A selective antibiotic for Lyme disease.

Lyme disease is on the rise. Caused by a spirochete Borreliella burgdorferi, it affects an estimated 500,000 people in the United States alone. The antibiotics currently used to treat Lyme disease are broad spectrum, damage the microbiome, and select for resistance in non-target bacteria. We therefore sought to identify a compound acting selectively against B. burgdorferi. A screen of soil micro-organisms revealed a compound highly selective against spirochetes, including B. burgdorferi. Unexpectedly, this compound was determined to be hygromycin A, a known antimicrobial produced by Streptomyces hygroscopicus. Hygromycin A targets the ribosomes and is taken up by B. burgdorferi, explaining its selectivity. Hygromycin A cleared the B. burgdorferi infection in mice, including animals that ingested the compound in a bait, and was less disruptive to the fecal microbiome than clinically relevant antibiotics. This selective antibiotic holds the promise of providing a better therapeutic for Lyme disease and eradicating it in the environment.

Inactivation of DRG1, encoding a translation factor GTPase, causes a recessive neurodevelopmental disorder.

PURPOSE: Developmentally regulated Guanosine-5'-triphosphate-binding protein 1 (DRG1) is a highly conserved member of a class of GTPases implicated in translation. Although the expression of mammalian DRG1 is elevated in the central nervous system during development, and its function has been implicated in fundamental cellular processes, no pathogenic germline variants have yet been identified. Here, we characterize the clinical and biochemical consequences of DRG1 variants. METHODS: We collate clinical information of 4 individuals with germline DRG1 variants and use in silico, in vitro, and cell-based studies to study the pathogenicity of these alleles. RESULTS: We identified private germline DRG1 variants, including 3 stop-gained p.Gly54∗, p.Arg140∗, p.Lys263∗, and a p.Asn248Phe missense variant. These alleles are recessively inherited in 4 affected individuals from 3 distinct families and cause a neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature, and craniofacial anomalies. We show that these loss-of-function variants (1) severely disrupt DRG1 messenger RNA/protein stability in patient-derived fibroblasts, (2) impair its GTPase activity, and (3) compromise its binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation of mouse Drg1 resulted in preweaning lethality. CONCLUSION: Our work defines a new Mendelian disorder of DRG1 deficiency. This study highlights DRG1's importance for normal mammalian development and underscores the significance of translation factor GTPases in human physiology and homeostasis.

Vitamin-D Status and Clinical Outcomes in Critically Ill Children.

Aims and background: To study if 25-hydroxy cholecalciferol levels correlate with clinical outcomes in a cohort of critically ill children requiring pediatric intensive care unit (PICU) admission. Materials and methods: All children between the ages of 1 month and 14 years admitted to a PICU were included in this study. The vitamin-D level was measured within 24 hours of admission to the PICU for each patient. The patient's clinical details, vitamin-D levels, and biochemical parameters were collected. Results: There were 119 critically ill children (47 females and 72 males) admitted to our PICU. A total of 56 children were in the vitamin-D-deficient group, giving a prevalence of 47.05%. Sixty-three children had either insufficient or normal levels of 25(OH)D. Mean serum 25-OH cholecalciferol was 22.82 ± 16.48 nmol/L. There were no significant differences in O2 utilization, ventilation requirement, length of PICU stay, or the frequencies of use of antibiotics and steroids between the groups. The overall mortality rate in this study was 5.8% (three children died in the deficient group as compared with four in the insufficient/normal group). Conclusion: Even though vitamin-D deficiency was highly prevalent in the PICU, there were no statistically significant differences in O2 utilization, length of PICU stay, duration of mechanical ventilation, the use of antibiotics/steroids, and mortality outcome for both deficient and insufficient/normal groups. How to cite this article: Loni R, Zameer S, Hasan FA, Abbas I, Mesrati H, George J, et al. Vitamin-D Status and Clinical Outcomes in Critically Ill Children. Indian J Crit Care Med 2023;27(7):503-509.

