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Abstract The use of herbal products for the treatment of malaria, has increased globally. However, inadequate scientific studies about the safety and effectiveness of such herbal products have been raised. Also, the reduced sensitivity of the malaria parasites to artemisinin-based combination therapies is of concern. There is therefore the need for new antimalarial medications including those from alternative sources such as herbal medicinal products. In this study, a prospective, comparative parallel group randomized, clinical study was done to assess the safety and effectiveness of Mist Amen Fevermix and Mist Edhec Malacure with Artemether/Lumefantrine as control at the Tafo Government Hospital, Kumasi between July and November 2019, after Committee on Human Research, Publication and Ethics approval (CHRPE/AP/424/19). The study was conducted in accordance with Good Clinical and Laboratory Practice (GCLP) and registered with the Pan African Clinical Trials Registry with trial number PACTR202109664146698. Participant completed an informed consent form. Randomization was based on a single sequence to allocate participants to a group. SPSS version 19. One-way ANOVA test and exploratory statistics was used for data analysis. Total sample size was 150 participants with 50 on each arm of the group. Male and female patients aged 15–45 years and meet inclusion criteria with clinically established malaria were treated with Mist Amen Fevermix and Mist Edhec Malacure, at the specified doses of 45 mls (0.1063 g) and 30 mls (0.0521 g) three times daily after meals for three days. Artemether/Lumefantrine was administered at a dose of 80/480 mg/kg twice daily after meals for three days. Baseline data was taken on day 0. Patients were then followed up on Day 3, 7 and 28 to establish treatment outcomes and any side effect using a checklist for signs and symptoms and Karnofsky’s scale to assess the quality of life. Mist Amen Fevermix was effective with a cure rate of 95.89%. Mist Edhec Malacure was also effective with a cure rate of 91.87%. The cure rate of Artemether/Lumefantrine was 97.25%. Kidney and liver panels were within normal reference range at the end of the 28-day study. This study supports the use of Mist Amen Fevermix and Mist Edhec Malacure, two multi-component products as safe and effective for the treatment of uncomplicated malaria. Both products achieved a comparable clinical treatment outcome with Artemether/Lumefantrine.

Abstract Terminally differentiated cells are commonly regarded as the most stable cell state in adult organisms, characterized by growth arrest while fulfilling their specialized functions. A better understanding of the mechanisms involved in promoting cell cycle exit will improve the ability to differentiate pluripotent cells into mature tissues for both pharmacological and therapeutic use. Here, it demonstrates that a hyperosmolar environment enforces a protective p53‐independent quiescent state in immature hepatoma cells and in pluripotent stem cell‐derived models of human hepatocytes and endothelial cells. Prolonged culture in hyperosmolar conditions stimulates changes in gene expression promoting functional cell maturation. Interestingly, hyperosmolar conditions do not only trigger growth arrest and cellular maturation but are also necessary to maintain this maturated state, as switching back to plasma osmolarity reverses the changes in expression of maturation and proliferative markers. Transcriptome analysis revealed sequential stages of osmolarity‐regulated growth arrest followed by cell maturation, mediated by activation of NF‐κВ, and repression of WNT signaling, respectively. This study reveals that a modulated increase in osmolarity serves as a biochemical signal to promote long‐term growth arrest and cellular maturation into different lineages, providing a practical method to generate differentiated hiPSCs that resemble their mature counterpart more closely.

Considering procurement process performance assessment, measurement systems such as balance scorecard and capability maturity models are used to assess procurement performance to give a reasonable indication of actual performance. These tools are ideal for practical applications that depend on other performance criteria but are short of comparing planned to actual timelines set for procurement processes. This fosters persistent delays in public procurement. Six Sigma implementation benefits including addressing process delays have fostered its implementation for service improvements. Unfortunately, Six Sigma implementation in public procurement is very rare largely due to its expensive nature. The objective of this study is to develop a Procurement Delay Index (PDindex): a performance measure in the context of a Six Sigma methodology that provides a specific value to describe the delays in the procurement process. To enhance uniformity in performance measurement of process timeliness, a rating scale for determining the timeliness of the procurement process is proposed. A practical demonstration of the application of PDindex for use by procurement professionals is also presented. PDindex serves as a standard by which to determine procurement processes’ timeliness and is less expensive to implement. A PDindex of 3σ has been recommended as the acceptable limit for procurement process delays.

