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Mosquito-borne La Crosse virus (LACV; family: Peribunyaviridae) is the leading cause of pediatric arboviral encephalitis in the United States, with clinical cases generally centered in the Midwest and Appalachian regions. Incidence of LACV cases in Appalachian states has increased, such that the region currently represents the majority of reported LACV cases in the USA. The amount of reported LACV cases from Virginia, however, is minimal compared to neighboring states such as North Carolina, West Virginia, and Tennessee, and non-Appalachian regions of Virginia are understudied. Here we examine the hypothesis that LACV is circulating widely in Virginia, despite a low clinical case report rate, and that the virus is circulating in areas not associated with LACV disease. In this study, we screened local mammalian wildlife in northwestern counties of Virginia using passive surveillance via patients submitted to wildlife rehabilitation centers. Blood sera (527 samples; 9 species, 8 genera) collected between October 2019 and December 2022 were screened for neutralizing antibodies against LACV, indicating prior exposure to the virus. We found an overall LACV seroprevalence of 1.90% among all wild mammals examined and reveal evidence of LACV exposure in several wild species not generally associated with LACV, including eastern cottontails and red foxes, along with established reservoirs, eastern gray squirrels, although there was no serological evidence in chipmunks. These data indicate the circulation of LACV in Virginia outside of Appalachian counties, however, at a lower rate than reported for endemic areas within the state and in other states.

A main objective of AACSB Standard A5 (AACSB 2018) is for accounting students to achieve information technology agility and greater adaptability in this age of rapid change to the profession. To this end, academic research identifies technological agility as a foundational skill required to educate accountants in data analytics. However, prior research indicates a resistance by accountants to adopt new technology. In light of increasing demands for accounting students to develop increased abilities and flexibility with technology and to adopt data analytics techniques, educators need a much better understanding of antecedents to technology resistance. This proposed study asks: Do personality characteristics and situational and organizational conditions influence the technological resistance of accounting students and faculty? Do these influences operate through the status quo bias (SQB) decision framework? Performing this suggested study may lead to insights and suggest educational interventions and curriculum guidance to meet that guidance.

Cryptosporidium parvum is a parasitic zoonotic pathogen responsible for diarrheal illness in humans and animals worldwide. We report an investigation of a cryptosporidiosis outbreak in raccoons and wildlife rehabilitation workers at a Virginia facility. Fifteen (31%) of 49 facility personnel experienced symptoms meeting the case definition, including four laboratory-confirmed cases. Seven juvenile raccoons were reported to have diarrhoea; six had laboratory-confirmed cryptosporidiosis. Cryptosporidium parvum of the same molecular subtype (IIaA16G3R2) was identified in two human cases and six raccoons. Raccoon illness preceded human illness by 11 days, suggesting possible zoonotic transmission from raccoons to humans. This appears to be the first report of a human cryptosporidiosis outbreak associated with exposure to raccoons infected with C. parvum. Raccoons might be an under-recognized reservoir for human C. parvum infections. Further study is needed to explore the prevalence of cryptosporidial species in raccoons and their role as a wildlife reservoir.

Twenty six new phenylurea substituted 2,4-diamino-pyrimidines active against Plasmodium falciparum (Pf) 3D7 are reported.

Especially when travel and gatherings were restricted during the pandemic, filming and livestreaming enabled more people to connect with funerals than could attend in person. Filming has also created another less well considered possibility: of revisiting a funeral via a recording. This Viewpoint outlines a range of experiences and opinions about this practice. We suggest careful attention is needed to its development and its implications for bereavement care in diverse circumstances.

