Search

To assess the long-term safety and effectiveness of canaloplasty in reducing intraocular pressure (IOP) and use of IOP-lowering medications in eyes with open-angle glaucoma (OAG).Surgical center (Augencentrum Köln, Köln, Germany).Retrospective study.206 eyes from 130 patients were included. Canaloplasty was performed using the VISCO360 or OMNI surgical system as a stand-alone procedure in 22 eyes and concomitantly with cataract extraction (CE) in 185 eyes with chronic OAG insufficiently controlled or intolerant to IOP-lowering medications. The number of hypotensive medications and IOP were recorded at baseline, day 1, week 1, month 1, month 3, and every 3 months thereafter, with the last follow-up visit at 36 ± 6 months postoperatively. Patients were stratified by baseline IOP (Group 1, IOP18 mm Hg; Group 2, IOP ≤18 mm Hg). Treatment success in Group 1 was defined as a reduction in IOP and the use of IOP-lowering medications; Group 2 success was defined as maintenance of a lower IOP and a reduction in medication use.The preoperative mean IOP of both groups was 21.1 ± 8.8 mm Hg, with a mean of 2.0 ± 0.9 hypotensive medications. The primary success end point was met by 73% of patients, with a mean IOP reduction in Group 1 (131 eyes; 21.8 to 15.6 mm Hg, P.0001) and a maintenance of IOP control in Group 2 (76 eyes; 15.4 to 13.9 mm Hg, P = .24). Medications decreased from 2.2 ± 0.9 to 0.9 ± 1.1 in Group 1 ( P = .024) and from 1.8 ± 0.8 to 0.7 ± 1.0 in Group 2 ( P = .003).Canaloplasty alone or in conjunction with CE with the VISCO360 or OMNI surgical system is a safe, tissue-sparing, and effective minimally invasive glaucoma surgery, using a clear corneal incision in phakic or pseudophakic eyes. Canaloplasty performed with both evaluated devices achieved statistically significant, consistent, and clinically meaningful reductions in IOP and use of IOP-lowering medications in adult patients with OAG. In the consistent cohort (n = 42), the IOP-lowering effect lasted up to 42 months, with ongoing data collection expected to describe long-term effectiveness of this intervention.

Background Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a major pathological hallmark of Alzheimer’s disease (AD) brain. Of special interest is the effect of cerebral amyloid beta deposition, the second main hallmark of AD, on human tau pathology. Therefore, studying the influence of cerebral amyloidosis on human tau in a novel human tau knock-in (htau-KI) mouse model could help to reveal new details on their interplay. Methods We studied the effects of a novel human htau-KI under fast-progressing amyloidosis in 5xFAD mice in terms of correlation of gene expression data with human brain regions, development of Alzheimer’s-like pathology, synaptic transmission, and behavior. Results The main findings are an interaction of human beta-amyloid and human tau in crossbred 5xFADxhtau-KI observed at transcriptional level and corroborated by electrophysiology and histopathology. The comparison of gene expression data of the 5xFADxhtau-KI mouse model to 5xFAD, control mice and to human AD patients revealed conspicuous changes in pathways related to mitochondria biology, extracellular matrix, and immune function. These changes were accompanied by plaque-associated MC1-positive pathological tau that required the htau-KI background. LTP deficits were noted in 5xFAD and htau-KI mice in contrast to signs of rescue in 5xFADxhtau-KI mice. Increased frequencies of miniature EPSCs and miniature IPSCs indicated an upregulated presynaptic function in 5xFADxhtau-KI. Conclusion In summary, the multiple interactions observed between knocked-in human tau and the 5xFAD-driven progressing amyloidosis have important implications for future model development in AD.

Background and objectives: Documenting patient data in psoriasis clinical practice can improve care, but standardized and transparent documentation is rare. The current project aimed to develop a data set for the documentation of psoriasis in daily practice. Material and methods: In four online Delphi rounds and one in-person meeting, 27 psoriasis experts allocated variables to a standard, an optimal and an optional data set. Most of the questions were standardized. Open questions were included to allow for the provision of reasons and to enlarge the data sets. Furthermore, in the in-person meeting we considered a) patients' attitudes and b) dermatologists' information on the current usage and acceptability in Germany. Results: The consensus approach resulted in a data set with 69 variables. The standard data set includes 20, the optimal data set 31 and the optional data set 18 variables. In summary, the data set can mainly be grouped into master data, general status and medical history data, medical history of psoriasis, status of psoriasis, diagnostics and comorbidity, therapies and patient-reported outcomes. Conclusions: The consensus recommendation of a standard, an optimal and an optional data set for routine care of psoriasis intends to be a decision-making aid and an orientation for both daily practice and further development of documentation systems.

Moderate to severe plaque psoriasis can be treated effectively with immunomodulating biologicals such as the interleukin-17A inhibitor secukinumab. In practice, however, questions often arise as to how to proceed in special situations, such as infections, comorbidity, pregnancy, or surgery.To address frequent questions about the treatment of plaque psoriasis with secukinumab in a consensus document of German psoriasis experts that supplements current guidelines.In a virtual expert meeting in May 2020, practical aspects of the treatment of psoriasis were discussed based on the experience of the participants and on current literature. The results of this discussion were summarized in the present consensus document.This article provides practical guidance on case history, documentation of previous therapies, severity of psoriasis, and comorbidities before starting therapy with secukinumab. For patients treated with secukinumab, the course of action in case of vaccinations, chronic or acute infections, surgical interventions, special manifestations of psoriasis, and comorbidities including history of cancer and autoimmune disorders is discussed. Questions regarding family planning and health policy regulations are also addressed.The recommendations for the treatment of psoriasis with secukinumab summarized in this consensus document may contribute to achieve optimal therapy for patients and to improve their quality of life.HINTERGRUND: Die mittelschwere bis schwere Psoriasis vulgaris kann wirksam mit immunmodulierenden Biologika wie dem Interleukin-17A-Inhibitor Secukinumab behandelt werden. In der Praxis stellt sich jedoch oft die Frage nach dem Vorgehen in besonderen Situationen, beispielsweise bei Infektionen, Komorbidität, Schwangerschaft oder operativen Eingriffen.In diesem Konsensdokument deutscher Psoriasisexperten sollen in Ergänzung zu den aktuellen Leitlinien häufige Fragen aus dem Therapiealltag zur Behandlung der Psoriasis mit Secukinumab beantwortet werden.In einem virtuellen Expertentreffen im Mai 2020 wurden auf Grundlage von Erfahrungen der Teilnehmer und aktueller Literatur praxisrelevante Aspekte der Behandlung der Psoriasis erörtert. Darauf basierend wurde ein Konsensdokument verfasst.Die vorliegende Arbeit bietet praktische Hinweise zur Anamnese einschließlich der Erfassung von Vortherapien, Schweregrad der Psoriasis und Begleiterkrankungen vor Beginn einer Therapie mit Secukinumab. Ferner wird auf das Vorgehen bei Impfungen, Infektionen, operativen Eingriffen, Sondermanifestationen der Psoriasis und Komorbiditäten einschließlich vorbestehenden Autoimmunerkrankungen und Tumorerkrankungen unter Therapie mit Secukinumab eingegangen. Auch Fragen zur Familienplanung und zu gesundheitspolitischen Regularien werden diskutiert.Die in diesem Konsensdokument zusammengefassten unterstützenden Empfehlungen zur Behandlung der Psoriasis mit Secukinumab sollen dazu beitragen, für die Patienten eine optimale Therapie zu erreichen und ihre Lebensqualität zu verbessern.

Purpose Genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly. Methods We investigated 150 adult/elderly individuals with NDDE by conventional karyotyping, FMR1 testing, chromosomal microarray, panel sequencing, and for unresolved cases, also by exome sequencing (nsingle = 71, ntrios = 24). Results We identified (likely) pathogenic variants in 71 cases (47.3%) comprising fragile X syndrome (n = 1), disease-causing copy number (n = 23), and single-nucleotide variants (n = 49). Seven individuals displayed multiple independent genetic diagnoses. The diagnostic yield correlated with the severity of intellectual disability. Individuals with anecdotal evidence of exogenic early-life events (e.g., nuchal cord, complications at delivery) with alleged/unproven association to the disorder had a particularly high yield of 58.3%. Screening for disease-specific comorbidities was indicated in 45.1% and direct treatment consequences arose in 11.8% of diagnosed individuals. Conclusion Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE.

