Structure and bioactivity of an insecticidal trans-defensin from assassin bug venom.

Disulfide-rich peptides such as defensins play diverse roles in immunity and ion channel modulation, as well as constituting the bioactive components of many animal venoms. We investigated the structure and bioactivity of U-RDTX-Pp19, a peptide previously discovered in venom of the assassin bug Pristhesancus plagipennis. Recombinant Pp19 (rPp19) was found to possess insecticidal activity when injected into Drosophila melanogaster. A bioinformatic search revealed that domains homologous to Pp19 are produced by assassin bugs and diverse other arthropods. rPp19 co-eluted with native Pp19 isolated from P. plagipennis, which we found is more abundant in hemolymph than venom. We solved the three-dimensional structure of rPp19 using 2D 1H NMR spectroscopy, finding that it adopts a disulfide-stabilized structure highly similar to known trans-defensins, with the same cystine connectivity as human α-defensin (I-VI, II-IV, and III-V). The structure of Pp19 is unique among reported structures of arthropod peptides.

Phylogeny, envenomation syndrome, and membrane permeabilising venom produced by Australia's electric caterpillar Comana monomorpha.

Zygaenoidea is a superfamily of lepidopterans containing many venomous species, including the Limacodidae (nettle caterpillars) and Megalopygidae (asp caterpillars). Venom proteomes have been recently documented for several species from each of these families, but further data are required to understand the evolution of venom in Zygaenoidea. In this study, we examined the 'electric' caterpillar from North-Eastern Australia, a limacodid caterpillar densely covered in venomous spines. We used DNA barcoding to identify this caterpillar as the larva of the moth Comana monomorpha (Turner, 1904). We report the clinical symptoms of C. monomorpha envenomation, which include acute pain, and erythema and oedema lasting for more than a week. Combining transcriptomics of venom spines with proteomics of venom harvested from the spine tips revealed a venom markedly different in composition from previously examined limacodid venoms that are rich in peptides. In contrast, the venom of C. monomorpha is rich in aerolysin-like proteins similar to those found in venoms of asp caterpillars (Megalopygidae). Consistent with this composition, the venom potently permeabilises sensory neurons and human neuroblastoma cells. This study highlights the diversity of venom composition in Limacodidae.

Discriminatory ability of perioperative heart rate variability in predicting postoperative complications in major urologic surgery: a prospective cohort study.

We aimed to determine if continuous perioperative heart rate variability (HRV) monitoring could improve risk stratification compared to a short preoperative measurement in radical cystectomy patients. Electrocardiography (ECG) recordings were collected continuously preoperatively to discharge in 83 patients. Two, 5-min ECG signal segments (preoperative and at 24-h post ECG placement) were analyzed offline to extract HRV metrics. HRV metric discriminatory ability to identify patients with 30-day postoperative complications were analyzed using receiver operating characteristics curves. Sixty participants were included for analysis of which 27 (45%) developed a complication within 30 days postoperative. HRV was reduced in patients with complications. Postoperative standard deviation NN intervals and root mean square of successive differences had area under the curves (AUC) of 0.67 (95% CI 0.54 to 0.81) and 0.68 (95% CI 0.54 to 0.82), respectively. Significant discriminatory abilities were also reported for postoperative frequency metrics of absolute low frequency (LF) [AUC = 0.65 (95% CI 0.51 to 0.79)] and high frequency (HF) powers [AUC = 0.69 (95% CI 0.55 to 0.83)] and total power [AUC = 0.66 (95% CI 0.53 to 0.80)]. Postoperative acquired HRV metrics demonstrated improved discriminatory ability. Our findings suggest that longer-term perioperative HRV monitoring presents with superior ability to stratify complication risk.

Allopurinol and cardiovascular outcomes in patients with ischaemic heart disease: the ALL-HEART RCT and economic evaluation.