Intravenous Amisulpride Does Not Meaningfully Prolong the QTc Interval at Doses Effective for the Management of Postoperative Nausea and Vomiting.

BACKGROUND: Postoperative nausea and vomiting (PONV) are significant issues in surgical patients, and additional treatment options are needed. Dopaminergic antiemetics have been popular for their efficacy, but their use has been limited by safety concerns, especially the potential for torsade de pointes arising from QT interval prolongation. Intravenous (IV) amisulpride, a dopamine D2 and D3 antagonist shown to be effective at preventing and treating PONV at doses of 5 and 10 mg, respectively, has a dose-dependent effect on QT but at 5 mg is not associated with clinically meaningful prolongation of the heart rate-corrected QT (QTc) interval. This study was designed to evaluate the QT effect of a 10-mg dose of amisulpride, alone and when simultaneously coadministered with ondansetron, an antiemetic of a different class, also known to prolong the QT interval. METHODS: In this randomized, double-blind, placebo-controlled, 3-period, crossover study, healthy male and female volunteers 18-65 years of age received IV, in a random sequence: (1) amisulpride 10 mg given twice, 2 hours apart; (2) amisulpride 10 mg and ondansetron 4 mg, given simultaneously; and (3) placebo. RESULTS: Thirty subjects were enrolled, and 29 completed all 3 treatment periods. The largest mean placebo-corrected change-from-baseline QT interval corrected for heart rate using Fridericia's formula (QTcF) (ΔΔQTcF) after the first and second amisulpride dose was 5.2 milliseconds (90% confidence interval [CI], 3.53-6.96 milliseconds) and 8.0 milliseconds (90% CI, 5.49-10.58 milliseconds), respectively. After coadministration of amisulpride and ondansetron, the largest mean ΔΔQTcF was 7.3 milliseconds (90% CI, 5.48-9.16 milliseconds). The slope of the amisulpride concentration-change-from-baseline QTcF (ΔQTcF) relationship was 0.006 ms/ng/mL (90% CI, 0.0020-0.0098). No QTc outliers (absolute QTcF value >480 milliseconds or increase from baseline >30 milliseconds) were seen in any period. CONCLUSIONS: A 10-mg dose of IV amisulpride, given alone or in combination with ondansetron, does not have a clinically significant effect on the QT interval.

Amisulpride for the Rescue Treatment of Postoperative Nausea or Vomiting in Patients Failing Prophylaxis: A Randomized, Placebo-controlled Phase III Trial.

BACKGROUND: Although antiemetics are commonly used to prevent postoperative nausea or vomiting, the failure rate is appreciable and there is currently no generally accepted standard for rescue treatment of postoperative nausea or vomiting after failed prophylaxis. This prospective, randomized, double-blind, parallel-group, placebo-controlled, multicenter study was designed to test the hypothesis that intravenous amisulpride, a dopamine D2/D3-antagonist, is superior to placebo at treating established postoperative nausea or vomiting after failed prophylaxis. METHODS: A total of 2,285 adult patients undergoing surgery under general inhalational anesthesia and receiving standard antiemetic prophylaxis were enrolled at 23 sites in Canada, France, Germany, and the United States. Of these, 702 patients experienced postoperative nausea or vomiting in the 24-h period after surgery and were randomized to receive a single dose of 5 or 10 mg intravenous amisulpride or matching placebo. The primary endpoint was complete response, defined as no emesis or rescue antiemetic use for 24 h after study drug administration, excluding emesis in the first 30 min. Secondary endpoints included incidence of emesis and rescue medication use, nausea burden, time to treatment failure, and length of stay in postanesthesia care unit and hospital. RESULTS: Complete response occurred in significantly more patients receiving 10 mg amisulpride (96 of 230, 41.7%) than placebo (67 of 235, 28.5%), a 13.2% difference (95% CI, 4.6 to 21.8; odds ratio, 1.80; P = 0.006). A 5-mg dose of amisulpride did not show a significant benefit (80 of 237, 33.8%); the difference from placebo was 5.2% (95% CI, 3.1 to 13.6; odds ratio, 1.24; P = 0.109). The total number of adverse events recorded and proportion of patients with at least one adverse event were comparable between the placebo and amisulpride groups. No clinically relevant toxicities were observed. CONCLUSIONS: A single 10-mg dose of intravenous amisulpride was safe and more effective than placebo at treating established postoperative nausea or vomiting in patients failing postoperative nausea or vomiting prophylaxis.