Demand for data analysis skills in the accounting profession is well-documented and necessarily informs accounting curriculum and pedagogy. This empirical survey study focuses on small- and medium-sized entities (SMEs). SME cluster research suggests different adoption rates for technology between this segment and large firms. Investigating SME demands for skills and abilities of new job entrants differs from the large organizations that served as the original drivers of analytic skills and technology recommendations. Findings in this study suggest SMEs continue performing their leading accounting tasks using Excel spreadsheets and lag in adoption of data analytics technology. SMEs are a significant business sector in the economy, competing with large firms but with fewer resources. The findings presented here may inform educators in SME markets regarding SME firms' need for a unique skillset from new hires.

Anxiety and depression have deleterious effects on health. Numerous studies have demonstrated the negative impact of emotions such as stress and anxiety on heart rate (HR), blood pressure (BP), and heart disease. These mood states have been linked to stroke, heart failure, diabetes, heart disease, respiratory problems, and drug abuse. Negative emotions can affect the HR and BP through the link between the nervous system and the cardiovascular system. Our study demonstrates the positive effect of classical music on HR, BP parameters, and mood states.

This article describes the rationale behind and development of a novel methodological combination of autobiographical reflection and semi-structured interviewing. The resulting “autobiographical elicitation” methodology was first used for a recent study of the relationship between work and faith as experienced by evangelical medics working in the National Health Service (NHS) in England. The article argues that autobiographical elicitation successfully fulfilled aims of facilitating lived religion research and generating qualitative data which was directed by what research participants deemed important and meaningful, while remaining conducive to comparative analysis. It also alleviated concerns regarding the limited reflection time offered by semi-structured interviews in isolation, and offered busy participants welcomed convenience and flexibility. The article concludes, therefore, that autobiographical elicitation is a promising methodological combination for lived religion researchers, and more broadly for those keen to generate rich qualitative insights in partnership with busy participants.

There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with in vivo efficacy, which was hampered by poor solubility and genotoxicity. The work on the original scaffold failed to lead to developable compounds, so an extensive scaffold-hopping exercise involving medicinal chemistry design, in silico profiling, and subsequent synthesis was utilized, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modeling of different scaffolds into a cryo-EM structure and the impact this has on our understanding of the series' structure-activity relationships.

We explore whether an integrated professional-student learning experience can better address the urgent demand for data-savvy, collaborative students ready to contribute on day one of their professional careers. The interactive professional learning experience (IPLE) brings practitioners into the classroom to work with students in an active learning setting. Our IPLE includes four steps: a guest speaker presentation to introduce the topic, assignment of a data analytics and visualization case project to student teams, a collaborative lab session with professionals and student teams, and finally, presentations to the original guest speaker and class. Pre- and post-test assessments indicate significantly positive improvement in student learning as compared to two other instructional methods that did not include the full IPLE. Questionnaire responses indicate overwhelmingly positive student perceptions, including improved learning, satisfaction, and effectiveness. Overall, student feedback indicates the IPLE was an effective learning mechanism.

With the emergence of multi-drug-resistant strains of Mycobacterium tuberculosis, there is a pressing need for new oral drugs with novel mechanisms of action. A number of scaffolds with potent anti-tubercular in vitro activity have been identified from phenotypic screening that appear to target MmpL3. However, the scaffolds are typically lipophilic, which facilitates partitioning into hydrophobic membranes, and several contain basic amine groups. Highly lipophilic basic amines are typically cytotoxic against mammalian cell lines and have associated off-target risks, such as inhibition of human ether-a-go-go related gene (hERG) and IKr potassium current modulation. The spirocycle compound 3 was reported to target MmpL3 and displayed promising efficacy in a murine model of acute tuberculosis (TB) infection. However, this highly lipophilic monobasic amine was cytotoxic and inhibited the hERG ion channel. Herein, the related spirocycles (1-2) are described, which were identified following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis. The novel N-alkylated pyrazole portion offered improved physicochemical properties, and optimization led to identification of a zwitterion series, exemplified by lead 29, with decreased HepG2 cytotoxicity as well as limited hERG ion channel inhibition. Strains with mutations in MmpL3 were resistant to 29, and under replicating conditions, 29 demonstrated bactericidal activity against M. tuberculosis. Unfortunately, compound 29 had no efficacy in an acute model of TB infection; this was most likely due to the in vivo exposure remaining above the minimal inhibitory concentration for only a limited time.