Background: Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid and is used to prevent acute gout flares in patients with gout. Observational and small interventional studies have suggested beneficial cardiovascular effects of allopurinol. Objective: To determine whether allopurinol improves major cardiovascular outcomes in patients with ischaemic heart disease. Design: Prospective, randomised, open-label, blinded endpoint multicentre clinical trial. Setting: Four hundred and twenty-four UK primary care practices. Participants: Aged 60 years and over with ischaemic heart disease but no gout. Interventions: Participants were randomised (1 : 1) using a central web-based randomisation system to receive allopurinol up to 600 mg daily that was added to usual care or to continue usual care. Main outcome measures: The primary outcome was the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes were non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, all-cause mortality, hospitalisation for heart failure, hospitalisation for acute coronary syndrome, coronary revascularisation, hospitalisation for acute coronary syndrome or coronary revascularisation, all cardiovascular hospitalisations, quality of life and cost-effectiveness. The hazard ratio (allopurinol vs. usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis. Results: From 7 February 2014 to 2 October 2017, 5937 participants were enrolled and randomised to the allopurinol arm (n = 2979) or the usual care arm (n = 2958). A total of 5721 randomised participants (2853 allopurinol; 2868 usual care) were included in the modified intention-to-treat analysis population (mean age 72.0 years; 75.5% male). There was no difference between the allopurinol and usual care arms in the primary endpoint, 314 (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years), hazard ratio 1.04 (95% confidence interval 0.89 to 1.21); p = 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, hazard ratio 1.02 (95% confidence interval 0.87 to 1.20); p = 0.77. The pre-specified health economic analysis plan was to perform a 'within trial' cost-utility analysis if there was no statistically significant difference in the primary endpoint, so NHS costs and quality-adjusted life-years were estimated over a 5-year period. The difference in costs between treatment arms was +£115 higher for allopurinol (95% confidence interval £17 to £210) with no difference in quality-adjusted life-years (95% confidence interval -0.061 to +0.060). We conclude that there is no evidence that allopurinol used in line with the study protocol is cost-effective. Limitations: The results may not be generalisable to younger populations, other ethnic groups or patients with more acute ischaemic heart disease. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment, but an on-treatment analysis gave similar results to the main analysis. Conclusions: The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve cardiovascular outcomes compared to usual care in patients with ischaemic heart disease. We conclude that allopurinol should not be recommended for the secondary prevention of cardiovascular events in patients with ischaemic heart disease but no gout. Future work: The effects of allopurinol on cardiovascular outcomes in patients with ischaemic heart disease and co-existing hyperuricaemia or clinical gout could be explored in future studies. Trial registration: This trial is registered as EU Clinical Trials Register (EudraCT 2013-003559-39) and ISRCTN (ISRCTN 32017426). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/36/41) and is published in full in Health Technology Assessment; Vol. 28, No. 18. See the NIHR Funding and Awards website for further award information.

The purpose of the ALL-HEART study was to determine whether giving allopurinol to people with ischaemic heart disease (also commonly known as coronary heart disease) would reduce their risk of having a heart attack, stroke or of dying from cardiovascular disease. Allopurinol is a medication usually given to patients with gout to prevent acute gout flares. It is not currently used to treat ischaemic heart disease. We randomly allocated people aged over 60 years with ischaemic heart disease to take up to 600 mg of allopurinol daily (in addition to their usual care) or to continue with their usual care. We then monitored participants for several years and recorded any major health events such as heart attacks, strokes and deaths. We obtained most of the follow-up data from centrally held electronic hospital admissions and death records, making the study easier for participants and more cost-efficient. We asked participants in both groups to complete questionnaires to assess their quality of life during the study. We also collected data to determine whether there was any economic benefit to the NHS of using allopurinol in patients with ischaemic heart disease. There was no difference in the risk of heart attacks, strokes or death from cardiovascular disease between the participants given allopurinol and those in the group continuing their usual care. We also found no difference in the risks of other cardiovascular events, deaths from any cause or quality-of-life measurements between the allopurinol and usual care groups. The results of the ALL-HEART study suggest that we should not recommend that allopurinol be given to people with ischaemic heart disease to prevent further cardiovascular events or deaths.