Randomized, Double-Blind, Placebo-Controlled Study of Intravenous Amisulpride as Treatment of Established Postoperative Nausea and Vomiting in Patients Who Have Had No Prior Prophylaxis.

BACKGROUND: Postoperative nausea and vomiting (PONV) occurs commonly in surgical patients despite widespread prophylactic antiemetic use. Rescue options are currently limited. 5HT3 antagonists are most frequently used for prophylaxis, but if they fail, additional doses are not effective as rescue medication. Intravenous (IV) amisulpride, a well-studied D2/D3 antagonist, has been shown in trials to prevent PONV. This study was designed to determine if amisulpride could be used to treat established PONV in patients at low-to-moderate risk of PONV who had not received any prior prophylaxis. METHODS: Men and women aged over 18 years were permitted to enroll if they were to undergo general inhalational anesthesia, expected to last at least 1 hour, for an outpatient or inpatient surgical procedure. Patients who then suffered PONV were randomized equally to 1 of 3 single-dose IV regimens: placebo or 5 or 10 mg amisulpride. The primary end point was complete response, defined as no emesis in the period 30 minutes to 24 hours after study drug treatment and no use of rescue medication in the entire 24-hour period. RESULTS: One thousand nine hundred eighty-eight patients were enrolled preoperatively, of whom 560 were randomized to a treatment arm. Complete response occurred in 39 of 181 patients (21.5%) in the placebo group compared to 60 of 191 patients (31.4%; P = .016) and 59 of 188 patients (31.4%; P = .016) in the amisulpride 5 and 10 mg groups, respectively. The adverse event profile of amisulpride at either dose was similar to placebo. CONCLUSIONS: IV amisulpride at 5 and 10 mg was safe and efficacious in the treatment of established PONV in surgical patients undergoing general anesthesia with no prior PONV prophylaxis.

Amisulpride Prevents Postoperative Nausea and Vomiting in Patients at High Risk: A Randomized, Double-blind, Placebo-controlled Trial.

BACKGROUND: Postoperative nausea and vomiting causes distress for patients and can prolong care requirements. Consensus guidelines recommend use of multiple antiemetics from different mechanistic classes as prophylaxis in patients at high risk of postoperative nausea and vomiting. The prophylactic efficacy of the dopamine D2/D3 antagonist amisulpride in combination with other antiemetics was investigated. METHODS: This double-blind, randomized, placebo-controlled, international, multicenter trial was conducted in 1,147 adult surgical patients having three or four postoperative nausea and vomiting risk factors. Patients were randomized to receive either intravenous amisulpride (5 mg) or matching placebo at induction of general anesthesia, in addition to one standard, nondopaminergic antiemetic, most commonly ondansetron or dexamethasone. Vomiting/retching, nausea, and use of rescue medication were recorded for 24 h after wound closure. The primary endpoint was complete response, defined as no emesis or rescue medication use in the 24-h postoperative period. RESULTS: Complete response occurred in 330 of 572 (57.7%) of the amisulpride group and 268 of 575 (46.6%) of the control group (difference 11.1 percentage points; 95% CI, 5.3 to 16.8; P < 0.001). The incidences of emesis (13.8% vs. 20.0%, P = 0.003), any nausea (50.0% vs. 58.3%, P = 0.002), significant nausea (37.1% vs. 47.7%, P < 0.001), and rescue medication use (40.9% vs. 49.4%, P = 0.002) were significantly lower in the amisulpride group. Adverse events and laboratory and electrocardiogram abnormalities occurred no more frequently with amisulpride than with placebo. CONCLUSIONS: Intravenous amisulpride was safe and effective as prophylaxis of postoperative nausea and vomiting when given in combination with an antiemetic from another class to adult patients at high risk for suffering postoperative nausea and vomiting undergoing elective surgery under inhalational general anesthesia. VISUAL ABSTRACT: An online visual overview is available for this article at http://links.lww.com/ALN/B727.

