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© 2016 by the Congress of Neurological Surgeons.Background: Neuromodulation-based treatments have become increasingly important in epilepsy treatment. Most patients with epilepsy treated with neuromodulation do not achieve complete seizure freedom, and, th

The role of somatic mitochondrial DNA (mtDNA) mutations in leukemogenesis remains poorly characterized. To determine the impact of somatic mtDNA mutations on this process, we assessed the leukemogenic potential of hematopoietic progenitor cells (HPCs) from mtDNA mutator mice (Polg D257A) with or without NMyc overexpression. We observed a higher incidence of spontaneous leukemogenesis in recipients transplanted with heterozygous Polg HPCs and a lower incidence of NMyc-driven leukemia in those with homozygous Polg HPCs compared to controls. Although mtDNA mutations in heterozygous and homozygous HPCs caused similar baseline impairments in mitochondrial function, only heterozygous HPCs responded to and supported altered metabolic demands associated with NMyc overexpression. Homozygous HPCs showed altered glucose utilization with pyruvate dehydrogenase inhibition due to increased phosphorylation, exacerbated by NMyc overexpression. The impaired growth of NMyc-expressing homozygous HPCs was partially rescued by inhibiting pyruvate dehydrogenase kinase, highlighting a relationship between mtDNA mutation burden and metabolic plasticity in leukemogenesis.

Background: Hypertension is a key risk factor for death and disability, and blood pressure reduction is associated with significant reductions in cardiovascular risk. Large trials have shown that interventions including self-monitoring of blood pressure can reduce blood pressure but real-world data from wider implementation are lacking., Aim: The self-monitoring and management service evaluation in primary care (SHIP) study will evaluate a novel digital intervention for hypertension management and medication titration platform ("Hypertension-Plus") that is currently undergoing initial implementation into primary care in several parts of the UK., Methods and Analyses: The study will use a mixed methods approach including both quantitative analysis of anonymised electronic health record data and qualitative analyses of interview and customer support log data. Pseudonymised data will be extracted from electronic health records and outcomes compared between those using the digital intervention and their own historical data, as well as to those not registered to the system. The primary outcome will be difference in systolic blood pressure in the 12 months before and after implementation. A further analysis will utilise self-monitored blood pressure data from the Hypertension-Plus system itself. Semi-structured qualitative interviews will be completed with implementation and clinical leads, staff and patients in six general practices located in two different geographical areas in England. Informed by the non-adoption, abandonment, scale-up, spread, and sustainability (NASSS) framework, our analysis will identify the challenges to successful implementation and sustainability of the digital intervention in routine clinical practice and in patients' homes., Ethics and Dissemination: The analyses of pseudonymised data were assessed by the sponsor (The University of Oxford) as service evaluation not requiring individual consent and hence did not require ethical approval. Ethics approval for the qualitative analyses was provided by Wales REC 4 (21/WA/0280) and individual written informed consent will be gained for all participants. Results will be published in peer-reviewed journals, presented at national and international conferences and disseminated via patient and health service organisations., Discussion: This study will provide an in-depth analysis of the impact and acceptance of initial implementation of a novel digital intervention, enhancing our understanding and supporting more effective implementation of telemonitoring based hypertension management systems for blood pressure control in England., Competing Interests: Declarations. Ethics approval and consent to participate: The analyses of pseudonymised data were assessed by our sponsor as service evaluation not requiring individual consent and hence did not require ethical approval. Ethics approval for the qualitative analyses was provided by Wales REC 4 (21/WA/0280). Individual informed written consent will be gained for all participants in the qualitative work. Consent for publication: Not applicable (this is a protocol with no individual data). Competing interests: The author(s) declare that they have no competing interests apart from: FDRH acknowledges part support as Director of the NIHR Applied Research Collaboration (ARC) Oxford Thames Valley, and Theme Lead of the NIHR OUH BRC. FDRH has also received occasional fees or expenses for speaking or consultancy from AZ, BI, Bayer, BMS/Pfizer, and Novartis not related to this research. RJMcM has previously received BP monitors for research purposes from Omron. The University of Oxford has licenced algorithms from the TASMINH4 trial to Omron for use in Hypertension-Plus. This work describes an independent evaluation of the impact of Hypertension-Plus in primary care and no authors receive personal payments associated with Hypertension-Plus., (© 2024. The Author(s).)