Instability of the HLA-E peptidome of HIV presents a major barrier to therapeutic targeting.

Naturally occurring T cells that recognize microbial peptides via HLA-E, a nonpolymorphic HLA class Ib molecule, could provide the foundation for new universal immunotherapeutics. However, confidence in the biological relevance of putative ligands is crucial, given that the mechanisms by which pathogen-derived peptides can access the HLA-E presentation pathway are poorly understood. We systematically interrogated the HIV proteome using immunopeptidomic and bioinformatic approaches, coupled with biochemical and cellular assays. No HIV HLA-E peptides were identified by tandem mass spectrometry analysis of HIV-infected cells. In addition, all bioinformatically predicted HIV peptide ligands (>80) were characterized by poor complex stability. Furthermore, infected cell elimination assays using an affinity-enhanced T cell receptor bispecific targeted to a previously reported HIV Gag HLA-E epitope demonstrated inconsistent presentation of the peptide, despite normal HLA-E expression on HIV-infected cells. This work highlights the instability of the HIV HLA-E peptidome as a major challenge for drug development.

Two Novel Mosquitocidal Peptides Isolated from the Venom of the Bahia Scarlet Tarantula (Lasiodora klugi).

Effective control of diseases transmitted by Aedes aegypti is primarily achieved through vector control by chemical insecticides. However, the emergence of insecticide resistance in A. aegypti undermines current control efforts. Arachnid venoms are rich in toxins with activity against dipteran insects and we therefore employed a panel of 41 spider and 9 scorpion venoms to screen for mosquitocidal toxins. Using an assay-guided fractionation approach, we isolated two peptides from the venom of the tarantula Lasiodora klugi with activity against adult A. aegypti. The isolated peptides were named U-TRTX-Lk1a and U-TRTX-Lk2a and comprised 41 and 49 residues with monoisotopic masses of 4687.02 Da and 5718.88 Da, respectively. U-TRTX-Lk1a exhibited an LD50 of 38.3 pmol/g when injected into A. aegypti and its modeled structure conformed to the inhibitor cystine knot motif. U-TRTX-Lk2a has an LD50 of 45.4 pmol/g against adult A. aegypti and its predicted structure conforms to the disulfide-directed ß-hairpin motif. These spider-venom peptides represent potential leads for the development of novel control agents for A. aegypti.

Global funding for cancer research between 2016 and 2020: a content analysis of public and philanthropic investments.

BACKGROUND: Cancer is a leading cause of disease burden globally, with more than 19·3 million cases and 10 million deaths recorded in 2020. Research is crucial to understanding the determinants of cancer and the effects of interventions, and to improving outcomes. We aimed to analyse global patterns of public and philanthropic investment in cancer research. METHODS: In this content analysis, we searched the UberResearch Dimensions database and Cancer Research UK data for human cancer research funding awards from public and philanthropic funders between Jan 1, 2016, and Dec 31, 2020. Included award types were project and programme grants, fellowships, pump priming, and pilot projects. Awards focused on operational delivery of cancer care were excluded. Awards were categorised by cancer type, cross-cutting research theme, and research phase. Funding amount was compared with global burden of specific cancers, measured by disability-adjusted life-years, years lived with disability, and mortality using data from the Global Burden of Disease study. FINDINGS: We identified 66 388 awards with total investment of about US$24·5 billion in 2016-20. Investment decreased year-on-year, with the largest drop observed between 2019 and 2020. Pre-clinical research received 73·5% of the funding across the 5 years ($18 billion), phase 1-4 clinical trials received 7·4% ($1·8 billion), public health research received 9·4% ($2·3 billion), and cross-disciplinary research received 5·0% ($1·2 billion). General cancer research received the largest investment ($7·1 billion, 29·2% of the total funding). The most highly funded cancer types were breast cancer ($2·7 billion [11·2%]), haematological cancer ($2·3 billion [9·4%]), and brain cancer ($1·3 billion [5·5%]). Analysis by cross-cutting theme revealed that 41·2% of investment ($9·6 billion) went to cancer biology research, 19·6% ($4·6 billion) to drug treatment research, and 12·1% ($2·8 billion) to immuno-oncology. 1·4% of the total funding ($0·3 billion) was spent on surgery research, 2·8% ($0·7 billion) was spent on radiotherapy research, and 0·5% ($0·1 billion) was spent on global health studies. INTERPRETATION: Cancer research funding must be aligned with the global burden of cancer with more equitable funding for cancer research in low-income and middle-income countries (which account for 80% of cancer burden), both to support research relevant to these settings, and build research capacity within these countries. There is an urgent need to prioritise investment in surgery and radiotherapy research given their primacy in the treatment of many solid tumours. FUNDING: None.