Amisulpride in the prevention of nausea and vomiting induced by cisplatin-based chemotherapy: a dose-escalation study.

PURPOSE: The purpose of this study was to investigate the antiemetic effect of the dopamine D2- and dopamine D3-receptor antagonist, amisulpride, in patients receiving cisplatin-based chemotherapy. METHODS: This dose-finding, non-comparative study investigated the antiemetic effect and safety of increasing doses (2.5, 7.5 and 20 mg) of amisulpride against acute nausea and vomiting in the period 0-24 h after initiation of cisplatin-based chemotherapy. The 20 mg dose was also investigated in combination with the 5-HT3-receptor antagonist, ondansetron. The primary parameter was complete response (0-24 h), defined as no emesis and no need for rescue antiemetics. Secondary parameters were number of emetic episodes, severity of nausea and time to first emetic episode and start of nausea. RESULTS: A total of 51 patients were enrolled and evaluable. None of the 10 patients in the 2.5 and 7.5 mg groups obtained a CR. In the 20 mg monotherapy cohort, two of the 18 subjects (11%) had a CR, 3/18 (17%) had no emesis and 12/18 (67%) had no significant nausea. Seven subjects (39%) had no nausea at all (a VAS score < 5 mm). In the combination (ondansetron plus amisulpride) cohort, 19/23 (83%; 90% confidence interval: 65-94%) had a CR and 14/23 (61%) had no nausea at all. CONCLUSIONS: Amisulpride has antiemetic effect against cisplatin-induced acute nausea and vomiting. The effect against nausea is of particular interest. Randomised studies are warranted to further explore the effect and safety of amisulpride.

X-ray crystal structures of the pheromone-binding domains of two quorum-hindered transcription factors, YenR of Yersinia enterocolitica and CepR2 of Burkholderia cenocepacia.

The ability of LuxR-type proteins to regulate transcription is controlled by bacterial pheromones, N-acylhomoserine lactones (AHLs). Most LuxR-family proteins require their cognate AHLs for activity, and some of them require AHLs for folding and stability, and for protease-resistance. However, a few members of this family are able to fold, dimerize, bind DNA, and regulate transcription in the absence of AHLs; moreover, these proteins are antagonized by their cognate AHLs. One such protein is YenR of Yersinia enterocolitica, which is antagonized by N-3-oxohexanoyl-l-homoserine lactone (OHHL). This pheromone is produced by the OHHL synthase, a product of the adjacent yenI gene. Another example is CepR2 of Burkholderia cenocepacia, which is antagonized by N-octanoyl-l-homoserine lactone (OHL), whose synthesis is directed by the cepI gene of the same bacterium. Here, we describe the high-resolution crystal structures of the AHL binding domains of YenR and CepR2. YenR was crystallized in the presence and absence of OHHL. While this ligand does not cause large scale changes in the YenR structure, it does alter the orientation of several highly conserved YenR residues within and near the pheromone-binding pocket, which in turn caused a significant movement of a surface-exposed loop.

Intravenous Amisulpride for the Prevention of Postoperative Nausea and Vomiting: Two Concurrent, Randomized, Double-blind, Placebo-controlled Trials.

