Potential of FX06 to prevent disease progression in hospitalized non-intubated COVID-19 patients — the randomized, EU-wide, placebo-controlled, phase II study design of IXION

Background: More than 2.7 million hospitalizations of COVID-19-infected patients have occurred in Europe alone since the outbreak of the coronavirus in 2020. Interventions against SARS-CoV-2 are still in high need to prevent admissions to ICUs worldwide. FX06, a naturally occurring peptide in humans and other mammals, has the potential to reduce capillary leak by improving endothelial dysfunction and thus preventing the deterioration of patients. With IXION, we want to investigate the potential of FX06 to prevent disease progression in hospitalized, non-intubated COVID-19 patients. Methods: IXION is an EU-wide, multicentre, placebo-controlled, double-blinded, parallel, randomized (2:1) phase II clinical study. Patient recruitment will start in September 2022 (to Q2/2023) in Germany, Italy, Lithuania, Spain, Romania, Portugal, and France. A total of 306 hospitalized patients (>= 18 years and < 75 years) with a positive SARS-CoV-2 PCR test and a COVID-19 severity of 4-6 according to the WHO scale will be enrolled. After randomization to FX06 or placebo, patients will be assessed until day 28 (and followed up until day 60). FX06 (2 x 200 mg per day) or placebo will be administered intravenously for 5 consecutive days. The primary endpoint is to demonstrate a difference in the proportion of patients with progressed/worsened disease state in patients receiving FX06 compared to patients receiving placebo. Secondary endpoints are lung function, oxygen saturation and breathing rate, systemic inflammation, survival, capillary refill time, duration of hospital stay, and drug accountability. Discussion: With IXION, the multidisciplinary consortium aims to deliver a new therapy in addition to standard care against SARS-CoV-2 for the clinical management of COVID-19 during mild and moderate stages. Potential limitations might refer to a lack of recruiting and drop-out due to various possible protocol violations. While we controlled for drop-outs in the same size estimation, recruitment problems may be subject to external problems difficult to control for

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

Bausteine für eine umwelt und klimafreundliche Destination GrimmHeimat NordHessen

Verändertes Verbraucherverhalten, neue Erwartungen an Reisedestinationen und höhere Unsicherheit hinsichtlich des Klimawandels und durch vermehrt auftretende Extremwetterereignisse führen schon jetzt zu verändertem Reise- und Suchverhalten beim Urlaub. Eine Tourismusdestination, die sich über ein Umwelt- und klimabewusstes Reiseangebot am Markt positionieren möchte, lebt von dem Engagement und der Zusammenarbeit der regionalen Akteure. Dabei kann jeder Tourismusakteur auch durch kleine Maßnahmen einen Schritt in diese Richtung gehen. Umwelt- und klimabewusste Tourismusangebote bieten eine Vielzahl an Möglichkeiten und Optionen zur Gestaltung von Maßnahmen. Das Handbuch will eine große Palette dieser Möglichkeiten aufzeigen, die individuell wie in einem Baukastensystem je nach Handlungsebene, Akteurskreis und auch den persönlichen Interessen kombiniert werden können

Tourismus in Nordhessen: Empfehlungen zur Berücksichtigung der Folgen des Klimawandels bei der strategischen Weiterentwicklung der Destination GrimmHeimat NordHessen

Die Tourismusstrategie 2022 für die GrimmHeimat NordHessen wurde im Sommer 2012 formuliert und besteht aus drei Elementen. Für die Bewertung ist es wichtig einzuschätzen, in welcher Form externe Einflussfaktoren die Entwicklung bis 2022 und darüber hinaus prägen werden. Im Folgenden wird der Einfluss des Klimawandels beurteilt und Anpassungserfordernisse abgeleitet. Ziel der Empfehlungen zur Anpassung ist es, auf die Auswirkungen durch den Klimawandel zu reagieren und somit die langfristige Wettbewerbsfähigkeit des Tourismussektors zu stärken. Die Empfehlungen orientieren sich an den sieben strategischen Handlungsfeldern, welche im Rahmen der Tourismusstrategie 2022 als ein Teilelement definiert werden

Umwelt- und klimabewusster Tourismus in der GrimmHeimat NordHessen

Factsheet zum Teilprojekt Tourismus KLIMZUG Nordhessen: Ziele, Prozess, Maßnahmen, Ergebnisse und Ausblick

A comparison of immediate release and delayed release cysteamine in 17 patients with nephropathic cystinosis

Background!#!Nephropathic cystinosis is a rare and severe metabolic disease leading to an accumulation of cystine in lysosomes which especially harms kidney function. A lifelong therapy with the aminothiol cysteamine can delay the development of end-stage renal disease and the necessity of kidney transplantation. The purpose of our study was to compare the effectiveness of immediate-release and delayed-release cysteamine on cystine and cysteamine levels as well as assessing the onset of adverse effects.!##!Methods!#!We retrospectively analysed cystine and cysteamine levels of 17 patients after a single dose of immediate-release cysteamine (Cystagon®, Mylan Pharmaceuticals, Canonsburg, PA and Recordati Pharma GmbH) as well as a single dose of delayed-release cysteamine (Procysbi®; Horizon Pharma USA and Chiesi Farmaceutici S.p.A., Parma, Italy) respectively. Data were collected during a period of three years in the context of optimizing the individual treatment regimens. The dose of DR-cysteamine was reduced to 70% of the equivalent dose of IR-cysteamine. The efficacy of both formulas in depleting white blood cells' cystine levels and their side effects were compared.!##!Results!#!Immediate (IR)- and delayed-release (DR) cysteamine effectively decreased intracellular cystine levels under the target value of 0.5 nmol cystine/mg protein, while fewer side effects occurred under DR-cysteamine. Mean maximum levels of cysteamine were reached after 60 min with IR-cysteamine and after 180 min with DR-cysteamine.!##!Conclusion!#!A therapy with DR-cysteamine is as effective as IR-cysteamine while less side effects were reported. Our data show that DR-cysteamine should be dosed higher than 70% of the equivalent dose of IR-cysteamine in order to decrease cystine levels over an extended period of time. Moreover, our data suggest increasing the dosing scheme of Procysbi® to three times daily, to prevent a rapid decrease and achieve a steadier decline in cystine levels. Due to the more convenient dosing scheme, DR-cysteamine might ameliorate therapy adherence and improve patients' quality of life