"It Becomes a Family I'm a Part of We Get to Carry Each Other": Themes from Qualitative Interview of Patients Enrolled in an Inpatient Palliative Care Support Program for Adolescents and Young Adults.

Background: The pediatric palliative care literature provides little evidence regarding the lived experiences of adolescents and young adults (AYAs). Objectives: We sought to evaluate the aspects of a palliative care peer support program, which were most helpful to patients, and identify areas for improvement to better address their psychosocial needs. Design: This was a retrospective, cross-sectional study, which described self-reported Streetlight program evaluation using thematic analysis of interviews with AYAs. A total of 10 interviews was completed. Setting/Subjects: Thirty-three current and former Streetlight participants (13-30), enrolled in the Streetlight program for at least six months, were recruited during hospital admissions and clinic visits at UF Health Shands Hospital in the United States. Of the 33, 2 participants died before interviews could be conducted. A total of 10 interviews were conducted. Results: Thematic analysis of the 10 individuals identified 5 themes. They were (1) normalization of life in hospital, (2) mental health and instillation of hope, (3) companionship and connection, (4) diversity of volunteers, and (5) gratitude. Conclusions: Results suggest that AYAs who participated in a peer support, palliative care program benefitted from their exposure to volunteer social support. Addressing the need for continued study of this population provides opportunities to expand peer support, pediatric palliative care programs to other hospitals and care facilities.

Venom composition and bioactive RF-amide peptide toxins of the saddleback caterpillar, Acharia stimulea (Lepidoptera: Limacodidae).

Limacodidae is a family of lepidopteran insects comprising >1500 species. More than half of these species produce pain-inducing defensive venoms in the larval stage, but little is known about their venom toxins. Recently, we characterised proteinaceous toxins from the Australian limacodid caterpillar Doratifera vulnerans, but it is unknown if the venom of this species is typical of other Limacodidae. Here, we use single animal transcriptomics and venom proteomics to investigate the venom of an iconic limacodid, the North American saddleback caterpillar Acharia stimulea. We identified 65 venom polypeptides, grouped into 31 different families. Neurohormones, knottins, and homologues of the immune signaller Diedel make up the majority of A.stimulea venom, indicating strong similarities to D. vulnerans venom, despite the large geographic separation of these caterpillars. One notable difference is the presence of RF-amide peptide toxins in A. stimulea venom. Synthetic versions of one of these RF-amide toxins potently activated the human neuropeptide FF1 receptor, displayed insecticidal activity when injected into Drosophila melanogaster, and moderately inhibited larval development of the parasitic nematode Haemonchus contortus. This study provides insights into the evolution and activity of venom toxins in Limacodidae, and provides a platform for future structure-function characterisation of A.stimulea peptide toxins.

How Are Retailers Describing Delta-8 THC?A Mixed-Methods Study in Fort Worth, Texas.

