tried to identify other predictors of long-term benefit of infliximab therapy. METHODS: We included CD patients treated with infliximab between October 2007 and March 2010 who responded to 3-dose induction followed by maintenance therapy and in whom blood samples taken at treatment week 14 or 22 were available in blood bank. Sustained response to infliximab was defined as absence of treatment failure due to loss of response or drug intolerance. RESULTS: Eighty four patients were included. Sustained response to infliximab was observed in 47 (56%) patients during a median follow-up of 25 months (14-37). Infliximab TL>3µg/ml were associated with a decreased risk of treatment failure (HR 0.34; 95% CI: 0.16-0.75), whereas the presence of antibodies against infliximab and need for corticosteroids increased this risk (HR 4.34; 95% CI: 1.51-12.5 and HR 2.49, 95% CI: 1.08-5.73, respectively). No impact of concomitant thiopurines was observed, although patients receiving thiopurines had higher infliximab TL than those without immunomodulators (5.51 vs. 0.71µg/ml; p=0.01). CONCLUSION: During a median follow up of 2 years sustained response to infliximab was observed in slightly more than half of CD patients. Infliximab TL>3µg/ml at the start of maintenance regime were predicative of sustained response to infliximab.

Atmospheric deposition of beryllium in Central Europe: comparison of soluble and insoluble fractions in rime and snow across a pollution gradient.

Little is known about atmospheric input of beryllium (Be) into ecosystems, despite its highly toxic behavior. For three consecutive winters (2009-2011), we measured Be concentrations in horizontal deposition (rime) and vertical deposition (snow) at 10 remote mountain-top locations in the Czech Republic, Central Europe. Beryllium was determined both in filtered waters, and in HF digests of insoluble particles. Across the sites, soluble Be concentrations in rime were 7 times higher, compared to snow (6.1 vs. 0.9ng·L(-1)). Rime scavenged the pollution-rich lower segments of clouds. The lowest Be concentrations were detected in the soluble fraction of snow. Across the sites, 34% of total Be deposition occurred in the form of soluble (bioavailable) Be, the rest were insoluble particles. Beryllium fluxes decreased in the order: vertical dry deposition insoluble>vertical dry deposition soluble>horizontal deposition soluble>vertical wet deposition insoluble>vertical wet deposition soluble>horizontal deposition insoluble. The average contributions of these Be forms to total deposition were 56, 21, 8, 7, 5 and 3%, respectively. Sites in the northeast were more Be-polluted than the rest of the country with sources of pollution in industrial Silesia.

Impact of local and systemic factors on the incidence of late oral implant loss.

BACKGROUND: This retrospective study was set to assess the influence of systemic and local bone and intra-oral factors on the occurrence of implant loss from abutment connection up to 2 years. MATERIALS AND METHODS: The files of 700 patients, have been collected randomly from the total patient group treated by means of endosseous Brånemark system implants (Nobel Biocare, Gothenburg, Sweden) at the Department of Periodontology of the University Hospital of the Catholic University of Leuven. The end point observation was evaluating the loss of the implants 2 years after abutment installation. The study involved all implants that did not encounter early loss and implants for which it was possible to evaluate its status 2 years after abutment surgery. Thus, data of 412 patients (240 females) provided with 1514 implants were analyzed. For each patient, the medical history was carefully checked. Data collection and analysis were mainly focused on endogenous factors such as hypertension, coagulation problems, osteoporosis, hypo- hyperthyroidism, chemotherapy, diabetes type I or II, Crohn's disease, some local factors [e.g. bone quality and quantity, implant (length, diameter, location), type of edentulism, PTV, radiotherapy], smoking habits, and breach of sterility during surgery. RESULTS: Radiotherapy, implant (diameter and location), and higher PTV at implant insertion and abutment connection, all affected significantly the implant loss. CONCLUSION: Implant location in the oral cavity and radiotherapy seem predominant to explain the occurrence of implant loss. On the other hand, smoking and systemic health factors do not seem to be prominent players in the etiology of late implant loss.

Impact of local and systemic factors on the incidence of failures up to abutment connection with modified surface oral implants.