Background Assessment of psoriasis is exclusively done measuring severity using somatic scores such as the psoriasis area and severity index or patient-reported outcomes such as the dermatology life quality index. There is no established tool to measure a patient's individual psoriasis activity over time. Objectives Development of a new tool to classify psoriasis activity types. Methods Open patient interviews were performed and adapted in several steps and by using different groups of patients. Wording of the tool's axis and description how to use it was optimized with the input of patients. The final ActiPso tool was used in a prospective study in psoriasis patients. Results Four activity types could be identified describing psoriasis intensity (e.g. severity, itch, pain) over one typical year and an event/trigger type describing flares. In the study in 586 psoriasis patients of the 536 patients eligible for analysis 40.9% self-classified as type 1 ('stable'), 22.6% as type 2 ('unstable'), 30.6% as type 3 ('winter type') and 6.0% as type 4 ('summer type'), respectively. Flares of psoriasis as identified by the event/trigger type were reported in 36.1% of patients with activity type 1, 67.8% with type 2, 73.8% of type 3 and 59.4% of type 4, respectively. Conclusions Interviewed patients were able to describe their course of psoriatic disease and to name potential triggering factors. By doing so, activity types of psoriasis were defined for the first time and the importance of events/triggers for flares described and integrated into ActiPso types as a basis for advanced patient-centric management. A limitation of ActiPso is that in regions with no seasonal variations types 3 and 4 may not apply.

CAPRIN1 is a ubiquitously expressed protein, abundant in the brain, where it regulates the transport and translation of mRNAs of genes involved in synaptic plasticity. Here we describe two unrelated children, who developed early-onset ataxia, dysarthria, cognitive decline and muscle weakness. Trio exome sequencing unraveled the identical de novo c.1535C T (p.Pro512Leu) missense variant in CAPRIN1, affecting a highly conserved residue. In silico analyses predict an increased aggregation propensity of the mutated protein. Indeed, overexpressed CAPRIN1

Background Medulloblastomas with chromothripsis developing in children with Li-Fraumeni Syndrome (germline TP53 mutations) are highly aggressive brain tumors with dismal prognosis. Conventional photon radiotherapy and DNA-damaging chemotherapy are not successful for these patients and raise the risk of secondary malignancies. We hypothesized that the pronounced homologous recombination deficiency in these tumors might offer vulnerabilities that can be therapeutically utilized in combination with high linear energy transfer carbon ion radiotherapy. Methods We tested high-precision particle therapy with carbon ions and protons as well as topotecan with or without PARP inhibitor in orthotopic primary and matched relapsed patient-derived xenograft models. Tumor and normal tissue underwent longitudinal morphological MRI, cellular (markers of neurogenesis and DNA damage-repair), and molecular characterization (whole-genome sequencing). Results In the primary medulloblastoma model, carbon ions led to complete response in 79% of animals irrespective of PARP inhibitor within a follow-up period of 300 days postirradiation, as detected by MRI and histology. No sign of neurologic symptoms, impairment of neurogenesis or in-field carcinogenesis was detected in repair-deficient host mice. PARP inhibitors further enhanced the effect of proton irradiation. In the postradiotherapy relapsed tumor model, median survival was significantly increased after carbon ions (96 days) versus control (43 days, P < .0001). No major change in the clonal composition was detected in the relapsed model. Conclusion The high efficacy and favorable toxicity profile of carbon ions warrants further investigation in primary medulloblastomas with chromothripsis. Postradiotherapy relapsed medulloblastomas exhibit relative resistance compared to treatment-naïve tumors, calling for exploration of multimodal strategies.

The purpose of this paper was to evaluate the impact of proportionality of secondary mitral regurgitation (SMR) in a large real-world registry of transcatheter edge-to-edge mitral valve repair (TMVr) BACKGROUND: Differences in the outcomes of recent randomized trials of TMVr for SMR may be explained by the proportionality of SMR severity to left ventricular (LV) volume.The ratio of pre-procedural effective regurgitant orifice area (EROA) to LV end-diastolic volume (LVEDV) was retrospectively assessed in patients undergoing TMVr for severe SMR between 2008 and 2019 from the EuroSMR registry. A recently proposed SMR proportionality scheme was adapted to stratify patients according to EROA/LVEDV ratio in 3 groups: MR-dominant (MD), MR-LV-co-dominant (MLCD), and LV-dominant (LD). All-cause mortality was assessed as a primary outcome, secondary heart failure (HF) outcomes included hospitalization for HF (HHF), New York Heart Association (NYHA) functional class, N-terminal pro-B-type natriuretic peptide (NT-proBNP), 6-min-walk distance, quality of life and MR grade.A total of 1,016 patients with an EROA/LVEDV ratio were followed for 22 months after TMVr. MR was reduced to grade ≤2+ in 92%, 96%, and 94% of patients (for MD, MLCD, and LD, respectively; p = 0.18). After adjustment for covariates including age, sex, diabetes, kidney function, body surface area, LV ejection fraction, and procedural MR reduction (grade ≤2+), adjusted rates of 2-year mortality in MD patients did not differ from those for MLCD patients (17% vs. 18%, respectively), whereas it was higher in LD patients (23%; p = 0.02 for comparison vs. MD+MLCD). The adjusted first HHF rate differed between groups (44% in MD, 56% in MLCD, 29% in LD; p = 0.01) as did the adjusted time for first death or HHF rate (66% in MD, 82% in MLCD, 68% in LD; p = 0.02). Improvement of NYHA functional class was seen in all groups (p 0.001). Values for 6-min-walk distances, quality of life and NT-proBNP improved in most patients.MD and MLCD patients had a comparable, adjusted 2-year mortality rate after TMVr which was slightly better than that of LD patients. Patients treated with TMVr had symptomatic improvement regardless of EROA/LVEDV ratio.

Annals of hematology 100(1), 97-104 (2021). doi:10.1007/s00277-020-04304-Y, Published by Springer, Berlin ; Heidelberg ; New York

The prevalence of left ventricular (LV) thrombus formation following percutaneous mitral valve edge-to-edge repair (TMVR) with the MitraClip system is unclear. Decreased total stroke volume and perfusion of the LV apex after mitral valve repair may facilitate thrombus formation especially in the context of reduced LV function. LV thrombus may cause disabling stroke or other thromboembolic events in this elderly and multimorbid patient cohort. Analyses of the prevalence of and risk factors for left ventricular thrombus formation in patients treated with the MitraClip system due to severe mitral valve regurgitation. All discharge and follow-up transthoracic echocardiographic examinations up to 6 months of 453 consecutive patients treated with the MitraClip system were screened for the presence of LV thrombus. Prevalence of LV thrombus formation was 1.1% (5/453). Importantly, LV thrombi were exclusively found in patients with severely depressed left ventricular systolic function (LV-EF

Objectives This study aimed to compare hemodynamic characteristics of different self-expanding (SE) and balloon-expandable (BE) transcatheter heart valves (THV) in relation to native aortic annulus anatomy. Background A patient centered THV selection becomes increasingly important as indications for transcatheter aortic valve replacement (TAVR) are extended towards lower risk populations. Methods Hemodynamic parameters including mean gradient (MG), effective orifice area (EOA), Doppler velocity index (DVI), degree of paravalvular regurgitation (PVR) and patient-prosthesis mismatch (PPM) were compared by valve type, label size and in relation to quintiles of native aortic annulus area. Results 2609 patients were treated at 3 centers in Germany with SAPIEN 3 (n = 1146), ACURATE Neo (n = 649), Evolut R (n = 546) or Evolut Pro (n = 268) THV. SE THVs provided superior hemodynamics in terms of larger EOA, higher DVI and lower MG compared to BE THV, especially in patients with small aortic annuli. Severe PPM was less frequent in SE treated patients. The rate of PVR ≥ moderate was comparable for SE and BE devices in smaller annular dimensions, but remarkably lower for BE TAVR in large aortic annular dimensions (> 547.64 mm2) (2% BE THV vs. > 10% for SE THV; p Conclusions Patients with small aortic annular dimensions may benefit hemodynamically from SE THV. With increasing annulus size, BE THV may have advantages since PVR ≥ moderate occurs less frequently. Graphical abstract