Objective: The primary objective was to investigate temporal trends and between-practice variability of paediatric test use in primary care., Methods and Analysis: This was a descriptive study of population-based data from Clinical Practice Research Datalink Aurum primary care consultation records from 1 January 2007 to 31 December 2019. Children aged 0-15 who were registered to one of the eligible 1464 general practices and had a diagnostic test code in their clinical record were included. The primary outcome measures were (1) temporal changes in test rates measured by the average annual percent change, stratified by test type, gender, age group and deprivation level and (2) practice variability in test use, measured by the coefficient of variation., Results: 14 299 598 diagnostic tests were requested over 27.8 million child-years of observation for 2 542 101 children. Overall test use increased by 3.6%/year (95% CI 3.4 to 3.8%) from 399/1000 child-years to 608/1000 child-years, driven by increases in blood tests (8.0%/year, 95% CI 7.7 to 8.4), females aged 11-15 (4.0%/year, 95% CI 3.7 to 4.3), and children from the most socioeconomically deprived group (4.4% /year, 95% CI 4.1 to 4.8). Tests subject to the greatest temporal increases were faecal calprotectin, fractional exhaled nitric oxide and vitamin D. Tests classified as high-use and high-practice variability were iron studies, coeliac testing, vitamin B 12 , folate, and vitamin D., Conclusions: In this first nationwide study of paediatric test use in primary care, we observed significant temporal increases and practice variability in testing. This reflects inconsistency in practice and diagnosis rates and a scarcity of evidence-based guidance. Increased test use generates more clinical activity with significant resource implications but conversely may improve clinical outcomes. Future research should evaluate whether increased test use and variability are warranted by exploring test indications and test results and directly examine how increased test use impacts on quality of care., Competing Interests: Competing interests: This project was funded by a grant from the NIHR SPCR grant (Award 624). The funders were not involved in the study design and conduct, data collection and interpretation, or manuscript preparation and approval to submit the manuscript for publication. ETT was supported by a Clarendon scholarship to study for a Doctor of Philosophy (DPhil) at the University of Oxford (2020–23). PG has received grants from the Canadian Institutes of Health Research (CIHR), the Physicians Services Incorporated Foundation and The Hospital for Sick Children. He has received non-financial support from the EBMLive Steering Committee (expenses reimbursed to attend conferences) and the CIHR Institute of Human Development, Child and Youth Health (as a member of the institute advisory board, expenses reimbursed to attend meetings), is a member of the CMAJ Open and BMJ Evidence Based Medicine Editorial Board. RP is partly supported by the NIHR Applied Research Collaboration (ARC) Oxford & Thames Valley, the NIHR Oxford BRC, the NIHR Oxford MedTech and In-Vitro Diagnostics Co-operative (MIC) and the Oxford Martin School. CJH receives funding support from the NIHR School of Primary Care Research. The funders had no role in study design, manuscript submission, or collection, management, analysis, or interpretation of study data. All other authors have no sources of funding to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Although employee selection is typically oriented toward the assessment of knowledge, skills, and abilities to identify employees who will complement such an environment, it is perhaps equally important to distinguish employees with the potential to disrupt it. Workers high in narcissistic grandiosity tend to abuse their power and control for personal gain, engage in abusive behaviors toward others, and disobey organizational policies. Across four studies, we sought to develop the Narcissism Interview Scale for Employment (NISE) to assess narcissistic grandiosity. Study 1 created interview questions that elicited responses with narcissistic grandiosity content, structured as both behavioral/situational and work-specific. Study 2 identified the best performing items and developed rating materials. Study 3 demonstrated the NISE is associated with traditional survey assessments of narcissistic grandiosity and predicted interpersonal aggression. Study 4 demonstrated that applicants are likely to perceive the NISE at least as favorably as other popular interview questions. Overall, the results showed that the NISE may be incorporated into the interview process to assess applicant narcissistic grandiosity tendencies, but additional research is needed to further establish the construct validity of the instrument, clarify applicant reactions to its use, and assess its predictive utility across a variety of work contexts.

Purpose: Solid organ transplant recipients comprise a unique population of immunosuppressed patients with increased risk of malignancy, including hematologic neoplasms. Clonal hematopoiesis of indeterminate potential (CHIP) represents a known risk factor for hematologic malignancy and this study describes the prevalence and patterns of CHIP mutations across several types of solid organ transplants., Experimental Design: We use two national biobank cohorts comprised of >650,000 participants with linked genomic and longitudinal phenotypic data to describe the features of CHIP across 2,610 individuals who received kidney, liver, heart, or lung allografts., Results: We find individuals with an allograft before their biobank enrollment had an increased prevalence of TET2 mutations (OR, 1.90; P = 4.0e-4), but individuals who received transplants post-enrollment had a CHIP mutation spectrum similar to that of the general population, without enrichment of TET2. In addition, we do not observe an association between CHIP and risk of incident transplantation among the overall population (HR, 1.02; P = 0.91). And in an exploratory analysis, we do not find evidence for a strong association between CHIP and rates of transplant complications such as rejection or graft failure., Conclusions: These results demonstrate that recipients of solid organ transplants display a unique pattern of clonal hematopoiesis with enrichment of TET2 driver mutations, the causes of which remain unclear and are deserving of further study., (©2024 American Association for Cancer Research.)

Emergency physicians are highly trained to deliver acute unscheduled care. The emergency physician core skillset gained during emergency medicine residency can be applied to many other roles that benefit patients and extend and diversify emergency physician careers. In 2022, the American College of Emergency Physicians (ACEP) convened the New Practice Models Task Force to describe new care models and emergency physician opportunities outside the 4 walls of the emergency department. The Task Force consisted of 21 emergency physicians with broad experience and 2 ACEP staff. Fifty-nine emergency physician roles were identified (21 established clinical roles, 16 emerging clinical roles, 9 established nonclinical roles, and 13 emerging nonclinical roles). A strength-weakness-opportunity-threat (SWOT) analysis was performed for each role. Using the analysis, the Task Force made recommendations for guiding ACEP internal actions, advocacy, education, and research opportunities. Emphasis was placed on urgent care, rural medicine, telehealth/virtual care, mobile integrated health care, home-based services, emergency psychiatry, pain medicine, addiction medicine, and palliative care as roles with high or rising demand that draw on the emergency physician skillset. Advocacy recommendations focused on removing state and federal regulatory and legislative barriers to the expansion of new and emerging roles. Educational recommendations focused on aggregating available resources, developing a centralized resource for career guidance, and new educational content for emerging roles. The Task Force also recommended promoting research on potential advantages (eg, improved outcomes, lower cost) of emergency physicians in certain roles and new care models (eg, emergency physician remote supervision in rural settings)., (Copyright © 2023 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Schistosomiasis (bilharzia) is an important, prevalent and neglected tropical disease for which new treatments are urgently required. In the DR Congo and other sub- and tropical countries, traditional medicines are widely used for the control of schistosomiasis., Aim of Study: To evaluate 43 Congolese plant species used traditionally for the treatment of urogenital schistosomiasis against Schistosoma mansoni., Materials and Methods: Methanolic extracts were screened against S. mansoni newly transformed schistosomula (NTS). Three of the most active extracts were evaluated for acute oral toxicity in guinea pigs and activity guided fractionation of the least toxic was carried out using S. mansoni NTS and adult stages. An isolated compound was identified by means of spectroscopic techniques., Results: Thirty-nine of 62 extracts killed S. mansoni NTS at 100 μg/mL and 7 extracts were active at ≥ 90% at 25 μg/mL; 3 extracts were selected for acute oral toxicity evaluation; the least toxic of these, Pseudolachnostylis maprouneifolia leaf was then subjected to activity-guided fractionation. 17 3 -ethoxyphaeophorbide a (1) was isolated as an active compound with 56% activity against NTS at 50 μg/mL and 22.5% activity against adult S. mansoni at 100 μg/mL but these activities are significantly less than those of the parent fractions suggesting that other active compounds are also present and/or that synergistic interactions are taking place., Conclusion: This study has identified 39 plant extracts with activity against S. mansoni NTS lending support to their traditional use in the treatment of schistosomiasis for which new treatments are urgently needed. P. maprouneifolia leaf extract was found to have potent anti-schistosomal activity and low in vivo oral toxicity in guinea pigs; activity-guided fractionation resulted in the isolation of an active compound, 17 3 -ethoxyphaeophorbide a. Phaeophorbides may merit exploration as potential anti-schistosomal agents and further work on plant species shown to have potent activity against S. mansoni NTS in this study would be worthwhile., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Disruptions in the gut epithelial barrier can lead to the development of chronic indications such as inflammatory bowel disease (IBD). Historically, barrier function has been assessed in cancer cell lines, which do not contain all human intestinal cell types, leading to poor translatability. To bridge this gap, we adapted human primary gut organoids grown as monolayers to quantify transcription factor phosphorylation, gene expression, cytokine production, and barrier function. In this work we describe and characterize a novel 96-well human gut organoid-derived monolayer system that enables quantitative assessment of candidate therapeutics. Normal human intestine differentiation patterns and barrier function were characterized and confirmed to recapitulate key aspects of in vivo biology. Next, cellular response to TNF-α (a central driver of IBD) was determined using a diverse cadre of quantitative readouts. We showed that TNF-α pathway antagonists rescued damage caused by TNF-α in a dose-dependent manner, indicating that this system is suitable for quantitative assessment of barrier modulating factors. Taken together, we have established a robust primary cell-based 96-well system capable of interrogating questions around mucosal response. This system is well suited to provide pivotal functional data to support translational target and drug discovery efforts., (© 2023. Springer Nature Limited.)

