Mpox in East Africa: Learning from COVID-19 and Ebola to Strengthen Public Health Responses.

The Africa Centers for Disease Control and Prevention declared mpox a Public Health Emergency of Continental Security (PHECS) in Africa. African public health systems have moved to mobilize a response against a backdrop of inherent significant challenges. With this commentary, we discuss how lessons from past public health emergencies, particularly COVID-19 and Ebola outbreaks, have prepared the region for improved disease surveillance, rapid response strategies, and effective public health communication and how these lessons can be applied to the mpox response, emphasizing the importance of strong healthcare infrastructure, effective data sharing, community engagement, targeted interventions, and robust contact tracing. Additionally, addressing misinformation and building public trust are crucial for controlling the spread of any disease. By leveraging these strategies, African countries can enhance their response to mpox. This includes improving diagnostic capabilities, strengthening cross-border collaborations, and prioritizing vaccination campaigns where needed. Ultimately, by applying the hard-earned lessons from the COVID-19 pandemic and Ebola outbreak, the East Africa region can better address the challenges posed by mpox and safeguard public health.

Extracting metal ions from basic oxygen steelmaking dust by using bio-hydrometallurgy.

This study aimed to optimise metal extraction from secondary hazardous sources, such as basic oxygen steelmaking dust (BOS-D). Initially, three batch systems approaches, including bioleaching using Acidithiobacillus ferrooxidans, chemical leaching using choline chloride-ethylene glycol (ChCl-EG) and a combined approach were compared. Then, scaling up was evaluated through a semi-continuous bioleaching column system with varied leachate recirculation over 21 days, focusing on Y, Ce, Nd, Li, Co, Cu, Zn, Mn, and Al. Bioleaching outperformed the control experiments within 3 days in the batch, demonstrating the key role of A. ferrooxidans. Chemical leaching conducted with a solid concentration of 12.5 % (w/v) successfully dissolved over 50 % of all metals within 2 h. For rare earth elements (REE), both bioleaching and hybrid leaching outperformed chemical leaching. However, considering factors such as process duration, overall efficiency, and ease of extraction, chemical leaching was the most effective method. Leachate recirculation reached a plateau after 11 days, resulting in extraction efficiency of 39 % when semi-continuous column set-up was used. Interestingly, variations in recirculation rates did not influence the extraction efficiency. Overall, this study emphasizes the considerable potential of bioleaching for metal recovery, but also highlights the need for further studies for enhancing permeability for percolation methods and optimisation, particularly in parameters such as aeration rate, when transitioning to larger scale systems.

Mathematical Assessment of the Role of Intervention Programs for Malaria Control.

Malaria remains a global health problem despite the many attempts to control and eradicate it. There is an urgent need to understand the current transmission dynamics of malaria and to determine the interventions necessary to control malaria. In this paper, we seek to develop a fit-for-purpose mathematical model to assess the interventions needed to control malaria in an endemic setting. To achieve this, we formulate a malaria transmission model to analyse the spread of malaria in the presence of interventions. A sensitivity analysis of the model is performed to determine the relative impact of the model parameters on disease transmission. We explore how existing variations in the recruitment and management of intervention strategies affect malaria transmission. Results obtained from the study imply that the discontinuation of existing interventions has a significant effect on malaria prevalence. Thus, the maintenance of interventions is imperative for malaria elimination and eradication. In a scenario study aimed at assessing the impact of long-lasting insecticidal nets (LLINs), indoor residual spraying (IRS), and localized individual measures, our findings indicate that increased LLINs utilization and extended IRS coverage (with longer-lasting insecticides) cause a more pronounced reduction in symptomatic malaria prevalence compared to a reduced LLINs utilization and shorter IRS coverage. Additionally, our study demonstrates the impact of localized preventive measures in mitigating the spread of malaria when compared to the absence of interventions.

Assessing metal extraction from metalliferous waste: A study using deep eutectic solvents and chelating agents vs. ethylenediaminetetraacetic acid.