Background: Mist Campa-T (MCT) is a mono-herbal formulation has gained popularity in Ghana for its acclaimed effectiveness in improving sexual function in men. Its main active ingredient is Thoningia sanguinea, a plant known for its aphrodisiac property in folk medicine. This research focused on investigating the aphrodisiac effect of (MCT) and its toxicological profile. Methods: The effect of MCT on sexual function was investigated by the mounting and mating frequency assays followed by serum testosterone and sperm analysis. The toxicological assessment was performed by the acute and sub-acute toxicity assays. Microbial load and elemental/heavy metal content analysis of the product was ascertained. Results: MCT (250, 500, 1000 mg/kg/day) exhibited significant (P ≤ 0.0001) increase in mounting and mating frequencies, in male rats. There was a significant (P ≤ 0.0001) rise in testosterone level for the MCT-treated rats. The LD50 of Mist Campa-T was found to be above 2000 mg/kg bodyweight. There was no significant variation (P > 0.05) in haematological indices as well as renal or hepatic enzymes in the treated groups compared to the untreated group after 28 days of treatment with MCT. There was a notable increase (P

Abstract Although human pluripotent stem cell (PSC)‐derived brain organoids have enabled researchers to gain insight into human brain development and disease, these organoids contain solely ectodermal cells and are not vascularized as occurs during brain development. Here it is created less complex and more homogenous large neural constructs starting from PSC‐derived neuroprogenitor cells (NPC), by fusing small NPC spheroids into so‐called concentroids. Such concentroids consisted of a pro‐angiogenic core, containing neuronal and outer radial glia cells, surrounded by an astroglia‐dense outer layer. Incorporating PSC‐derived endothelial cells (EC) around and/or in the concentroids promoted vascularization, accompanied by differential outgrowth and differentiation of neuronal and astroglia cells, as well as the development of ectodermal‐derived pericyte‐like mural cells co‐localizing with EC networks. Single nucleus transcriptomic analysis revealed an enhanced neural cell subtype maturation and diversity in EC‐containing concentroids, which better resemble the fetal human brain compared to classical organoids or NPC‐only concentroids. This PSC‐derived “vascularized” concentroid brain model will facilitate the study of neurovascular/blood‐brain barrier development, neural cell migration, and the development of effective in vitro vascularization strategies of brain mimics.

Abstract Vaginal birth causes pelvic floor injury which may lead to urinary incontinence. Cell therapy has been proposed to assist in functional recovery. We aim to assess if intra-arterial injection of rat mesoangioblasts (MABs) and stable Vascular Endothelial Growth Factor (VEGF)-expressing MABs, improve recovery of urethral and vaginal function following simulated vaginal delivery (SVD). Female rats (n = 86) were assigned to either injection of saline (control), allogeneic-MABs (MABsallo), autologous-MABs (MABsauto) or allogeneic-MABs transduced to stably expressed VEGF (MABsallo-VEGF). One hour after SVD, 0.5 × 106 MABs or saline were injected into the aorta. Primary outcome was urethral (7d and 14d) and vaginal (14d) function; others were bioluminescent imaging for cell tracking (1, 3 and 7d), morphometry (7, 14 and 60d) and mRNAseq (3 and 7d). All MABs injected rats had external urethral sphincter and vaginal function recovery within 14d, as compared to only half of saline controls. Functional recovery was paralleled by improved muscle regeneration and microvascularization. Recovery rate was not different between MABsallo and MABsauto. MABsallo-VEGF accelerated functional recovery and increased GAP-43 expression at 7d. At 3d we detected major transcriptional changes in the urethra of both MABsallo and MABsallo-VEGF-injected animals, with upregulation of Rho/GTPase activity, epigenetic factors and dendrite development. MABSallo also upregulated transcripts that encode proteins involved in myogenesis and downregulated pro-inflammatory processes. MABsallo-VEGF also upregulated transcripts that encode proteins involved in neuron development and downregulated genes involved in hypoxia and oxidative stress. At 7d, urethras of MABsallo-VEGF-injected rats showed downregulation of oxidative and inflammatory response compared to MABSallo. Intra-arterial injection of MABsallo-VEGF enhances neuromuscular regeneration induced by untransduced MABs and accelerates the functional urethral and vaginal recovery after SVD.

Signal transduction and gene expression regulation via downstream transcription factors shape the early mammalian embryo. Here the authors show that Wnt/TCF7L1 transcriptional repressive activity is required for primitive endoderm lineage formation.