OBJECTIVE: Delta-8 tetrahydrocannabinol (THC) is a largely unregulated psychoactive substance rising in popularity in the United States. This study aimed to understand how retailers explained Delta-8 THC to potential customers and if these descriptions were associated with socioeconomic deprivation surrounding the retail location. METHOD: In Fort Worth, Texas, stores with retail alcohol, cannabidiol (CBD), or tobacco licenses were called. Among the 133 stores that sold Delta-8 THC, 125 retailers (94%) answered the question "What is Delta-8?" Qualitative methods were used to identify related themes; logistic regression models tested associations between themes and area deprivation index (ADI) scores, a measure of socioeconomic deprivation (1-10; 10 = most deprived areas). RESULTS: Retailers often compared Delta-8 THC to other substances (49%). Although most often described as a type of cannabis (34%), several retailers likened Delta-8 to CBD (19%) or hemp (7%), which are nonpsychoactive. Retailers also described potential effects from use (35%). Some retailers reported that they were unsure of what Delta-8 was (21%), told surveyors to look it up themselves (6%), or withheld information (9%). Higher ADI scores were associated with higher odds of retailers communicating limited information (odds ratio = 1.21, 95% CI [1.04, 1.40], p = .011). CONCLUSIONS: Study findings may inform the development of marketing regulations, as well as informational campaigns for both retailers and consumers.

Oral cancer awareness and education within the pharmacy profession.

The incidence of oral cancers are rising in the UK, with early detection a significant positive prognostic factor. The Covid-19 pandemic has negatively impacted patients access to dental services, reducing a potential avenue to diagnosis. Community pharmacists are well positioned to play an expanded role in supporting earlier detection. This study seeks to identify levels of awareness and knowledge of oral cancer amongst community pharmacists, to inform development of educational resources.A cross-sectional digital survey was distributed via social media between August and September 2021. Data were collected on participant's demographics, oral cancer awareness and educational resources relevant to oral cancer. The results obtained were analysed using descriptive statistics in IBM SPSS software.61 pharmacists completed the survey. The majority were female (n = 40; 65.6%) aged 18-30 (n = 33; 54.1%). Less than half of respondents reported feeling confident in recognising risk factors (37.7%; n = 23). A substantial minority (n = 8; 13.1%) incorrectly selected fluoride toothpaste use as a risk factor for oral cancer. Most respondents correctly suggested signposting patients with signs or symptoms of oral cancer to a General Medical or General Dental Practitioner (GDP) (n = 35; 57.3%, n = 46; 75.4%). 91.8% of respondents (n = 56) would welcome an educational resource to support professional development.This study demonstrates a need for further educational resources regarding oral cancer, specifically aimed at community pharmacists. Community Pharmacists have a crucial role in efforts to improve rates of early detection of oral cancers. Work should be completed to explore the establishment of direct referral pathways from community pharmacy to secondary care.

International society of oncology pharmacy practitioners (ISOPP) position statement: The role of oncology pharmacy practitioners in immunotherapy treatment with immune checkpoint inhibitors for malignant conditions.

Oncology pharmacists, pharmacy technicians and assistants are key members of the multidisciplinary health care team (MHT) caring for patients receiving immunotherapy with immune checkpoint inhibitors. The International Society of Oncology Pharmacy Practitioners (ISOPP) developed this position statement to provide guidance on the role of oncology pharmacy practitioners in caring for patients receiving immune checkpoint inhibitors.Four key recommendations were identified: 1) participation as an integrated, collaborative member of the MHT;2) provision of education and training for patients, students, residents, fellows and other members of the MHT;3) involvement in clinical governance to optimise the use of immune checkpoint inhibitors and4) involvement in research and development in the field of immunotherapy.In summary, oncology pharmacy practitioners play essential roles within the MHT in caring for patients receiving immune checkpoint inhibitors.

Immunosuppressive, antimicrobial and insecticidal activities of inhibitor cystine knot peptides produced by teratocytes of the endoparasitoid wasp Cotesia flavipes (Hymenoptera: Braconidae).

