Feasibility of Exenatide, a GLP-1R Agonist, for Treating Cocaine Use Disorder: A Case Series Study.

Cocaine use remains a serious public health problem associated with a marked increase in overdose deaths in the past decade. No medications have yet been proven to be effective for the treatment of cocaine use disorder (CUD). Among the highly promising medications have been glucagon-like peptide 1 receptor agonists (GLP-1RA) that are currently used for the treatment of type 2 diabetes mellitus and weight management. Preclinically, GLP-1RAs have been shown to attenuate cocaine self-administration, however, this has not yet been demonstrated in a human laboratory study. The GLP-1RA extended-release exenatide is given as a once-weekly injection, which may be clinically advantageous for addressing medication nonadherence among individuals with CUD. Here, we assess feasibility and safety by reporting on 3 cases of patients with CUD who received 6 weeks of exenatide 2 mg subcutaneously once-weekly in an open-label fashion, along with standard individual drug counseling. We observed excellent attendance and compliance, along with positive end-of-study satisfaction ratings. The medication was well tolerated and without unexpected or severe adverse events. Results for cocaine use and related clinical effects were more mixed, yet encouraging. Future empirical testing of exenatide for treating CUD should utilize a randomized controlled trial design and longer treatment duration.

Acute pharmacodynamic responses to exenatide: Drug-induced increases in insulin secretion and glucose effectiveness.

AIM: Glucagon-like peptide-1 receptor agonists provide multiple benefits to patients with type 2 diabetes, including improved glycaemic control, weight loss and decreased risk of major adverse cardiovascular events. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. METHODS: Exenatide (5 µg, subcutaneously) or saline (0.2 ml, subcutaneously) was administered to 62 healthy volunteers. Frequently sampled intravenous glucose tolerance tests were conducted to assess the impact of exenatide on insulin secretion and insulin action. This pilot study was a crossover design in which participants received exenatide and saline in random order. RESULTS: Exenatide increased first phase insulin secretion 1.9-fold (p = 1.9 × 10-9 ) and accelerated the rate of glucose disappearance 2.4-fold (p = 2 × 10-10 ). Minimal model analysis showed that exenatide increased glucose effectiveness (Sg ) by 32% (p = .0008) but did not significantly affect insulin sensitivity (Si ). The exenatide-induced increase in insulin secretion made the largest contribution to interindividual variation in exenatide-induced acceleration of glucose disappearance while interindividual variation in the drug effect on Sg contributed to a lesser extent (ß = 0.58 or 0.27, respectively). CONCLUSIONS: This pilot study provides validation for the value of a frequently sampled intravenous glucose tolerance test (including minimal model analysis) to provide primary data for our ongoing pharmacogenomic study of pharmacodynamic effects of semaglutide (NCT05071898). Three endpoints provide quantitative assessments of the effects of glucagon-like peptide-1 receptor agonists on glucose metabolism: first phase insulin secretion, glucose disappearance rates and glucose effectiveness.

Effect of glucagon-like peptide-1 receptor agonists administration during coronary artery bypass grafting: a systematic review and meta-analysis of randomized control trials.

Aim: To determine if glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can benefit patients receiving coronary artery bypass graft (CABG), GLP-1 RAs administration alongside standard insulin was compared with perioperative insulin alone. Materials & methods: All articles from Pubmed and Scopus databases that compared GLP-1 RA administration to insulin alone during CABG were included for meta-analysis. Short-term postoperative outcomes were analyzed between groups. Results: Average postoperative blood glucose levels significantly favored GLP-1 RA with a mean difference of -0.72 (p < 0.001). No other variables were significantly different between GLP-1 RA and insulin alone. Conclusion: GLP-1 RA is a safe option for perioperative care of CABG patients that can potentially improve postoperative outcomes of CABG patients by improving glycemic control and reducing hyperglycemic episodes.

