Paracelsus Medical University Salzburg
  • Salzburg, Salzburg, Austria
Recent publications
Background Endovascular embolization techniques are nowadays well established in the management of acute arterial bleedings. However, the education and training of the next generation of interventionalists are still based on the traditional apprenticeship model, where the trainee learns and practices directly at the patient, which potentially affects the patient’s safety. The objective of this study was to design and develop a standardized endovascular simulation concept for the training of acute bleeding embolizations, based on real-life cases. Results An adaptable and cost-effective endovascular simulator was developed using an in-house 3D print laboratory. All thoracic and abdominal acute bleeding embolizations over more than a year with appropriate pre-interventional computed tomography scans were included to manufacture 3D printed vascular models. A peristaltic pump was used to generate pulsatile flow curves. Forty embolization cases were engaged in this study, and 27 cases were fully reproduced in the simulation setting (69.23%). The simulation success was significantly lower in pulmonary embolizations ( p = 0.031) and significantly higher in soft tissue ( p = 0.032) and coil embolizations ( p = 0.045). The overall simulation success was 7.8 out of 10 available points. Conclusions Using stereolithography 3D printing in a standardized simulation concept, endovascular embolization techniques for treating acute internal hemorrhages in the chest and abdomen can be simulated and trained based on the patient-specific anatomy in a majority of the cases and at a broad spectrum of different causes.
Background Alterations in the MYH7 gene can cause cardiac and skeletal myopathies. MYH7 -related skeletal myopathies are extremely rare, and the vast majority of causal variants in the MYH7 gene are predicted to alter the rod domain of the of ß-cardiac myosin molecule, resulting in distal muscle weakness as the predominant manifestation. Here we describe two unrelated patients harboring an in-frame deletion in the MYH7 gene that is predicted to result in deletion of a single amino acid (p.Glu500del) in the head domain of ß-cardiac myosin. Both patients display an unusual skeletal myopathy phenotype with congenital axial stiffness and muscular hypertonus, but no cardiac involvement. Results Clinical data, MRI results and histopathological data were collected retrospectively in two unrelated boys (9 and 3.5 years old). Exome sequencing uncovered the same 3-bp in-frame deletion in exon 15 (c.1498_1500delGAG) of the MYH7 gene of both patients, a mutation which deletes a highly conserved glutamate residue (p.Glu500del) in the relay loop of the head domain of the ß-cardiac myosin heavy chain. The mutation occurred de novo in one patient, whereas mosaicism was detected in blood of the father of the second patient. Both boys presented with an unusual phenotype of prenatal polyhydramnios, congenital axial stiffness and muscular hypertonus. In one patient the phenotype evolved into an axial/proximal skeletal myopathy without distal involvement or cardiomyopathy, whereas the other patient exhibited predominantly stiffness and respiratory involvement. We review and compare all patients described in the literature who possess a variant predicted to alter the p.Glu500 residue in the ß-cardiac myosin head domain, and we provide in-silico analyses of potential effects on polypeptide function. Conclusion The data presented here expand the phenotypic spectrum of mutations in the MYH7 gene and have implications for future diagnostics and therapeutic approaches.
Background Noninvasive ventilation (NIV) is a promising alternative to invasive mechanical ventilation (IMV) with a particular importance amidst the shortage of intensive care unit (ICU) beds during the COVID-19 pandemic. We aimed to evaluate the use of NIV in Europe and factors associated with outcomes of patients treated with NIV. Methods This is a substudy of COVIP study—an international prospective observational study enrolling patients aged ≥ 70 years with confirmed COVID-19 treated in ICU. We enrolled patients in 156 ICUs across 15 European countries between March 2020 and April 2021.The primary endpoint was 30-day mortality. Results Cohort included 3074 patients, most of whom were male (2197/3074, 71.4%) at the mean age of 75.7 years (SD 4.6). NIV frequency was 25.7% and varied from 1.1 to 62.0% between participating countries. Primary NIV failure, defined as need for endotracheal intubation or death within 30 days since ICU admission, occurred in 470/629 (74.7%) of patients. Factors associated with increased NIV failure risk were higher Sequential Organ Failure Assessment (SOFA) score (OR 3.73, 95% CI 2.36–5.90) and Clinical Frailty Scale (CFS) on admission (OR 1.46, 95% CI 1.06–2.00). Patients initially treated with NIV (n = 630) lived for 1.36 fewer days (95% CI − 2.27 to − 0.46 days) compared to primary IMV group (n = 1876). Conclusions Frequency of NIV use varies across European countries. Higher severity of illness and more severe frailty were associated with a risk of NIV failure among critically ill older adults with COVID-19. Primary IMV was associated with better outcomes than primary NIV. Clinical Trial Registration NCT04321265 , registered 19 March 2020, https://clinicaltrials.gov .
Context: The chemo-free immunotherapy tafasitamab + lenalidomide has been granted FDA accelerated approval and EU conditional marketing authorization for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) treatment in autologous stem cell transplant–ineligible adults. Treatment schedule optimization aims to reduce the frequency of hospital visits and decrease treatment burden and healthcare utilization. MINDway (NCT05222555) will investigate if tafasitamab administration at levels higher than the approved 12 mg/kg dose at a reduced dosing frequency maintains the benefit–risk relationship of tafasitamab + lenalidomide for patients with R/R DLBCL. Objective: To assess an optimized tafasitamab treatment schedule in patients with R/R DLBCL. Design: Open-label, multicenter, Phase Ib/II study. Setting: Currently enrolling; the planned sample size is 51 patients. Patients: Eligible patients are aged 18–80 years with histologically confirmed R/R DLBCL and 1–3 prior systemic regimens, including CD20-targeted therapy. Patients previously treated with CD19-targeted therapy or immunomodulatory imide drugs, such as lenalidomide, are excluded. Interventions: The modified dosing regimen will be investigated in a stepwise design: two sequential dose-finding cohorts (planned n=6 each) followed by an expansion cohort (planned n=39). Lenalidomide 25 mg will be administered in all cohorts on Days 1–21 of each 28-day cycle for up to 12 cycles. After Cycle 12, patients will continue tafasitamab monotherapy at the assigned dosing regimen until progression. After reviewing safety and pharmacokinetic data from Cohorts 1 and 2, patients will be enrolled in an expansion cohort to receive tafasitamab + lenalidomide (tafasitamab dose: 24 or 30 mg/kg) for further evaluation. No intra-patient dose escalation from 24 to 30 mg/kg is permitted. Main Outcome Measures: The primary endpoints are the incidence and severity of treatment-emergent adverse events. Key secondary endpoints are tafasitamab serum concentration after 3 and 12 cycles, best objective response rate, duration of response, and progression-free survival. Results: Not yet available. Conclusions: MINDway will evaluate an optimized tafasitamab dosing regimen to reduce the frequency of hospital/clinic visits for tafasitamab-treated patients with R/R DLBCL. Reducing the frequency of visits by half is expected to reduce patient burden and support long-term treatment compliance. Fewer visits may result in less exposure to hospital infections in this already susceptible population. Funding: MorphoSys AG.
Context: The Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib, was designed for high BTK specificity and minimal toxicity. SEQUOIA (NCT03336333) is a global, open-label, randomized phase 3 study in treatment-naïve patients with CLL/SLL without del(17p) who were unsuitable for fludarabine/cyclophosphamide/rituximab. Design: Patients were randomized to receive zanubrutinib (160 mg twice daily) or bendamustine (day 1-2: 90 mg/m²) and rituximab (cycle 1: 375 mg/m²; cycles 2-6: 500 mg/m²); stratification factors were age (<65 years vs ≥65 years), Binet Stage, IGHV mutation, and geographic region. Main Outcome Measures: Primary endpoint was an independent review committee (IRC)-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed (INV) PFS, overall response rate (ORR), overall survival (OS), and safety. Results: From October 31, 2017, to July 22, 2019, 479 patients were enrolled (zanubrutinib=241; BR=238). Baseline characteristics (zanubrutinib vs BR): median age, 70.0 years versus 70.0 years; unmutated IGHV, 53.4% versus 52.4%; del(11q), 17.8% versus 19.3%. With median follow-up of 26.2 months, PFS was significantly prolonged with zanubrutinib by IRC (HR 0.42; 2-sided P<.0001) and INV (HR 0.42; 2-sided P=.0001). Zanubrutinib treatment benefit occurred across age, Binet stage, bulky disease, del(11q) status, and unmutated IGHV (HR 0.24; 2-sided P<.0001), but not mutated IGHV (HR 0.67; 2-sided P=.1858). For zanubrutinib versus BR, 24-month PFS-IRC=85.5% versus 69.5%; ORR-IRC=94.6% versus 85.3%; complete response rate=6.6% versus 15.1%; ORR-INV=97.5% versus 88.7%; and 24-month OS=94.3% versus 94.6%. Select adverse event (AE) rates (zanubrutinib vs BR): atrial fibrillation (3.3% vs 2.6%), bleeding (45.0% vs 11.0%), hypertension (14.2% vs 10.6%), infection (62.1% vs 55.9%), and neutropenia (15.8% vs 56.8%). Treatment discontinuation due to AEs (zanubrutinib vs BR)=20 patients (8.3%) versus 31 patients (13.7%); AEs leading to death=11 patients (4.6%) versus 11 patients (4.8%). No sudden deaths occurred. Conclusions: In summary, zanubrutinib significantly improved PFS-IRC versus BR and was well tolerated, supporting the potential utility of frontline zanubrutinib in treatment-naïve CLL/SLL.
Context: R-CHOP is the standard of care for newly diagnosed DLBCL patients; however, 40% remain uncured. Polatuzumab vedotin (Pola), a CD79b-targeting antibody-drug conjugate, has shown promising activity/safety in a Phase Ib/II study (Tilly, et al. Lancet Oncol 2019). We report the Phase III double-blind, placebo-controlled, international POLARIX study (NCT03274492), which compared Pola-R-CHP with R-CHOP in treatment-naïve DLBCL patients with an International Prognostic Index score of 2–5. Design: Patients were randomized (1:1) to six cycles of Pola-R-CHP or R-CHOP and on Day 1 of each cycle received Pola 1.8mg/kg or vincristine 1.4mg/m2, plus intravenous rituximab 375mg/m2, cyclophosphamide 750mg/m2, and doxorubicin 50mg/m². Patients also received oral prednisone 100mg once daily (Days 1–5) and two further cycles of rituximab. The primary endpoint was investigator-assessed progression-free survival (PFS). Results: Overall, 879 patients (median age 65 [range 19–80] years) were randomized (Pola-R-CHP: n=440; R-CHOP: n=439). At primary data cut-off (28 June 2021), median follow-up was 28.2 months. PFS was superior with Pola-R-CHP vs R-CHOP (hazard ratio [HR] 0.73; 95% confidence interval [CI]: 0.57–0.95; P=0.02) and 2-year PFS rate was improved (76.7% [95% CI: 72.7–80.8] vs 70.2% [95% CI: 65.8–74.6], respectively). Investigator-assessed event-free survival favored Pola-R-CHP vs R-CHOP (HR 0.75; 95% CI: 0.58–0.96; P=0.02) and overall survival was comparable (HR 0.94; 95% CI: 0.65–1.37; P=0.75). While independent review committee-assessed end-of-treatment complete response rate by positron emission tomography-computed tomography was not significantly different with Pola-R-CHP (78.0%) vs R-CHOP (74.0%; P=0.16), disease-free survival suggested more durable responses with Pola-R-CHP vs R-CHOP (HR 0.70; 95% CI: 0.50–0.98). Safety profiles were similar for Pola-R-CHP vs R-CHOP: grade 3–4 adverse event (AE) rates, 57.7% vs 57.5%, respectively; serious AEs, 34.0% vs 30.6%; grade 5 AEs, 3.0% vs 2.3%; AEs leading to dose reduction, 9.2% vs 13.0%; and peripheral neuropathy, any grade, 52.9% vs 53.9%. At data cut-off, fewer patients treated with Pola-R-CHP (23%) vs R-CHOP (30%) had received ≥1 subsequent anti-lymphoma therapy. Conclusions: As the first-line treatment of DLBCL, Pola-R-CHP demonstrated a 27% reduction in the relative risk of disease progression, relapse, or death, and a similar safety profile, compared with R-CHOP.
A series of derivatives of the potent dual soluble epoxide hydrolase (sEH)/5-lipoxygenase-activating protein (FLAP) inhibitor diflapolin was designed, synthesised, and characterised. These novel compounds, which contain a benzimidazole subunit were evaluated for their inhibitory activity against sEH and FLAP. Molecular modelling tools were applied to analyse structure–activity relationships (SAR) on both targets and to predict solubility and gastrointestinal (GI) absorption. The most promising dual inhibitors of these series are 5a, 6b, and 6c.
Introduction Chronic diseases in older adults are one of the major epidemiological challenges of current times and leading cause of disability, poor quality of life, high healthcare costs and death. Self-management of chronic diseases is essential to improve health behaviours and health outcomes. Technology-assisted interventions have shown to improve self-management of chronic diseases. Virtual avatars can be a key factor for the acceptance of these technologies. Addison Care is a home-based telecare solution equipped with a virtual avatar named Addison, connecting older persons with their caregivers via an easy-to-use technology. A central advantage is that Addison Care provides access to self-management support for an up-to-now highly under-represented population—older persons with chronic disease(s), which enables them to profit from e-health in everyday life. Methods and analysis A pragmatic, non-randomised, one-arm pilot study applying an embedded mixed-methods approach will be conducted to examine user experience, usability and user engagement of the virtual avatar Addison. Participants will be at least 65 years and will be recruited between September 2022 and November 2022 from hospitals during the discharge process to home care. Standardised instruments, such as the User Experience Questionnaire, System Usability Scale, Instrumental Activities of Daily Living scale, Short-Form-8-Questionnaire, UCLA Loneliness Scale, Geriatric Depression Scale, Stendal Adherence with Medication Score and Self-Efficacy for Managing Chronic Diseases Scale, as well as survey-based assessments, semistructured interviews and think-aloud protocols, will be used. The study seeks to enrol 20 patients that meet the criteria. Ethics and dissemination The study protocol has been approved by the ethic committee of the German Society for Nursing Science (21-037). The results are intended to be published in peer-reviewed journals and disseminated through conference papers. Trial registration number DRKS00025992.
Aims Lithium has long been believed to reduce the risk of suicide and suicidal behaviour in people with mood disorders. Previous meta-analyses appeared to support this belief, but excluded relevant data due to the difficulty of conducting meta-analysis of rare events. The current study is an updated systematic review and meta-analysis that includes all eligible data, and evaluates suicide, non-fatal suicidal behaviour (including suicidal ideation) and suicide attempts. Methods We searched PubMed, PsycINFO and Embase and some trial registers. We included all randomised trials comparing lithium and placebo or treatment as usual in mood disorders published after 2000, to ensure suicide was reliably reported. Trial quality was assessed using the Cochrane Risk of Bias tool. Pooled data were analysed using Fisher's Exact test. In addition, meta-analysis was conducted using various methods, prioritizing the Exact method. All trials were included in the analysis of suicide initially, regardless of whether they reported on suicide or not. We conducted a sensitivity analysis with trials that specifically reported on suicides and one that included trials published before 2000. Pre-specified subgroup analyses were performed involving suicide prevention trials, trials excluding people already taking lithium, trials involving people with bipolar disorder exclusively and those involving people with mixed affective diagnoses. Non-fatal suicidal behaviour and suicide attempts were analysed using the same methods, but only trials that reported these outcomes were included. PROSPERO registration: CRD42021265809. Results Twelve eligible studies involving 2578 participants were included. The pooled suicide rate was 0.2% for people randomised to lithium and 0.4% with placebo or treatment as usual, which was not a statistically significant difference; odds ratio (OR) = 0.41 (95% confidence interval 0.03–2.49), p = 0.45. Meta-analysis using the Exact method produced an OR of 0.42 (95% confidence interval 0.01–4.5). The result was not substantially different when restricted to 11 trials that explicitly reported suicides and remained statistically non-significant when including 15 trials published before 2000 (mostly in the 1970s). There were no significant differences in any subgroup analysis. There was no difference in rates of all non-fatal suicidal behaviour in seven trials that reported this outcome, or in five trials that reported suicide attempts specifically. Meta-analyses using other methods also revealed no statistically significant differences. Conclusions Evidence from randomised trials is inconclusive and does not support the idea that lithium prevents suicide or suicidal behaviour.
Upper blepharoplasty is one of the most frequently performed aesthetic surgeries worldwide. While it is considered a low risk procedure, patients have high expectations regarding the outcome of elective surgery of the face and the majority of residents usually have little exposure to cosmetic surgeries in the early years of their training. All eligible patients who had undergone bilateral upper blepharoplasty at the senior author's institution between January 2016 and August 2019 were invited to participate in an online questionnaire. Our study used a 27-item questionnaire to evaluate postoperative patient satisfaction and compared the patient reported outcome between operations conducted by surgeons with more than 3 years of experience and less than 3 years. In total, 102 patients returned the completed questionnaire and were included in our study after further screening. There was no significant difference in patient reported satisfaction concerning the aesthetic outcome (8.75 vs. 8.29, p=0.49), and complications (6.2 vs. 18.6%, p=0.63), related to the experience of the surgeons. Overall patient satisfaction was very high, while the rate of complications was low. Patient reported aesthetic outcomes after blepharoplasty demonstrated no significant difference comparing the experience of the surgeons.
PurposeAim of this study was to compare the use of split-thickness skin graft (STSG) with and without additional MatriDerm® application in a predominantly one-step procedure for the treatment of severe traumatic soft tissue defects of the lower limb.Methods This retrospective study included patients treated in a European level I trauma center between June 2013 and July 2018 in terms of a severe traumatic soft tissue defect of the lower extremity using STSG alone or in combination with the acellular dermal substitute MatriDerm®. The healing of the soft tissue defect was measured by assessment of the take rate. Outcome quality of the scar tissue was assessed using the Vancouver Scar Scale.ResultsA total of 147 cases were included in this study. The overall healing rate (number of patients with take rate ≥ 75%) was 88/147 (60%) and did not demonstrate significant differences between the treatment groups (p = 0.15). Despite the difference in wound complexity between the treatment groups, there was no difference regarding the scar tissue quality 12 months postoperatively. In about 25% of all cases, a post-operative event was mentioned that had to be revised surgically.Conclusion Surgical treatment with STSG and additional MatriDerm® application can be recommended as satisfactory alternative for dermis replacement in patients with severe skin defects, independent of age. The additional MatriDerm® use allows for bridging of exposed ligaments, tendons, vessels or bones without relevant differences in cosmetical outcome.
Background: Scabies is an itchy, parasitic infection of the skin. Recent reports indicate there is a decreasing efficacy of the standard treatment of choice, topical 5% permethrin cream. Objective: To evaluate the comparative efficacy, safety and tolerability of topical benzyl benzoate (BB) with oral ivermectin in the treatment of scabies. Methods: Patients with dermoscopy-verified scabies visiting the dermatologic outpatient clinic were assessed for enrollment in the study. In total, 224 patients were enrolled and sequentially randomized into two equally sized groups. Group A received topical 25% or 10% BB for the daily use over a period of three consecutive days, group B received oral ivermectin (200μg/kg body weight) twice, one week apart. Treatment outcome was evaluated by dermoscopy at a 3-weeks follow-up visit. Results: Treatment resulted in a cure rate of 87% in group A and 86% in group B. After initial therapy failure in group A 6 out of 8 patients showed treatment response upon repeated application of BB, 5 of 5 when retreated with ivermectin and 2 of 2 with BB plus ivermectin, respectively. In group B successful retreatment was observed in 3 out of 3 patients with ivermectin, 2 of 2 patients with BB and 11 of 11 patients with the combination of BB plus ivermectin, respectively. Tolerability and safety profile of oral ivermectin was excellent, while BB produced short burning sensations in 14%. Conclusion: Topical BB and oral ivermectin have shown comparable good therapeutic efficacy. Therefore, both agents constitute an adequate first-line therapy in the treatment of scabies. A combination of both agents may be considered in recalcitrant and extensively infested cases, additionally to crusted scabies.
Complementary and alternative medicine (CAM) use in children with cancer has a high prevalence. If (parents of) patients bring up the topic of CAM, pediatric oncologists (POs) face considerable challenges regarding knowledge and professional behavior. In this study, we explore German POs’ understanding of CAM and related attitudes as well as challenges and strategies related to CAM discussions by means of semi-structured interviews analyzed according to principles of qualitative thematic analysis with parents of children with cancer. We could conduct 14 interviews prior to theoretical saturation. The interviews had a duration of 15–82 min (M = 30.8, SD = 18.2). Professional experience in pediatric oncology was between 0.5 and 26 years (M = 13.8, SD = 7.6). Main themes identified were a heterogeneous understanding and evaluation of CAM, partly influenced by personal experiences and individual views on plausibility; the perception that CAM discussions are a possible tool for supporting parents and their children and acknowledgement of limitations regarding implementation of CAM discussions; and uncertainty and different views regarding professional duties and tasks when being confronted with CAM as a PO. Our interdisciplinary interpretation of findings with experts from (pediatric) oncology, psychology, and ethics suggests that there is need for development of a consensus on the minimal professional standards regarding addressing CAM in pediatric oncology.
Zusammenfassung Die entscheidende und zumeist einzig notwendige Maßnahme für die erfolgreiche Reanimation eines Neugeborenen nach der Geburt ist die effektive Ventilation der Lunge [1]. Bereits eine kurze Maskenbeatmung führt, bei einem zunächst nicht oder nicht suffizient spontan atmenden Neugeborenen, in den meisten Fällen zum Einsetzen einer effektiven Eigenatmung und damit zu einer raschen klinischen Stabilisierung. In den meisten Fällen gelingt eine Maskenbeatmung problemlos, allerdings bereitet sie immer wieder auch Schwierigkeiten. In Kursen, die sich mit der Versorgung des kritisch kranken Neugeborenen befassen (u. a. die Newborn-Life-Support-Kurse des Austrian Resuscitation Council (ARC), des German Resuscitation Council (GRC) und der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI)) [2], liegt daher ein Schwerpunkt auf Maßnahmen zur Optimierung einer nichtinvasiven Beatmung, die häufig nur unzureichend bekannt sind. Dieser Artikel widmet sich Strategien, wie eine nichtinvasive Beatmung beim Neugeborenen optimiert werden kann, und schlägt mit dem deutschsprachigen Akronym „ RALPH “ eine Möglichkeit vor, wie Schwierigkeiten bei der Maskenbeatmung strukturiert und zielgerichtet überwunden werden können.
There is growing interest in exploring Digitalis cardenolides as potential antiviral agents. Hence, we herein investigated the influence of structural features and lipophilicity on the antiherpes activity of 65 natural and semisynthetic cardenolides assayed in vitro against HSV‐1. The presence of an α,β‐unsaturated lactone ring at C‐17, a β‐hydroxyl group at C‐14 and C‐3β‐OR substituents were considered essential requirements for this biological activity. Glycosides were more active than their genins, especially monoglycosides containing a rhamnose residue. The activity enhanced in derivatives bearing an aldehyde group at C‐19 instead of a methyl group, whereas inserting a C‐5β‐OH improved the antiherpes effect significantly. The cardenolides lipophilicity was accessed by measuring experimentally their log P values ( n ‐octanol‐water partition coefficient) and disclosed a range of lipophilicity (log P 0.75 ± 0.25) associated with the optimal antiherpes activity. In silico studies were carried out and resulted in the establishment of two predictive models potentially useful to identify and/or optimize novel antiherpes cardenolides. The effectiveness of the models was confirmed by retrospective analysis of the studied compounds. This is the first SAR study addressing the antiherpes activity of cardenolides. The developed computational models were able to predict the active cardenolides and their log P values.
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1,422 members
Clemens Hufnagl
  • Institute for Neurointervention CDK
Wolfgang H. Muss
  • University Institute of Pathology (retiree)
Renate Gehwolf
  • Research Institute of Tendon and Bone Regeneration
Manuela Aspalter
  • University Clinic of Surgery
Eva Murauer
  • University Clinic of Dermatology
Information
Address
Strubergasse 21, A-5020, Salzburg, Salzburg, Austria
Head of institution
Univ.-Prof. Dr. Herbert Resch
Website
http://www.pmu.ac.at/en/research.html