Background Stereotactic body radiotherapy (SBRT) is an established local treatment method for patients with hepatic oligometastasis or oligoprogression. Liver metastases often occur in close proximity to radiosensitive organs at risk (OARs). This limits the possibility to apply sufficiently high doses needed for optimal local control. Online MR-guided radiotherapy (oMRgRT) is expected to hold potential to improve hepatic SBRT by offering superior soft-tissue contrast for enhanced target identification as well as the benefit of gating and daily real-time adaptive treatment. The MAESTRO trial therefore aims to assess the potential advantages of adaptive, gated MR-guided SBRT compared to conventional SBRT at a standard linac using an ITV (internal target volume) approach. Methods This trial is conducted as a prospective, randomized, three-armed phase II study in 82 patients with hepatic metastases (solid malignant tumor, 1–3 hepatic metastases confirmed by magnetic resonance imaging (MRI), maximum diameter of each metastasis ≤ 5 cm (in case of 3 metastases: sum of diameters ≤ 12 cm), age ≥ 18 years, Karnofsky Performance Score ≥ 60%). If a biologically effective dose (BED) ≥ 100 Gy (α/β = 10 Gy) is feasible based on ITV-based planning, patients will be randomized to either MRgRT or ITV-based SBRT. If a lesion cannot be treated with a BED ≥ 100 Gy, the patient will be treated with MRgRT at the highest possible dose. Primary endpoint is the non-inferiority of MRgRT at the MRIdian Linac® system compared to ITV-based SBRT regarding hepatobiliary and gastrointestinal toxicity CTCAE III or higher. Secondary outcomes investigated are local, locoregional (intrahepatic) and distant tumor control, progression-free survival, overall survival, possible increase of BED using MRgRT if the BED is limited with ITV-based SBRT, treatment-related toxicity, quality of life, dosimetric parameters of radiotherapy plans as well as morphological and functional changes in MRI. Potential prognostic biomarkers will also be evaluated. Discussion MRgRT is known to be both highly cost- and labor-intensive. The MAESTRO trial aims to provide randomized, higher-level evidence for the dosimetric and possible consecutive clinical benefit of MR-guided, on-table adaptive and gated SBRT for dose escalation in critically located hepatic metastases adjacent to radiosensitive OARs. Trial registration The study has been prospectively registered on August 30th, 2021: Clinicaltrials.gov, “Magnetic Resonance-guided Adaptive Stereotactic Body Radiotherapy for Hepatic Metastases (MAESTRO)”, NCT05027711.

SummaryVaccines are the most important means to overcome the SARS-CoV-2 pandemic. They induce specific antibody and T-cell responses but it remains open how well vaccine-induced immunity is preserved over time following homologous and heterologous immunization regimens. Here, we compared the dynamics of humoral and cellular immune responses up to 5 months after homologous or heterologous vaccination with either ChAdOx1-nCoV-19 (ChAd) or BNT162b2 (BNT) or both. Antibody responses significantly waned after vaccination, irrespective of the regimen. The capacity to neutralize SARS-CoV-2 – including variants of concern such as Delta or Omicron – was superior after heterologous compared to homologous BNT vaccination, both of which resulted in longer-lasting humoral immunity than homologous ChAd immunization. T-cell responses showed less waning irrespective of the vaccination regimen. These findings demonstrate that heterologous vaccination with ChAd and BNT is a potent approach to induce long-term humoral and cellular immune protection.Research in contextEvidence before this studyDue to some rare severe side effects after the administration of the adenoviral vaccine, ChAdOx1 nCoV-19, many countries recommended a heterologous vaccination scheme including mRNA vaccines like BNT162b2 for the second dose. We performed a PubMed search (with no restrictions on time span) using the search terms “SARS-CoV-2” and “heterologous vaccination” and obtained 247 results. Only a fraction of manuscripts included direct comparisons of patient cohorts that received either a heterologous or a homologous vaccination regimen. Of those, the vast majority investigated only short-term immunogenicity after vaccination. Thus, little is known about the long-term maintenance of immunity by heterologous compared to homologous vaccination.Added value of this studyWe add a very comprehensive and comparative study investigating heterologous and homologous vaccination regimens early and late after vaccination. Key features include the number of patients (n = 473), the number of vaccination cohorts (n= 3), the fact that samples were derived from three independent study centers and comparative analyses were performed at two independent study centers, as well as in-depth investigation of humoral and T cellular immunity.Implications of all the available evidenceThe recent data creates a line of evidence that heterologous vaccination, compared to homologous vaccination regimens, results in at least non-inferior maintenance of humoral and cellular immunity. The enhanced understanding of immunity induced by individual vaccination regimens is crucial for further recommendations regarding the necessity, timing and choice of additional vaccinations and public health policies.

BACKGROUND Secukinumab is a fully human monoclonal antibody that selectively neutralizes interleukin-17A and shows long-lasting efficacy and safety in plaque psoriasis. More evidence is required to optimize secukinumab dosing according to clinical response. OBJECTIVES GAIN compared the efficacy and safety of secukinumab 300 mg every 2 weeks (q2w) with 300 mg every 4 weeks (q4w) in patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) but not PASI 90 after 16 weeks. METHODS In total, 772 patients with moderate-to-severe plaque psoriasis received secukinumab 300 mg subcutaneously at baseline and weeks 1, 2, 3 and 4, then q4w until week 16. At week 16, patients with PASI ≥ 75 to PASI

Objectives and background Percutaneous edge-to-edge mitral valve (MV) repair (PMVR) is broadly applied in high-risk patients with relevant mitral regurgitation (MR). We investigated the incidence of cleft-like indentations (CLI) and their impact on PMVR. Methods and results In a retrospective single center analysis including 263 patients undergoing PMVR with the MitraClip®-system between 11/2012 and 7/2016, MV anatomy was assessed by 3-dimensional transesophageal echocardiography. CLI were present in 37/263 patients (14.1%). Of these, 62.2% had 1 CLI, 27% had 2 CLI, and 10.8% had 3 CLI, mostly concerning segment P2 or P2/3 of the MV. Baseline characteristics were similarly distributed. Interestingly, most patients with CLI suffered from secondary MR (n = 29, 78%). The number of deployed MitraClips was higher in patients with CLI (2 [1.25-2] vs. 2 [1, 2], p = .035), whereas procedural as well as clinical success was similar: MR grade (1.2 vs. 1.5, p = .061), vena contracta width (4.2 vs. 4.5 mm, p = .293), dPmean (4.2 vs. 4.0 mmHg, p = .618) at discharge and NYHA class at 30 days did not differ between groups. Periprocedural complications were rare and equally distributed between groups. At 30 days, MR reduction persisted in patients with CLI (95.8% of these selected patients had a MR grade ≤ 2). Conclusions CLI of the MV are common in patients undergoing PMVR, also when presenting mainly with secondary MR. While the number of clips needed to address MR is slightly higher in patients with CLI, procedural success rates appear not to be affected. PMVR seems to be a safe treatment option for patients with CLI.

