Background/Objectives: There is an increasing need for cross-sectional imaging in pediatric patients with congenital heart disease. This patient group is highly sensitive to ionizing radiation. The purpose of this article was to evaluate differences in radiation dose and image quality between a first-generation photon-counting (PC)-CT system and a 256-slice single-source energy-integrating detector (EID)-CT in these patients. Methods: We retrospectively assessed effective dose, CT dose index-volume (CTDIvol), dose length product (DLP), and image quality of all prospectively electrocardiography-gated CTs of the thorax in all patients < 18 years of age examined between February 2021 and August 2024 (n = 43). Two independent observers subjectively scored image quality, vascular contrast, and noise on a 5-point Likert scale. In addition, we assessed the signal-to-noise-ratio (SNR) and contrast-to-noise-ratio (CNR) quantitatively. Results: All dose parameters were significantly lower in the PC-CT (n = 27) versus the EID-CT (n = 16) group (mean effective dose: 0.8 ± 0.64 versus 2.2 ± 0.88 mSv, p < 0.001; mean CTDIvol: 1.22 ± 0.96 versus 4.8 ± 1.08 mGy, p < 0.001; mean DLP: 30.7 ± 31.9 versus 73.7 ± 50.7 mGy*cm, p < 0.001). Overall subjective image quality and contrast were rated higher in the PC-CT group (p = 0.046 and < 0.001, respectively). Quantitative CNR was significantly higher in the PC-CT group (mean 39.1 ± 12.9 versus 26.2 ± 10.8, p = 0.002). Conclusions: PC-CT enables high-quality examinations for the evaluation of congenital heart disease with a highly significant dose reduction compared with a 256-slice single-source EID-CT.

Objective Cardiac echinococcosis is rare and associated with a high risk of rupture, systemic embolization, and anaphylaxis. We present a technique-focused case of contamination-controlled surgical cystectomy of an intramyocardial hydatid cyst of the left ventricle with ventricular wall reconstruction. Methods A 17-year-old male with a large intramyocardial cystic lesion underwent median sternotomy and cardiopulmonary bypass. The cyst was localized using epimyocardial ultrasound. Staged hypertonic saline–based field isolation was applied to prevent contamination. Ultrasound-guided puncture, aspiration, scolicidal inactivation, controlled cyst opening under continuous suction, and careful extraction of the parasitic membrane were performed. Ventricular wall reconstruction was achieved using pledget-reinforced sutures and over-sewing. Results The procedure was completed without intraoperative rupture or contamination. Histopathology and microbiology confirmed echinococcosis. Postoperative imaging showed no residual parasitic disease. Early postoperative ventricular dysfunction improved clinically under medical therapy. Conclusions Contamination-controlled cystectomy with structured ventricular reconstruction is a reproducible and safe strategy for intramyocardial hydatid cysts.

Mucopolysaccharidosis II is a rare, X-linked disease, with very few reports of affected female patients. Natural history data describe a predominantly male population, and appropriate disease characterization in female patients is lacking. This analysis explores the somatic disease burden and clinical progression of female patients with MPS II enrolled in the Hunter Outcome Survey (HOS; NCT03292887), a global disease registry. In total, 15 female patients were identified, representing 1.1% of the total patients in HOS. The median ages at first symptom onset and diagnosis were 1.8 and 3.1 years, respectively. A total of 8/14 (57.1%) of patients had cognitive impairment at the latest visit. X-chromosome abnormalities were reported in two patients. Most patients (11/15, 73.3%) had received at least one dose of idursulfase, which was generally well tolerated; no serious adverse events during follow-up were considered treatment-related. Musculoskeletal and ear symptoms were present in all 14 patients with data recorded. Almost all females also experienced neurological, abdominal/gastrointestinal, and pulmonary disease, similar to the symptomatology reported in males. Most patients underwent surgery (41 procedures in 12 patients). Two participants had a male sibling with MPS II who was also enrolled in HOS. Both sibling sets had missense variants and demonstrated several differences in signs/symptoms between the male and female siblings. Notably, only the female siblings displayed cognitive impairment. This report illustrates the disease burden in female patients with MPS II, helping to inform clinicians about the likely prognosis for this extremely rare subgroup of patients.