BACKGROUND: Two essentially identical, randomized, double-blind, placebo-controlled, parallel-group phase III studies evaluated the efficacy of intravenous amisulpride, a dopamine D2/D3 antagonist, in the prevention of postoperative nausea and vomiting in adult surgical patients. METHODS: Adult inpatients undergoing elective surgery during general anesthesia and having at least two of the four Apfel risk factors for postoperative nausea and vomiting were enrolled at 9 U.S. and 10 European sites. A single 5-mg dose of amisulpride or matching placebo was given at induction of anesthesia. The primary endpoint was complete response, defined as no vomiting/retching and no use of antiemetic rescue medication in the 24-h postoperative period. Nausea incidence was a secondary endpoint. RESULTS: Across the two studies, 689 patients were randomized and dosed with study medication, of whom 626 were evaluable per protocol. In the U.S. study, 46.9% (95% CI, 39.0 to 54.9) of patients achieved complete response in the amisulpride group compared to 33.8% (95% CI, 26.2 to 42.0) in the placebo group (P = 0.026). In the European study, complete response rates were 57.4% (95% CI, 49.2 to 65.3) for amisulpride and 46.6% (95% CI, 38.8 to 54.6) for placebo (P = 0.070). Nausea occurred less often in patients who received amisulpride than those who received placebo. There was no clinically significant difference in the safety profile of amisulpride and placebo; in particular, there were no differences in terms of QT prolongation, extrapyramidal side effects, or sedation. CONCLUSIONS: One of the two trials demonstrated superiority, while pooling both in a post hoc change to the plan of analysis supported the hypothesis that amisulpride was safe and superior to placebo in reducing the incidence of postoperative nausea and vomiting in a population of adult inpatients at moderate to high risk of postoperative nausea and vomiting.

Thorough QT study of the effect of intravenous amisulpride on QTc interval in Caucasian and Japanese healthy subjects.

AIM: The D2 /D3 antagonist amisulpride has shown promising efficacy against postoperative nausea and vomiting (PONV) at low doses. We investigated whether intravenous amisulpride has an effect on the QTc interval in a formal Thorough QT study (TQT). METHODS: This was a randomized, double-blind, placebo and positive-controlled, four-way crossover study. Forty healthy Caucasian and Japanese subjects were included to receive a single administration of 5 mg and 40 mg of i.v. amisulpride or a single oral dose of moxifloxacin or placebo per period. RESULTS: The therapeutic dose of 5 mg amisulpride was associated with a slight, transient increase in mean ΔΔQTcF, from 2.0 ms prior to dosing to a peak of 5 ms (90% CI: 2.8, 7.1 ms) at 8 min, decreasing to 2.1 ms at 30 min after dosing. The supra-therapeutic dose of 40 mg given at twice the infusion rate was associated with prolongation in ΔΔQTcF peaking at 23.4 ms (90% CI: 21.3, 25.5 ms) at the end of infusion (8 min), returning below 10 ms within 1.5 h. Assay sensitivity was confirmed; ΔΔQTcF had increased by 12.3 ms (90% CI 10.1, 14.6 ms) at 4 h post-dose. The PK-PD relationship revealed no differences between Caucasian and Japanese subjects (p-value > 0.5). CONCLUSIONS: Amisulpride has a plasma concentration-dependent effect on the QTc interval. The proposed therapeutic dose for management of PONV does not lead to a prolongation of QTcF above the threshold of regulatory concern, while such effect could not be excluded for the supratherapeutic dose.

Acute Viral Encephalitis Mimicking Idiopathic Intracranial Hypertension in an Immunocompetent Obese Adolescent Girl.

Varicella zoster virus (VZV) is common worldwide and one of the main causes of infectious encephalitis. We report the case of a 13-year-old girl who presented to the emergency department with complaints of recurrent episodes of vague headaches associated with photophobia multiple times within three days before hospitalization. The patient had a history of morbid obesity without other metabolic complications as well as a history of chicken pox in childhood. Doctors subsequently diagnosed her with increased intracranial pressure owing to suspected VZV encephalitis. A lumbar puncture confirmed the presence of VZV in the cerebrospinal fluid. After admitting the diagnosis of VZV encephalitis, doctors treated the patient with intravenous acyclovir and discharged her with oral acyclovir. This case highlights the importance of considering VZV encephalitis in the differential diagnosis for patients presenting with headaches, especially in the presence of typical vesicular skin rashes. The case has an unusual complication associated with shingles, which doctors diagnosed early and treated appropriately.

Gastrointestinal Panel Performance for the Diagnosis of Acute Gastroenteritis in Pediatric Patients.