Background The generalizability of the COAPT trial results on the benefit of TMVR in patients with secondary mitral regurgitation is unclear. Methods Functional and long-term clinical outcome were examined in 122 consecutive patients with secondary mitral regurgitation and reduced ejection fraction undergoing TMVR. “COAPT-like” patients were defined according to principal COAPT inclusion/exclusion criteria if all of the following was fulfilled: symptomatic mitral regurgitation grade 3+ or more according to American guidelines; left ventricular ejection fraction ≥ 20%, left ventricular end-systolic dimension ≤ 70 mm, estimated pulmonary artery systolic pressure ≤ 70 mmHg, mitral valve orifice area ≥ 4 cm2, no prior mitral valve procedure, no right sided congestive heart failure, no COPD requiring home oxygen therapy and NYHA class less than IVb. Results 51% of 122 patients (mean age 74 ± 10 years, 76% male) showed COAPT-like characteristics. COAPT-like patients showed a significantly lower hazard for the composite endpoint of mortality and heart failure hospitalization (HR 0.51, 95%CI 0.30–0.89, p = .017) during a mean follow-up of 16 ± 6 months, with an estimated 1-year event rate of 20% vs 43%, respectively. The improvement in functional outcomes 6 min walking distance (76 ± 136 m vs. 31 ± 90 m), Minnesota Living with Heart Failure Questionnaire (−6 ± 19 vs. −10 ± 23) and Short Form 36 physical component score (3.8 ± 10 vs. 5.5 ± 11) was similar in COAPT-like and the other patients. Conclusion In this first real world cohort half of the patients undergoing TMVR showed COAPT-like characteristics and these patients showed a substantially better clinical outcome. The mid-term functional benefit was similar in COAPT-like and other patients.

Aims Patients undergoing percutaneous mitral valve repair (PMVR) show a substantial heterogeneity of prognostic and symptomatic benefit. Iron deficiency and anaemia are associated with worse outcomes in heart failure patients. We investigated the impact of these comorbidities on functional and clinical outcome after PMVR. Methods and results Iron deficiency and anaemia were prospectively assessed in 130 patients undergoing PMVR with MitraClip. Associations with functional outcomes at 6 weeks [6 min walking distance (6MWD), Short‐Form‐36 physical component score, and Minnesota Living with Heart Failure Questionnaire score, New York Heart Association class] and long‐term clinical outcome were examined. Iron deficiency and anaemia were frequent with 52% and 50%, respectively. Patients with anaemia showed significant worse baseline functional measures, whereas patients with iron deficiency showed only a trend for lower baseline 6MWD. The benefit in functional outcomes after PMVR was notable and did not differ significantly by iron deficiency or anaemia status (range of median changes in 6MWD 35 to 45 m, physical component score 5.6 to 7.2, Minnesota Living with Heart Failure Questionnaire −8.0 to −10.5; improvement of ≥1 New York Heart Association class 69% to 80%). Anaemia was associated with higher risk for the combined endpoint of mortality and heart failure hospitalization (hazard ratio: 2.51; 95% confidence interval: 1.24–5.1; P = 0.01), whereas iron deficiency showed a trend towards more heart failure hospitalizations (hazard ratio: 2.94; 95% confidence interval: 0.94–9.03; P = 0.09). Conclusions The prevalence of iron deficiency and anaemia is high in patients undergoing MitraClip. Clinical baseline status and long‐term outcome were worse particularly in patients with anaemia. However, the functional benefit of PMVR was equal in patients with and without iron deficiency and anaemia.

The slow delayed rectifier potassium current (IKs) is formed by the KCNQ1 (Kv7.1) channel, an ion channel of four α‐subunits that modulates KCNE1 β‐subunits. IKs is central to the repolarization of the cardiac action potential. Loss of function mutation reducing ventricular cardiac IKs cause the long‐QT syndrome (LQTS), a disorder that predisposes patients to arrhythmia and sudden death. Current therapy for LQTS is inadequate. Rottlerin, a natural product of the kamala tree, activates IKs and has the potential to provide a new strategy for rational drug therapy. In this study, we show that simple modifications such as penta‐acetylation or penta‐methylation of rottlerin blunts activation activity. Total synthesis was used to prepare side‐chain‐modified derivatives that slowed down KCNQ1/KCNE1 channel deactivation to different degrees. A binding hypothesis of rottlerin is provided that opens the way to improved IKs activators as novel therapeutics for the treatment of LQTS., The polyphenolic natural product rottlerin, isolated from Kamala powder, has been used for centuries in traditional Indian medicine. Among other biological effects, rottlerin has been shown to activate KCNQ1 potassium channels. Rottlerin analogues were synthesized and evaluated electrophysiologically in X. laevis oocytes. A molecular modeling based model was developed to explain the binding‐mode of rottlerin and other KCNQ1 ligands.

Background: Relative Psoriasis Area and Severity Index (PASI) improvement, also called ‘PASI response’, is recommended in major guidelines for assessment of treatment response in psoriasis patients. However, under certain circumstances it has some limitations, e.g. when baseline values are missing or during long-term treatment. Improvement of health-related quality of life (HrQoL) can be measured by the Dermatology Life Quality Index (DLQI). Objective: To evaluate the association of HrQoL and relative and absolute PASI outcomes during therapy. Material and methods: Data of plaque psoriasis patients of two clinical trials (CLEAR and SCULPTURE) were pooled. The rates of patients achieving DLQI 0/1 at week 16 were compared for different categories of absolute PASI and PASI response values. The correlation of DLQI and absolute or relative PASI goals was assessed over 52 weeks. Results: One thousand and fifty-four patients with available assessments of PASI and DLQI were included. 76% of the patients with an absolute PASI ≤ 2 (N = 548) and patients with a 90% improvement in PASI (N = 559) achieved DLQI 0/1 at week 16. Achievement of DLQI 0/1 was equally reflected by absolute PASI and PASI response. Conclusion: Absolute PASI appeared to be a feasible alternative to PASI response for determining treatment success, reflecting HrQoL improvements in an equal manner.

Background Scientific evidence suggests an association between psoriasis and cardiovascular and metabolic diseases. However, there are hardly any sex-specific results from population-based studies reporting the prevalence of cardiovascular risk factors in patients with psoriasis and point estimates of the association between psoriasis and cardiovascular and metabolic disorders. Objective Aims are to evaluate the sex-specific prevalence of psoriasis and cardiovascular risk factors, and to estimate sex-specific associations between psoriasis and diabetes type 2 (DM) and metabolic syndrome (MetS). Methods We used data of 3723 participants (45-75 years, 54.1% women) without coronary heart disease and missing data (psoriasis, DM, MetS) from the Heinz Nixdorf Recall study. Standardized information on health outcomes and risk factors was assessed. We performed descriptive statistics and multiple regression analyses to calculate prevalence rate ratios (PR) and 95% confidence intervals (95% CI). Results The prevalence of psoriasis was 3.8% (n = 143), with no differences between sex. We observed more often metabolic and cardiovascular risk factors in women with psoriasis compared to women without psoriasis. Interestingly, in men, this pattern was partly reversed. Multiple regression analyses revealed distinctly elevated PRs for DM for both women and men with psoriasis (fully adjusted PR: 2.43; 95% CI: 1.17-5.07, resp. 2.09; 1.16-3.76). Regarding the MetS, the results were inconsistent, showing a positive association between psoriasis and MetS in women (1.84; 1.14-2.98), but a negative association in men, even though with a wide 95% CI (0.69; 0.42-1.12). Conclusion The results of our cross-sectional, population-based analysis show a distinct association between psoriasis and DM, whereas for the MetS the results contrasted between men and women, translating in women with MetS showing a higher and in men a lower chance to be psoriatic. Our results emphasize the urgent need for sex-specific research, studying the effects of psoriasis on metabolic disorders as well as effective sex tailored prevention measures.

In X-linked hypohidrotic ectodermal dysplasia, the most frequent ectodermal dysplasia, an inherited deficiency of the signalling protein ectodysplasin A1 (EDA1) impairs the development of the skin and its appendages, various eccrine glands, and dentition. The severe hypohidrosis common to X-linked hypohidrotic ectodermal dysplasia patients may lead to life-threatening hyperthermia, especially during hot weather or febrile illness. Fc-EDA, an EDA1 replacement protein known to prevent the disease in newborn animals, was tested in 2 clinical trials (human adults and neonates) and additionally administered under compassionate use to 3 infants in utero. The data support the safety of Fc-EDA and efficacy if applied prenatally. Anti-drug antibodies were detected after intravenous administration in adult males and nonpregnant females, but not in pregnant women when Fc-EDA was delivered intra-amniotically. Most importantly, there was no detectable immune response to the investigational drug in neonates treated by intravenous infusions and in infants who had received Fc-EDA in utero. In conclusion, the safety profile of this drug encourages further development of prenatal EDA1 replacement therapy.