Background: In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC., Results: Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside., Conclusion: Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Plants are a rich source of bioactive compounds and a number of plant-derived antiplasmodial compounds have been developed into pharmaceutical drugs for the prevention and treatment of malaria, a major public health challenge. However, identifying plants with antiplasmodial potential can be time-consuming and costly. One approach for selecting plants to investigate is based on ethnobotanical knowledge which, though having provided some major successes, is restricted to a relatively small group of plant species. Machine learning, incorporating ethnobotanical and plant trait data, provides a promising approach to improve the identification of antiplasmodial plants and accelerate the search for new plant-derived antiplasmodial compounds. In this paper we present a novel dataset on antiplasmodial activity for three flowering plant families - Apocynaceae, Loganiaceae and Rubiaceae (together comprising c. 21,100 species) - and demonstrate the ability of machine learning algorithms to predict the antiplasmodial potential of plant species. We evaluate the predictive capability of a variety of algorithms - Support Vector Machines, Logistic Regression, Gradient Boosted Trees and Bayesian Neural Networks - and compare these to two ethnobotanical selection approaches - based on usage as an antimalarial and general usage as a medicine. We evaluate the approaches using the given data and when the given samples are reweighted to correct for sampling biases. In both evaluation settings each of the machine learning models have a higher precision than the ethnobotanical approaches. In the bias-corrected scenario, the Support Vector classifier performs best - attaining a mean precision of 0.67 compared to the best performing ethnobotanical approach with a mean precision of 0.46. We also use the bias correction method and the Support Vector classifier to estimate the potential of plants to provide novel antiplasmodial compounds. We estimate that 7677 species in Apocynaceae, Loganiaceae and Rubiaceae warrant further investigation and that at least 1300 active antiplasmodial species are highly unlikely to be investigated by conventional approaches. While traditional and Indigenous knowledge remains vital to our understanding of people-plant relationships and an invaluable source of information, these results indicate a vast and relatively untapped source in the search for new plant-derived antiplasmodial compounds., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Richard-Bollans, Aitken, Antonelli, Bitencourt, Goyder, Lucas, Ondo, Pérez-Escobar, Pironon, Richardson, Russell, Silvestro, Wright and Howes.)

Computed Tomography (CT) is a standard clinical tool utilized to diagnose known lung pathologies based on established grading methods. However, for preclinical trials and toxicity investigations in animal models, more comprehensive datasets are typically needed to determine discriminative features between experimental treatments, which oftentimes require analysis of multiple images and their associated differential quantification using manual segmentation methods. Furthermore, for manual segmentation of image data, three or more readers is the gold standard of analysis, but this requirement can be time-consuming and inefficient, depending on variability due to reader bias. In previous papers, microCT image manual segmentation was a valuable tool for assessment of lung pathology in several animal models; however, the manual segmentation approach and the commercial software used was typically a major rate-limiting step. To improve the efficiency, the semi-manual segmentation method was streamlined, and a semi-automated segmentation process was developed to produce:•Quantifiable segmentations: using manual and semi-automated analysis methods for assessing experimental injury and toxicity models,•Deterministic results and efficiency through automation in an unbiased and parameter free process, thereby reducing reader variance, user time, and increases throughput in data analysis,•Cost-Effectiveness: portable with low computational resource demand, based on a cross-platform open-source ImageJ program., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Simple blood tests can play an important role in identifying patients for cancer investigation. The current evidence base is limited almost entirely to tests used in isolation. However, recent evidence suggests combining multiple types of blood tests and investigating trends in blood test results over time could be more useful to select patients for further cancer investigation. Such trends could increase cancer yield and reduce unnecessary referrals. We aim to explore whether trends in blood test results are more useful than symptoms or single blood test results in selecting primary care patients for cancer investigation. We aim to develop clinical prediction models that incorporate trends in blood tests to identify the risk of cancer., Methods: Primary care electronic health record data from the English Clinical Practice Research Datalink Aurum primary care database will be accessed and linked to cancer registrations and secondary care datasets. Using a cohort study design, we will describe patterns in blood testing (aim 1) and explore associations between covariates and trends in blood tests with cancer using mixed-effects, Cox, and dynamic models (aim 2). To build the predictive models for the risk of cancer, we will use dynamic risk modelling (such as multivariate joint modelling) and machine learning, incorporating simultaneous trends in multiple blood tests, together with other covariates (aim 3). Model performance will be assessed using various performance measures, including c-statistic and calibration plots., Discussion: These models will form decision rules to help general practitioners find patients who need a referral for further investigation of cancer. This could increase cancer yield, reduce unnecessary referrals, and give more patients the opportunity for treatment and improved outcomes., (© 2022. The Author(s).)