BACKGROUND: Various methods are used to identify the causative organisms of acute gastroenteritis (AGE) in children. The gastrointestinal (GI) panel has the potential to detect up to 22 pathogens rapidly through the multiplex real-time PCR test. We studied the impact of the GI panel on clinical management in the pediatric population. METHODS: A retrospective study was conducted to collect data on GI panel results and clinical details of inpatient children presenting with AGE at King Hamad University Hospital, Kingdom of Bahrain, over the course of one year. RESULTS: One hundred nine samples were collected. The GI panel was positive in 96 samples (88.1%), with the majority detected in the toddler age group. Forty-one (42.7%) samples were positive for at least one organism. Salmonella was the most frequently encountered bacteria as a single isolate, 10/55 (18.2%), while enteropathogenic Escherichia coli was the most common co-infected organism, 16/41 (39%). Norovirus was the most common virus among the viruses. Bacterial detection peaked from July to October, while viral detection plateaued throughout the year. The GI panel and stool culture were positive for the same organism in 17 samples, versus one sample with a different organism. Sixty-two (56.9%) samples had a positive GI panel but negative stool cultures and stool analysis, and half of those detected viruses. The GI panel was positive in 86.2% of severely ill patients; the majority were bacteria. Bacterial detection was associated with a higher CRP compared to viruses. CONCLUSION: The GI panel is an informative tool for detecting the causative pathogen of AGE in children. However, it can detect multiple organisms, indicating a possible carrier status, which points toward future studies.

Extraskeletal chondroma of the toe in a child with DICER1 tumor predisposition syndrome: support for a dominant negative mechanism.

DICER1 tumor predisposition syndrome is a pleiotropic disorder that gives rise to various mainly pediatric-onset lesions. We report an extraskeletal chondroma (EC) of the great toe occurring in a child who, unusually, carries a germline "hotspot" missense DICER1 variant rather than the more usual loss-of-function (LOF) variant. No heterozygous LOF allele was identified in the EC. We demonstrate this variant impairs 5p cleavage of precursor-miRNA (pre-miRNA) and competes with wild-type (WT) DICER1 protein for pre-miRNA processing. These results suggest a mechanism through which a germline RNase IIIb variant could impair pre-miRNA processing without complete LOF of the WT DICER1 allele.

Pulcherrimin protects Bacillus subtilis against oxidative stress during biofilm development.

Pulcherrimin is an iron-binding reddish pigment produced by various bacterial and yeast species. In the soil bacterium Bacillus subtilis, this pigment is synthesized intracellularly as the colorless pulcherriminic acid by using two molecules of tRNA-charged leucine as the substrate; pulcherriminic acid molecules are then secreted and bind to ferric iron extracellularly to form the red-colored pigment pulcherrimin. The biological importance of pulcherrimin is not well understood. A previous study showed that secretion of pulcherrimin caused iron depletion in the surroundings and growth arrest on cells located at the edge of a B. subtilis colony biofilm. In this study, we identified that pulcherrimin is primarily produced under biofilm conditions and provides protection to cells in the biofilm against oxidative stress. We presented molecular evidence on how pulcherrimin lowers the level of reactive oxygen species (ROS) and alleviates oxidative stress and DNA damage caused by ROS accumulation in a mature biofilm. We also performed global transcriptome profiling to identify differentially expressed genes in the pulcherrimin-deficient mutant compared with the wild type, and further characterized the regulation of genes by pulcherrimin that are related to iron homeostasis, DNA damage response (DDR), and oxidative stress response. Based on our findings, we propose pulcherrimin as an important antioxidant that modulates B. subtilis biofilm development.

Multisystem Inflammatory Syndrome in Children (MIS-C) Post COVID-19 Infection: Diagnosis and Treatment from the Paediatric Intensive Care Unit (PICU) at a Tertiary Hospital in the Kingdom of Bahrain.