Visceral leishmaniasis (VL) is a parasitic infection that results in approximately 26 000–65 000 deaths annually. The available treatments are hampered by issues such as toxicity, variable efficacy...

Visceral leishmaniasis (VL) affects millions of people across the world, largely in developing nations. It is fatal if left untreated and the current treatments are inadequate. As such, there is an urgent need for new, improved medicines. In this paper, we describe the identification of a 6-amino-N-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine scaffold and its optimization to give compounds which showed efficacy when orally dosed in a mouse model of VL.

African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites

With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.

Wildlife rehabilitators are important One Health professionals. Though this is arguably one of the most impactful aspects of our work, it is often undervalued or not recognized at all by the public. Evaluating how you as a rehabilitator are contributing to the protection of human, animal, and environmental health and highlighting your involvement with the public has the potential to benefit one health, but also the rehabilitation community and the public’s perception of wildlife rehabilitation in general.

While many business publications stress the importance of data analytics skills and technology, The Wall Street Journal reports strong reactions of accountants faced with a move away from Excel. Accountants are traditionally the reliable source for business information, but that position may be eroded by the emerging profession of data analysts. Looking to the future, Big Four accounting firms stress the need for data analysis skills, and universities are launching degree programs. But what is the reaction of current working professionals? Are they heeding the call for data analytics? Evidence indicates there is some resistance to adoption of data analytics practices. This research proposes the use of Status Quo Bias Theory to investigate the reactions of accounting professionals across the spectrum of accounting sub-disciplines. The study seeks to understand factors that may influence practicing accountants' resistance to adopting new data analysis technologies.

Our proposed study applies Psychological Capital (PsyCap) to the Industry 4.0 literature, and specifically, to Robotic Process Automation (RPA). We examine two issues: are accountants ready for the changes brought about by RPA, and will accountants overrely on RPA to provide accurate information? PsyCap is a core construct that encompasses four dimensions of an individual's mental state. Drawn from positive psychology, it focuses on individuals' strengths, rather than weaknesses. We expect higher levels of PsyCap will be associated with higher levels of readiness for and reliance on RPA. This could be dangerous, because the output of RPA may not always be reliable. We propose a quasi-experiment to gather data from accountants. Understanding the relationship between PsyCap and behavior is important because PsyCap is a state-like construct, which can be developed and strengthened. Accounting firms and organizations can implement mechanisms to encourage readiness for RPA but discourage overreliance without assurance.

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N‐(3‐chloro‐4‐fluorophenyl)‐2‐methyl‐2‐{[4‐methyl‐3‐(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low‐nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter‐screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification., New roads to novel chemotypes: Compound selection from the TCAMS library (GSK), followed by iterative rounds of inhibitor design and synthesis afforded a single‐digit nanomolar inhibitor of P. falciparum (3D7), based on an aminoacetamide core. Compound 28 is a potent antimalarial and displayed excellent selectivity in a mammalian counter‐screen. This compound could be used as a suitable chemical tool for drug target identification or as a lead compound for further optimization.

Approximately 6-7 million people around the world are estimated to be infected with Trypanosoma cruzi, the causative agent of Chagas disease. The current treatments are inadequate and therefore new medical interventions are urgently needed. In this paper we describe the identification of a series of disubstituted piperazines which shows good potency against the target parasite but is hampered by poor metabolic stability. We outline the strategies used to mitigate this issue such as lowering logD, bioisosteric replacements of the metabolically labile piperazine ring and use of plate-based arrays for quick diversity scoping. We discuss the success of these strategies within the context of this series and highlight the challenges faced in phenotypic programs when attempting to improve the pharmacokinetic profile of compounds whilst maintaining potency against the desired target.