Conventional methods of metal recovery involving solvents have raised environmental concerns. To address these concerns and promote sustainable resource recovery, we explored the use of deep eutectic solvents (DES) and chelating agents (CA) as more environmentally friendly alternatives. Goethite and blast oxide slag dust (BOS-D) from heap piles at their respective sites and characterised via ICP-MS. The greatest extraction of critical metals was from goethite, removing 38% of all metals compared to 21% from the blast oxide slag. Among the tested CA, nitrilotriacetic acid (NTA) was the most effective, while for DES, choline chloride ethylene glycol (ChCl-EG) demonstrated superior performance in extracting metals from both blast oxide slag dust and goethite. The study further highlighted the selectivity for transition metals and metalloids was influenced by the carboxyl groups of DES. Alkaline metals and rare earth lanthanides extractions were favoured with DES due to improved mass transfer and increased denticity, respectively. In comparison to ethylenediaminetetraacetic acid (EDTA), typically used for metal extraction, CA and DES showed comparable extraction efficiency for Fe, Cu, Pb, Li, Al, Mn, and Ni. Using these greener chelators and solvents for metal extraction show significant promise in enhancing the sustainability of solvometallurgy. Additional conditions e.g., temperature and agitation combined with a cascading leaching process could further enhance metal extraction potential.

Exploring the Utility and Fairness of a Multi-institutional Situational Judgment Test.

OBJECTIVE: To pilot a situational judgment test (SJT) developed to assess empathy, integrity, and teamwork and explore differences in performance between first-year (P1) and fourth-year (P4) student pharmacists based on gender, race or ethnicity, and geographical region. METHODS: An SJT was developed to assess empathy, integrity, and teamwork, using best practices. The SJT was piloted tested with P1 and P4 student pharmacists at 5 institutions. Scores were adjusted for elevation and scatter to minimize the subgroup differences in response styles. RESULTS: The unadjusted mean SJT scores for P1 and P4 student pharmacists were 79.7 % and 80.7 %, respectively. The adjusted scores for P1 and P4 student pharmacists were 86.3 % and 87.2 %, respectively. Small differences were observed across institutions which can likely explained by multiple factors. The mean scores were higher among students who were older, female, identified as White, and spoke English as their first language. The subgroup differences persisted even after adjusting scores for elevation and scatter. CONCLUSION: Performance on an SJT designed to assess empathy, integrity, and teamwork was similar to others in the literature; however, differences in performance were observed across subgroups. Additional research is needed to determine whether these differences reflect test bias or other possible factors.

Working memory involvement in action planning does not include timing initiation structure.

A fundamental limitation in the type of information that can be retained in working memory is identified in this theoretical / review article. The analysis is based on studies of skilled motor performance that were not initially conceived in terms of working memory. Findings from a long history of experimentation involving reaction time (RT) prior to making a brief motor response indicate that although the parameters representing the goal to be achieved by the response can be retained in working memory, the control code that implements timing of action components cannot. This lack of working memory requires that the "timing code" must be compiled immediately prior to the moment that it is to be utilized; it is not possible to be fully ready to respond earlier. This compiling process increases RT and may also underlie both the psychological refractory period effect and the difficulty of generating concurrent motor actions with independent timing. These conclusions extend, but do not conflict with, other models of working memory.

Human Cytomegalovirus Dysregulates Cellular Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases and Sonic Hedgehog Pathway Proteins in Neural Astrocyte and Placental Models.

Human cytomegalovirus (CMV) infection is the leading non-genetic cause of congenital malformation in developed countries, causing significant fetal injury, and in some cases fetal death. The pathogenetic mechanisms through which this host-specific virus infects then damages both the placenta and the fetal brain are currently ill-defined. We investigated the CMV modulation of key signaling pathway proteins for these organs including dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) and Sonic Hedgehog (SHH) pathway proteins using human first trimester placental trophoblast (TEV-1) cells, primary human astrocyte (NHA) brain cells, and CMV-infected human placental tissue. Immunofluorescence demonstrated the accumulation and re-localization of SHH proteins in CMV-infected TEV-1 cells with Gli2, Ulk3, and Shh re-localizing to the CMV cytoplasmic virion assembly complex (VAC). In CMV-infected NHA cells, DYRK1A re-localized to the VAC and DYRK1B re-localized to the CMV nuclear replication compartments, and the SHH proteins re-localized with a similar pattern as was observed in TEV-1 cells. Western blot analysis in CMV-infected TEV-1 cells showed the upregulated expression of Rb, Ulk3, and Shh, but not Gli2. In CMV-infected NHA cells, there was an upregulation of DYRK1A, DYRK1B, Gli2, Rb, Ulk3, and Shh. These in vitro monoculture findings are consistent with patterns of protein upregulation and re-localization observed in naturally infected placental tissue and CMV-infected ex vivo placental explant histocultures. This study reveals CMV-induced changes in proteins critical for fetal development, and identifies new potential targets for CMV therapeutic development.

