Neuauftreten von Vorhofflimmern nach perkutanem Verschluss des Persistierenden Foramen Ovale (PFO) bei 1349 Patienten

Hintergrund: Bisher gibt es nur wenige Daten bezüglich des Neuauftretens von Vorhofflimmern nach dem Verschluss des persistierenden Foramen ovale (PFO). Methodik: In der Zeit von 1994 bis Januar 2007 wurde bei 1349 Patienten, im Alter von 17 bis 85 Jahren (mittleres Alter 50 Jahre), ein PFO kathetertechnisch verschlossen. Vor der Intervention erlitten 696 einen ischämischen Schlaganfall, 610 eine transitorisch Ischämische Attacke (TIA), 22 eine periphere Embolie, 8 Migräneattacken und 13 Patienten eine Dekompressionskrankheit. Es wurden 535 Amplatzer-, 379 Helex-, 270 STARFlex-, 131 Premere-, 9 SIDERIS-, 9 ASDOS-, 7 CardioSEAL-, 5 AngelWings- und 4 PFO-Star-Okkluder implantiert. Die Nachuntersuchungen beinhalteten ein EKG nach einem, drei und sechs Monaten. Jedes Jahr wurde ein EKG wiederholt und Fragebögen an die Patienten verschickt. Ergebnisse: Die Nachbeobachtungszeit betrug im Mittel 38,1 ± 28 Monate. 1324 von 1334 (99.3%) nahmen an der 6-Monats-Nachuntersuchung, 1198 von 1220 (98.2%) an der 1-Jahres-Nachuntersuchung -, 747 von 778 (96%) an der 3-, 374 von 393 (95.2%) an der 5- und 21 von 21 (100%) an der 10-Jahres-Nachuntersuchung teil. Vorhofflimmern trat bei 50 Patienten, kombiniert mit Vorhofflattern bei zwei weiteren, nur Vorhofflattern bei einem Patient auf (insgesamt 53 von 1349, 3,9%). Bei 33 Patienten wurde das Vorhofflimmern innerhalb der ersten vier Wochen diagnostiziert, bei 8 Patienten innerhalb sechs Monaten, bei 12 Patienten noch später. 23 Patienten entwickelten paroxysmales, 4 von ihnen rezidivierend, 28 persistierendes und 2 permanentes Vorhofflimmern. Die Inzidenz beim Amplatzer-Okkluder betrug 3% (16/535), 1,8% (7/379) beim Helex-, 10% (27/270) beim STARFlex-, 1,5% (2/131) beim Premere-, 11% (1/9) beim SIDERIS-, 0/9 beim ASDOS-, 0/7 beim CardioSEAL-, 0/5 beim AngelWings- und 0/4 beim PFO-Star-Okkluder. Der Unterschied zwischen dem STARFlex- versus Premere- (+), Amplatzer- (+) und Helex- (+) Okkluder war statistisch signifikant (jedes p<0,05). Bei 13 Patienten wurde Vorhofflimmern während einer Routinenachuntersuchung entdeckt, die anderen 40 Patienten waren symptomatisch. Bei 22 Patienten wurde der Sinusrhythmus mittels medikamentöser Konversion erreicht, bei 7 Patienten mittels elektrischer Kardioversion. 20 Patienten erhielten eine medikamentöse Prophylaxe, 22 zusätzlich Marcumar. 1 Patient erlitt eine TIA, 2 Patienten einen Schlaganfall (1 während einer Episode von Vorhofflimmern). Das Alter war ein positiver Prädiktor für Vorhofflimmern (p=0,0009). Bei 3 Patienten wurde ein Thrombus auf dem Okkluder diagnostiziert. Bei 1 von 3 Patienten wurde Vorhofflimmern eine Woche vor Diagnosestellung des Thrombus entdeckt, bei 2 von 3 Patienten wurde Vorhofflimmern und Thrombus zeitgleich diagnostiziert. Patienten mit Vorhofflimmern (3/53) haben eine signifikant höhere Inzidenz (p=0,02) Thromben zu entwickeln, verglichen mit Patienten ohne Vorhofflimmern (13/1296). Schlussfolgerung: Permanentes oder symptomatisches Vorhofflimmern ist eine seltene Komplikation nach PFO-Verschluss. Es trat häufiger beim STARFlex-Okkluder auf. Für gewöhnlich war es vorübergehend, es kann jedoch zur Thrombusbildung auf dem Okkluder führen. Eine frühzeitige Diagnostik und Behandlung sind wichtig.Background: There is limited information available about the incidence of atrial fibrillation after transcatheter PFO-closure. Methods: 1349 patients, age 17 to 85 years (mean 50), underwent PFO-closure at our center with one of the in Europe approved devices from August 1994 through January 2007. Before intervention 610 patients had a TIA, 696 a stroke, 22 a peripheral embolism, 8 migraine, 13 a decompression illness. 535 Amplatzer, 379 Helex, 270 STARFlex, 131 Premere, 9 SIDERIS, 9 ASDOS, 7 CardioSEAL, 5 AngelWings and 4 PFO-Star have been implanted. Follow-up included history and ECG after 1, 3 and 6 months, questionnaires yearly thereafter. Results: Mean follow-up of all patients was 38.1 ± 28 months. 1324 of 1334 (99.3%) underwent 6 months-, 1198/1220 (98.2%) 1 year-, 747/778 (96%) 3 year-, 374/393 (95.2%) 5 year- and 21/21 (100%) 10 year follow-up. Atrial fibrillation was diagnosed in 50 out of 1349, atrial fibrillation combined with atrial flutter in 2, only atrial flutter in one (totally 53/1349, 3.9%). In 33 patients it was diagnosed within four weeks after PFO-closure, in 8 patients within 6 months, in 12 patients later on. Twenty-three patients developed paroxysmal, 4 of them recurrent, 28 persistent and 2 permanent atrial fibrillation. The incidence of atrial fibrillation was 3% (16/535) in the Amplatzer, 1.8% (7/379) in the Helex, 10% (27/270) in the STARFlex, 1.5% (2/131) in the Premere, 11% (1/9) in the SIDERIS, 0/9 in the ASDOS, 0/7 in the CardioSEAL, 0/5 in the AngelWings and 0/4 in the PFO-Star device. The difference between STARFlex vs. Premere (+), Amplatzer (+) and Helex (+) was statistically significant (each p<0.05) in patients who had at least the 6 months follow-up. In 13 patients atrial fibrillation or flutter was detected during routine follow-up examination, 40 patients were symptomatic. In 22 patients sinus rhythm was achieved by medical conversion, in 7 by electroshock. Twenty received medical prophylaxis, 22 additionally coumadin. One patient developed a TIA, 2 patients a stroke (1 during an episode of atrial fibrillation). The age may be a possible predictor to develop atrial fibrillation (p=0.0009). In 3 patients thrombi were detected during follow-up. In 1/3 atrial fibrillation was diagnosed one week before the thrombi was detected, in 2/3 thrombi and atrial fibrillation were diagnosed at the same time. Patients with atrial fibrillation had a statistically significant (p=0.02) higher incidence of thrombi on the device (3/53) than patients without atrial fibrillation (13/1296). Conclusion: Permanent or symptomatic atrial fibrillation is a rare complication of PFO-closure. It was more frequent in STARFlex. It is usually transient, but it may cause thrombus formation on the device. Early diagnosis and treatment are important

Dupilumab but not cyclosporine treatment shifts the microbiome toward a healthy skin flora in patients with moderate‐to‐severe atopic dermatitis

Background: Atopic dermatitis (AD) patients display an altered skin microbiome which may not only be an indicator but also a driver of inflammation. We aimed to investigate associations among AD patients' skin microbiome, clinical data, and response to systemic therapy in patients of the TREATgermany registry. Methods: Skin swabs of 157 patients were profiled with 16S rRNA gene amplicon sequencing before and after 3 months of treatment with dupilumab or cyclosporine. For comparison, 16s microbiome data from 258 population-based healthy controls were used. Disease severity was assessed using established instruments such as the Eczema Area and Severity Index (EASI). Results: We confirmed the previously shown correlation of Staphylococcus aureus abundance and bacterial alpha diversity with AD severity as measured by EASI. Therapy with Dupilumab shifted the bacterial community toward the pattern seen in healthy controls. The relative abundance of Staphylococci and in particular S. aureus significantly decreased on both lesional and non-lesional skin, whereas the abundance of Staphylococcus hominis increased. These changes were largely independent from the degree of clinical improvement and were not observed for cyclosporine. Conclusions: Systemic treatment with dupilumab but not cyclosporine tends to restore a healthy skin microbiome largely independent of the clinical response indicating potential effects of IL-4RA blockade on the microbiome

Interfacial properties of binary azeotropic mixtures of simple fluids: Molecular dynamics simulation and density gradient theory

Interfacial properties of binary azeotropic mixtures of Lennard-Jones truncated and shifted fluids were studied by molecular dynamics (MD) simulation and density gradient theory (DGT) in combination with an equation of state. Three binary mixtures were investigated, which differ in the energetic cross interaction parameter that yields different types of azeotropic behavior. This study covers a wide temperature and composition range. Mixture A exhibits a heteroazeotrope at low temperatures, which changes to a low-boiling azeotrope at high temperatures, mixture B exhibits a low-boiling azeotrope, and mixture C exhibits a high-boiling azeotrope. The phase behavior and fluid interfacial properties as well as their relation were studied. Vapor–liquid, liquid–liquid, and vapor–liquid–liquid equilibria and interfaces were considered. Density profiles, the surface tension, the interfacial thickness, as well as the relative adsorption and enrichment of the components at the interface were studied. The results obtained from the two independent methods (MD and DGT) are overall in good agreement. The results provide insights into the relation of the phase behavior, particularly the azeotropic behavior, of simple fluid mixtures and the corresponding interfacial properties. Strong enrichment was found for the mixture with a heteroazeotrope in the vicinity of the three-phase equilibrium, which is related to a wetting transition

Combined treatment of hidradenitis suppurativa with intense pulsed light (IPL) and radiofrequency (RF)

Background: Hidradenitis suppurativa is a chronic inflammatory disease with high burden. Treatment options are often unsatisfactory. We assessed the effect of a combination therapy of intense pulsed light (IPL) and radiofrequency (RF). Methods: The explorative study included 47 patients and was performed as a prospective, monocentric, randomized, three-arm parallel-group design trial with a prior 12?weeks observation period. Treatment arms were IPL and RF monotherapies or IPL?+?RF combination therapy. After 12?weeks, all patients received IPL?+?RF for additional 12?weeks (cross-over). Primary endpoint was the change in active lesion numbers, secondary endpoint the change in Dermatology Quality of Life Index (DLQI). Results: After 12?weeks, active lesion counts of the IPL?+?RF group decreased more than in the IPL group (p?=?.044); the decrease in DLQI was significantly higher in the IPL?+?RF and RF groups compared to IPL. Prolonged 24-week treatment with IPL?+?RF obtained better results as 12?weeks. Overall, disease burden after 24?weeks of treatment compared to disease fluctuation during the observation period was significantly lower (change in active lesions ?3.6, p?=?.001; in DLQI ?5.2, p?=?.003). Conclusions: IPL?+?RF treatment appears to represent a promising therapeutic option that leads to reduction of disease activity without severe side effects

LAight (R) Therapy Is an Effective Treatment Option to Maintain Long-Term Remission of Hurley I and II Hidradenitis Suppurativa: Results from Period B of RELIEVE, a Multicenter Randomized, Controlled Trial

Background: Hidradenitis suppurativa is a chronic, inflammatory, burdensome skin disease where current first-line treatments are limited to topical and/or systemic antibiotics which cannot be applied for long-term disease management. Period B of the RELIEVE study analyzes whether LAight (R) therapy can sustain or even increase remission after a first topical antibiotic treatment cycle. Methods: The RELIEVE study was performed as a two-period multicenter randomized controlled trial with blinded assessment. For period A from week 0 to week 16, the 88 participating Hurley I and II patients were randomized to either a group receiving topical clindamycin 1% solution combined with 8 additional bi-weekly treatments with LAight (R) therapy (group TC + L) or a group which was treated with topical clindamycin 1% solution only (group TC). After 16 weeks, patients entered open-label period B and both groups were treated exclusively with LAight (R) therapy for an additional 16 weeks (8 sessions, group TC + L/L and group TC/L). Results: In total, 88 patients were enrolled in RELIEVE. Seventy-eight patients entered period B; 39 belonged to group TC + L/L and 39 to group TC/L. The IHS4-response at the start of period B was 62% (group TC + L/L) and 33% (group TC + L). During the 16 weeks of additional monotherapy with LAight, in both groups > 90% of patients who responded to therapy in period A maintained their IHS4-response at week 32. IHS4 response rates continued to rise up to 79% of the TC + L/L group and up to 71% of the TC/L group during period B at week 32. Achievement of HiSCR and certain patient reported outcomes confirmed primary endpoint results. Conclusion: LAight (R) therapy is an effective approved therapy option for Hurley I and II HS that can be used continuously to maintain treatment success. During 16 weeks of follow-up in period B, over 90% of patients with response after period A maintained their treatment outcome, while more than 60% of prior nonresponders gained response. The fact that LAight (R) therapy can be applied continuously, is very effective and is well tolerated makes it a valuable treatment tool in the design of HS long-term treatment modalities. (C) 2022 The Author(s).Published by S. Karger AG, Base

LAight (R) Therapy Significantly Enhances Treatment Efficacy of 16 Weeks of Topical Clindamycin Solution in Hurley I and II Hidradenitis Suppurativa: Results from Period A of RELIEVE, a Multicenter Randomized, Controlled Trial

Background: Hidradenitis suppurativa (HS) is a chronic, inflammatory, burdensome skin disease where medical first-line treatment is still limited to long-term, topical and/or systemic antibiotics. The RELIEVE study aimed at evaluating the efficacy of LAight (R) therapy - a combination of intense pulsed light and radiofrequency - as an adjunct treatment to first-line therapies in Hurley stage I and II HS. Methods: The RELIEVE study was performed as a two-period multicenter randomized controlled trial with blinded assessment. For period A from week 0 to week 16, the 88 participating subjects were randomized into either an intervention group (IG) or a control group (CG). The IG received topical clindamycin 1% solution combined with 8 additional bi-weekly treatments with LAight (R) therapy. The CG was treated with topical clindamycin 1% solution only. After 16 weeks, patients entered open-label period B and both groups were treated exclusively with LAight (R) therapy for an additional 16 weeks (8 sessions). The primary efficacy endpoint was the change in International Hidradenitis Suppurativa Score System (increment IHS4) at week 16 to baseline. Secondary endpoints were DLQI, HiSCR, Pain-NRS, and HADS. Results: In total, from the 88 patients enrolled in RELIEVE, 81 patients were included in the endpoint analysis after period A. After 16 weeks of treatment, the increment IHS4 of the group treated with the combination of LAight (R) therapy and topical clindamycin 1% solution was -7.2 +/- 6.7 (-60.0%), which was significantly higher in magnitude than the increment IHS4 in the group treated with clindamycin 1% solution alone (-1.8 +/- 5.6, -17.8%, p < 0.001). Secondary endpoints, including other clinical scores as well as patient-reported outcomes, confirmed that the efficacy of the combined treatment was superior to monotherapy. Conclusion: The results of the primary endpoint analysis of period A of the RELIEVE study show that the combined therapy with LAight (R) and topical clindamycin 1% solution, resulted in a significantly higher decrease in disease severity and an improvement of quality of life in comparison to topical clindamycin 1% solution monotherapy. Treatment was well tolerated, and side effects were all mild and transitory. These data speak for the implementation of the combined treatment as a first-line therapy in Hurley stage I and II HS. LAight (R) therapy as long-term monotherapy (results from period B), will be analyzed in a consecutive paper. (c) 2021 S. Karger AG, Base

Quality by Design (QbD) Approach for a Nanoparticulate Imiquimod Formulation as an Investigational Medicinal Product

The present article exemplifies the application of the concept of quality by design (QbD) for the systematic development of a nanoparticulate imiquimod (IMQ) emulsion gel formulation as an investigational medicinal product (IMP) for evaluation in an academic phase-I/II clinical trial for the treatment of actinic keratosis (AK) against the comparator Aldara (EudraCT: 2015-002203-28). The design of the QbD elements of a quality target product profile (QTPP) enables the identification of the critical quality attributes (CQAs) of the drug product as the content of IMQ, the particle-size distribution, the pH, the rheological properties, the permeation rate and the chemical, physical and microbiological stability. Critical material attributes (CMAs) and critical process parameters (CPPs) are identified by using a risk-based approach in an Ishikawa diagram and in a risk-estimation matrix. In this study, the identified CPPs of the wet media ball-milling process’s milling time and milling speed are evaluated in a central composite design of experiments (DoEs) approach, revealing criticality for both factors for the resulting mean particle size, while only the milling time is significantly affecting the polydispersity. To achieve a mean particle size in the range of 300–400 nm with a minimal PdI, the optimal process conditions are found to be 650 rpm for 135 min. Validating the model reveals a good correlation between the predicted and observed values. Adequate control strategies were implemented for intermediate products as in-process controls (IPCs) and quality control (QC) tests of the identified CQAs. The IPC and QC data from 13 “IMI-Gel” batches manufactured in adherence to good manufacturing practice (GMP) reveal consistent quality with minimal batch-to-batch variability

A center-based, ambulatory care concept for hidradenitis suppurativa improves patient outcomes and is also cost-effective

AbstractBackground Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting approximately 1% of the population. The patient journey through the German health care system leads to high disease burden and substantial treatment costs. The EsmAiL study showed that an innovative, interprofessional, multimodal care-concept reduces disease activity and burden of HS compared to standard care. This paper examines the costs of treating HS in Germany and compares them with those of the innovative care concept implemented in EsmAiL.Methods EsmAiL was a two-arm, multicenter, prospective randomized controlled trial including 553 adults with HS. The study was registered in the German Clinical Trials Registry (DRKS00022135). The control group (CG) remained in standard care, whereas the intervention group (IG) was referred to specialized so-called ‘acne-inversa-centres (AiZ)’ where patients were treated with a structured, interdisciplinary approach. The present paper analyses the treatment costs for a subpopulation based on health insurance cost data from the two largest German health insurers. Quality-Adjusted Life Years (QALY) was assessed based on Dermatology Life Quality Index (DLQI).Results Total annual treatment costs per patient were €3,966.07 in standard care (n = 89) and €3,974.37 in the innovative care (n = 93). The costs per additional QALY amounted to €12,698.72 in the IG. Given the conventional and established threshold of €22,600 to €33,900 per QALY, the innovative treatment in AiZ proved to be cost-effective.Conclusion Treatment costs of HS are substantial and increase with disease severity. The new form of care is cost-effective and is expected to decrease costs in the long run