ABSTRACT: Background: Motor function in patients with spinal metastatic disease (SMD) directly impacts a patient's ability to receive systemic therapy and overall survival. Spine surgeons may be in the challenging position to advise a patient on expected motor function outcomes and determine a patient's suitability as a surgical candidate. We present this study to provide this critical information on anticipated motor function change to spine surgeons. Methods: Consecutive patients undergoing spinal surgery for SMD at a National Cancer Institute-designated cancer institute were prospectively enrolled. Patient motor function status before and after surgery was assessed using the standard 0 to 5 five-point muscle strength grading scale. The difference in presurgical and postsurgical motor function (proximal and distal) was used to assess motor function changes following surgery. Results: A total of 171 patients were included. The mean age was 62.7±10.46 years and 40.9% (70) were female. Common primary malignancy types were lung (49), kidney (28), breast (25), and prostate (23). The average proximal and distal motor function difference was 0.38 (standard deviation=1.02, p

Abattoirs are facilities where livestock are slaughtered and are an important aspect in the food production chain. There are several types of abattoirs, which differ in infrastructure and facilities, sanitation and PPE practices, and adherence to regulations. In each abattoir facility, worker exposure to animals and animal products increases their risk of infection from zoonotic pathogens. Backyard abattoirs and slaughter slabs have the highest risk of pathogen transmission because of substandard hygiene practices and minimal infrastructure. These abattoir conditions can often contribute to environmental contamination and may play a significant role in disease outbreaks within communities. To assess further the risk of disease, we conducted a scoping review of parasites and pathogens among livestock and human workers in abattoirs across 13 Eastern African countries, which are hotspots for zoonoses. Our search results (n = 104 articles) showed the presence of bacteria, viruses, fungi, and macroparasites (nematodes, cestodes, etc.) in cattle, goats, sheep, pigs, camels, and poultry. Most articles reported results from cattle, and the most frequent pathogen detected was Mycobacterium bovis, which causes bovine tuberculosis. Some articles included worker survey and questionnaires that suggested how the use of PPE along with proper worker training and safe animal handling practices could reduce disease risk. Based on these findings, we discuss ways to improve abattoir biosafety and increase biosurveillance for disease control and mitigation. Abattoirs are a ‘catch all’ for pathogens, and by surveying animals at abattoirs, health officials can determine which diseases are prevalent in different regions and which pathogens are most likely transmitted from wildlife to livestock. We suggest a regional approach to biosurveillance, which will improve testing and data gathering for enhanced disease risk mapping and forecasting. Next generation sequencing will be key in identifying a wide range of pathogens, rather than a targeted approach.

Abstract Biomaterials can control cell and nuclear morphology. Since the shape of the nucleus influences chromatin architecture, gene expression and cell identity, surface topography can control cell phenotype. This study provides fundamental insights into how surface topography influences nuclear morphology, histone modifications, and expression of histone‐associated proteins through advanced histone mass spectrometry and microarray analysis. The authors find that nuclear confinement is associated with a loss of histone acetylation and nucleoli abundance, while pathway analysis reveals a substantial reduction in gene expression associated with chromosome organization. In light of previous observations where the authors found a decrease in proliferation and metabolism induced by micro‐topographies, they connect these findings with a quiescent phenotype in mesenchymal stem cells, as further shown by a reduction of ribosomal proteins and the maintenance of multipotency on micro‐topographies after long‐term culture conditions. Also, this influence of micro‐topographies on nuclear morphology and proliferation is reversible, as shown by a return of proliferation when re‐cultured on a flat surface. The findings provide novel insights into how biophysical signaling influences the epigenetic landscape and subsequent cellular phenotype.

Skeletal muscle holds an intrinsic capability of growth and regeneration both in physiological conditions and in case of injury. Chronic muscle illnesses, generally caused by genetic and acquired factors, lead to deconditioning of the skeletal muscle structure and function, and are associated with a significant loss in muscle mass. At the same time, progressive muscle wasting is a hallmark of aging. Given the paracrine properties of myogenic stem cells, extracellular vesicle-derived signals have been studied for their potential implication in both the pathogenesis of degenerative neuromuscular diseases and as a possible therapeutic target. In this study, we screened the content of extracellular vesicles from animal models of muscle hypertrophy and muscle wasting associated with chronic disease and aging. Analysis of the transcriptome, protein cargo, and microRNAs (miRNAs) allowed us to identify a hypertrophic miRNA signature amenable for targeting muscle wasting, consisting of miR-1 and miR-208a. We tested this signature among others in vitro on mesoangioblasts (MABs), vessel-associated adult stem cells, and we observed an increase in the efficiency of myogenic differentiation. Furthermore, injections of miRNA-treated MABs in aged mice resulted in an improvement in skeletal muscle features, such as muscle weight, strength, cross-sectional area, and fibrosis compared to controls. Overall, we provide evidence that the extracellular vesicle-derived miRNA signature we identified enhances the myogenic potential of myogenic stem cells.