Techno-economic assessment of bioleaching for metallurgical by-products.

This study focused on the economic feasibility of two potential industrial-scale bioleaching technologies for metal recovery from specific metallurgical by-products, mainly basic oxygen steelmaking dust (BOS-D) and goethite. The investigation compared two bioleaching scaling technology configurations, including an aerated bioreactor and an aerated and stirred bioreactor across different scenarios. Results indicated that bioleaching using Acidithiobacillus ferrooxidans proved financially viable for copper extraction from goethite, particularly when 5% and 10% pulp densities were used in the aerated bioreactor, and when 10% pulp density was used in the aerated and stirred bioreactor. Notably, a net present value (NPV) of $1,275,499k and an internal rate of return (IRR) of 65% for Cu recovery from goethite were achieved over 20-years after project started using the aerated and stirred bioreactor plant with a capital expenditure (CAPEX) of $119,816,550 and an operational expenditure (OPEX) of $5,896,580/year. It is expected that plant will start to make profit after one year of operation. Aerated and stirred bioreactor plant appeared more reliable alternative compared to the aerated bioreactor plant as the plant consists of 12 reactors which can allow better management and operation in small volume with multiple reactors. Despite the limitations, this techno-economic assessment emphasized the significance of selective metal recovery and plant design, and underscored the major expenses associated with the process.

Reconsidering Pharmacy: We Need to Turn Career Regret into Career Options.

Declining interest in pharmacy as a career is a growing concern. This commentary investigates the factors contributing to career regret among pharmacy graduates, based on data from the American Association of Colleges of Pharmacy National Graduating Student Survey. We identify 3 key contributing factors: workplace environment, professional identity formation, and marketing of the Doctor of Pharmacy degree. We argue that students observe, in many work environments, a lack of autonomy, repetitive tasks, and unfulfilling work. This leads to diminished job satisfaction and disillusionment. Additionally, marketing tactics and curricular structures can inadvertently contribute to career regret. We propose potential interventions, emphasizing the need for improved working conditions, more versatile roles in pharmacy, and enhanced career development services within colleges/schools of pharmacy. Additional research is needed to fully understand career regret and the steps that academic institutions can proactively take to mitigate career dissatisfaction among their graduates.

Human cytomegalovirus (CMV) dysregulates neurodevelopmental pathways in cerebral organoids.

Human cytomegalovirus (CMV) infection is the leading non-genetic aetiology of congenital malformation in developed countries, causing significant fetal neurological injury. This study investigated potential CMV pathogenetic mechanisms of fetal neural malformation using in vitro human cerebral organoids. Cerebral organoids were permissive to CMV replication, and infection dysregulated cellular pluripotency and differentiation pathways. Aberrant expression of dual-specificity tyrosine phosphorylation-regulated kinases (DYRK), sonic hedgehog (SHH), pluripotency, neurodegeneration, axon guidance, hippo signalling and dopaminergic synapse pathways were observed in CMV-infected organoids using immunofluorescence and RNA-sequencing. Infection with CMV resulted in dysregulation of 236 Autism Spectrum Disorder (ASD)-related genes (p = 1.57E-05) and pathways. This notable observation suggests potential links between congenital CMV infection and ASD. Using DisGeNET databases, 103 diseases related to neural malformation or mental disorders were enriched in CMV-infected organoids. Cytomegalovirus infection-related dysregulation of key cerebral cellular pathways potentially provides important, modifiable pathogenetic mechanisms for congenital CMV-induced neural malformation and ASD.

Native Circular RNA Pulldown Method to Simultaneously Profile RNA and Protein Interactions.

