TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes.

BACKGROUND: TLR9 agonists are being developed as immunotherapy against malignancies and infections. TLR9 is primarily expressed in B cells and plasmacytoid dendritic cells (pDCs). TLR9 signalling may be critically important for B cell activity in lymph nodes but little is known about the in vivo impact of TLR9 agonism on human lymph node B cells. As a pre-defined sub-study within our clinical trial investigating TLR9 agonist MGN1703 (lefitolimod) treatment in the context of developing HIV cure strategies (NCT02443935), we assessed TLR9 agonist-mediated effects in lymph nodes. METHODS: Participants received MGN1703 for 24 weeks concurrent with antiretroviral therapy. Seven participants completed the sub-study including lymph node resection at baseline and after 24 weeks of treatment. A variety of tissue-based immunologic and virologic parameters were assessed. FINDINGS: MGN1703 dosing increased B cell differentiation; activated pDCs, NK cells, and T cells; and induced a robust interferon response in lymph nodes. Expression of Activation-Induced cytidine Deaminase, an essential regulator of B cell diversification and somatic hypermutation, was highly elevated. During MGN1703 treatment IgG production increased and antibody glycosylation patterns were changed. INTERPRETATION: Our data present novel evidence that the TLR9 agonist MGN1703 modulates human lymph node B cells in vivo. These findings warrant further considerations in the development of TLR9 agonists as immunotherapy against cancers and infectious diseases. FUND: This work was supported by Aarhus University Research Foundation, the Danish Council for Independent Research and the NovoNordisk Foundation. Mologen AG provided study drug free of charge.

The role of afferent input in postamputation pain: a randomized, double-blind, placebo-controlled crossover study.

In this randomized, double-blind, placebo-controlled crossover study, we investigated whether a peripheral nerve block could temporarily eliminate phantom and stump pain after amputation. Amputees with constant postamputation pain were included and randomized to receive a nerve block with lidocaine 2% with adrenaline or saline in a crossover design. Spontaneous phantom and stump pain and evoked responses were assessed at baseline and at fixed time-points until 120 minutes after lidocaine or saline injection. The primary outcome was the difference in absolute change between worst pain intensity, either phantom or stump pain, at baseline and at 30 minutes after lidocaine or saline injection. Twelve amputees were randomized and 9 patients were included in the analysis. The absolute change in median worst pain intensity between lidocaine and saline injection was -2.0 (interquartile range, -4.0 to 0.0) (n = 9, P = 0.12). Nine of 9 patients reported at least some pain relief after lidocaine injection compared with only 2 of 9 patients after saline injection (P = 0.02). Phantom pain intensity was significantly reduced after lidocaine compared with saline injection (P = 0.04), whereas there was no significant change in stump pain intensity between the 2 interventions (P = 0.17). In all 9 amputees, evoked responses were eliminated after lidocaine injection. Thus, our findings suggest that afferent input from the peripheral nervous system plays an important role in postamputation pain.

[Postoperative nausea and vomiting]. / Postoperativ kvalme og opkastning.

During the last years huge amounts of literature have been reviewed systematically. Recently, guidelines have been proposed. For the first time a large prospective study has been performed on the effect of combining antiemetics. In this review we try to propose a rational approach to postoperative nausea and vomiting. The scoring of patients at risk, rational anaesthetic agents, prophylactic administration of antiemetics to patients at risk and effective postoperative antiemetic treatment are suggested.

[Outpatient laparoscopic cholecystectomy. Experience with the first 300 operations]. / Dagkirurgisk laparoskopisk kolecystektomi. Erfaring med de første 300 operationer.

INTRODUCTION: In Denmark, outpatient laparoscopic cholecystectomy (LC) has been evaluated only in small studies. MATERIALS AND METHODS: The first 300 consecutive patients undergoing LC in a university hospital outpatient clinic were evaluated prospectively. Complications, lack of same-day discharge (SDD), postoperative symptoms, and possibilities for training were recorded. RESULTS: The median length of surgery was 65 minutes. The conversion rate was 4%. The SDD failure rate was 23%. The percentage of readmissions was 5%. The mortality rate was 0%. Blood transfusions were given in two cases. Two umbilical port sites were infected and needed surgical drainage. No major bile duct injury occurred. Two cystic duct lesions and two small bile leaks from the gallbladder bed were diagnosed and treated. LCs" being performed by junior residents had no influence on the perioperative risks. DISCUSSION: Outpatient LC is safe when performed by trainees under supervision.