Aberrant alternative splicing (AS) of pre-mRNAs promotes the development and proliferation of cancerous cells. Accordingly, we had previously observed higher levels of the aryl hydrocarbon receptor nuclear translocator (ARNT) spliced variant isoform 1 in human lymphoid malignancies compared to that in normal lymphoid cells, which is a consequence of increased inclusion of alternative exon 5. ARNT is a transcription factor that has been implicated in the survival of various cancers. Notably, we found that ARNT isoform 1 promoted the growth and survival of lymphoid malignancies, but the regulatory mechanism controlling ARNT AS is unclear. Here, we report cis- and trans -regulatory elements which are important for the inclusion of ARNT exon 5. Specifically, we identified recognition motifs for the RNA-binding protein RBFOX2, which are required for RBFOX2-mediated exon 5 inclusion. RBFOX2 upregulation was observed in lymphoid malignancies, correlating with the observed increase in ARNT exon 5 inclusion. Moreover, suppression of RBFOX2 significantly reduced ARNT isoform 1 levels and cell growth. These observations reveal RBFOX2 as a critical regulator of ARNT AS in lymphoid malignancies and suggest that blocking the ARNT -specific RBFOX2 motifs to decrease ARNT isoform 1 levels is a viable option for targeting the growth of lymphoid malignancies.

The prospect of eradicating malaria continues to be challenging in the face of increasing parasite resistance to antimalarial drugs so that novel antimalarials active against asexual, sexual, and liver-stage malaria parasites are urgently needed. In addition, new antimalarials need to be affordable and available to those most in need and, bearing in mind climate change, should ideally be sustainable. The West African climbing shrub Cryptolepis sanguinolenta is used traditionally for the treatment of malaria; its principal alkaloid, cryptolepine ( 1 ), has been shown to have antimalarial properties, and the synthetic analogue 2,7-dibromocryptolepine ( 2 ) is of interest as a lead toward new antimalarial agents. Cryptolepine ( 1 ) was isolated using a two-step Soxhlet extraction of C. sanguinolenta roots, followed by crystallization (yield 0.8% calculated as a base with respect to the dried roots). Semi-synthetic 7-bromo- ( 3 ), 7, 9-dibromo- ( 4 ), 7-iodo- ( 5 ), and 7, 9-dibromocryptolepine ( 6 ) were obtained in excellent yields by reaction of 1 with N -bromo- or N -iodosuccinimide in trifluoroacetic acid as a solvent. All compounds were active against Plasmodia in vitro , but 6 showed the most selective profile with respect to Hep G2 cells: P. falciparum (chloroquine-resistant strain K1), IC 50 = 0.25 µM, SI = 113; late stage, gametocytes, IC 50 = 2.2 µM, SI = 13; liver stage, P. berghei sporozoites IC 50 = 6.13 µM, SI = 4.6. Compounds 3 - 6 were also active against the emerging zoonotic species P. knowlesi with 5 being the most potent (IC 50 = 0.11 µM). In addition, 3 - 6 potently inhibited T. brucei in vitro at nM concentrations and good selectivity with 6 again being the most selective (IC 50 = 59 nM, SI = 478). These compounds were also cytotoxic to wild-type ovarian cancer cells as well as adriamycin-resistant and, except for 5 , cisplatin-resistant ovarian cancer cells. In an acute oral toxicity test in mice, 3 - 6 did not exhibit toxic effects at doses of up to 100 mg/kg/dose × 3 consecutive days. This study demonstrates that C. sanguinolenta may be utilized as a sustainable source of novel compounds that may lead to the development of novel agents for the treatment of malaria, African trypanosomiasis, and cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abacha, Forkuo, Gbedema, Mittal, Ottilie, Rocamora, Winzeler, van Schalkwyk, Kelly, Taylor, Reader, Birkholtz, Lisgarten, Cockcroft, Lisgarten, Palmer, Talbert, Shnyder and Wright.)

Aflatoxin B1 (AFB1) is a food-borne toxin produced by Aspergillus flavus and a few similar fungi. Natural anti-aflatoxigenic compounds are used as alternatives to chemical fungicides to prevent AFB1 accumulation. We found that a methanolic extract of the food additive Zanthoxylum bungeanum shuts down AFB1 production in A. flavus. A methanol sub-fraction (M20) showed the highest total phenolic/flavonoid content and the most potent antioxidant activity. Mass spectrometry analyses identified four flavonoids in M20: quercetin, epicatechin, kaempferol-3-O-rhamnoside, and hyperoside. The anti-aflatoxigenic potency of M20 (IC 50 : 2-4 µg/mL) was significantly higher than its anti-proliferation potency (IC 50 : 1800-1900 µg/mL). RNA-seq data indicated that M20 triggers significant transcriptional changes in 18 of 56 secondary metabolite pathways in A. flavus, including repression of the AFB1 biosynthesis pathway. Expression of aflR, the specific activator of the AFB1 pathway, was not changed by M20 treatment, suggesting that repression of the pathway is mediated by global regulators. Consistent with this, the Velvet complex, a prominent regulator of secondary metabolism and fungal development, was downregulated. Decreased expression of the conidial development regulators brlA and Medusa, genes that orchestrate redox responses, and GPCR/oxylipin-based signal transduction further suggests a broad cellular response to M20. Z. bungeanum extracts may facilitate the development of safe AFB1 control strategies., (© 2022. The Author(s).)