AIM: This study aimed to assess the influence of systemic and local bone and intra-oral factors on the occurrence of early TiUnite implant failures. MATERIAL AND METHODS: A total of 283 consecutive patients (187 females; mean age 56.2), who received a total of 720 TiUnite implants, at the Department of Periodontology of the University Hospital of the Catholic University of Leuven, were prospectively followed. The following aspects were particularly assessed: hypertension, cardiac problems, gastric problems, osteoporosis, hypo- or hyperthyroid, hypercholesterolaemia, asthma, diabetes types I or II, Crohn's disease, rheumatoid arthritis, chemotherapy, hysterectomy and intake of medication (antidepressants, steroids, hormone replacement), radiotherapy of the concerned area, breach of sterility during surgery, implant parameters, bone (quality, quantity, dehiscence or perforation), type of edentulism, antibiotics prescription, fenestration of the implant in the sinus/nasal cavity, immediate implant placement, apical lesion detection and insertion torque. RESULTS AND CONCLUSION: A global failure rate of 1.9% was recorded. Owing to the very few failures, no definitive conclusion concerning statistical significance can be achieved. However, a tendency for more failures was noticed for apical lesions, vicinity with natural dentition, smoking, hormone replacement, gastric problems, Crohn's disease, diabetes I and radical hysterectomy.

Baseline and treatment effect heterogeneity for survival times between centers using a random effects accelerated failure time model with flexible error distribution.

Nowadays, most clinical trials are conducted in different centers and even in different countries. In most multi-center studies, the primary analysis assumes that the treatment effect is constant over centers. However, it is also recommended to perform an exploratory analysis to highlight possible center by treatment interaction, especially when several countries are involved. We propose in this paper an exploratory Bayesian approach to quantify this interaction in the context of survival data. To this end we used and generalized a random effects accelerated failure time model. The generalization consists in using a penalized Gaussian mixture as an error distribution on top of multivariate random effects that are assumed to follow a normal distribution. For computational convenience, the computations are based on Markov chain Monte Carlo techniques. The proposed method is illustrated on the disease-free survival times of early breast cancer patients collected in the EORTC trial 10854.

Impact of local and systemic factors on the incidence of oral implant failures, up to abutment connection.

AIM: The aim of this retrospective study was to assess the influence of systemic and local bone and intra-oral factors on the occurrence of early implant failures, i.e. up to the abutment connection. MATERIAL AND METHODS: The surgical records of 2004 consecutive patients from the total patient population who had been treated in the period 1982-2003 (with a total of 6946 Brånemark system implants) at the Department of Periodontology of the Catholic University Leuven were evaluated. For each patient the medical history was carefully checked. Data collection and analysis mainly focused on endogenous factors such as hypertension, coagulation problems, osteoporosis, hypo-hyperthyroidy, chemotherapy, diabetes type I or II, Crohn's disease, some local factors [e.g. bone quality and quantity, implant (length, diameter, location), type of edentulism, Periotest value at implant insertion, radiotherapy], smoking habits and breach of sterility during surgery. RESULTS: A global failure rate of 3.6% was recorded. Osteoporosis, Crohn's disease, smoking habits, implant (length, diameter and location) and vicinity with the natural dentition were all significantly associated with early implant failures (p<0.05). CONCLUSION: The indication for the use of oral implants should sometimes be reconsidered when alternative prosthetic treatments are available in the presence of possibly interfering systemic or local factors.

Factors influencing the survival of cryopreserved homografts. The second homograft performs as well as the first.

OBJECTIVE: To determine the life span of cryopreserved homografts implanted in the right ventricular outflow tract and the factors influencing it. METHODS: From 1989 through 2003, we reconstructed the pulmonary valve with 301 homografts in 272 patients (median age 13 years; range 4 days-69 years). Indications were tetralogy of Fallot (136), truncus (23), Rastelli repair (11), double outlet ventricle (13), endocarditis (5), and the Ross operation (84). Median follow-up was 5.7 years (range 0-14). We analyzed possible predictors of graft replacement by simple and multiple Cox regression. RESULTS: Actuarial survival was 96+/-1.2% at 1, 95+/-1.4% at 5, and 94+/-1.5% at 10 years follow-up. Three homografts were explanted because of endocarditis (excluded from the analysis). Freedom from explantation was 99.6+/-0.4% at 1, 94.5+/-1.7% at 5, and 81.8+/-4.1% at 10 years. Variables, significantly related to explantation in the univariate analysis, were younger age, small graft size, implantation in a non-anatomical position, the aortic donor homograft, a shorter aortic cross-clamp time and the implantation of a second homograft. In the multiple model, non-anatomical position (P=0.001), smaller graft size (P<0.0001) or younger age (on square root scale, P<0.0001) and clamp time (P=0.01) remain as independent risk factors. Immunological variables, like blood group incompatibility, implantation of a second homograft and short warm ischemic time were not significant. CONCLUSIONS: The life span of a cryopreserved homograft is determined by graft size (correlates with age) and the non-anatomic position (correlates with indication). In a specific patient, the second homograft performs as well as the first.