Circular RNAs (circRNAs) are a widespread, cell-, tissue-, and disease-specific class of largely non-coding RNA transcripts. These single-stranded, covalently-closed transcripts arise through non-canonical splicing of pre-mRNA, a process called back-splicing. Back-splicing results in circRNAs which are distinguishable from their cognate mRNA as they possess a unique sequence of nucleic acids called the backsplice junction (BSJ). CircRNAs have been shown to play key functional roles in various cellular contexts and achieve this through their interaction with other macromolecules, particularly other RNA molecules and proteins. To elucidate the molecular mechanisms underlying circRNA function, it is necessary to identify these interacting partners. Herein, we present an optimized strategy for the simultaneous purification of the circRNA interactome within eukaryotic cells, allowing the identification of both circRNA-RNA and circRNA-protein interactions.

Avoidance, confusion or solitude? Modelling how noise pollution affects whale migration.

Many baleen whales are renowned for their acoustic communication. Under pristine conditions, this communication can plausibly occur across hundreds of kilometres. Frequent vocalisations may allow a dispersed migrating group to maintain contact, and therefore benefit from improved navigation via the "wisdom of the crowd". Human activities have considerably inflated ocean noise levels. Here we develop a data-driven mathematical model to investigate how ambient noise levels may inhibit whale migration. Mathematical models allow us to simultaneously simulate collective whale migration behaviour, auditory cue detection, and noise propagation. Rising ambient noise levels are hypothesised to influence navigation through three mechanisms: (i) diminished communication space; (ii) reduced ability to hear external sound cues and; (iii) triggering noise avoidance behaviour. Comparing pristine and current soundscapes, we observe navigation impairment that ranges from mild (increased journey time) to extreme (failed navigation). Notably, the three mechanisms induce qualitatively different impacts on migration behaviour. We demonstrate the model's potential predictive power, exploring the extent to which migration may be altered under future shipping and construction scenarios.

TRPV4 is expressed by enteric glia and muscularis macrophages of the colon but does not play a prominent role in colonic motility.

Background: Mechanosensation is an important trigger of physiological processes in the gastrointestinal tract. Aberrant responses to mechanical input are associated with digestive disorders, including visceral hypersensitivity. Transient Receptor Potential Vanilloid 4 (TRPV4) is a mechanosensory ion channel with proposed roles in visceral afferent signaling, intestinal inflammation, and gut motility. While TRPV4 is a potential therapeutic target for digestive disease, current mechanistic understanding of how TRPV4 may influence gut function is limited by inconsistent reports of TRPV4 expression and distribution. Methods: In this study we profiled functional expression of TRPV4 using Ca2+ imaging of wholemount preparations of the mouse, monkey, and human intestine in combination with immunofluorescent labeling for established cellular markers. The involvement of TRPV4 in colonic motility was assessed in vitro using videomapping and contraction assays. Results: The TRPV4 agonist GSK1016790A evoked Ca2+ signaling in muscularis macrophages, enteric glia, and endothelial cells. TRPV4 specificity was confirmed using TRPV4 KO mouse tissue or antagonist pre-treatment. Calcium responses were not detected in other cell types required for neuromuscular signaling including enteric neurons, interstitial cells of Cajal, PDGFRα+ cells, and intestinal smooth muscle. TRPV4 activation led to rapid Ca2+ responses by a subpopulation of glial cells, followed by sustained Ca2+ signaling throughout the enteric glial network. Propagation of these waves was suppressed by inhibition of gap junctions or Ca2+ release from intracellular stores. Coordinated glial signaling in response to GSK1016790A was also disrupted in acute TNBS colitis. The involvement of TRPV4 in the initiation and propagation of colonic motility patterns was examined in vitro. Conclusions: We reveal a previously unappreciated role for TRPV4 in the initiation of distension-evoked colonic motility. These observations provide new insights into the functional role of TRPV4 activation in the gut, with important implications for how TRPV4 may influence critical processes including inflammatory signaling and motility.

Seroepidemiological investigation of Crimean Congo hemorrhagic fever virus in livestock in Uganda, 2017.