Background: It remains unclear to what extent reductions in urgent referrals for suspected cancer during the COVID-19 pandemic were the result of fewer patients attending primary care compared to GPs referring fewer patients., Methods: Cohort study including electronic health records data from 8,192,069 patients from 663 English practices. Weekly consultation rates, cumulative consultations and referrals were calculated for 28 clinical features from the NICE suspected cancer guidelines. Clinical feature consultation rate ratios (CRR) and urgent referral rate ratios (RRR) compared time periods in 2020 with 2019., Findings: Consultations for cancer clinical features decreased by 24.19% (95% CI: 24.04-24.34%) between 2019 and 2020, particularly in the 6-12 weeks following the first national lockdown. Urgent referrals for clinical features decreased by 10.47% (95% CI: 9.82-11.12%) between 2019 and 2020. Overall, once patients consulted with primary care, GPs urgently referred a similar or greater proportion of patients compared to previous years., Conclusion: Due to the significant fall in patients consulting with clinical features of cancer there was a lower than expected number of urgent referrals in 2020. Sustained efforts should be made throughout the pandemic to encourage the public to consult their GP with cancer clinical features., (© 2021. The Author(s).)

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor present in immune cells as a long and short isoform, referred to as isoforms 1 and 3, respectively. However, investigation into potential ARNT isoform–specific immune functions is lacking despite the well-established heterodimerization requirement of ARNT with, and for the activity of, the aryl hydrocarbon receptor (AhR), a critical mediator of immune homeostasis. Here, using global and targeted transcriptomics analyses, we show that the relative ARNT isoform 1:3 ratio in human T cell lymphoma cells dictates the amplitude and direction of AhR target gene regulation. Specifically, shifting the ARNT isoform 1:3 ratio lower by suppressing isoform 1 enhances, or higher by suppressing isoform 3 abrogates, AhR responsiveness to ligand activation through preprograming a cellular genetic background that directs explicit gene expression patterns. Moreover, the fluctuations in gene expression patterns that accompany a decrease or increase in the ARNT isoform 1:3 ratio are associated with inflammation or immunosuppression, respectively. Molecular studies identified the unique casein kinase 2 (CK2) phosphorylation site within isoform 1 as an essential parameter to the mechanism of ARNT isoform–specific regulation of AhR signaling. Notably, CK2-mediated phosphorylation of ARNT isoform 1 is dependent on ligand-induced AhR nuclear translocation and is required for optimal AhR target gene regulation. These observations reveal ARNT as a central modulator of AhR activity predicated on the status of the ARNT isoform ratio and suggest that ARNT-based therapies are a viable option for tuning the immune system to target immune disorders.

Ethnopharmacological Relevance: Helminthosis (worm infection) is a disease of grazing livestock, with significant economic implications. Increasing resistance to existing synthetic anthelmintics used to control helminthosis and the unwanted presence of residues of the anthelmintics reported in meat and dairy products present a serious global health challenge. These challenges have necessitated the development of novel anthelmintics that could combat drug resistance and exhibit better safety profiles. Spondias mombin L. (Anacardiaceae) is a plant that has been used traditionally as a worm expeller., Aim of Study: The aim of the work reported herein was to isolate and characterise anthelmintic compound(s) from S. mombin leaf, establishing their bioactivity and safety profile., Materials and Methods: Adult Haemonchus placei motility assay was used to assess anthelmintic bioactivity. Bioassay-guided chromatographic fractionation of acetone extract of S. mombin leaf was carried out on a silica gel stationary phase. The structure of the compound was elucidated using spectroscopy ( 1 H and 13 C NMR) and Liquid Chromatography-Mass Spectrometry (LC-ESI-MS). Screening to exclude potential cytotoxicity against mammalian cells (H460, Caco-2, MC3T3-E1) was done using alamar blue (AB) and CellTitreGlo (CTG) viability reagents., Results: The acetone extract yielded an active fraction 8 (Ethyl acetate: methanol 90:10; anthelmintic LC 50 : 3.97 mg/mL), which yielded an active sub-fraction (Ethyl acetate: Methanol 95:5; anthelmintic LC 50 : 53.8 μg/mL), from which active compound 1 was isolated and identified as phaeophorbide-a (LC 50 : 23.0 μg/mL or 38.8 μM). The compound was not toxic below 200 μM but weakly cytotoxic at 200 μM., Conclusions: Phaeophorbide-a (1) isolated from S. mombin leaf extract and reported in the plant for the first time in this species demonstrated anthelmintic activity. No significant toxicity to mammalian cells was observed. It therefore represents a novel anthelmintic pharmacophore as a potential lead for the development of novel anthelmintics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Accurate and comprehensive identification of residual glycerides in biodiesel is an important part of fuel characterization due to the impact of glycerides on the fuel physicochemical properties. However, analysis of bound glycerol in biodiesel samples faces challenges due to lack of readily available standards of structurally complex glyceride species in nontraditional biodiesel feedstocks and a risk of misannotation in the presence of impurities in gas chromatographic separations. Here, we evaluate methane and isobutane chemical ionization-single quadrupole mass spectrometry combined with high-temperature gas chromatography separations for mapping monoacylglycerols, diacylglycerols, and triacylglycerols in biodiesel. Unlike electron impact ionization, which produces mostly in-source fragments, isobutane chemical ionization spectra of tetramethylsilyl-derivatized monoacylglycerols and diacylglycerols are dominated by molecular ions and M-SiO(CH 3 ) 3 + ions, which provide important diagnostic information. We demonstrate the utility of isobutane chemical ionization in identifying structurally complex glycerolipid standards as well as species in biodiesel samples from different plant and animal feedstocks.

Donor-to-donor variability in primary human organoid cultures has not been well characterized. As these cultures contain multiple cell types, there is greater concern that variability could lead to increased noise. In this work we investigated donor-to-donor variability in human gut adult stem cell (ASC) organoids. We examined intestinal developmental pathways during culture differentiation in ileum- and colon-derived cultures established from multiple donors, showing that differentiation patterns were consistent among cultures. This finding indicates that donor-to-donor variability in this system remains at a manageable level. Intestinal metabolic activity was evaluated by targeted analysis of central carbon metabolites and by analyzing hormone production patterns. Both experiments demonstrated similar metabolic functions among donors. Importantly, this activity reflected intestinal biology, indicating that these ASC organoid cultures are appropriate for studying metabolic processes. This work establishes a framework for generating high-confidence data using human primary cultures through thorough characterization of variability., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The common fern, bracken ( Pteridium aquilinum ), is well known for its toxic effects on livestock due principally to the carcinogenic constituent ptaquiloside ( 1: ), although other toxins are present including the cyanogenic glycoside, prunasin ( 2: ). Here, we report an improved and relatively "green" process for the isolation of 1: and 2: from fresh bracken fronds and the evaluation of 1: for cytotoxicity against several cancer cell lines. The results indicate that 1: displays selective toxicity against cancer cells relative to noncancer retinal epithelial cells, and the improved method for the isolation of 1: is expected to facilitate further exploration of its pharmacological properties., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Ethnopharmacological Relevance: The leaf of Sarcocephalus latifolius is known to be used traditionally by the Fulanis in Nigeria to deworm animals. As helminthosis remains a major constraint to profitable livestock production worldwide, a precarious situation aggravated by the advent of resistant parasites, the discovery of new anthelmintics is a priority, necessitating exploration of medicinal plants for their anthelmintic principles., Aim of the Study: To identify and characterise compounds with anthelmintic activity from the leaf of Sarcocephalus latifolius., Materials and Methods: Powdered S. latifolius leaves were extracted by successive maceration with n-hexane, chloroform and acetone. The dried extracts were evaluated for anthelmintic activity against Haemonchus placei adult worms, and the most active extract was subjected to bioassay-guided chromatographic separations. The isolated compounds were evaluated for cytotoxicity against the mammalian HeLa and MC3T3-E1 cell lines, using alamar blue and CellTitreGlo TM to quantify cell viability. LC 50 values were computed from the in vitro anthelmintic activity data by fitting to a non-linear regression equation (variable slope). Isolated compounds were characterized using spectroscopic and mass spectrometric analyses., Results: Anthelmintic activity LC 50 values for n-hexane, chloroform and acetone extracts were 47.85, 35.76 and 5.72 (mg/mL), respectively. Chromatographic separation of acetone extract afforded two bioactive epimers, identified as vincosamide (LC 50 14.7 mg/mL) and strictosamide (LC 50 12.8 mg/mL). Cytotoxicity evaluation showed that, below 200 μg/mL (400 μM), neither compound was toxic to the HeLa or MC3T3-E1 cells., Conclusion: Vincosamide and strictosamide could serve as novel scaffolds for the development of anthelmintic derivatives with improved potency and helminth selectivity., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Slow progress in the fight against neurodegenerative diseases (NDs) motivates an urgent need for highly controlled in vitro systems to investigate organ-organ- and organ-immune-specific interactions relevant for disease pathophysiology. Of particular interest is the gut/microbiome-liver-brain axis for parsing out how genetic and environmental factors contribute to NDs. We have developed a mesofluidic platform technology to study gut-liver-cerebral interactions in the context of Parkinson's disease (PD). It connects microphysiological systems (MPSs) of the primary human gut and liver with a human induced pluripotent stem cell-derived cerebral MPS in a systemically circulated common culture medium containing CD4 + regulatory T and T helper 17 cells. We demonstrate this approach using a patient-derived cerebral MPS carrying the PD-causing A53T mutation, gaining two important findings: (i) that systemic interaction enhances features of in vivo-like behavior of cerebral MPSs, and (ii) that microbiome-associated short-chain fatty acids increase expression of pathology-associated pathways in PD., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background: Cissus incisa is a Vitaceae with a pantropical distribution. In northern Mexico, its leaves have traditionally been used to treat skin infections, abscesses and tumors. Despite its medicinal uses, few studies have been reported., Objective: The objective of this study is to summarize the phytochemical and biological studies carried out so far on the leaves of C. incisa, since this part of the plant is the one frequently used, and awaken scientific interest towards the plant., Methods: Since C. incisa was an undocumented species, most of the information comes from reports of our research group. Databases, books, and websites were also consulted. The information collected was organized and presented in a synthesized way. Plant name was checked with the database "The Plant List"., Results: 171, 260, and 114 metabolites were identified by UHPLC-QFTOF-MS in the hexane, chloroform/ methanol, and aqueous extracts, respectively. Fatty acyls, sphingolipids, sterols, glycerolipids, prenol lipids, and terpenes are common metabolites found in these extracts. 2-(2´-hydroxydecanoyl amino)-1,3,4-hexadecanotriol-8-ene, 2,3-dihydroxypropyl tetracosanoate, β-sitosterol, β-sitosterol-D-glucopyranoside, α-amyrin-3-O-β-D-glucopyranoside were also isolated and characterized. Extracts, phytocompounds and semi-synthetic derivatives showed antimicrobial activity against multi-drug resistant bacteria and various cancer cell lines. Results from Perturbation- Theory-Machine Learning-Information-Fusion model (PTMLIF), molecular docking, and vesicular contents assay identified potential targets on the cell membrane, suggesting an antibacterial mechanism of action for ceramides from C. incisa leaves., Conclusion: This review reports the efforts of the scientific community in authenticating species used in traditional medicine. Moreover, it gives a compendium of phytochemistry and the biological activities of the components from C. incisa leaves., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cryptolepine, the principal constituent of the West African climbing shrub Cryptolepis sanguinolenta, continues to be of interest as a lead to new therapeutic agents, especially for the treatment of protozoal infections and cancer. This contribution reviews the research published in the last decade, highlighting new synthesis routes to cryptolepine and to analogs of this alkaloid, as well as their pharmacology. Studies relating to the use of C. sanguinolenta as an herbal medicine for the treatment of malaria are discussed, as well as the development of analogs of cryptolepine as leads to new agents for the treatment of malaria, trypanosomiasis, and cancer with an emphasis on the pharmacological mechanisms involved. Other potential therapeutic applications include antimicrobial, antidiabetic, and anti-inflammatory activities; the pharmacokinetics and toxicity of cryptolepine are also reviewed.