Twenty eight new N

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class.

Chagas disease is caused by the protozoan parasite

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. It is endemic in South and Central America and recently has been found in other parts of the world, due to migration of chronically infected patients. The current treatment for Chagas disease is not satisfactory, and there is a need for new treatments. In this work, we describe the optimization of a hit compound resulting from the phenotypic screen of a library of compounds against T. cruzi. The compound series was optimized to the level where it had satisfactory pharmacokinetics to allow an efficacy study in a mouse model of Chagas disease. We were able to demonstrate efficacy in this model, although further work is required to improve the potency and selectivity of this series.

Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, affects 8–10 million people across the Latin American population and is responsible for around 12,500 deaths per annum. The current frontline treatments, benznidazole and nifurtimox, are associated with side effects and lack efficacy in the chronic stage of the disease, leading to an urgent need for new treatments. A high throughput screening campaign against the physiologically relevant intracellular form of the parasite identified a series of 2,4-diamino-6-methylpyrimidines. Demonstrating the series did not work through the anti-target TcCYP51, and was generally cytocidal, confirmed its suitability for further development. This study reports the optimisation of selectivity and metabolic stability of the series and identification of a suitable lead for further optimisation.

Despite attempts to encourage whistleblowing, lingering reluctance to report questionable acts remains frustratingly apparent. Our objective is to examine the regret a professional anticipates when...

Twenty eight new N2,N4-diphenylpyrimidine-2,4-diamines have been prepared in order to expand our understanding of the anti-malarial SAR of the scaffold. The aim of the study was to make structural modifications to improve the overall potency, selectivity and solubility of the series by varying the anilino groups attached to the 2- and 4-position. We evaluated the activity of the compounds against Plasmodium falciparum (Pf) 3D7, cytotoxicity against HepG2, % inhibition at a panel of 10 human kinases, solubility, permeability and lipophilicity, and human and rat in vitro clearance. 11 was identified as a potent anti-malarial with an IC50 of 0.66 µM at the 3D7 strain and a selectivity (SI) of ~ 40 in terms of cytotoxicity against the HepG2 cell line. It also displayed low experimental logD7.4 (2.27), reasonable solubility (124 µg/ml), good metabolic stability, but low permeability. A proteo-chemometric workflow was employed to identify putative Pf targets of the most promising compounds. Ligand-based similarity searching of the ChEMBL database led to the identification of most probable human targets. These were then used as input for sequence-based searching of the Pf proteome. Homology modelling and molecular docking were used to evaluate whether compounds could indeed bind to these targets with valid binding modes. In vitro biological testing against close human analogs of these targets was subsequently undertaken. This allowed us to identify potential Pf targets and human anti-targets that could be exploited in future development.

Common scab disease on root and tuber plants is caused by Streptomyces scabies and related species which use the cellulose synthase inhibitor thaxtomin A as the main phytotoxin. Thaxtomin production is primarily triggered by the import of cello-oligosaccharides. Once inside the cell, the fate of the cello-oligosaccharides is dichotomized into i) fueling glycolysis with glucose for the saprophytic lifestyle through the action of β-glucosidase(s) (BG), and ii) eliciting the pathogenic lifestyle by inhibiting the CebR-mediated transcriptional repression of thaxtomin biosynthetic genes. Here we investigated the role of scab57721 encoding a putative BG (BglC) in the onset of the pathogenicity of S. scabies. Enzymatic assays showed that BglC was able to release glucose from cellobiose, cellotriose and all other cello-oligosaccharides tested. Its inactivation resulted in a phenotype opposite to what was expected as we monitored reduced production of thaxtomin when the mutant was cultivated on media containing cello-oligosaccharides as unique carbon source. This unexpected phenotype could be attributed to the highly increased activity of alternative intracellular BGs, probably as a compensation of bglC inactivation, which then prevented cellobiose and cellotriose accumulation to reduce the activity of CebR. In contrast, when the bglC null mutant was cultivated on media devoid of cello-oligosaccharides it instead constitutively produced thaxtomin. This observed hypervirulent phenotype does not fit with the proposed model of the cello-oligosaccharide-mediated induction of thaxtomin production and suggests that the role of BglC in the route to the pathogenic lifestyle of S. scabies is more complex than currently presented. This article is protected by copyright. All rights reserved.