BACKGROUND:Mucopolysaccharidosis II (MPS II) is a rare, progressive, X-linked lysosomal storage disease. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase has been approved for the treatment of patients with MPS II since 2005. The Hunter Outcome Survey (HOS; NCT03292887) was established as a condition of approval to monitor the long-term safety and effectiveness of idursulfase. Here, we report the final results from HOS. METHODS:HOS was a multicenter, long-term, observational registry that enrolled patients with a biochemically and/or genetically confirmed diagnosis of MPS II who were untreated or treated with idursulfase and/or bone marrow transplant. Patients were enrolled prospectively (alive at enrollment) and retrospectively (deceased at enrollment). For prospectively enrolled patients, it was requested that data from routine examinations were recorded after each follow-up visit and/or a minimum of every 6 months. The safety population (SP) included patients who received at least one dose of idursulfase and were alive at HOS entry. The treatment outcomes population (TOP) included patients who received at least one dose of idursulfase and were alive at HOS entry, excluding patients who received a bone marrow transplant, patients for whom an informed consent form could not be generated by the center, and patients with a missing date of birth. Safety and effectiveness endpoints were analyzed with descriptive statistics. RESULTS:In total, 1332 patients were enrolled in HOS. For patients in the SP (N = 1014), the median (10th percentile, 90th percentile) age at initiation of ERT with idursulfase was 5.7 (1.6, 18.1) years, ranging from 0.0 to 65.5 years. In the TOP (N = 989), a consistent and sustained decline in urinary glycosaminoglycan levels, trends of sustained improvements in walking capacity and left ventricular mass index, and reductions in liver and spleen size were observed. Treated patients also demonstrated a median increase in survival time of approximately 10 years and a 57.9 % lower risk of death compared with an unmatched cohort of untreated patients. In the SP, 691 patients (68.1 %) experienced at least one adverse event and 269 (26.5 %) experienced at least one infusion-related reaction (IRR); most were mild or moderate in severity. There was no relationship observed between anti-drug antibody status and IRR rates. CONCLUSION:Data from HOS, collected for over 18 years, represent the largest dataset of patients with MPS II to date. The effectiveness and safety profile of idursulfase support its use for the long-term treatment of patients with MPS II.

IntroductionPercutaneous balloon valvuloplasty is the treatment of choice for critical pulmonary valve stenosis (CPS) and pulmonary valve atresia with intact ventricular septum (PA/IVS) if the ventricle has a suitable size. This study aimed to evaluate the long-term outcomes and predictors for surgical intervention and pulmonary valve replacement in patients with CPS or with PA/IVS after PBV, considering different morphological and hemodynamic parameters.MethodsNeonates with PA/IVS or CPS who were admitted to the University Medicine Mainz and University Hospital Erlangen between November 1994 and March 2013 and underwent successful PBV as an initial procedure, with a follow-up of at least 5 years (median 13.1 years), were included. The Z-scores of pulmonary valve diameter, balloon/annulus ratio, number of cusps, and persisting stenosis were analyzed. The endpoint was the need for surgical procedures or valve replacement.ResultsA total of 62 neonates (median age at intervention 5 days) were included. Among them, 15 patients (24.2%) reached the endpoint. The mean time of freedom from surgery differed according to the number of cusps (P < 0.001), pulmonary valve diameter Z-scores (P = 0.04), and degree of persisting stenosis (P = 0.008), but did not differ according to the balloon/annulus ratio (≤1.2 vs. >1.2).ConclusionPulmonary valve perforation and PBV achieved favorable long-term outcomes in neonates with PA/IVS and CPS. A small pulmonary valve diameter, reduced number of cusps, and persisting gradient of >40 mmHg increased the risk for reduced time of freedom from surgical intervention and/or pulmonary valve replacement.

Background:Analyses of up to 20 years of data from the Fabry Outcome Survey (FOS) assessed the long-term effectiveness of agalsidase alfa enzyme replacement therapy. Methods:The impact of agalsidase alfa treatment on renal, cardiac, morbidity, and mortality outcomes in FOS was compared with untreated external Fabry disease (FD) cohorts. Results:A total of 2171 FOS patients (1014 men, 919 women, 163 boys, 75 girls) received agalsidase alfa (median [range] duration of treatment: 5.38 [0.0-20.8] years). Annual rates of decline in estimated glomerular filtration rate improved in treated patients versus untreated external cohorts regardless of sex or baseline urinary protein levels. Annual left ventricular mass index rates were stable in treated patients regardless of sex or baseline left ventricular hypertrophy status, and better than in untreated external cohorts. The mean age at which 50 % of patients had their first composite morbidity event was later in the agalsidase-alfa-treated population than in the untreated external cohort (51.7 vs 41 years [males]; 60.8 vs 53 years [females]). After 24 months of treatment, the probability of a composite morbidity event was ∼34 % in treated patients and ∼ 45 % in untreated patients. Treated patients were older at death than untreated patients (mean [range]: 61.7 [26.2-87.6] vs 50.3 [34.5-70.1] years). The mean age at which 50 % of male patients were still alive was higher in treated patients than in untreated external cohorts (75.5 vs 60.0 years). Conclusions:Long-term treatment with agalsidase alfa may provide renal, cardiac, and overall survival protection in FD.

BACKGROUND:We present the final report from the Fabry Outcome Survey (FOS) on long-term effectiveness and safety of agalsidase alfa in adults (≥18 years old). METHODS:FOS was an international, multicentre, observational registry (NCT03289065), designed to enhance the understanding of Fabry disease and improve clinical management. Primary effectiveness endpoints were annualized change in estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI), and time to and age at composite morbidity event (comprising renal, cardiac or stroke events) and death. Safety outcomes were also assessed. RESULTS:FOS included data for 1864 adults (female/male, n = 907/957) who received agalsidase alfa only for a median (minimum, maximum) of 6.0 (0, 21.6) years, and 1613 untreated adults (female/male, n = 1235/378). At baseline, mean (standard deviation [SD]) eGFR was 94.01 (27.60) mL/min/1.73 m2 in treated adults; annualized changes in eGFR (slope [standard error; SE]) remained relatively stable in females and declined slightly in males (-1.07 [.12] vs. -2.17 [.12] mL/min/1.73 m2). At baseline, mean (SD) LVMI was 58.25 (25.01) g/m2.7 and LVMI (slope [SE]) remained stable (.34 [.16] vs. .38 [.15] g/m2.7/year in females and males, respectively). Time (median [95% confidence interval]) from treatment initiation to first composite event was longer for females than males (83.4 [65.7-98.0] vs. 56.3 [45.6-66.7] months); age (median [minimum, maximum]) at death was also higher for treated females than males (69.9 [32.5, 87.7] vs. 59.1 [26.2, 79.6] years). Agalsidase alfa was generally well tolerated. CONCLUSIONS:This report further supports the long-term effectiveness and safety of agalsidase alfa in adults with Fabry disease.

Mucopolysaccharidosis (MPS) encompasses a group of genetic lysosomal storage disorders, linked to reduced life expectancy and a significant lack of effective treatment options. Immunomodulatory drugs could have the potential to be a relevant medical approach, as the accumulation of undegraded substances initiates an innate immune response, which leads to inflammation and clinical deterioration. However, immunomodulators are not licensed for this indication. Consequently, we aim to provide evidence advocating fast access to innovative individual treatment trials (ITTs) with immunomodulatory drugs and high-quality evaluation of drug effects by implementing a risk-benefit model tailored for MPS. The iterative methodology of our novel decision analysis framework (DAF) involves three key steps: (i) literature review on promising treatment targets and immunomodulators in MPS; (ii) quantitative risk-benefit assessment (RBA) of selected molecules; (iii) assigning phenotypic profiles and quantitative evaluations. The results facilitate a personalized application of the model and are based on published evidence as well as interdisciplinary experts' consensus and patient perspectives. Four promising immunomodulators have been identified: adalimumab, abatacept, anakinra, and cladribine. An improvement in mobility is most likely with adalimumab, while anakinra is anticipated as a treatment of choice for neuronopathic MPS patients. Nevertheless, a comprehensive RBA should always be completed on an individual basis. Our evidence-based DAF tool for ITTs directly addresses the substantial unmet medical need in MPS and characterizes an initial stride toward precision medicine with immunomodulators.

Hintergrund Die Systemische Sklerodermie (SSc) im Kindesalter ist bei einer Inzidenz von ungefähr 3 Patienten pro 10 Mio. Kinder eine sehr seltene Erkrankung. Die kardiopulmonale Beteiligung findet sich bei 45% der Patienten. Diese interstitielle Lungenerkrankung kann mit zunehmender Fibrose zur pulmonalen Hypertension mit sekundärer Rechtsherzbelastung führen; die häufigste letale Komplikation dieser Erkrankung. Diese Symptome können vor einer Hautmanifestation auftreten. Wir möchten den Fall einer 11-jährigen Patientin mit SSc präsentieren.

Objectives: To evaluate correlations between cardiac magnetic resonance imaging (cMRI) at rest including strain imaging and variables derived from quantitative cardiopulmonary exercise testing using a treadmill in patients with pectus excavatum. Methods: We retrospectively correlated the results of cMRI and cardiopulmonary exercise testing in 17 patients with pectus excavatum, in whom both examinations were performed during their pre-operative clinical evaluation. In addition to cardiac volumetry, we assessed the strain rates of both ventricles using a feature-tracking algorithm of a piece of commercially available post-processing software. Results: Right ventricular (RV) ejection fraction correlated negatively with heart rate at anaerobic threshold (rho = −0.543, p = 0.024). A positive correlation between radial strain rate at the RV base and percentage of predicted maximum heart rate (rho = 0.72, p = 0.001) was shown, with equivalent results for circumferential strain rate (rho = −0.64, p = 0.005). Radial strain rate at the RV base correlated in a strongly negative way with maximum oxygen uptake (rho = −0.8, p < 0.001), with a correspondingly positive correlation for circumferential strain rate (rho = 0.73, p = 0.001). Conclusions: Quantitative parameters derived from cMRI at rest, especially those acquired at the most severely compressed RV base, correlated with cardiopulmonary exercise testing variables. The compression of the RV base by the sternum might be partially compensated by an increased strain rate to induce higher heart frequencies during exercise. However, high strain rates were associated with a higher disease severity and a lower maximum oxygen uptake, indicating a limitation of this compensation mechanism.

Mucopolysaccharidosis II (MPS II, Hunter syndrome) is a rare, X-linked lysosomal storage disease caused by reduced activity of iduronate-2-sulfatase (I2S), with subsequent cellular accumulation of the glycosaminoglycans (GAGs), heparan sulfate, and dermatan sulfate (DS). DS is a major component of the extracellular matrix of heart valves, which can be affected in MPS II. We investigated the natural history of valve disease in MPS II and the impact of long-term intravenous enzyme replacement therapy (ERT) with recombinant I2S (idursulfase). In total, 604 cardiac examinations were assessed from serial follow-up of 80 male patients (49 neuronopathic). Valve disease was classified according to standard practice from hemodynamic features evident from echocardiography. The natural history group comprised 48 patients (up to 14.8 years of follow-up; median, 2.6 years; 24 patients started ERT during the study); 56 patients were treated (up to 14.2 years of follow-up; median, 6.2 years). Lifetime GAG burden (calculated from urinary GAG measurements) correlated significantly with the degree of valve disease. Onset of moderate-to-severe valve disease was significantly delayed in treated (median age at onset, 29.1 ± 2 [95% CI: 25.2-32.9] years; Kaplan-Meier estimation) versus untreated patients (17.6 ± 1 [95% Cl: 15.8-19.4] years; p < 0.0001). Cox regression modeling found that long-term ERT reduced the probability of developing severe valve disease (χ2, 32.736; significant after 5 years of ERT). Overall, this study found that valve disease severity in MPS II correlates with GAG burden and that progression is delayed by long-term ERT.

The growing understanding of the innate immune response in Mucopolysaccharidosis (MPS) revealed potential targets for intervening, including the repurposing of immunomodulatory drugs. Individual treatment trials (ITT) could efficiently translate this knowledge into clinical use. However, despite the limited efficacy of approved drugs and the high level of suffering this has so far hardly been used - at least these are not reported or published. We analysed the subjective need for, utilisation of and barriers to ITT by an international MPS-expert survey. Based on that and by adapting a validated decision analysis framework (DAF) we developed an innovative, quantitative, personalizable benefit-risk assessment model to overcome barriers to ITT in MPS. Our strategy is based on the following steps i) MPS-expert survey on ITT in MPS, (ii) systematic literature review regarding relevant targets and clinical pharmacology of immunomodulatory drugs, (iii) quantitative DAF data acquisition with the creation of a framed decision context and assigning weights to relevant outcomes, (iv) enabling personali-zability by phenotypic profiling and assessing specific probabilities of expected beneficial out-comes, (v) an assessment standard for ITT with immunomodulatory drugs in MPS. These steps are in accordance with an international, interdisciplinary board of experts as well as patient representatives. Our survey (n=27) demonstrated that the majority of MPS-experts is familiar with the concept of ITT (73%), however only few ever conducted (35%) or published those (6%) reported those. A free service for data-driven treatment choices is expected to in-crease the utilization and quality of ITT by 85%. We identified Anakinra, Adalimumab, Abatacept and Cladribine as top candidates and defined first and second choices for different phenotypes. Our developed evidence-based, personalizable, quantitative DAF model for ITT characterizes the first step towards precision medicine with immunomodulatory drugs in MPS.

The journal retracts the article, An Innovative Tool for Evidence-Based, Personalized Treatment Trials in Mucopolysaccharidosis [...].

This was a retrospective data analysis to evaluate the treatment response to enzyme replacement therapy (ERT) with Velaglucerase alfa using whole-body magnetic resonance imaging (MRI).A baseline and follow-up MRI were performed on 18 Gaucher Type 1 patients at an interval of 11.6 months. The MRI score systems determined the Bone-Marrow-Burden (BMB) score, the Düsseldorf-Gaucher score (DGS), and the Vertebra-Disc-Ratio (VDR). The Severity Score Index Type 1 (GD-DS3) was also assessed.The baseline MRI medians were: BMB, 7.00; DGS, 3.00; and VDR: 1.70; while, the follow-up MRI medians were: BMB, 7.00; DGS, 3.00; and VDR: 1.73. The baseline GD-DS3 median was 2.40 (BMB excl.: 0.50) and the follow-up median was 2.00 (BMB excl.: 0.50). There was weak statistical significance with the Wilcoxon signed-rank test for the DGS (p = 0.034) and GD-DS3 (p = 0.047) between both MRIs.Velaglucerase alfa therapy is a effective long-term treatment for Gaucher Type 1 patients who are newly diagnosed or switching therapies. Measurements with whole-body MRI and an objective scoring system were reliable tools for detecting early stage bone marrow activity. Further research is needed to evaluate the "Booster-Effect" of Velaglucerase alfa therapy in Gaucher skeletal disease.

Zinc Lysinate-riboflavinate is a new improved form of zinc that could be used to enrich whole milk products. This paper presents the findings of a study of the zinc Lysinate-riboflavinate phase composition. Its space group and crystal lattice type have been determined. The microstructure of zinc Lysinate-riboflavinate was investigated, and it was discovered that the samples are needle-shaped crystals with lengths ranging from hundreds of nanometers to several microns. Energy-dispersive microanalysis was used to determine the elemental composition of the material.

Introduction Mucopolysaccharidoses (MPS), comprise a group of rare chronically debilitating metabolic diseases and associated with reduced life expectancy and a substantial unmet clinical need. Current research directs towards a number of new treatment targets and strategies. Individual treatment trials (ITT) could make these options rapidly available to patients. Based on scientific publication, this is hardly used. We assess the utilization of and relevant barriers to ITT in MPS as well as potential solutions. Methods Phase 1 was done with 5 international top experts. After this interim analysis, the survey will be rolled out to a broader group of experts. Results Five MPS experts from Austria, Brazil, Germany and Italy have been enrolled. In total these clinicians manage about 350 MPS patients. Only three experts ever ran 1–3 numbers of ITT in MPS patients, solely MPS type II (n=2) and VI (n=1), summing up to a total of five ITTs, which is about 1.4% of their patients. The treatments used in ITTs comprise Montelukast, THC, Curcuma and a viral vector with transgene. As barriers for a wider use of ITTs, the im-practicability for implementation (n=1) and the insufficient training in ITT (n=1) have been indicated. All experts consider it highly likely that a decision analysis tool increases the use of ITT in MPS. Conclusions ITT are used in about 1% of MPS patients. This seems extremely low, considering the commonness of off label use in children with severe conditions, the high unmet medical need in MPS and the number of research results, which indicate various promising repurposing strategies. This interim analysis already demonstrates several relevant barriers and high potential of the planned decision framework tool to overcome this.