Objective The objective of this study was to assess imaging predictors of mitral regurgitation (MR) improvement and to evaluate the impact of MR regression on long-term outcome in patients undergoing transcatheter aortic valve replacement (TAVR). Background Concomitant MR is a frequent finding in patients with severe aortic stenosis but usually left untreated at the time of TAVR. Methods Mitral regurgitation was graded by transthoracic echocardiography before and after TAVR in 677 consecutive patients with severe aortic stenosis. 2-year mortality was related to the degree of baseline and discharge MR. Morphological echo analysis was performed to determine predictors of MR improvement. Results 15.2% of patients presented with baseline MR ≥ 3 +, which was associated with a significantly decreased 2-year survival (57.7% vs. 74.4%, P P Conclusion Unresolved severe MR is a critical determinant of long term mortality following TAVR. Persistence of severe MR following TAVR can be predicted using selected parameters derived from TTE-imaging. These data call for close follow up and additional mitral valve treatment in this subgroup. Graphic abstract Factors associated with MR persistence or regression after TAVR

Fast track programs have been introduced to reduce perioperative complication rates and to quickly reintegrate the patient into everyday life. The aim of this retrospective case-control study was to identify patient characteristics and patient-independent factors that influence fast track programs in hip arthroplasty. A total of 1138 patients were examined. A hospital stay of more than seven days was used to define the case group. In addition to the causes for the longer hospitalisation, age, sex, BMI, chronic nicotine and alcohol abuse, ASA score, surgical duration, anaemia and blood transfusion as well as concomitant diseases were assessed. The statistical analysis included two-sample t-test, chi-square test and logistic regression analyses. An 95% confidence interval was calculated (p100 mg/l), and internal complications (19.7%). At a mean of 69.2 ± 10.7 years, the age of the case group was significantly higher than that of the control group, which had a mean of 63.3 ± 10.3 years (p

Purpose Superior vena cava syndrome (SVCS) often results from external vessel compression due to tumor growth. Urgent symptom-guided radiotherapy (RT) remains a major treatment approach in histologically proven, rapidly progressive disease. Despite several publications, recent data concerning symptom relief and oncological outcome as well as potential confounders in treatment response are still scarce. Methods We performed a retrospective single-center analysis of patients receiving urgent RT between 2000 and 2021 at the University Medical Center Göttingen. Symptom relief was evaluated by CTCAE score during the RT course. Effects of variables on symptom relief were assessed by logistic regression. The impact of parameters on overall survival (OS) was evaluated using Kaplan–Meier plot along with the log-rank test and by Cox regression analyses. Statistically significant (p-value Results A total of 79 patients were included. Symptom relief was achieved in 68.4%. Mean OS was 59 days, 7.6% (n = 6) of patients showed long-term survival (> 2 years). Applied RT dose > 39 Gy, clinical target volume (CTV) size Conclusion Symptom relief by urgent RT for SVCS was achieved in the majority of patients. RT dose and completion of the RT course were documented as predictors for OS and symptom relief, CTV

Background: Severe tricuspid regurgitation (TR) is independently associated with increased morbidity and mortality. Percutaneous transcatheter approaches may offer an alternative for patients not amenable to surgery. Methods: TriCLASP is a prospective, single-arm, multicenter European post-market clinical follow-up study (NCT04614402) to evaluate the safety and performance of the PASCAL system (Edwards Lifesciences) in patients with severe or greater TR. At 30 days, a composite of major adverse events (MAEs) adjudicated by a clinical events committee, echocardiographic parameters adjudicated by core laboratory, and clinical, functional, and quality-of-life measures were evaluated. Results: Mean age of the 74 enrolled patients was 80.3 years, with 58.1% female, 90.5% systemic hypertension, and 77.0% in New York Heart Association (NYHA) class III/IV. Mean Society for Thoracic Surgeons score (MV repair) was 9.0%. TR severity was significantly reduced at discharge (p < 0.001) and sustained at 30 days (p < 0.001), and 90.0% of patients achieved ≤moderate TR. The composite MAE rate at 30 days was 3.0%, including 4 events in 2 patients: cardiovascular mortality 1.5%, stroke 1.5%, renal complications requiring unplanned dialysis or renal replacement therapy 1.5%, and severe bleeding 1.5%. There were no nonelective tricuspid valve reinterventions, major access site and vascular complications, major cardiac structural complications, or device embolizations. NYHA class I/II was achieved in 55.8%, 6-minute walk distance improved by 38.2 m (p < 0.001), and Kansas City cardiomyopathy questionnaire scores improved by 13.4 points (p < 0.001). Conclusion: Experience with the PASCAL transcatheter valve repair system in a European post-market setting confirms favorable safety and effectiveness at 30 days. TR significantly reduced, and clinical, functional, and quality-of-life outcomes significantly improved. This study is ongoing. Clinical Trial Registration: The study is ongoing and registered on ClinicalTrials.gov as NCT04614402. The current analysis is an interim report.

BACKGROUND: Severe tricuspid regurgitation (TR) has limited treatment options and is associated with high morbidity and mortality. AIMS: We evaluated the safety and effectiveness of the Cardioband tricuspid valve reconstruction system from the ongoing European single-arm, multicentre, prospective TriBAND post-market clinical follow-up study. METHODS: Eligible patients had chronic symptomatic functional TR despite diuretic therapy and were deemed candidates for transcatheter tricuspid repair by the local Heart Team. RESULTS: Sixty-one patients had ≥severe functional TR. At baseline, 85% of patients were in NYHA Class III-IV, 94% had ≥severe TR (core laboratory-assessed) with 6.8% EuroSCORE II and 53% LVEF. Device success was 96.7%. At discharge, 59% (p

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450–1098) ml/m in Null/null, 403 (260–538) ml/m in Null/mis, 230 (169–357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150–267) ml/m in CKD stage 1, 472 (266–880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies. © 2021, The Author(s)., ESPN 2014.2; PKD Foundation, PKDF; Bundesministerium für Bildung und Forschung, BMBF: 01GM1515, 01GM1903; Universität zu Köln, UoC; Marga und Walter Boll-Stiftung; Universitätsklinikum Köln, We thank the German Society for Pediatric Nephrology (GPN), the ESCAPE Network, and the European Society for Paediatric Nephrology (ESPN; Working Groups CAKUT and Inherited Renal Diseases) for their support. ML was supported by grants of the GPN, ESPN (Grant ESPN 2014.2), and the German PKD foundation. KB and ML were supported by the Medical Faculty of the University of Cologne (Koeln Fortune program), and the Marga and Walter Boll-Foundation. FS and ML are supported by the German Federal Ministry of Research and Education (BMBF grant 01GM1515 and 01GM1903). This work was generated within the European Reference Network for Rare Kidney Disorders (ERKNet).

PCDH12 is a member of the non-clustered protocadherin family of calcium-dependent cell adhesion proteins, which are involved in the regulation of brain development and endothelial adhesion. To date, only 15 families have been reported with PCDH12 associated disease. The main features previously associated with PCDH12 deficiency are developmental delay, movement disorder, epilepsy, microcephaly, visual impairment, midbrain malformations, and intracranial calcifications. Here, we report novel clinical features such as onset of epilepsy after infancy, episodes of transient developmental regression, and dysplasia of the medulla oblongata associated with three different novel truncating PCDH12 mutations in five cases (three children, two adults) from three unrelated families. Interestingly, our data suggests a clinical overlap with interferonopathies, and we show an elevated interferon score in two pediatric patients. This case series expands the genetic and phenotypic spectrum of PCDH12 associated diseases and highlights the broad clinical variability.

