Development of a highly effective combination monoclonal antibody therapy against Herpes simplex virus.

BACKGROUND Infections with Herpes simplex virus (HSV)-1 or -2 usually present as mild chronic recurrent disease, however in rare cases can result in life-threatening conditions with a large spectrum of pathology. Monoclonal antibody therapy has great potential especially to treat infections with virus resistant to standard therapies. HDIT101, a humanized IgG targeting HSV-1/2 gB was previously investigated in phase 2 clinical trials. The aim of this study was to develop a next-generation therapy by combining different antiviral monoclonal antibodies. METHODS A lymph-node derived phage display library (LYNDAL) was screened against recombinant gB from Herpes simplex virus (HSV) -1 and HDIT102 scFv was selected for its binding characteristics using bio-layer interferometry. HDIT102 was further developed as fully human IgG and tested alone or in combination with HDIT101, a clinically tested humanized anti-HSV IgG, in vitro and in vivo. T-cell stimulating activities by antigen-presenting cells treated with IgG-HSV immune complexes were analyzed using primary human cells. To determine the epitopes, the cryo-EM structures of HDIT101 or HDIT102 Fab bound to HSV-1F as well as HSV-2G gB protein were solved at resolutions < 3.5 Å. RESULTS HDIT102 Fab showed strong binding to HSV-1F gB with Kd of 8.95 × 10-11 M and to HSV-2G gB with Kd of 3.29 × 10-11 M. Neutralization of cell-free virus and inhibition of cell-to-cell spread were comparable between HDIT101 and HDIT102. Both antibodies induced internalization of gB from the cell surface into acidic endosomes by binding distinct epitopes in domain I of gB and compete for binding. CryoEM analyses revealed the ability to form heterogenic immune complexes consisting of two HDIT102 and one HDIT101 Fab bound to one gB trimeric molecule. Both antibodies mediated antibody-dependent phagocytosis by antigen presenting cells which stimulated autologous T-cell activation. In vivo, the combination of HDIT101 and HDIT102 demonstrated synergistic effects on survival and clinical outcome in immunocompetent BALB/cOlaHsd mice. CONCLUSION This biochemical and immunological study showcases the potential of an effective combination therapy with two monoclonal anti-gB IgGs for the treatment of HSV-1/2 induced disease conditions

The impact of a standardised intramuscular sedation protocol for acute behavioural disturbance in the emergency department

Background: Acute behavioural disturbance (ABD) is an increasing problem in emergency departments. This study aimed to determine the impact of a structured intramuscular (IM) sedation protocol on the duration of ABD in the emergency department. Methods: A historical control study was undertaken comparing 58 patients who required physical restraint and parenteral sedation with the structured IM sedation protocol, to 73 historical controls treated predominantly by intravenous sedation, according to individual clinician preference. The primary outcome was the duration of the ABD defined as the time security staff were required. Secondary outcomes were the requirement for additional sedation, drug related-adverse effects and patient and staff injuries. Results: The median duration of the ABD in patients with the new sedation protocol was 21 minutes (IQR: 15 to 35 minutes; Range: 5 to 78 minutes) compared to a median duration of 30 minutes (IQR: 15 to 50 minutes; Range: 5 to 135 minutes) in the historical controls which was significantly different (p = 0.03). With IM sedation only 27 of 58 patients (47%; 95% CI: 34% to 60%) required further sedation compared to 64 of 73 historical controls (88%; 95%CI: 77% to 94%). There were six (10%) drug-related adverse events with the new IM protocol [oxygen desaturation (5), oxygen desaturation/airway obstruction (1)] compared to 10 (14%) in the historical controls [oxygen desaturation (5), hypoventilation (4) and aspiration (1)]. Injuries to staff occurred with three patients using the new sedation protocol and in seven of the historical controls. Two patients were injured during the new protocol and two of the historical controls. Conclusion: The use of a standardised IM sedation protocol was simple, more effective and as safe for management of ABD compared to predominantly intravenous sedation

Proceedings in Marine Biology

“Proceedings in Marine Biology” is an international journal publishing original research by graduate students on all aspects of marine biology. Subjects covered include: ecological surveys and population studies of oceanic, coastal and shore communities; physiology and experimental biology; taxonomy, morphology and life history of marine animals and plants. Papers are also published on techniques em- ployed at sea for sampling, recording, capture and observation of marine organisms.Zeitschrift zur Kursabschlussreise der Humboldt-Universität zu Berlin (Deutschland) im Bereich Elektronenmikroskopie.Peer Reviewe

Untersuchungen zur Gehäusewahl von Clibanarius erythropus an der französischen Atlantikküste

Beim Gang durch das Felswatt bei Le Cabellou fiel auf, dass Clibanarius erythropus scheinbar das Schneckenhaus von Tritia reticulata bevorzugte, da diese Häuser am meisten belegt waren. Daraufhin haben wir ca. 6000 Einsiedlerkrebse von 6 Standorten (einer davon in Concarneau) eingesammelt, die Schneckenhäuser bestimmt und sortiert und anschließend eine statistische Erhebung der Daten erstellt. Auffällig war, dass in Concarneau im Gegensatz zu Le Cabellou Nucella lapillus bevorzugt wurde. Zusätzlich wurden im Labor Versuche zur Gehäusewahl durchgeführt, um eine mögliche Präferenz bei freier Auswahl zu untersuchen. Dabei stellte sich heraus, dass im Labor das Schneckenhaus von Phorcus lineatus bevorzugt wurde.While walking through the mud flats near Le Cabellou, it was noticed that Clibanarius erythropus apparently preferred the snail shell of Tritia reticulata, as these houses were the most occupied. We then collected around 6000 hermit crabs from 6 locations (one of them in Concarneau), identified and sorted the snail shells and then created a statistical survey of the data. It was noticeable that in Concarneau, in contrast to Le Cabellou, Nucella lapillus was preferred. In addition, tests were carried out in the laboratory on the choice of housing in order to investigate a possible preference with a free choice. It turned out that the Phorcus lineatus snail shell was preferred in the laboratory.Peer Reviewe