Mucopolysaccharidosis (MPS) is a group of rare metabolic diseases associated with reduced life expectancy and a substantial unmet medical need. Immunomodulatory drugs could be a relevant treatment approach for MPS patients, although they are not licensed for this population. Therefore, we aim to provide evidence justifying fast access to innovative individual treatment trials (ITTs) with immunomodulators and a high-quality evaluation of drug effects by implementing a risk–benefit model for MPS. The iterative methodology of our developed decision analysis framework (DAF) consists of the following steps: (i) a comprehensive literature analysis on promising treatment targets and immunomodulators for MPS; (ii) a quantitative risk–benefit assessment (RBA) of selected molecules; and (iii) allocation phenotypic profiles and a quantitative assessment. These steps allow for the personalized use of the model and are in accordance with expert and patient representatives. The following four promising immunomodulators were identified: adalimumab, abatacept, anakinra, and cladribine. An improvement in mobility is most likely with adalimumab, while anakinra might be the treatment of choice for patients with neurocognitive involvement. Nevertheless, a RBA should always be completed on an individual basis. Our evidence-based DAF model for ITTs directly addresses the substantial unmet medical need in MPS and characterizes a first approach toward precision medicine with immunomodulatory drugs.

Background: The severity of pectus excavatum is classified by the Haller Index (HI) and/or Correction Index (CI). These indices measure only the depth of the defect and, therefore, impede a precise estimation of the actual cardiopulmonary impairment. We aimed to evaluate the MRI-derived cardiac lateralization to improve the estimation of cardiopulmonary impairment in Pectus excavatum in connection with the Haller and Correction Indices. Methods: This retrospective cohort study included a total of 113 patients (mean age = 19.03 ± 7.8) with pectus excavatum, whose diagnosis was verified on cross-sectional MRI images using the HI and CI. For the development of an improved HI and CI index, the patients underwent cardiopulmonary exercise testing to assess the influence of the right ventricle’s position on cardiopulmonary impairment. The indexed lateral position of the pulmonary valve was utilized as a surrogate parameter for right ventricle localization. Results: In patients with PE, the heart’s lateralization significantly correlated with the severity of pectus excavatum (p ≤ 0.001). When modifying HI and CI for the individual’s pulmonary valve position, those indices are present with greater sensitivity and specificity regarding the maximum oxygen-pulse as a pathophysiological correlate of reduced cardiac function (χ2 10.986 and 15.862, respectively). Conclusion: The indexed lateral deviation of the pulmonary valve seems to be a valuable cofactor for HI and CI, allowing for an improved description of cardiopulmonary impairment in PE patients.

Introduction Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage diseases caused by different enzyme deficiencies that lead to accumulation of glycosaminoglycans (GAGs) in lysosomes and the extracellular matrix. This storage-induced inflammation is a key driver of cytopathology in MPS, and pharmacological immunomodulation can improve brain, cartilage and bone symptoms in rodents. As the approved enzyme replacement therapy cannot stop the progression of CNS involvement and several other symptoms, we develop a rational for personalized treatment to address the unmet clinical need in MPS patients. Methods First, we conducted comprehensive literature reviews on MPS type specific inflammatory immune response and on the safety and efficacy of Adalimumab, Infliximab, Abatacept, Alemtuzumab, Anakinra. Second, by expert consensus top candidates for innovative personalized drug repurposing in MPS patients were identified and ranked. Results The key process is the upregulation of toll-like receptor-4 (TLR4) pathway induced by the accumulation of heparan sulfate (HS) in MPS type I, II and III. This and other relevant mech-anisms indicate TNF-alpha and IL-1 as most promising targets. Systematic analysis of the clinical pharmacology of all relevant candidates and several expert focus group meetings identified Anakinra, Adalimumab, Cladribine and Abatacept as top candidate’s dependent on the individual clinical situation. Conclusions These results provide the rational for individual treatment trials (ITTs) with the aim to evaluate immunomodulatory molecules, repurposed in MPS. Furthermore, they will – together with the results of the ITTs – be utilized for the development of a decision tool for the personalized treatment of unmet clinical needs in these patients.