Objective: This review of serotonin syndrome or serotonin toxicity covers the years 2014 to 2019, including information on pathophysiology, etiology, and diagnosis, 3 criteria for diagnosing serotonin syndrome, and criteria for neuroleptic malignant syndrome., Importance: The review highlights the potential lethal combinations of commonly prescribed medications used to treat both veteran and nonveteran patients and includes the latest information on offending medications., Conclusions: Prevention of serotonin toxicity includes informed clinicians, patient education, careful prescribing and monitoring, and avoidance of multidrug regimens., Competing Interests: Author disclosures The author reports no actual or potential conflicts of interest with regard to this article., (Copyright © 2020 Frontline Medical Communications Inc., Parsippany, NJ, USA.)

Although the association between the microbiome and IBD and liver diseases is known, the cause and effect remain elusive. By connecting human microphysiological systems of the gut, liver, and circulating Treg and Th17 cells, we created a multi-organ model of ulcerative colitis (UC) ex vivo. The approach shows microbiome-derived short-chain fatty acids (SCFAs) to either improve or worsen UC severity, depending on the involvement of effector CD4 T cells. Using multiomics, we found SCFAs increased production of ketone bodies, glycolysis, and lipogenesis, while markedly reducing innate immune activation of the UC gut. However, during acute T cell-mediated inflammation, SCFAs exacerbated CD4 + T cell-effector function, partially through metabolic reprograming, leading to gut barrier disruption and hepatic injury. These paradoxical findings underscore the emerging utility of human physiomimetic technology in combination with systems immunology to study causality and the fundamental entanglement of immunity, metabolism, and tissue homeostasis., Competing Interests: Declaration of Interests L.G.G. has patents on predicate technology (Liverchip) that are licensed to CN Bioinnovations (Cambridge, UK). L.G.G. and D.T. have applied for patents on multi-organ interacting systems., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Executive Summary: Patient-reported outcome measures (PROMs) are used in research and have the potential to improve clinical care. We sought to develop a strategy for integrating PROMs into routine clinical care at an academic health center. The implementation strategy consisted of three phases. The first, exploratory phase, focused on engaging leadership and conducting an inventory of current efforts to collect PROMs. The inventory revealed 87 patient-reported outcome efforts, 47 of which used validated PROMs (62% for research, 21% for clinical care, 17% for quality). In the second, preparatory phase, we identified three pilot implementation sites chosen with facilitators determined in the exploratory phase. Using data from local needs assessments at the pilot sites, we constructed a timeline for inclusion of PROM efforts across the clinical enterprise. In the third phase, we adapted a technology platform for capturing PROMs using the electronic health record and began implementing this platform at the pilot sites. We found that integrating PROMs into routine clinical practice is highly complex. This complexity necessitates change management at the enterprise level.

Background: The high volume of US-Mexico land border crossings can facilitate international dissemination of influenza viruses., Methods: We surveyed adult pedestrians crossing into the United States at two international land ports of entry to assess vaccination coverage during the 2009H1N1 influenza pandemic and 2011-2012 influenza season., Results: Of 559 participants in 2010, 23.4% reported receipt of the 2009H1N1 vaccine. Of 1423 participants in 2012, 33.7% received the 2011-2012 influenza vaccine. Both years, those crossing the border ≥8 times per month had lower vaccination coverage than those crossing less frequently. US-border residents had lower H1N1 coverage than those in other locations. Vaccination coverage was higher for persons age ≥65 years and, in 2010 only, those with less than high school education. Although most participants believed it is important to get vaccinated, only half believed the influenza vaccine was safe and effective. The main reasons for not receiving the influenza vaccine were beliefs of low risk of disease, time constraints, and concerns about vaccine safety (in 2010) or efficacy (in 2012)., Conclusions: International land border crossers are a large and unique category of travelers that require targeted binational strategies for influenza vaccination and education., (Published by Elsevier Ltd.)

A mathematical model for a two-pathogen, one-tick, one-host system is presented and explored. The model system is based on the dynamics of Amblyomma americanum , Rickettsia parkeri , and Rickettsia amblyommatis . The goal of this model is to determine how long an invading pathogen, R. parkeri , persists within a tick population, A. americanum , in which a resident pathogen, R. amblyommatis , is already established. The numerical simulations of the model demonstrate the parameter ranges that allow for coexistence of the two pathogens. Sensitivity analysis highlights the importance of vector-borne, tick-to-host, transmission rates on the invasion reproductive number and persistence of the pathogens over time. The model is then applied to a case study based on a reclaimed swampland field site in south-eastern Virginia using field and laboratory data. The results pinpoint the thresholds required for persistence of both pathogens in the local tick population. However, R. parkeri , is not predicted to persist beyond 3 years. Understanding the persistence and coexistence of tick-borne pathogens will allow public health officials increased insight into tick-borne disease dynamics.