Crimean-Congo Hemorrhagic fever (CCHF) is an important zoonotic disease transmitted to humans both by tick vectors and contact with fluids from an infected animal or human. Although animals are not symptomatic when infected, they are the main source of human infection. Uganda has reported sporadic human outbreaks of CCHF in various parts of the country since 2013. We designed a nationwide epidemiological study to investigate the burden of CCHF in livestock. A total of 3181 animals were sampled; 1732 cattle (54.4%), 1091 goats (34.3%), and 358 sheep (11.3%) resulting in overall livestock seropositivity of IgG antibodies against CCHF virus (CCHFV) of 31.4% (999/3181). Seropositivity in cattle was 16.9% and in sheep and goats was 48.8%. Adult and juvenile animals had higher seropositivity compared to recently born animals, and seropositivity was higher in female animals (33.5%) compared to male animals (24.1%). Local breeds had higher (36.8%) compared to exotic (2.8%) and cross breeds (19.3%). Animals that had a history of abortion or stillbirth had higher seropositivity compared to those without a history of abortion or stillbirth. CCHFV seropositivity appeared to be generally higher in northern districts of the country, though spatial trends among sampled districts were not examined. A multivariate regression analysis using a generalized linear mixed model showed that animal species, age, sex, region, and elevation were all significantly associated with CCHFV seropositivity after adjusting for the effects of other model predictors. This study shows that CCHFV is actively circulating in Uganda, posing a serious risk for human infection. The results from this study can be used to help target surveillance efforts for early case detection in animals and limit subsequent spillover into humans.

Opening the Black Box: Agreement and Reliability of a Situational Judgment Test Across Multiple Institutions.

OBJECTIVE: The primary objective of this study was to examine the levels of agreement and reliability of a situational judgment test (SJT) using a diverse pool of pharmacy practice faculty as subject matter experts. Secondary aims included analyses to build support for test validity and fairness. METHODS: An SJT containing 18 scenarios and 118 responses assessing empathy, integrity, and teamwork was developed and delivered to pharmacy practice faculty at 5 schools of pharmacy across the United States. Reliability was assessed by examining internal consistency, inter-rater reliability, and split-half reliability. Only responses which attained an inter-rater agreement>0.7 were included in the final version of the SJT. All responses were scored using a near-miss system, allowing higher scores for answers more closely aligned with the key, which was determined by the faculty who completed the SJT. Test fairness was reported using descriptive statistics. RESULTS: Thirty-nine faculty across the 5 participating institutions completed the SJT. The final version of the SJT included 105 responses, achieving an inter-rater agreement of>0.7 (inter-rater reliability of 0.98). Split-half reliability was 0.72. The average score was 85.7%, and no differences in performance were observed based on demographic characteristics. CONCLUSION: An SJT designed to assess empathy, integrity, and teamwork achieved reasonable levels of reliability among pharmacy practice faculty across the United States, and the results provided initial support for test validity and fairness. These results support a pilot to assess this SJT among students representing multiple institutions.

Guidance for Pharmacy Curricula to Incorporate Health, Wellness, and Health Inequities Stemming From Climate Change: The Report of the 2022-2023 AACP Argus Commission.

The 2022-2023 American Association of College of Pharmacy Argus Commission was charged to provide guidance to schools, curriculum committees, and faculty on how to incorporate health, wellness, and health inequities stemming from climate change into pharmacy curricula. The Argus Commission does not advocate for major changes in the curriculum or standards but suggests a concerted effort across the Academy to enhance the awareness of graduating students of the potential impact of climate change on health both now and in the future. Various examples, along with recommendations and suggestions, are provided of how the impact of climate change on health is currently being integrated into curricula in member schools, as well as a list of resources faculty can use to enhance their awareness of issues related to climate change and health. The Commission was also charged to provide guidance to the American Association of College of Pharmacy regarding future fundraising and business development opportunities. Recommendations in that regard are also included in this report.

Free and Interfacial Boundaries in Individual-Based Models of Multicellular Biological systems.