An 11-yr-old dromedary camel (Camelus dromedarius) at a zoo in south Florida presented with diarrhea while being treated with enrofloxacin and dexamethasone for a chronic skin condition. Three weeks after initiation of therapy with dexamethasone, the camel developed diarrhea, which worsened despite treatment with antibiotics. The animal became increasingly debilitated, developed hemorrhagic diarrhea, declined rapidly over the next 3 days, and died despite aggressive fluid therapy and supportive care. Histologic examination revealed intralesional protozoal tissue cysts consistent with Toxoplasma gondii in the intestines, lungs, and liver, as well as lymphoid depletion of the spleen suggesting immunosuppression. To the author's knowledge this is the first reported case of disseminated toxoplasmosis that clinically manifested as hemorrhagic enterocolitis in a camel.

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.

Background and Objectives: Providing pasteurized donor human milk (DHM) to healthy newborns is an emerging practice. The content of hospital policies that govern this practice is unknown. Materials and Methods: We collected policies from 15 Northeast U.S. hospitals through (1) a 2017 survey on DHM use and (2) an e-mail listserv of levels 1 and 2 newborn care staff maintained by a regional milk bank. Two authors reviewed each policy and identified how they addressed three predetermined themes: who is eligible to receive DHM, how DHM is used and described, and how lactation is supported. Responses were compared, discussed, and reconciled. Level 1 newborn care was defined as basic care for healthy newborns ≥35 weeks' gestation. Results: Thirteen of 15 policies stated criteria for DHM eligibility, most commonly as a bridge until mother's supply comes in (73%) or for infant medical conditions (67%). All required consent for DHM. Most did not limit number of days infants could receive DHM (60%). Nine specified that DHM be discarded 24 hours after thaw, whereas five recommended discarding at 48 hours. Although many (53%) policies endorsed human milk as the preferred diet for newborns, only 27% specifically endorsed DHM as the preferred supplementation type. Parent education (73%) was emphasized, but few (27%) discussed the importance of establishing mother's milk supply. Conclusions: Many DHM policies address eligibility criteria for receiving DHM and show how to provide DHM, but few address how to support lactation while DHM is provided, which may be crucial for optimizing long-term breastfeeding outcomes.

Wildlife patients often present as emergencies. For veterinarians who do not typically treat wildlife, it is important to be able to stabilize and determine the underlying cause of the animal's signs. This article discusses initial assessment, stabilization, and treatment of common emergency presentations in wild birds, reptiles, and mammals.

News coverage, social media and protests alike tend to polarise people’s stances on abortion. Moreover, these also often reveal category slippage between ‘pro-life’ and ‘Christian’ or ‘religious,’ perpetuating the impression that to be religious is to reject abortion. Contrary to both tendencies, this article engages with abortion from a lived religion perspective. It listens to evangelical healthcare practitioners as they talk about their attitudes towards abortion. This reveals a complex picture, their ethical engagement variously taking the form of resistance, neutrality, uncertainty, compartmentalisation, change and situational negotiation, while drawing upon multiple sources of ethical authority, including their own ‘experiential knowledge.’ Having presented these complexities, the article concludes by exploring their implications. First, it considers the value of foregrounding emotion when engaging in lived religion research around ethics and controversial topics. Secondly, it suggests that combining social bioethics with emotional narratives might represent a means of communicating this complexity.

Graphical abstract, Highlights • Identification of soft drug S1PR agonists. • Development of a process for the evaluation of topical esterase soft drugs. • Study skin and plasma esterase SAR., The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma.