Lateral Quadratus Lumborum Block Versus Acupuncture for Postcaesarean Analgesia: A Randomized Clinical Trial.

BACKGROUND: Improved pain control after caesarean section remains a challenging objective. Although both the lateral quadratus lumborum block and acupuncture have been reported to provide superior postoperative analgesia after caesarean section when compared to placebo, the efficacy of these techniques has never been compared head-to-head. OBJECTIVE: This study was conducted to investigate the comparative analgesic efficacy of lateral quadratus lumborum block and acupuncture following elective caesarean section. STUDY DESIGN: In this prospective, randomized, controlled clinical trial, a total of 190 patients with singleton term pregnancies scheduled for caesarean section under spinal-epidural anesthesia were enrolled. Patients were randomized 1:1 to acupuncture group or lateral quadratus lumborum block group. Lateral quadratus lumborum block group received bilateral lateral quadratus lumborum block with 0.33% ropivacaine and sham acupuncture, acupuncture group received transcutaneous electrical acupoint stimulation and press needle therapy and sham lateral quadratus lumborum block. All patients received the standard postoperative pain treatment. The primary outcome was pain scores on movement at 24 h. Secondary endpoints included pain scores in the first 48 h postoperatively, patient-controlled intravenous analgesia demands, analgesia-related adverse effects, postoperative complications, QoR-15, the time to mobilization, and gastrointestinal function. RESULTS: Median (IQR [range]) pain scores at 24 h on movement was similar in patients receiving acupuncture or lateral quadratus lumborum block (3 (2-4) vs. 3 (2-4), respectively; P = 0.40). Patient-controlled intravenous analgesia consumption and pain scores within 48 h postoperatively also showed no difference between the two groups. The acupuncture improved QoR-15 scores at 24 and 48 h postoperatively (P<0.001), as well as shortened the time to first flatus (P=0.03) and first drinking (P<0.001) compared to lateral quadratus lumborum block. In addition, the median time to mobilization in the lateral quadratus lumborum block group was markedly prolonged compare with acupuncture group (17.0 (15.0-19.0) h vs. 15.3 (13.3-17.0) h, estimated median difference, 1.5; 95%CI, 1-2; P<0.001;). CONCLUSIONS: As a component of multimodal analgesia regimen after caesarean section, acupuncture did not lower postoperative pain scores or reduce analgesic medication consumption compared to lateral quadratus lumborum block.

Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway.

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.

Dual RNA-seq identifies human mucosal immunity protein Mucin-13 as a hallmark of Plasmodium exoerythrocytic infection.

The exoerythrocytic stage of Plasmodium infection is a critical window for prophylactic intervention. Using genome-wide dual RNA sequencing of flow-sorted infected and uninfected hepatoma cells we show that the human mucosal immunity gene, mucin-13 (MUC13), is strongly upregulated during Plasmodium exoerythrocytic hepatic-stage infection. We confirm MUC13 transcript increases in hepatoma cell lines and primary hepatocytes. In immunofluorescence assays, host MUC13 protein expression distinguishes infected cells from adjacent uninfected cells and shows similar colocalization with parasite biomarkers such as UIS4 and HSP70. We further show that localization patterns are species independent, marking both P. berghei and P. vivax infected cells, and that MUC13 can be used to identify compounds that inhibit parasite replication in hepatocytes. This data provides insights into host-parasite interactions in Plasmodium infection, and demonstrates that a component of host mucosal immunity is reprogrammed during the progression of infection.

Development of a Potent Inhibitor of the Plasmodium Proteasome with Reduced Mammalian Toxicity.

Naturally derived chemical compounds are the foundation of much of our pharmacopeia, especially in antiproliferative and anti-infective drug classes. Here, we report that a naturally derived molecule called carmaphycin B is a potent inhibitor against both the asexual and sexual blood stages of malaria infection. Using a combination of in silico molecular docking and in vitro directed evolution in a well-characterized drug-sensitive yeast model, we determined that these compounds target the ß5 subunit of the proteasome. These studies were validated using in vitro inhibition assays with proteasomes isolated from Plasmodium falciparum. As carmaphycin B is toxic to mammalian cells, we synthesized a series of chemical analogs that reduce host cell toxicity while maintaining blood-stage and gametocytocidal antimalarial activity and proteasome inhibition. This study describes a promising new class of antimalarial compound based on the carmaphycin B scaffold, as well as several chemical structural features that serve to enhance antimalarial specificity.