BACKGROUND: Post coronavirus disease 2019 (COVID-19) infections, children presented with varying clinical manifestations of a Multisystem Inflammatory Syndrome in Children (MIS-C). The aim of our study is to identify the clinical manifestations upon admission to paediatric intensive care unit (PICU) and to identify how different treatments affected post-treatment outcomes.  Methods: A retrospective cross-sectional study included 11 patients diagnosed with multisystem inflammatory syndrome based on the World Health Organization (WHO) classification and treated by intravenous immunoglobulin (IVIG) with/without corticosteroids.  Results: There were six female and five male patients with an average age of 5.08±4.7 years. Ten had a confirmed positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological antibody test or polymerase chain reaction (PCR) test, with one having only contact history. The most common systems affected by MIS-C were gastrointestinal and ophthalmological presentations. All presented with fever and raised inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, procalcitonin, ferritin, d-dimer, and lactate dehydrogenase). There was no statistical difference between both treatment groups. Clinical and inflammatory markers significantly improved in both groups. CONCLUSION: This study highlights an improved outcome associated with combination therapy, although there is no statistical significance between both groups.

Intravenous buspirone for the prevention of postoperative nausea and vomiting.

RATIONALE: Buspirone, a partial 5HT(1A) agonist and D2 and D3 antagonist, has shown promising antiemetic efficacy when given parenterally in animal models, but its efficacy for the prevention of postoperative nausea and vomiting (PONV) is unknown. OBJECTIVE: To study the efficacy and dose-responsiveness of intravenous buspirone for the prevention of PONV. METHODS: A randomised, double-blind, placebo-controlled study was performed in adults at moderate to high PONV risk undergoing surgery with a general anaesthetic. Patients were randomised to receive an intravenous dose of buspirone (0.3, 1.0, 2.0, 3.0 mg) or placebo at the end of surgery. The primary endpoint was the cumulative 24-h PONV incidence (i.e. any nausea and/or vomiting). Vomiting included retching. Nausea was defined as a score of ≥ 4 on an 11-point verbal rating scale running from zero (no nausea) to ten (the worst nausea imaginable). RESULTS: A total of 257 patients received the study drug and fulfilled the criteria for inclusion in the primary efficacy and safety analyses. With placebo, the mean 24-h PONV incidence was 49.0 % (90 % confidence interval [CI] 37.5-60.5 %). With buspirone, that incidence ranged from a mean of 40.8 % (29.3-52.4 %) in the 1 mg arm to 58.0 % (46.5-69.5 %) in the 0.3 mg arm (P > 0.05 for all comparisons). There was no difference between placebo and buspirone at any dose for any other efficacy endpoint, nor in the number or severity of adverse events or any other safety measures. CONCLUSION: We were unable to show that intravenous single-dose buspirone, at the tested dose-range, was effective at preventing PONV in surgical adult patients. The present study emphasises the difficulty in extrapolating from animal models of emesis to clinical efficacy in PONV.

"This Is Not Our Disease": A Qualitative Study of Influencers of COVID-19 Preventive Behaviours in Nguenyyiel Refugee Camp (Gambella, Ethiopia).

The COVID-19 pandemic has infected more than 263 million people and claimed the lives of over 5 million people worldwide. Refugees living in camp settings are particularly vulnerable to infection because of the difficulty implementing preventive measures and lack of medical resources. However, very little is known about the factors that influence the behavioural response of refugees towards COVID-19. There is an urgent need for field evidence to inform the design and implementation of a robust social and behaviour change communication strategy to respond to the threat posed by COVID-19 in humanitarian settings. This study examines factors influencing COVID-19-related behavioural decisions in the Nguenyyiel refugee camp located in Gambella, Ethiopia using data collected from focus group discussions and key informant interviews in September 2020. The evidence suggests that while a number of factors have been facilitating the adoption of COVID-19 prevention measures, including good general knowledge about the virus and the necessary preventive strategies and the active engagement by community leaders and non-governmental organisations, important structural and cultural factors have hindered the uptake of COVID-19 prevention measures. These include: difficultly staying at home to minimise physical contact; overcrowding in the camp and within home dwellings; a lack of hand sanitizers and masks and of funds to purchase these; inconsistent use of facemasks when available; COVID-19 denial and misconceptions about the disease, and other cultural beliefs and habits. Overall, the study found that refugees perceived COVID-19 to pose a low threat (susceptibility and severity) and had mixed beliefs about the efficacy of preventive behaviours. This study identified gaps in the existing information education and communication strategy, including a lack of consistency, inadequate messaging, and a limited use of communication channels. While awareness of COVID-19 is a necessary first step, it is not sufficient to increase adoption of prevention measures in this setting. The current communication strategy should move beyond awareness raising and emphasise the threat posed by COVID-19 especially among the most vulnerable members of the camp population. This should be accompanied by increased community support and attention to other barriers and incentives to preventive behaviours.