Coordination of cell behaviour is key to a myriad of biological processes including tissue morphogenesis, wound healing, and tumour growth. As such, individual-based computational models, which explicitly describe inter-cellular interactions, are commonly used to model collective cell dynamics. However, when using individual-based models, it is unclear how descriptions of cell boundaries affect overall population dynamics. In order to investigate this we define three cell boundary descriptions of varying complexities for each of three widely used off-lattice individual-based models: overlapping spheres, Voronoi tessellation, and vertex models. We apply our models to multiple biological scenarios to investigate how cell boundary description can influence tissue-scale behaviour. We find that the Voronoi tessellation model is most sensitive to changes in the cell boundary description with basic models being inappropriate in many cases. The timescale of tissue evolution when using an overlapping spheres model is coupled to the boundary description. The vertex model is demonstrated to be the most stable to changes in boundary description, though still exhibits timescale sensitivity. When using individual-based computational models one should carefully consider how cell boundaries are defined. To inform future work, we provide an exploration of common individual-based models and cell boundary descriptions in frequently studied biological scenarios and discuss their benefits and disadvantages.

Unlocking the hidden value of industrial by-products: Optimisation of bioleaching to extract metals from basic oxygen steelmaking dust and goethite.

In this study, the potential of bioleaching to extract valuable metals from industrial by-products, specifically basic oxygen steelmaking dust (BOS-D) and goethite was investigated. These materials are typically discarded due to their high zinc content and lack of efficient regeneration processes. By using Acidithiobacillus ferrooxidans, successful bioleaching of various metals, including heavy metals, critical metals, and rare earth elements was achieved. The Taguchi orthogonal array design was used to optimise the bioleaching process, considering four variables at three different levels. After 14 days, the highest metal extraction for the BOS-D (11.2 mg Zn/g, 3.2 mg Mn/g, 1.6 mg Al/g, 0.0013 mg Y/g, and 0.0026 mg Ce/g) was achieved at 1% solid concentration, 1% energy source concentration, 1% inoculum concentration, and pH 1.5. For goethite, the optimal conditions were 1% solid concentration, 4% energy source concentration, 10% inoculum concentration, and pH 2 resulting in a extraction of 26.6 mg Zn/g, 2.1 mg/g Mn, 1.8 mg Al/g, 0.01 mg Co/g, 0.0022 mg Y/g. These findings are significant, as they demonstrate the potential to extract valuable metals from previously discarded industrial by-products. The extraction of such metals can have substantial economic and environmental implications, while simultaneously reducing waste in the metallurgical industry. Furthermore, the preservation of initial concentration of iron in both BOS-D and goethite residues represents a significant step towards implementing more sustainable industrial practices.

Cytomegalovirus cyclin-dependent kinase ortholog vCDK/pUL97 undergoes regulatory interaction with human cyclin H and CDK7 to codetermine viral replication efficiency.

Human cytomegalovirus (HCMV) infection is shaped by a tightly regulated interplay between viral and cellular proteins. Distinct kinase activities, such as the viral cyclin-dependent kinase ortholog (vCDK) pUL97 and cellular CDK7 are both crucial for efficient viral replication. Previously, we reported that both kinases, vCDK/pUL97 and CDK7, interact with cyclin H, thereby achieving an enhanced level of kinase activity and overall functionality in viral replication. Here we provide a variety of novel results, as generated on a methodologically extended basis, and present a concept for the codetermination of viral replication efficiency through these kinase activities: (i) cyclin H expression, in various human cell types, is substantially upregulated by strains of HCMV including the clinically relevant HCMV Merlin; (ii) vCDK/pUL97 interacts with human cyclin H in both HCMV-infected and plasmid-transfected cell systems; (iii) a doxycycline-inducible shRNA-dependent knock-down (KD) of cyclin H significantly reduces pUL97 activity (qSox in vitro kinase assay); (iv) accordingly, pUL97 in vitro kinase activity is seen significantly increased upon addition of recombinant cyclin H; (v) as a point of specific importance, human CDK7 activity shows an increase by vCDK/pUL97-mediated trans-stimulation (whereas pUL97 is not stimulated by CDK7); (vi) phosphosite-specific antibodies indicate an upregulated CDK7 phosphorylation upon HCMV infection, as mediated through a pUL97-specific modulatory effect (i.e. shown by pUL97 inhibitor treatment or pUL97-deficient viral mutant); (vii) finally, an efficient KD of cyclin H in primary fibroblasts generally results in an impaired HCMV replication efficiency as measured on protein and genomic levels. These results show evidence for the codetermination of viral replication by vCDK/pUL97, cyclin H and CDK7, thus supporting the specific importance of cyclin H as a central regulatory factor, and suggesting novel targeting options for antiviral drugs.