What is this article about? Coronary artery bypass graft (CABG) is a common surgery for patients who have blocked blood vessels in their heart preventing their heart from functioning properly. Compared with other treatment options, CABG has better long-term outcomes and chances of survival, especially for patients with diabetes. Some medications that lower blood sugar levels in patients with diabetes, are also well known to improve heart health in this population. Because of these benefits, the specific medication called GLP-1 RA, has been proposed as an option to improve outcomes of people receiving CABG surgery. What were the results? By taking a systematic approach, 1375 articles were screened to find seven trials that tested the comparison of GLP-1 RA versus a control of just insulin in CABG patients. Analyzing this data, CABG patients receiving GLP-1 RA had significantly lower blood sugar levels compared with patients getting the control. The GLP-1 RA group also, on average, had similar or lower levels of heart rate arrhythmias, events of critically low blood sugar and the need of serious interventions compared with the control group. What do the results of the study mean? These results demonstrate that GLP-1 RA have similar or improved outcomes compared with standard therapy alone, suggesting it as a safe option for CABG patients. By lowering blood sugar levels, GLP-1 RA could also decrease complication rates and improve patient management compared with standard therapy alone, since high blood sugar levels are correlated with increased complications and worse postoperation outcomes.

Therapeutic Plasma Exchange for Venom-Induced Thrombotic Microangiopathy Following Hump-Nosed Pit Viper (Genus: Hypnale) Bites: A Prospective Observational Study.

INTRODUCTION: -Thrombotic microangiopathy (TMA), which is the triad of acute kidney injury (AKI), microangiopathic hemolytic anemia (MAHA), and thrombocytopenia, is a rare complication of snakebites, and in Sri Lanka, it is commonly seen with hump-nosed pit viper (HNPV) bites. METHODS: -We conducted a prospective observational study of patients with AKI caused by HNPV bites in Teaching Hospital, Ratnapura, Sri Lanka for 6 y, commencing in June 2015. Some patients with TMA underwent therapeutic plasma exchange (TPE) and some did not. These 2 groups were compared. Statistical analysis was carried out using Minitab 18.1. Data were presented as median (IQR). RESULTS: -There were 52 (8%) patients with TMA, of whom 21 (45%) were in the TPE group and 26 (55%) were in the non-TPE group. TPE improved time to platelet correction (4 d [IQR, 4-5 d] vs 7 d [IQR, 5-9 d]; P=0.009), time to MAHA correction (5 d [IQR, 3-4 d] vs 7 d [IQR, 6-9 d]; P=0.004), time to prothrombin time (PT)/international normalized ratio (INR) correction (1 d [IQR, 1-2 d] vs 3 d [IQR, 3-4 d]; P=0.003), and time to 20 min whole blood clotting test (WBCT20) correction (2 d [IQR, 1-2 d] vs 3 d [1QR 2-3 d]; P=0.020). Renal recovery was predicted by TPE (P=0.048) and highest creatinine level (P=0.001). There was no association between TPE and dialysis dependency at discharge (P=0.597), length of hospital stay (P=0.220), and the number of dialysis cycles prior to discharge (P=0.540). TPE did not improve the number of blood transfusions (5 packs [IQR, 3-8.5 packs] vs 4 packs [IQR, 0-9 packs]; P=0.290). CONCLUSIONS: -TPE is effective for TMA in the early correction of platelet counts, MAHA, PT/INR, and WBCT20 in HNPV bites.

Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial.

BackgroundAlcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduces alcohol consumption in rodents and nonhuman primates, but its efficacy in patients with AUD is unknown.MethodsIn a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26 weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed functional MRI (fMRI) and single-photon emission CT (SPECT) brain scans.ResultsA total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared with placebo, it significantly attenuated fMRI alcohol cue reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, dopamine transporter availability was lower in the exenatide group compared with the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI > 30 kg/m2). Adverse events were mainly gastrointestinal.ConclusionThis randomized controlled trial on the effects of a GLP-1 receptor agonist in AUD patients provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction.Trial registrationEudraCT: 2016-003343-11. ClinicalTrials.gov (NCT03232112).FundingNovavi Foundation; Research Foundation, Mental Health Services, Capital Region of Denmark; Research Foundation, Capital Region of Denmark; Ivan Nielsen Foundation; A.P. Moeller Foundation; Augustinus Foundation; Woerzner Foundation; Grosserer L.F. Foghts Foundation; Hartmann Foundation; Aase and Ejnar Danielsen Foundation; P.A. Messerschmidt and Wife Foundation; and Lundbeck Foundation.

Unraveling the venom chemistry with evidence for histamine as key regulator in the envenomation by caterpillar Automeris zaruma.

Over the past decades, envenomation by caterpillars of Automeris spp. became an increasing health problem in Latin America. Accidental contact with the stinging spines of these caterpillars cause acute local pain, itching, inflammation and skin rashes that persists for days. Even when the cause is obvious, the exact molecular mechanisms responsible for the observed symptoms are yet to be elucidated. Here, we describe for the first time, an active compound in the venom and the study of the bioactivity of the venom extracted from the spines of the caterpillar Automeris zaruma. Electrophysiological screening of a library of membrane proteins important for pain and itch enabled us to investigate and reveal the mode of action of the venom of A. zaruma. Further mass spectrometric analysis (Q-TOF-MS) made it possible to establish a link between the bioactivity and the components found in the venom. We show that the spine extract of A. zaruma contains histamine that potently activates the four types of the human histamine receptors (H1R, H2R, H3R and H4R) with a selectivity preference towards H3R and H4R. Furthermore, a modulation of the target MRGPRX2 was found. Together, these findings are the first to explain the symptomology of A. zaruma envenomation, enabling us a better understanding of caterpillar envenomation and predict that the hurdle of the scarce efficacy of the currently used antihistaminic drugs can be overcome by including H3R and H4R blockers in the clinical used medication. Such an approach might be used for other caterpillar envenomation in the world and represent a significant improvement for the well-being of the patient.

Once-Weekly Exenatide in Youth With Type 2 Diabetes.

OBJECTIVE: Approved treatments for type 2 diabetes in pediatric patients include metformin, liraglutide, and insulin. However, approximately one-half of the youth fail metformin monotherapy within 1 year, insulin therapy is associated with challenges, and liraglutide requires daily injections. Consequently, the efficacy and safety of once-weekly injections of exenatide for the treatment of youth with type 2 diabetes was evaluated. RESEARCH DESIGN AND METHODS: Participants (aged 10 to <18 years) were randomized (5:2) to once-weekly exenatide 2 mg or placebo, respectively. The primary efficacy end point was change in glycated hemoglobin from baseline to week 24. Secondary efficacy end points were also evaluated, and the frequency of adverse events (AEs) was assessed. RESULTS: A total of 83 participants were randomized (exenatide, 59; placebo, 24) and 72 completed 24-week treatment (exenatide, 49; placebo, 23). At 24 weeks, the least squares mean change in glycated hemoglobin was -0.36% for the exenatide and +0.49% for the placebo groups (between-group difference, -0.85%; 95% CI -1.51, -0.19; P = 0.012). Nonsignificant least squares mean differences from baseline to 24 weeks favoring exenatide were observed: fasting glucose -21.6 mg/dL (-49.0, 5.7; P = 0.119), systolic blood pressure -2.8 mmHg (-8.0, 2.4; P = 0.284), and body weight -1.22 kg (-3.59, 1.15; P = 0.307). AEs occurred in 36 (61.0%) and 17 (73.9%) participants in the exenatide and placebo groups, respectively. CONCLUSIONS: In youth with type 2 diabetes suboptimally controlled with current treatments, once-weekly exenatide reduced glycated hemoglobin at 24 weeks and was well tolerated.

BITES study: A qualitative analysis among emergency medicine physicians on snake envenomation management practices.

INTRODUCTION: Antivenom is currently considered standard treatment across the full spectrum of severity for snake envenomation in the United States. Although safe and effective antivenoms exist, their use in clinical practice is not universal. OBJECTIVE: This study explored physicians' perceptions of antivenom use and experience with snake envenomation treatment in order to identify factors that influence treatment decisions and willingness to administer. METHODS: We conducted a qualitative study including in-depth interviews via online video conferencing with physicians practicing in emergency departments across the United States. Participants were selected based on purposive sampling methods. Data analysis followed inductive strategies, conducted by two researchers. The codebook and findings were discussed within the research team. FINDINGS: Sixteen in-depth interviews with physicians from nine states across the US were conducted. The participants' specialties include emergency medicine (EM), pediatric EM, and toxicology. The experience of treating snakebites ranged from only didactic education to having treated over 100 cases. Emergent themes for this manuscript from the interview data included perceptions of antivenom, willingness to administer antivenom and influencing factors to antivenom usage. Overall, cost-related concerns were a major barrier to antivenom administration, especially in cases where the indications and effectiveness did not clearly outweigh the potential financial burden on the patient in non-life- or limb-threatening cases. The potential to decrease recovery time and long-term functional impairments was not commonly reported by participants as an indication for antivenom. In addition, level of exposure and perceived competence, based on prior education and clinical experience, further impacted the decision to treat. Resources such as Poison Center Call lines were well received and commonly used to guide the treatment plan. The need for better clinical guidelines and updated treatment algorithms with clinical and measurable indicators was stated to help the decision-making process, especially among those with low exposure to snake envenomation patients. CONCLUSIONS: A major barrier to physician use of antivenom is a concern about cost, cost transparency and cost-benefit for the patients. Those concerns, in addition to the varying degrees of awareness of potential long-term benefits, further influence inconsistent clinical treatment practices.