Teratocytes are specialized cells released by parasitoid wasps into their hosts. They are known for producing regulatory molecules that aid the development of immature parasitoids. We have recently reported the primary structures of cystine-rich peptides, including some containing inhibitor cystine knot (ICK) motifs, produced by teratocytes of the parasitoid Cotesia flavipes (Hymenoptera: Braconidae). ICKs are known for their stability and diverse biological functions. In this study, we produced four putative ICK peptides from the teratocytes of C. flavipes using solid-phase peptide synthesis or recombinant expression in E. coli, and investigated their functions on host immune modulation as well their potential to impair the development of two lepidopterans after ingestion of the peptides. In addition, the peptides were assayed against pathogens and human cells. The peptides did not influence total hemocyte count but suppressed cellular immunity, detectable as a reduction of hemocyte encapsulation (CftICK-I, CftICK-II, CftICK-III) and spread indexes (CftICK-IV) in the host. None of the peptides influenced the activities of prophenoloxidase and phenoloxidase in the hemolymph of larval Diatraea saccharalis (Lepidoptera: Crambidae). CftICK-I and CftICK-II with previously unknown function showed antifungal activity against Candida albicans but were non-toxic to human cells. CftICK-I, CftICK-II, and CftICK-III increased larval mortality and reduced leaf consumption of D. saccharalis, a permissive host for C. flavipes. The CftICK-III also increased larval mortality and reduced leaf consumption of Spodoptera frugiperda (Lepidoptera: Noctuidae), a non-permissive host for C. flavipes. This study highlights biological functions and biotechnological potential of ICK peptides from the teratocytes of C. flavipes.

A Novel Palliative Care Peer Support Program for Adolescents and Young Adults: Survey and Factor Analytic Study.

Background: Palliative care literature indicates a dearth of programs addressing the psychosocial needs of adolescents and young adults (AYAs). Objectives: This study assessed patient-reported experiences of a palliative care peer support program, analyzed psychometric qualities of the program evaluation, and examined associations with quality-of-life scores to assess validity and potential impact on aspects of AYA quality of life. Design: This retrospective, cross-sectional study described self-reported Streetlight program evaluation and quality of life of AYA patients, exploratory factor analysis of survey responses, and analysis of associations with quality of life. Setting/Subjects: AYA participants (13-30) enrolled in the Streetlight program for at least six months were recruited during hospital admissions and clinic visits at UF Health Shands Hospital. Results: Participants' (n = 69) scores were high for Youth Quality of Life Instrument-Short Form (YQOL-SF) (82.6 of 100), and Streetlight evaluations (4.47 of 5). Patients endorsed themes of: high-quality friendships with volunteers, transformative impacts to wellbeing, and benefits to mental health and coping in open-ended responses. Analyses identified three factors explaining 61% of variance in Streetlight program evaluation responses: "Friendships and Support" (26%); "Coping, Family, and Providers" (20%); and "Diversion and Respect" (15%). Significant positive associations were found between Streetlight evaluation scores and YQOL-SF Belief in Self and Family factor scores, as well as between Streetlight evaluation Friendships and Support factor scores, and YQOL-SF total and factor-specific scores. Conclusions: Results suggest that the Streetlight program is a viable model to facilitate positive experiences, opportunities for socialization, and meaningful peer support for AYA patients.

Growth curve modeling of virtual events and online engagement in a palliative care peer support online health community for adolescents and young adults.