OBJECTIVE The construct of Patient Competencies (PCs) has been suggested to allow a more comprehensive understanding of cancer patients' abilities to confront emotion- and problem-focused coping tasks arising from the diagnosis, treatment and survivorship of cancer. While providing a reliable and valid measure of PCs, research thus far has not clarified whether PCs change across time and/or through intervention. This study asks whether PCs change during oncological inpatient rehabilitation and beyond. METHODS N = 377 breast, colorectal, and prostate cancer patients from clinics for oncological rehabilitation were included to complete self-report measures of PC, coping and self-efficacy for coping with cancer at the beginning and the end of rehabilitation and 9 months afterward. In order to determine differences between tumor diagnostic groups and changes across time 3 (tumor site) x 3 (time) repeated measures analyses of variance were computed. RESULTS Tumor diagnostic groups differed only marginally in PCs, coping self-efficacy and coping. The PCs of self-regulation and managing distress and coping self-efficacy improved slightly during rehabilitation but returned to initial levels at 9 months. Differential improvement was evident in the competencies of seeking information and interest in social services. Two of five coping behaviors decreased markedly from the end of rehabilitation to follow-up. CONCLUSIONS This study suggests that oncological inpatient rehabilitation may contribute to advancing PCs, albeit to a limited extent. Aside from addressing conceptual, diagnostic and measurement issues, future research should clarify which interventions may be most effective for advancing problem- and emotion-focused PCs.

This study aimed to improve echocardiographic assessment of pulmonary hypertension (PH) in patients presenting with severe tricuspid regurgitation (TR).Echocardiographic assessment of PH in patients with severe TR carries several pitfalls for underestimation, hence concealing the true severity of PH in very sick patients in particular, and ultimately obscuring the impact of PH on survival after transcatheter tricuspid valve intervention (TTVI).All patients in this study underwent TTVI for severe TR between 2016 and 2020. To predict the mean pulmonary artery pressure (mPAP) solely based on echocardiographic parameters, we trained an extreme gradient boosting (XGB) algorithm. The derivation cohort was constituted by 116 out of 162 patients with both echocardiography and right heart catheterization data, preprocedurally obtained, from a bicentric registry. Moreover, 142 patients from an independent institution served for external validation.Systolic pulmonary artery pressure was consistently underestimated by echocardiography in comparison to right heart catheterization (40.3 ± 15.9 mm Hg vs 44.1 ± 12.9 mm Hg; P = 0.0066), and the assessment was most discrepant among patients with severe defects of the tricuspid valve and impaired right ventricular systolic function. Using 9 echocardiographic parameters as input variables, an XGB algorithm could reliably predict mPAP levels (R = 0.96, P 2.2 × 10PH in patients with severe TR can be reliably assessed based on echocardiographic parameters in conjunction with an XGB algorithm, and elevations in predicted mPAP levels translate into increased mortality after TTVI.

BackgroundThe cellular mechanisms involved in the lack of protective antibody response after hepatitis B vaccination are still rather unclear. Regulatory B cells (Breg) known as modulators of B-and T-cell responses may contribute to poor vaccine responsiveness. The current study aimed to investigate the role of regulatory B cells (Breg) in hepatitis B vaccine non-responsiveness after immunization with second- or third-generation hepatitis B vaccines.MethodWe performed comparative phenotypic and frequency analysis of Breg subsets (CD24+CD27+ and CD24highCD38high Breg) in second-generation hepatitis B vaccine non-responders (2nd HBvac NR, n = 11) and responders (2nd HBvac R, n = 8) before (d0), on day 7 (d7), and 28 (d28) after booster vaccination. Cryopreserved peripheral blood mononuclear cells were stimulated ex vivo with a combination of CpG, PMA, and Ionomycin (CpG+P/I) and analyzed for numbers and IL-10 expression levels of Breg by flow cytometry-based analyses.ResultsFlow cytometry-based analyses revealed elevated frequencies of CD24+CD27+ Breg at all time points and significantly higher frequencies of CD24highCD38high Breg on d0 (p = 0.004) and 28 (p = 0.012) in 2nd HBvac NR compared to 2nd HBvac R. In parallel, we observed significantly lower levels of CpG+P/I-induced IL-10 expression levels of CD24+CD27+ and CD24highCD38high Breg (d0: p < 0.0001; d7: p = 0.0004; d28: p = 0.0003 and d0: p = 0.016; d7: p = 0.016, respectively) in 2nd HBvac NR compared to 2nd HBvac R before and after booster immunization. Frequencies of CD24+CD27+ and CD24highCD38high Breg significantly decreased after third-generation hepatitis B booster vaccination (d7: p = 0.014; d28: p = 0.032 and d7: p = 0.045, respectively), whereas IL-10 expression levels of both Breg subsets remained stable.ConclusionHere we report significantly higher frequencies of CD24highCD38high Breg in parallel with significantly lower IL-10 expression levels of CD24+CD27+ and CD24highCD38high Breg in 2nd HBvac NR compared to 2nd HBvac R. Anti-HBs seroconversion accompanied by a decrease of Breg numbers after booster immunization with a third-generation hepatitis B vaccine could indicate a positive effect of third-generation hepatitis B vaccines on Breg-mediated immunomodulation in hepatitis B vaccine non-responders.

Background: Given their advanced age and high comorbidity, individual risk assessment is crucial in patients undergoing transcatheter mitral and tricuspid valve repair. Therefore, we evaluated the use of a comprehensive geriatric assessment score, the multidimensional prognostic index (MPI), for risk stratification in these patients. Methods: We conducted a prospective, observational single-center study, including 226 patients undergoing percutaneous repair for mitral or tricuspid regurgitation. The MPI was calculated preprocedural and covers 8 domains (activities of daily living, instrumental activities of daily living, mental status, nutrition, risk of pressure ulcers, comorbidity, medication, and marital/cohabitation status). We sought to identify an association of MPI score with procedural outcomes and 6-month mortality. Results: A total of 53.1% of patients were stratified as low risk according to MPI (MPI-1 group), 44.2% as medium risk (MPI-2 group), and 2.7% as high risk (MPI-3 group). Procedural efficacy and safety were similar between groups. The estimated survival rate at 6 months was 97±2% in MPI-1 group, 79±4% in MPI-2 group (hazard ratio, 6.90 [95% CI, 2.36–12.2]; P ≤0.001) and 50±20% in MPI-3 group (hazard ratio, 20.3 [95% CI, 4.51–91.3]; P P ≤0.001) for death after 6 months. The risk association of the MPI with mortality remained significant in multivariate analysis including risk factors, such as peripheral artery disease and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Conclusions: A comprehensive geriatric assessment with the MPI score provides additional information on mortality risk beyond established cardiovascular risk factors.

Background: Treatment options for secondary tricuspid regurgitation (TR) remain limited. Early real-world data of a new percutaneous direct annuloplasty system for tricuspid repair were examined. Methods: The first 60 patients treated with the Cardioband tricuspid valve repair system at 4 centers were included in this retrospective study. The primary efficacy end point was technical success with reduction of TR ≥2 grades at discharge. Combined primary safety end point was major adverse events (death, myocardial infarction, cardiothoracic surgery, and stroke) at 30 days. Results: Median patient age was 76 years (73–82), median EuroScore II was 3.9% (2.2–8.1), heart failure with preserved ejection fraction was present in 78%, and 81.7% were in the New York Heart Association class III/IV. Massive or torrential TR was found in 51.7%, and severe TR in 48.3%. The primary efficacy end point was achieved in 45%, while 60.3% of patients had less-than-severe TR at discharge. Vena contracta was reduced by 47% from 12.9±4.8 to 7.0±3.4 mm ( P P P =0.817) when comparing procedure numbers 11 or more to the earliest 5 procedures per center. Conclusions: This first real-world experience suggests that transcatheter treatment of advanced secondary TR using direct annuloplasty is feasible and reasonably safe early in the learning curve, with significant symptomatic benefit. Further studies are warranted to provide data on long-term outcome and patient prognosis.