Radish (Raphanus sativus L.), an important root vegetable crop of the Brassicaceae family, has a high level of anthocyanin accumulation in its pigment root tissues. It was reported that MYB transcription factors (TFs) play vital roles in plant development and anthocyanin metabolism, and the PAP1/2 could promote expression of anthocyanin biosynthesis genes. In this study, a total of 187 radish MYB genes (RsMYBs) were identified in the radish genome and clustered into 32 subfamilies. Among them, 159 RsMYBs were localized on nine radish chromosomes. Interestingly, 14 RsMYBs exhibited differential expression profiles in different taproot developmental stages among four differently colored radish lines. A number of RsMYBs were highly expressed in the pigmented root tissues at the maturity stage, several genes including RsMYB41, RsMYB117, and RsMYB132 being homologous to PAP1/2, showed high expression levels in the red skin of NAU-YH (red skin-white flesh) taproot, while RsMYB65 and RsMYB159 were highly expressed in the purple root skin of NAU-YZH (purple skin-red flesh), indicating that these RsMYBs might positively regulate the process of anthocyanin accumulation in radish taproot. These results would provide valuable information for further functional characterization of RsMYBs, and facilitate clarifying the molecular mechanism underlying anthocyanin biosynthesis in radish.

Globally, biosecurity is instrumental in prevention, control and management of livestock diseases and protection of human health. It is defined, prescribed, adopted and enforced through global, regional and national frameworks, laws, policies and strategies. There is more biosecurity practice research conducted in developed countries than developing ones. Consequently, the gap between the ideals recommended in biosecurity frameworks and what is practical in under-resourced rural settings is poorly understood. This anthropological study sought to assess adoption of biosecurity practices across a cattle, sheep and goat value chains continuum to demonstrate where risks lie. The cross-sectional mixed-methods study took place in Baringo County, Kenya. Qualitatively, it utilized 26 focus group discussions with community members and 10 observational interviews with slaughter facility workers. Quantitatively, it included a household survey with 560 community members and a separate survey with 231 livestock traders. Results show that producers, traders and slaughter facility workers did observe some biosecurity practices but not others due but not limited to personal preference, limitations in veterinary service delivery and enforcement of some biosecurity measures, and lack of requisite infrastructure. The study concludes that the implementation of biosecurity measures in rural settings is more complex than envisioned in biosecurity policies and frameworks. It can be hampered by resource limitations, poor enforcement, and contestations with cultural practices. The study recommends that further studies on willingness to adopt biosecurity measures targeting community members in under-resourced settings be conducted to identify possible critical points of intervention at county and national levels.

Despite advances in techniques, methods, and theory, northeastern North American archaeologists continue to use early to mid-twentieth century culture historical taxa as units of analysis and narrative. There is a distinct need to move away from this archaeological practice to enable fuller understandings of past human lives. One tool that enables such a move is Bayesian analysis of radiocarbon dates, which provides a means of constructing continuous chronologies. A large dataset of radiocarbon dates for late prehistoric (ca AD 900/1000-1650) sites in the lower upper Ohio River basin in southwestern Pennsylvania and adjacent portions of Maryland, Ohio, and West Virginia is used here as an example. The results allow a preliminary assessment of how the settlement plans of contemporaneous villages varied considerably, reflecting decisions of the village occupants how to structure built environments to meet their needs.

Triple-Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype, characterized by limited treatment options and higher relapse rates than hormone-receptor-positive breast cancers. Chemotherapy remains the mainstay treatment for TNBC, and platinum salts have been explored as a therapeutic alternative in neo-adjuvant and metastatic settings. However, primary and acquired resistance to chemotherapy in general and platinum-based regimens specifically strongly hampers TNBC management. In this study, we used carboplatin-resistant in vivo patient-derived xenograft and isogenic TNBC cell-line models and detected enhanced Wnt/β-catenin activity correlating with an induced expression of stem cell markers in both resistant models. In accordance, the activation of canonical Wnt signaling in parental TNBC cell lines increases stem cell markers’ expression, formation of tumorspheres and promotes carboplatin resistance. Finally, we prove that Wnt signaling inhibition resensitizes resistant models to carboplatin both in vitro and in vivo, suggesting the synergistic use of Wnt inhibitors and carboplatin as a therapeutic option in TNBC. Here we provide evidence for a prominent role of Wnt signaling in mediating resistance to carboplatin, and we establish that combinatorial targeting of Wnt signaling overcomes carboplatin resistance enhancing chemotherapeutic drug efficacy.