Venenos de serpentes do gênero Bothrops: impacto da glicosilação na complexidade dos proteomas e função de toxinas / Bothrops snake venoms: impact of glycosylation on the complexity of proteomes and toxins function

A variabilidade estrutural é uma característica das proteínas de venenos de serpentes, e a glicosilação é uma das principais modificações pós-traducionais que contribui para a diversificação de seus proteomas. Recentes estudos de nosso grupo demonstraram que venenos do gênero Bothrops são marcadamente definidos pelo seu conteúdo de glicoproteínas, e que a maioria das estruturas de N-glicanos dos tipos híbrido e complexo identificados em oito venenos deste gênero contêm unidades de ácido siálico. Em paralelo, em glicoproteínas do veneno de B. cotiara foi identificada a presença de uma estrutura de N-acetilglicosamina bissecada. Assim, com o objetivo de investigar a variação do conteúdo de glicoproteínas, assim como os mecanismos envolvidos na geração dos diferentes venenos de Bothrops, neste estudo foram analisados comparativamente os glicoproteomas de nove venenos do gênero Bothrops (B. atrox, B. cotiara, B. erythromelas, B. fonsecai, B. insularis, B. jararaca, B. jararacussu, B. moojeni e B. neuwiedi). As abordagens glicoproteômicas envolveram cromatografia de afinidade e ensaio de pull-down utilizando, respectivamente, as lectinas SNA (aglutinina de Sambucus nigra) e MAL I (lectina de Maackia amurensis), que mostram afinidade por unidades de ácido siálico nas posições, respectivamente, α2,6 e α2,3; e cromatografia de afinidade com a lectina PHA-E (eritroaglutinina de Phaseolus vulgaris), que reconhece N-acetilglicosamina bissecada. Ainda, eletroforese de proteínas, blot de lectina, e identificação de proteínas por espectrometria de massas foram empregadas para caracterizar os glicoproteomas. As lectinas geraram frações dos venenos enriquecidas de diferentes componentes, onde as principais classes de glicoproteínas identificadas foram metaloprotease, serinoprotease, e L-amino ácido oxidase, além de outras enzimas pouco abundantes nos venenos. Os diferentes conteúdos de proteínas reconhecidas por essas lectinas, com especificidades distintas, ressaltaram novos aspectos da variabilidade dos subproteomas de glicoproteínas desses venenos, dependendo da espécie. Ainda, considerando que metaloproteases e serinoproteases são componentes abundantes nesses venenos e fundamentais no quadro de envenenamento botrópico, e que estas enzimas contêm diversos sítios de glicosilação, o papel das unidades de ácido siálico na atividade proteolítica das mesmas foi avaliado. Assim, a remoção enzimática de ácido siálico (i) alterou o padrão de gelatinólise em zimografia da maioria dos venenos, (ii) diminuiu a atividade proteolítica de alguns venenos sobre o fibrinogênio e a atividade coagulante do plasma humano de todos os venenos, e (iii) alterou o perfil de hidrólise de proteínas plasmáticas pelo veneno de B. jararaca, indicando que este carboidrato pode desempenhar um papel na interação das proteases com seus substratos proteicos. Em contraste, o perfil da atividade amidolítica dos venenos não se alterou após a remoção de ácido siálico e incubação com o substrato Bz-Arg-pNA, indicando que ácido siálico não é essencial em N-glicanos de serinoproteases atuando sobre substratos não proteicos. Em conjunto, esses resultados expandem o conhecimento sobre a variabilidade de proteomas de venenos do gênero Bothrops e apontam a importância das cadeias de carboidratos contendo ácido siálico nas atividades enzimáticas das proteases desses venenos

Structural variability is a feature of snake venom proteins, and glycosylation is one of the main post-translational modifications that contributes to the diversification of venom proteomes. Recent studies by our group have shown that Bothrops venoms are markedly defined by their glycoprotein content, and that most hybrid and complex N-glycan structures identified in eight venoms of this genus contain sialic acid units. In parallel, the presence of a bisected N-acetylglucosamine structure was identified in B. cotiara venom glycoproteins. Thus, with the aim of investigating the variation in the content of glycoproteins, as well as the mechanisms involved in the generation of different Bothrops venoms, in this study the glycoproteomes of nine Bothrops venoms (B. atrox, B. cotiara, B. erythromelas, B. fonsecai, B. insularis, B. jararaca, B. jararacussu, B. moojeni e B. neuwiedi) were comparatively analyzed. The glycoproteomic approaches involved affinity chromatography and pulldown using, respectively, the lectins SNA (Sambucus nigra agglutinin) and MAL I (Maackia amurensis lectin), which show affinity for sialic acid units at positions, respectively, α2,6 and α2,3, and affinity chromatography with PHA-E (Phaseolus vulgaris erythroagglutinin), which recognizes bisected N-acetylglucosamine. In addition, protein electrophoresis, lectin blot, and protein identification by mass spectrometry were employed for glycoproteome characterization. The lectins generated venom fractions enriched with different components, where the main classes of glycoproteins identified were metalloprotease, serine protease, and L-amino acid oxidase, in addition to other low abundant enzymes. The different contents of proteins recognized by these lectins of distinct specificities highlighted new aspects of the variability of the glycoprotein subproteomes of these venoms, depending on the species. Furthermore, considering that metalloproteases and serine proteases are abundant components of these venoms and essential in Bothrops envenomation, and that these enzymes contain several glycosylation sites, the role of sialic acid units in their proteolytic activities was evaluated. Thus, enzymatic removal of sialic acid (i) altered the pattern of gelatinolysis in zymography of most venoms, (ii) decreased the proteolytic activity of some venoms on fibrinogen and the clotting activity of human plasma of all venoms, and (iii) altered the hydrolysis profile of plasma proteins by B. jararaca venom, indicating that this carbohydrate may play a role in the interaction of proteases with their protein substrates. In contrast, the profile of amidolytic activity of the venoms did not change after removal of sialic acid and incubation with the substrate Bz-Arg-pNA, indicating that sialic acid is not essential in N-glycans of serine proteases acting on small substrates. Together, these results expand the knowledge about the variability of proteomes of Bothrops venoms and point to the importance of carbohydrate chains containing sialic acid in the enzymatic activities of venom proteases

The Curious Case of the "Neurotoxic Skink": Scientific Literature Points to the Absence of Venom in Scincidae.

In contrast to the clearly documented evolution of venom in many animal lineages, the origin of reptilian venom is highly debated. Historically, venom has been theorised to have evolved independently in snakes and lizards. However, some of the recent works have argued for the common origin of venom in "Toxicofera" reptiles, which include the order Serpentes (all snakes), and Anguimorpha and Iguania lizards. Nevertheless, in both these contrasting hypotheses, the lizards of the family Scincidae are considered to be harmless and devoid of toxic venoms. Interestingly, an unusual clinical case claiming neurotoxic envenoming by a scincid lizard was recently reported in Southern India. Considering its potentially significant medicolegal, conservation and evolutionary implications, we have summarised the scientific evidence that questions the validity of this clinical report. We argue that the symptoms documented in the patient are likely to have resulted from krait envenomation, which is far too frequent in these regions.

Integrative multiomics analysis of Premolis semirufa caterpillar venom in the search for molecules leading to a joint disease.

The joint disease called pararamosis is an occupational disease caused by accidental contact with bristles of the caterpillar Premolis semirufa. The chronic inflammatory process narrows the joint space and causes alterations in bone structure and cartilage degeneration, leading to joint stiffness. Aiming to determine the bristle components that could be responsible for this peculiar envenomation, in this work we have examined the toxin composition of the caterpillar bristles extract and compared it with the differentially expressed genes (DEGs) in synovial biopsies of patients affected with rheumatoid arthritis (RA) and osteoarthritis (OA). Among the proteins identified, 129 presented an average of 63% homology with human proteins and shared important conserved domains. Among the human homologous proteins, we identified seven DEGs upregulated in synovial biopsies from RA or OA patients using meta-analysis. This approach allowed us to suggest possible toxins from the pararama bristles that could be responsible for starting the joint disease observed in pararamosis. Moreover, the study of pararamosis, in turn, may lead to the discovery of specific pharmacological targets related to the early stages of articular diseases.

Efficacy and safety of exenatide as add-on therapy for patients with type 2 diabetes with an intensive insulin regimen: A randomized double-blind trial.

AIM: To assess the safety and efficacy of the short-acting glucagon-like peptide-1 receptor agonist exenatide on a population of patients with type 2 diabetes (T2D) mostly treated with continuous subcutaneous insulin injection (CSII). MATERIALS AND METHODS: A phase 2/3, multicentre, randomized, parallel-group, double-blind, placebo-controlled, 6-month trial was conducted. Patients were randomized to receive subcutaneous (SC) injections of exenatide (10 µg BID) or matched placebo. RESULTS: A total of 46 patients with T2D and elevated HbA1c were randomized (42% of the planned sample size): exenatide (n = 28) and placebo (n = 18). CSII treatment was used by 75% and 89% of patients of the exenatide and placebo groups, respectively. At 6 months, the change in HbA1c was -0.62% ± 0.94% and 0.08% ± 0.81% in the exenatide and placebo groups, respectively (difference, -0.70%; 95% CI [-1.24%; -0.15%], P = .014); body weight and body mass index decreased in the exenatide group (-2.55 ± 3.25 kg and -1.00 ± 1.31 kg/m2 ) and increased in the placebo group (1.29 ± 2.82 kg and 0.46 ± 1.16 kg/m2 ) (observed difference, -3.85 and -1.45, respectively, both P < .001); the postdinner capillary blood glucose value was lower in the exenatide group compared with the placebo group (162.4 ± 80.5 vs. 259.1 ± 94.4 mg/dL, respectively; observed difference, -96.7, P < .01). Hypoglycaemic risk, quality of life and overall safety were not different between the groups, apart from the expected occurrence of digestive effects in the exenatide group. CONCLUSIONS: Although we failed to reach our planned sample size, the addition of exenatide treatment 10 µg BID SC in T2D patients with uncontrolled HbA1c despite an intensified insulin regimen, resulted in a significant reduction of HbA1c and body weight with a good overall safety profile and acceptance.

Severe Heloderma spp. envenomation: a review of the literature.

Context: Heloderma bites are rare and generally mild, but a few cases can be life threatening. Methods: Description of Heloderma bite was searched in medical literature. Discussion: We present a synthesis of clinical and biomedical effects of envenomation by Heloderma sp. based on 22 well identified cases described in medical literature. Three life-threatening syndromes, concomitant or not, may be involved: (a) angioedema which can lead to respiratory tract obstruction, (b) significant fluid losses due to diarrhea, vomiting and sweating, associated with hypokalemia and sometimes metabolic acidosis, and (c) atrioventricular conduction disorders simulating cardiac ischemia. Conclusion: Heloderma bite are quite rare and generally mild. However, few severe cases may require emergency resuscitation. There is no antivenom, and the treatment is only symptomatic and supportive.

Apoptosis-mediated vasa down-regulation controls developmental transformation in Japanese Copidosoma floridanum female soldiers.

Copidosoma floridanum is a polyembryonic, caste-forming, wasp species. The ratio of investment in different castes changes with environmental stressors (e.g. multi-parasitism with competitors). The vasa gene was first identified in Drosophila melanogaster as a germ-cell-determining factor, and C. floridanum vasa (Cf-vas) gene positive cells have been known to develop into reproductive larvae. Cf-vas seems to control the ratio of investment in C. floridanum larval castes. In this study, we identified environmental factors that control Cf-vas mRNA expression in Japanese C. floridanum by examining Cf-vas mRNA expression under competitor (Meteorus pulchricornis) venom stress; we treated the male and female morulae with M. pulchricornis venom. We also assessed the effects of multi-parasitism of Japanese C. floridanum with M. pulchricornis and found an increasing number of female soldier larvae. The results showed that several amino acid sequences differ between the Japanese and US Cf-vas. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) showed that Japanese Cf-vas mRNA is expressed in both male and female larvae and pupae, but mRNA expression decreases in adults. Cf-vas mRNA expression significantly decreased, while C. floridanum dronc (Cf-dronc) mRNA expression increased, in female morulae after M. pulchricornis venom treatment at 20 h and 0 h of the culture period, respectively. Females and males showed different Cf-vas or Cf-dronc mRNA expression after M. pulchricornis venom treatment. Therefore, M. pulchricornis venom could affect the ratio of investment in different female castes of Japanese C. floridanum by decreasing Cf-vas mRNA expression via apoptosis.

Epidemiology of Anaphylaxis in Critically Ill Children in the United States and Canada.

BACKGROUND: Anaphylaxis is a rapid-onset, multisystem, and potentially fatal hypersensitivity reaction with varied reports of prevalence, incidence, and mortality. There are limited cases reported of severe and/or fatal pediatric anaphylaxis. OBJECTIVE: This study describes the largest cohort of intensive care unit pediatric anaphylaxis admissions with a comprehensive analysis of identified triggers, clinical and demographic information, and probability of death. METHODS: We describe the epidemiology of pediatric anaphylaxis admissions to North American pediatric intensive care units (PICUs) that were prospectively enrolled in the Virtual Pediatric Systems database from 2010 to 2015. One hundred thirty-one PICUs in North America (United States and Canada) were queried for anaphylaxis International Classification of Diseases, Ninth Revision or International Classification of Diseases, Tenth Revision codes from the Virtual Pediatric Systems database from 2010 to 2015 in the United States and Canada. One thousand nine hundred eighty-nine patients younger than 18 years were identified out of 604,279 total number of patients admitted to a PICU in the database during this time frame. RESULTS: The primary outcome was mortality, which was compared with patient and admission data using Fisher exact test. Secondary outcomes (intubation, length of stay, mortality risk scores, systolic blood pressure, and pupillary reflex) were analyzed using the Kruskal-Wallis test or Wilcoxon rank-sum test, as appropriate. One thousand nine hundred eighty-nine patients with an anaphylaxis International Classification of Diseases code were identified in the database. One percent of patients died because of critical anaphylaxis. Identified triggers for fatal cases were peanuts, milk, and blood products. Peanuts were the most common trigger. Children were mostly male when younger than 13 years, and mostly female when 13 years and older. Average length of stay was 2 days. There was a higher proportion of Asian patients younger than 2 years or when the trigger was food. CONCLUSIONS: This is the largest study to describe pediatric critical anaphylaxis cases in North America and identifies food as the most common trigger. Death occurs in 1% of cases, with intubation occurring most commonly in the first hour. The risk for intensive care unit admission in children underscores the serious nature of anaphylaxis in this population.

Evaluation of Prehospital Management in a Canadian Emergency Department Anaphylaxis Cohort.

BACKGROUND: Studies assessing the use of antihistamines and corticosteroids for the treatment of anaphylaxis have not supported a conclusive effect. OBJECTIVE: To assess prehospital management of anaphylaxis by measuring the effect of epinephrine use compared with antihistamines and corticosteroids on negative outcomes of anaphylaxis (intensive care unit/hospital ward admission, multiple doses of epinephrine in the emergency department [ED], and intravenous fluids given in the ED). METHODS: The Cross-Canada Anaphylaxis Registry is a cohort study that enrolls anaphylaxis cases presenting to EDs in 5 Canadian provinces over a 6-year period. Participants were recruited prospectively and retrospectively and were excluded if the case did not meet the definition of anaphylaxis. RESULTS: A total of 3498 cases of anaphylaxis, of which 80.3% were children, presented to 9 EDs across Canada. Prehospital treatment with epinephrine was administered in 31% of cases, whereas antihistamines and corticosteroids were used in 46% and 2% of cases, respectively. Admission to the intensive care unit/hospital ward was associated with prehospital treatment with corticosteroids (adjusted odds ratio, 2.84; 95% confidence interval [CI], 1.55, 6.97) while adjusting for severity, treatment with epinephrine and antihistamines, asthma, sex, and age. Prehospital treatment with epinephrine (adjusted odds ratio, 0.23; 95% CI, 0.14, 0.38) and antihistamines (adjusted odds ratio, 0.61; 95% CI, 0.44, 0.85) decreased the likelihood of receiving multiple doses of epinephrine in the ED, while adjusting for severity, treatment with corticosteroids, asthma, sex, and age. CONCLUSIONS: Prompt epinephrine treatment is crucial. Use of antihistamines in conjunction with epinephrine may reduce the risk of uncontrolled reactions (administration of 2 or more doses of epinephrine in the ED), although our findings do not support the use of corticosteroids.