Our purpose was to investigate whether liver stereotactic body radiation therapy treatment planning can be harmonized across different treatment planning systems, delivery techniques, and institutions by using a specific prescription method and to minimize the knowledge gap concerning intersystem and interuser differences. We provide best practice guidelines for all used techniques.A multiparametric specification of target dose (gross target volume [GTV]GTVThis study showed the feasibility of harmonizing liver stereotactic body radiation therapy treatment plans across different treatment planning systems and delivery techniques when a sufficient set of clinical goals is given.

Neuroblastomas are tumors of the sympathetic nervous system that arise from the sympathetic trunk and adrenal glands. Tissue compositions, molecular genetics, and overall prognosis are heterogeneous. With an incidence of 1:6000, neuroblastomas account for 5.5% of childhood tumors. They usually occur in children up to preschool age with the mean age of 14 months. Adults are very rarely affected. Imaging, especially magnetic resonance imaging (MRI), plays an essential role in diagnosis, risk stratification, and therapy control.Based on a selective literature search in the PubMed database, the national and international societies' guidelines and study protocols, the imaging standards and the latest developments are presented.Imaging plays a key role in neuroblastomas due to the heterogeneous prognosis and the resulting very different therapy. A high degree of standardization in implementation and interpretation is important in every phase of the disease process. Sonography, MRI with diffusion weighting, andHINTERGRUND: Neuroblastome sind Tumoren des sympathischen Nervensystems, die im Bereich des Grenzstrangs und der Nebennieren wachsen. Sie sind bezüglich ihrer gewebespezifischen Zusammensetzungen, ihrer Molekulargenetik und damit insgesamt auch ihrer Prognose sehr unterschiedlich. Bei einer Inzidenz von 1:6000 machen die Neuroblastome einen Anteil von 5,5 % der kindlichen Tumoren aus. Sie treten zumeist bis zum Vorschulalter auf, das mittlere Erkrankungsalter beträgt 14 Monate. Erwachsene sind sehr selten betroffen. Die radiologische Bildgebung, insbesondere die Magnetresonanztomographie (MRT), spielt für die Diagnose, die Risikostratifizierung und die Therapiekontrolle eine essenzielle Rolle.Auf der Basis selektiver Literaturrecherche in der Datenbank PubMed, der Leitlinien und Studienprotokolle der nationalen und internationalen Fachgesellschaften werden die bildgebenden Standards sowie die neuesten Entwicklungen dargestellt.Die Bildgebung nimmt beim Neuroblastom aufgrund der heterogenen Prognose und der daraus resultierenden sehr unterschiedlichen Therapie eine maßgebende Rolle ein. Ein hohes Maß an Standardisierung bei der Durchführung und Interpretation sind in jeder Phase des Krankheitsverlaufs von entscheidender Bedeutung. Die Sonographie, die MRT mit Diffusionsgewichtung sowie die 123I-mIBG-SPECT sind hierbei die wesentlichen Bausteine der Diagnostik. Das Ausmaß der Diffusionsrestriktion zur Abschätzung des Ausreifungsgrads und zur Beurteilung des Therapieansprechens gewinnt zunehmend Bedeutung in der klinischen Routine. Die Positronenemissionstomographie (PET) ist bisher meist noch komplementär. Neu entwickelte PET-Tracer können eine umfassende Diagnostik gewährleisten und auch im Rahmen von Theranostik eine große Rolle spielen.

The concern of higher radiation exposure during cryoballoon ablation (CBA) compared with radiofrequency ablation for atrial fibrillation (AF) was raised before. Previously, we compared CBA plus intracardiac echocardiography (ICE) to our former standard approach without ICE. A substantial reduction of radiation exposure without compromising safety or outcome was observed. We now investigate if at all and possibly to which amount radiation reduction can be achieved with growing experience. We retrospectively analysed procedure time, dose area product (DAP), fluoroscopy time (FT) and contrast media (CM) use for all patients receiving CBA between 2013 and 2017 for AF. In 1131 procedures, procedure time decreased significantly between 2013 and 2017 (2013 111 ± 26 min, 2017 99 ± 25 min, p = 0.005). DAP halved between 2013 and 2014 without further significant decline (2013 1428 ± 1276 cGycm2, 2014 725 ± 551 cGycm2, p

OBJECTIVE To assess the feasibility of performing dose measurements in the target (prostate) and an adjacent organ at risk (rectum) using polymer dosimetry gel and thermoluminescence detectors (TLDs) in an anthropomorphic, deformable, and multimodal pelvis phantom (ADAM PETer). METHODS The 3D printed prostate organ surrogate of the ADAM PETer phantom was filled with polymer dosimetry gel. Nine TLD600 (LiF:Mg,Ti) were installed in 3 × 3 rows on a specifically designed 3D-printed TLD holder. The TLD holder was inserted into the rectum at the level of the prostate and fixed by a partially inflated endorectal balloon. Computed tomography (CT) images were taken and treatment planning was performed. A prescribed dose of 4.5 Gy was delivered to the planning target volume (PTV). The doses measured by the dosimetry gel in the prostate and the TLDs in the rectum ("measured dose") were compared to the doses calculated by the treatment planning system ("planned dose") on a voxel-by-voxel basis. RESULTS In the prostate organ surrogate, the 3D-γ-index was 97.7% for the 3% dose difference and 3 mm distance to agreement criterium. In the center of the prostate organ surrogate, measured and planned doses showed only minor deviations (

BACKGROUND: The Cardioband tricuspid valve reconstruction system is a size-adjustable tricuspid reconstruction device for interventional treatment of tricuspid regurgitation (TR). Contraction of the device after successful implantation can be associated with an acute deformation of the right coronary artery (RCA). AIMS: The aim of this study was to provide data on the persistence and clinical significance of acute RCA deformation following Cardioband implant procedures. METHODS: Data from all patients with intraprocedural RCA deformation during Cardioband implantation were collected from four centres between October 2018 and January 2020. Control angiographies were performed in all of these patients before discharge. RESULTS: RCA deformation occurred in 14 out of 51 patients. Follow-up coronary angiography showed a complete resolution of deformation in all cases while patients remained clinically asymptomatic and had an uneventful post-interventional course. Intraprocedural coronary stent implantation was performed in two of the earlier cases according to the personal assessment of the implanters. CONCLUSIONS: RCA deformation is relatively frequent following interventional tricuspid annuloplasty but appears to be completely reversible in the absence of flow impairment or vascular damage. Based on our early experience watchful waiting is the most appropriate strategy to avoid unnecessary coronary interventions.

Significance Evolution has shaped the human brain as a “single-trial” processor reacting fast and reliably to environmental threats. The noninvasive analysis of its electrical activity commonly draws on electroencephalography/magnetoencephalography (EEG/MEG) with a millisecond time resolution suitable even for short-lived neuronal output spikes. However, while standard EEG/MEG can detect very small evoked population spikes, it does so only after averaging over hundreds of trials. Here, MEG based on an ultralow-noise superconducting quantum interference device (SQUID) is shown to enable the first noninvasive single-trial characterization of human cortical population spikes, revealing amplitudes highly variable between trials and intertrial correlated response latencies. Thus, by expanding the scope of noninvasive neurotechnology, ultralow-noise MEG can support single-trial analyses of input–output characteristics in the human brain., Neuronal spiking is commonly recorded by invasive sharp microelectrodes, whereas standard noninvasive macroapproaches (e.g., electroencephalography [EEG] and magnetoencephalography [MEG]) predominantly represent mass postsynaptic potentials. A notable exception are low-amplitude high-frequency (∼600 Hz) somatosensory EEG/MEG responses that can represent population spikes when averaged over hundreds of trials to raise the signal-to-noise ratio. Here, a recent leap in MEG technology—featuring a factor 10 reduction in white noise level compared with standard systems—is leveraged to establish an effective single-trial portrayal of evoked cortical population spike bursts in healthy human subjects. This time-resolved approach proved instrumental in revealing a significant trial-to-trial variability of burst amplitudes as well as time-correlated (∼10 s) fluctuations of burst response latencies. Thus, ultralow-noise MEG enables noninvasive single-trial analyses of human cortical population spikes concurrent with low-frequency mass postsynaptic activity and thereby could comprehensively characterize cortical processing, potentially also in diseases not amenable to invasive microelectrode recordings.