A pharmacological profile of intravenous amisulpride for the treatment of postoperative nausea and vomiting.

INTRODUCTION: The issue of postoperative nausea and vomiting (PONV) remains important in surgical practice, contributing to patient distress, slower recovery, and increased use of healthcare resources. Many surgical patients report it to be a worse problem than the pain. New antiemetics of different classes are still needed to help manage PONV effectively, especially the treatment of established PONV after the failure of common prophylactic antiemetics such as 5-HT3-antagonists and corticosteroids. Intravenous amisulpride, a drug with a long history of safe use in oral form as an antipsychotic, has recently been approved in the US (trade name: Barhemsys) as an intravenous antiemetic for the prevention and treatment of PONV. AREAS COVERED: This review article summarizes the published data on the clinical pharmacology, safety, and efficacy of intravenous amisulpride as an antiemetic, supplemented by published data on oral amisulpride, where relevant to the intravenous form. Literature was obtained via the PubMed search terms 'intravenous amisulpride' and 'amisulpride AND safety.' Both primary and secondary pharmacology are covered, along with clinical pharmacokinetics (distribution, metabolism, and excretion). The review of clinical safety and efficacy includes data from four studies in the prevention of PONV, two in the treatment of PONV and two investigating effects on the QT interval of the electrocardiogram in healthy volunteers. EXPERT OPINION: Given the importance of sufficient PONV prevention for patients and the healthcare system, the availability of intravenous amisulpride is helpful, restoring the dopamine-antagonist class as a potential mainstay in both combination prophylaxis and treatment.

Metabolism and Excretion of Intravenous, Radio-Labeled Amisulpride in Healthy, Adult Volunteers.

PURPOSE: Intravenous amisulpride, a dopamine D2/D3 antagonist, has recently been shown in trials to be an effective antiemetic at low doses. This study was conducted to investigate the metabolism and elimination of a single dose of intravenous 14C-labeled amisulpride in healthy, adult volunteers. PATIENTS AND METHODS: Six healthy male volunteers aged 18-65 years were given a single 10 mg dose of 14C-labeled amisulpride containing not more than 1.8 MBq of radioactivity, infused over 4 mins. Concentrations of amisulpride and total radioactivity were measured in plasma, whole blood, urine and feces at various time points up to 168 hrs after dosing. Metabolites detected in plasma, urine and feces were characterized using liquid chromatography tandem mass spectrometry (LC-MS/MS) with in-line radiometric detection. RESULTS: The mean recovery of radioactivity in excreta was 96.4% (range 92.0-98.5%), of which 73.6% (range 70.6-79.2%) was recovered from urine and 22.8% (range 18.9-25.7%) from feces. Four metabolites of amisulpride were detected in urine, representing 15.0% of the excreted dose; three of these were also present in feces, representing 6.1% of the excreted dose. No metabolites were detected in plasma. Excretion was initially rapid, with about two-thirds of the drug-related material eliminated within 12 hrs, primarily in the urine. A second, slower phase of excretion was predominantly fecal and was essentially complete by 96 hrs after dosing. The terminal plasma elimination half-life of parent amisulpride was 3.7 hrs and that of total 14C-labeled drug material was 4.2 hrs. CONCLUSION: Intravenous amisulpride undergoes limited metabolism and is excreted primarily via the renal route. CLINICAL TRIAL REGISTRY NUMBER: ClinicalTrials.gov NCT02881840.