OBJECTIVE: Online health communities (OHCs) have been identified as important outlets for social support and community connection for adolescents and young adults (AYAs) living with chronic illnesses. Despite evident benefits, there remains a gap in research on methods to maximize sustained patient engagement within OHCs. This study assessed per-patient daily commenting rates over time, as well as associations with program staff and volunteer-facilitated events and engagement. MATERIALS AND METHODS: We utilized data from 662 daily patient, volunteer, and staff comment totals within a Discord server hosted through the Streetlight at UF Health Streetlight Gaming and Online Team, between January 2019 and January 2022. Multilevel models were used to assess per-patient daily commenting rates and examine associations with OHC-level predictors of staff and volunteer-facilitated daily and seasonal events, as well as the number of daily active users. RESULTS: Per-patient comment rates showed an overall negative slope with time in most models. Unadjusted and adjusted growth curve models showed that daily events (ß = .21), seasonal events (ß = .18), and total daily active users (ß = .09) were all significantly associated with increases in per-patient daily comment rates. DISCUSSION: Results suggest that social event facilitation strategies can be applied to increase AYA patient engagement in OHCs. Seasonal events and staff and volunteer engagement may be the effective means of maintaining engagement among long-term patients. CONCLUSION: Our findings highlight the importance of staff and volunteer presence in OHCs in driving long-term patient engagement and in considering patient needs and perspectives in developing OHC features.

Composition and toxicity of venom produced by araneophagous white-tailed spiders (Lamponidae: Lampona sp.).

Prey-specialised spiders are adapted to capture specific prey items, including dangerous prey. The venoms of specialists are often prey-specific and less complex than those of generalists, but their venom composition has not been studied in detail. Here, we investigated the venom of the prey-specialised white-tailed spiders (Lamponidae: Lampona), which utilise specialised morphological and behavioural adaptations to capture spider prey. We analysed the venom composition using proteo-transcriptomics and taxon-specific toxicity using venom bioassays. Our analysis identified 208 putative toxin sequences, comprising 103 peptides < 10 kDa and 105 proteins > 10 kDa. Most peptides belonged to one of two families characterised by scaffolds containing eight or ten cysteine residues. Toxin-like proteins showed similarity to galectins, leucine-rich repeat proteins, trypsins and neprilysins. The venom of Lampona was shown to be more potent against the preferred spider prey than against alternative cricket prey. In contrast, the venom of a related generalist was similarly potent against both prey types. These data provide insights into the molecular adaptations of venoms produced by prey-specialised spiders.

Venom composition and pain-causing toxins of the Australian great carpenter bee Xylocopa aruana.

Most species of bee are capable of delivering a defensive sting which is often painful. A solitary lifestyle is the ancestral state of bees and most extant species are solitary, but information on bee venoms comes predominantly from studies on eusocial species. In this study we investigated the venom composition of the Australian great carpenter bee, Xylocopa aruana Ritsema, 1876. We show that the venom is relatively simple, composed mainly of one small amphipathic peptide (XYTX1-Xa1a), with lesser amounts of an apamin homologue (XYTX2-Xa2a) and a venom phospholipase-A2 (PLA2). XYTX1-Xa1a is homologous to, and shares a similar mode-of-action to melittin and the bombilitins, the major components of the venoms of the eusocial Apis mellifera (Western honeybee) and Bombus spp. (bumblebee), respectively. XYTX1-Xa1a and melittin directly activate mammalian sensory neurons and cause spontaneous pain behaviours in vivo, effects which are potentiated in the presence of venom PLA2. The apamin-like peptide XYTX2-Xa2a was a relatively weak blocker of small conductance calcium-activated potassium (KCa) channels and, like A. mellifera apamin and mast cell-degranulating peptide, did not contribute to pain behaviours in mice. While the composition and mode-of-action of the venom of X. aruana are similar to that of A. mellifera, the greater potency, on mammalian sensory neurons, of the major pain-causing component in A. mellifera venom may represent an adaptation to the distinct defensive pressures on eusocial Apidae.

Delta-8 THC Retail Availability, Price, and Minimum Purchase Age.

Background: Retail sales of Delta-8 tetrahydrocannabinol (THC) products have increased in the U.S. market since the passing of the 2018 Farm Bill, and there is currently little regulation of marketing/sales and limited related safety standards in many states. After thousands of calls to poison control centers (40% for individuals under 18 years old and 70% requiring health care facility evaluation), the Food and Drug Administration issued warnings on Delta-8 THC products, stating their psychoactive effects and that some manufacturers may synthesize Delta-8 using unsafe household chemicals. The current study describes the Delta-8 THC retail sales environment in Fort Worth, Texas. Given its relatively inexpensive manufacturing and that low prices are a major determinant of cannabis use, the price of Delta-8 THC products was examined. This study also examined whether retail outlets in areas with greater socioeconomic deprivation had higher odds of selling Delta-8 THC products. This is important because if Delta-8 THC retailers are disproportionately located in more socioeconomically deprived communities, residents of these communities can more easily access these products and may have higher risk of adverse consequences. Methods: Potential Delta-8 THC retailers were selected by identifying lists of current retail locations with alcohol, cannabidiol, and/or tobacco licenses in Fort Worth. Trained research assistants called outlets in September and October 2021 to query about sales of products containing Delta-8 THC. The response rate was 69% (n=1,223). Outlets' 9-digit zip codes were merged with Area Deprivation Index scores. Products and purported minimum age were described. Chi-squared and Student's t-tests were used. Results: Eleven percent of outlets (n=133) reported selling Delta-8 THC. Ninety-six percent sold vapes and/or "flower" (i.e., hemp leaves coated with Delta-8 THC distillate) and 76% sold edibles. Among the least expensive products available, edibles cost, on average, $8.58 less than flower/vapes (p<0.001). Outlets that sold Delta-8 THC were located in areas with greater deprivation (p=0.02). Most reported a minimum purchase age of 21; however, 4% reported 18 years or no minimum age. Conclusions: Delta-8 THC retail outlets were disproportionately located in areas with more socioeconomic deprivation. Legal intervention such as zoning, minimum age, and tax laws may help reduce Delta-8 THC-related disparities.

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. METHODS: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. FINDINGS: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89-1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87-1·20], p=0·77). INTERPRETATION: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. FUNDING: UK National Institute for Health and Care Research.

A national assessment of on-premise drinking establishments near public universities: Drink prices, drink specials, indoor tobacco use, and state-level alcohol laws.

BACKGROUND: Inexpensive drinks and price promotions increase alcohol consumption and have been observed at on-premise drinking establishments near large colleges. Some bars may sell tobacco products and allow indoor tobacco use to encourage patrons to stay and drink more. This study examined drink prices/specials and associated practices of on-premise drinking establishments including tobacco sales and policies regarding tobacco use. METHODS: In 2018, telephone calls about prices/practices were made to 403 randomly selected bars/nightclubs within 2 miles of large residential universities in each U.S. state. The Alcohol Policy Information System provided data on state-level alcohol laws. Multivariable linear and logistic regression models examined associations between alcohol prices/specials, state laws, and establishment practices. RESULTS: The average price for the least expensive draft beer and a vodka shot at each location were $3.62 (SD = $1.15) and $4.77 (SD = $1.16), respectively. Most establishments (65%) had happy hour specials, 6% had 2-for-1 specials, 91% sold food, 9% sold cigarettes, 8% allowed smoking indoors, and 18% permitted electronic cigarette (e-cigarette) use indoors. Allowing e-cigarette use indoors (b = -0.54) and selling cigarettes (b = -0.79) were associated with lower vodka prices; allowing cigarette smoking indoors (b = -0.46) was associated with lower beer prices. Lower beer prices (OR = 1.38), selling food (OR = 2.97), and no state law banning happy hour specials altogether (OR = 4.24) or with full-day price reduction exemptions (OR = 12.74) were associated with higher odds of having happy hour specials. Allowing e-cigarette use indoors was associated with having 2-for-1 specials (OR = 6.38). CONCLUSION: In bars near large public universities, beers and shots were often available for less than $5 and drink specials were prevalent. Further, some establishments allowed tobacco use indoors and/or sold cigarettes. Laws that increase alcohol taxes, set minimum drink prices, and ban the sale and indoor use of tobacco products at on-premise drinking locations are important harm reduction tools.