Background Evidence from in vitro and rodent studies suggests that leptin, a key signal of long-term energy reserves, promotes IGF1 synthesis and linear growth. This effect of leptin has not been fully investigated in humans. The aim of our study was to investigate the effect of leptin substitution on growth factors and linear growth in children with congenital leptin deficiency (CLD). Methods In this cohort study we included eight pediatric patients (six males), age 0.9–14.8 years, who were diagnosed with CLD and received leptin substitution at our University Medical Center. We calculated standard deviation scores (SDS) for serum levels of IGF1 and IGFBP3, IGF1/IGFBP3 molar ratio, and height at baseline (T0) and 12 months (T12) after the initiation of substitution with metreleptin. Results All patients had severe obesity (BMI-SDS mean ± SD: 4.14 ± 1.51) at T0 and significant BMI-SDS reduction to 2.47 ± 1.05 at T12. At T0, all patients were taller than the mid-parental median, yet had low IGF1 and IGF1/IGFBP3 molar ratios (IGF1-SDS$$\overline x$$ x ¯ T0: −1.58 ± 0.92, IGF1/IGFBP3 molar ratio-SDS$$\overline x$$ x ¯ T0: −1.58 ± 0.88). At T12, IGF1-SDS increased significantly (∆T0–12: 1.63 ± 1.40, p = 0.01), and IGFBP3-SDS and IGF1/IGFBP3 molar ratio-SDS showed a trend toward an increase. In the three children within the childhood growth period (post-infancy, pre-puberty) height-SDS increased (∆height-SDST0–12: 0.57 ± 0.06, p = 0.003) despite substantial weight loss. Conclusions These results in CLD patients are contrary to observations in children with idiopathic obesity who typically have above-mean IGF1 levels that decrease with weight loss, and therefore suggest that leptin increases IGF1 levels and promotes linear growth.

Background Apart from biologics, no systemic drugs are approved in Europe for children with moderate-to-severe psoriasis. Retrospective observational studies have shown promising results for fumaric acid esters (FAE) in this setting. Objectives To show superiority of FAE over placebo in terms of treatment response after 20 weeks in children and adolescents aged 10–17 years. Methods In a multicentre, randomized, double-blind, placebo-controlled phase IIIb study, patients aged 10–17 years with moderate-to-severe plaque psoriasis requiring systemic therapy were randomized 2 : 1 to receive FAE (n = 91) or placebo (n = 43) over 20 weeks, followed by an open-label FAE treatment phase. The coprimary endpoints were ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and Physician’s Global Assessment (PGA) score of 0 or 1 (clear or almost clear) at week 20. The study was registered with EudraCT number 2012-000035-82. Results At week 20, 55% [95% confidence interval (CI) 0·44–0·65] of FAE-treated patients achieved a PASI 75 response vs. 19% (95% CI 0·08–0·33) in the placebo group (absolute difference 36%, 95% CI 0·20–0·53; P < 0·001). In total, 42% (95% CI 0·32–0·53) in the FAE group vs. 7% (95% CI 0·01–0·19) in the placebo group achieved a PGA score of 0 or 1 at week 20 (absolute difference 35%, 95% CI 0·21–0·49; P < 0·001). During the double-blind period, drug-related adverse events occurred more frequently in patients receiving FAE compared with placebo (76% vs. 47%). Gastrointestinal disorders were the most common adverse events. Conclusions FAE administered over a period of 20 weeks demonstrated a better response than placebo; the difference was statistically significant and clinically meaningful. Application up to 40 weeks was generally well tolerated. However, further studies are required.

Background X-linked hypohidrotic ectodermal dysplasia (XLHED), a rare genetic disorder, affects the normal development of ectodermal derivatives, such as hair, skin, teeth, and sweat glands. It is caused by pathogenic variants of the gene EDA and defined by a triad of hypotrichosis, hypo- or anodontia, and hypo- or anhidrosis which may lead to life-threatening hyperthermia. Although female carriers are less severely affected than male patients, they display symptoms, too, with high phenotypic variability. This study aimed to elucidate whether phenotypic differences in female XLHED patients with identical EDA genotypes might be explained by deviating X-chromosome inactivation (XI) patterns. Methods Six families, each consisting of two sisters with the same EDA variant and their parents (with either mother or father being carrier of the variant), participated in this study. XLHED-related data like sweating ability, dental status, facial dysmorphism, and skin issues were assessed. We determined the women`s individual XI patterns in peripheral blood leukocytes by the human androgen receptor assay and collated the results with phenotypic features. Results The surprisingly large inter- and intrafamilial variability of symptoms in affected females was not explicable by the pathogenic variants. Our cohort showed no higher rate of nonrandom XI in peripheral blood leukocytes than the general female population. Furthermore, skewed XI patterns in favour of the mutated alleles were not associated with more severe phenotypes. Conclusions We found no evidence for preferential XI in female XLHED patients and no distinct correlation between XLHED-related phenotypic features and XI patterns. Phenotypic variability seems to be evoked by other genetic or epigenetic factors.

Psoriasis has a strong impact on patients' lives and is closely linked to psychiatric disorders such as depression, anxiety and substance-related disorders, especially dependence on alcohol and nicotine. The aim of our study was to systematically assess the psychiatric comorbidity and possible associations between psychological factors, disease severity and dermatology-related quality of life in psoriatic patients from a high-need university hospital dermatology department. Consecutive psoriatic patients (new and permanent patients) at the Department of Dermatology, University Hospital Essen, Germany, were asked to fill out a paper-based questionnaire. In the first part of the questionnaire, baseline demographics, pre-existing mental disorders and data on substance abuse were collected. In the second part of the questionnaire, mental and physical health was explored using different validated self-rating tests. The current Psoriasis Area and Severity Index (PASI) was documented by a dermatologist. Patients with signs of mental disorders were offered an appointment with a board-certified psychiatrist. Between August 2016 and February 2019, 228 consecutive psoriatic patients (138 men [60.5%], 90 women [39.5%]; mean age, 48.3 years [standard deviation, 13.6; range, 18-80]) participated in the study. Approximately 50% of the patients had evidence of suffering from mental health problems, mostly depression and anxiety, as well as alcohol dependence. Patients with a PASI of 3 or more showed a statistically significant reduced Dermatology Life Quality Index (DLQI) and a significantly impaired psychological as well as physical quality of life. DLQI correlated with all psychological test results. The data indicate a significant psychological burden in a tertiary psoriatic population. Our findings underscore the importance of screening psoriatic patients for psychiatric disorders, with a focus on depression, anxiety as well as alcohol and nicotine dependence, in a multidimensional approach involving psychiatrists and psychologists.

Objectives: The objective of this study was to evaluate the MICRONAUT-S Carbapenemases Detection microtiter plate assay for detection of carbapenemases and Ambler class determination. Methods: The MICRONAUT-S Carbapenemases Detection microtiter plate was tested using a challenging collection of 154 carbapenemase-producing and 150 carbapenemase-negative clinical strains of Enterobacterales and Pseudomonas aeruginosa. Results: The MICRONAUT-S Carbapenemases Detection assay was able to detect 148/154 carbapenemase producers correctly, while 5/150 non-carbapenemase producing isolates were tested false-positive. This resulted in an overall sensitivity of 96 % and a specificity of 97 %. Regarding detection of the class of carbapenemase, sensitivities and specificities were 93 %/100 %, 96 %/100 and 97 %/99 % for class A (n = 27), class B (n = 54) and class D (n = 73) carbapenemases, respectively. Conclusions: The MICRONAUT-S Carbapenemases Detection microtiter plate represents an easy-to-use and valuable tool for accurate and reliable detection of carbapenemases. In addition, it provides identification of the class of carbapenemase in most cases which can provide significant therapy guidance.