Background: Single lung transplantation (SLT) and double lung transplantation (DLT) are associated with differences in morbidity and mortality, although the effects of transplant type on patient-reported outcomes are not widely reported and conclusions have differed. Previous studies compared mean health-related quality of life (HRQOL) scores but did not evaluate potentially different temporal trajectories in the context of longitudinal follow-up. To address this uncertainty, this study was designed to evaluate longitudinal HRQOL after SLT and DLT with the hypothesis that temporal trajectories differ between SLT and DLT., Methods: Patients transplanted at a single institution were eligible to be surveyed at 1 month, 3 months, 6 months, and then annually after transplant using the Short Form 36 Health Survey, with longitudinal physical component summary (PCS) and mental component summary (MCS) scores as the primary outcomes. Multivariable mixed-effects models were used to evaluate the effects of transplant type and time posttransplant on longitudinal PCS and MCS after adjusting age, diagnosis, rejection, Lung Allocation Score quartile, and intubation duration. Time by transplant type interaction effects were used to test whether the temporal trajectories of HRQOL differ between SLT and DLT recipients. HRQOL scores were referenced to general population norms (range, 40 to 60; mean, 50 ± 10) using accepted standards for a minimally important difference (½ SD, 5 points)., Results: Postoperative surveys (n = 345) were analyzed for 136 patients (52% male, 23% SLT, age 52 ± 13 years, LAS 42 ± 12, follow-up 37 ± 29 months [range, 0.6 to 133]) who underwent lung transplantation between 2005 and 2016. After adjusting for model covariates, overall posttransplant PCS scores have a significant downward trajectory (p = 0.015) whereas MCS scores remain stable (p = 0.593), with both averaging within general population norms. The time by transplant type interaction effect (p = 0.002), however, indicate that posttransplant PCS scores of SLT recipients decline at a rate of 2.4 points per year over the total observation period compared to DLT. At approximately 60 months, the PCS scores of SLT recipients, but not DLT recipients, fall below general population norms., Conclusions: The trajectory of physical HRQOL in patients receiving SLT declines over time compared with DLT, indicating that, in the longer term, SLT recipients are more likely to have physical HRQOL scores that fall substantively below general population norms. Physical HRQOL after 5 years may be a consideration for lung allocation and patient counseling regarding expectations when recommending SLT or DLT., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Infection with Rickettsia parkeri is an emerging tick-borne illness, often accompanied by fever and an eschar at the site of tick attachment. We present three cases of R. parkeri in Virginia residents., Case Presentations: Case 1 presented initially afebrile, failed to seroconvert to rickettsial antigens, and was diagnosed by DNA testing of the eschar. Case 2 presented febrile with eschar, no serologies were performed, and was diagnosed by DNA testing of the eschar. Case 3 presented febrile with eschar, serologies were negative for rickettsial antigens, and was diagnosed by DNA testing of the eschar., Conclusion: DNA testing of eschars represents an under-utilized diagnostic test and may aid in cases where the diagnosis is not made clinically.

Background: The United Network for Organ Sharing system allocates deceased donor kidneys based on the kidney donor profile index (KDPI), stratified as sequences (A ≤ 20%, B > 20-<35%, C ≥ 35-≤85%, and D > 85%), with increasing KDPI associated with decreased graft survival. While health-related quality of life (HRQOL) may improve after transplantation, the effect of donor kidney quality, reflected by KDPI sequence, on post-transplant HRQOL has not been reported., Methods: Health-related quality of life was measured using the eight scales and physical and mental component summaries (PCS, MCS) of the SF-36 ® Health Survey. Multivariable mixed effects models that adjusted for age, gender, rejection, and previous transplant and analysis of variance methods tested the effects of time and KDPI sequence on post-transplant HRQOL., Results: A total of 141 waitlisted adults and 505 recipients (>1700 observations) were included. Pretransplant PCS and MCS averaged, respectively, slightly below and within general population norms (GPN; 40-60). At 31 ± 26 months post-transplant, average PCS (41 ± 11) and MCS (51 ± 11), overall and within each KDPI sequence, were within GPN. KDPI sequence was not related to post-transplant HRQOL (P > .134) or its trajectory (interaction P > .163)., Conclusion: Increasing KDPI does not adversely affect the medium-term values and trajectories of HRQOL after kidney transplantation. This may reassure patients and centers when considering using high KDPI kidneys., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study examines the results of neuropsychological testing of 26 active welders and 17 similar controls and their relationship to welders' shortened MRI T1 relaxation time, indicative of increased brain manganese (Mn) accumulation. Welders were exposed to Mn for an average duration of 12.25 years to average levels of Mn in air of 0.11±0.05mg/m 3 . Welders scored significantly worse than controls on Fruit Naming and the Parallel Lines test of graphomotor tremor. Welders had shorter MRI T1 relaxation times than controls in the globus pallidus, substantia nigra, caudate nucleus, and the anterior prefrontal lobe. 63% of the variation in MRI T1 relaxation times was accounted for by exposure group. In welders, lower relaxation times in the caudate nucleus and substantia nigra were associated with lower neuropsychological test performance on tests of verbal fluency (Fruit Naming), verbal learning, memory, and perseveration (WHO-UCLA AVLT). Results indicate that verbal function may be one of the first cognitive domains affected by brain Mn deposition in welders as reflected by MRI T1 relaxation times., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Discovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study investigating the gametocytocidal activity of the plant and its major alkaloid, cryptolepine. This study also investigates the anti-malarial interaction of cryptolepine with standard anti-malarials, as the search for new anti-malarial combinations continues., Methods: The resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta and cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of cryptolepine with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7., Results: Cryptolepis sanguinolenta (IC 50  = 49.65 nM) and its major alkaloid, cryptolepine (IC 50  = 1965 nM), showed high inhibitory activity against the late stage gametocytes of P. falciparum (NF54). In the interaction assays in asexual stage, cryptolepine showed an additive effect with both lumefantrine and chloroquine with mean ΣFIC 50 s of 1.017 ± 0.06 and 1.465 ± 0.17, respectively. Cryptolepine combination with amodiaquine at therapeutically relevant concentration ratios showed a synergistic effect (mean ΣFIC 50  = 0.287 ± 0.10) whereas an antagonistic activity (mean ΣFIC 50  = 4.182 ± 0.99) was seen with mefloquine., Conclusions: The findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages of the parasite. Amodiaquine is a potential drug partner for cryptolepine in the development of novel fixed dose combinations.