Saroj Vadhan-Raj,1 Naomi V Dahl,2 Kristine Bernard,2 Zhu Li,2 William E Strauss2 1Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA; 2AMAG Pharmaceuticals, Inc., Waltham, MA, USA Purpose: Iron deficiency anemia (IDA) is common in cancer patients due to blood loss and inflammation. Many do not tolerate oral iron or adequately respond. Intravenous (IV) iron is commonly used as an adjunct to erythropoiesis-stimulating agents; data on the use of IV iron monotherapy in these patients are limited. This study aimed to evaluate IV ferumoxytol for the treatment of cancer patients with IDA with a history of unsatisfactory oral iron therapy or in whom oral iron could not be used. Patients and methods: This post hoc analysis of pooled data from two multicenter, randomized, controlled, Phase III trials evaluating IV ferumoxytol (510 mg ×2) vs placebo or iron sucrose (200 mg ×5) included a subgroup of 98 patients with cancer that the investigator identified as the primary cause of their IDA, or with cancer whose IDA was attributed to another comorbid condition (ferumoxytol, n=75; iron sucrose, n=13; placebo, n=10). Gastrointestinal cancers were most common (42), followed by breast (14), cervix (ten), and lung (nine). The primary endpoint was the mean change in hemoglobin (Hgb) from baseline to week 5. Results: At week 5, both ferumoxytol and iron sucrose produced significant increases in Hgb from baseline (1.8 g/dL [P20% nor initiated in any treatment group. Overall rates of adverse events and serious adverse events in the cancer subgroup mirrored those in the overall study population. Conclusion: Monotherapy with IV iron appears to be an effective option for cancer patients with IDA who do not respond to or cannot tolerate oral iron therapy. Keywords: anemia, cancer, ferumoxytol, hemoglobin, efficacy, intravenous iron

N Franklin Adkinson,1 William E Strauss,2 Kristine Bernard,2 Robert F Kaper,2 Iain C Macdougall,3 Julie S Krop2 1Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2AMAG Pharmaceuticals, Inc., Waltham, MA, USA; 3Department of Renal Medicine, King’s College Hospital, London, UK Background: Intravenous (IV) iron is often used to treat iron deficiency anemia in patients who are unable to tolerate or are inadequately managed with oral iron. However, IV iron treatment has been associated with acute hypersensitivity reactions. The comparative risk of adverse events (AEs) with IV iron preparations has been assessed by a few randomized controlled trials, which are most often limited by small patient numbers, which lack statistical power to identify differences in low-frequency AE such as hypersensitivity reactions.Materials and methods: Ferumoxytol versus Ferric Carboxymaltose for the Treatment of Iron Deficiency Anemia (FIRM) is a randomized, double-blind, international, multicenter, Phase III study designed to compare the safety of ferumoxytol and ferric carboxymaltose (FCM). The study includes adults with hemoglobin

This article examines the missionary and educational work and impact of Kenneth Spooner, an African-American missionary among the BaFokeng African community in Rustenburg district, South Africa from 1915 to 1937. Originally from Barbados, Spooner immigrated to the USA from where he came to South Africa as an International Pentecostal Holiness Church (IPHC) missionary. Spooner’s church became very popular among the African communities of Rustenburg. His school, for example, for the first time in the region used English as a medium of teaching, unlike the much older German Lutheran Church school’s teaching medium of Setswana; in the mid-1910s in rural South Africa, a black man preaching only in English, with another black person interpreting into an African language, was a spectacle – and another of Spooner’s draw-cards. The article situates Spooner and his work in the sociopolitical context of agitation by white politicians for more and stronger racial discrimination and segregation.

Fatigue increases the risk of injury during sports training and rehabilitation. Early detection of fatigue during exercises would help adapt the training in order to prevent over-training and injury. This study lays the foundation for a data-driven model to automatically predict the onset of fatigue and quantify consequent fatigue changes using a force plate (FP) or inertial measurement units (IMUs). The force plate and body-worn IMUs were used to capture movements associated with exercises (squats, high knee jacks, and corkscrew toe-touch) to estimate participant-specific fatigue levels in a continuous fashion using random forest (RF) regression and convolutional neural network (CNN) based regression models. Analysis of unseen data showed high correlation (up to 89%, 93%, and 94% for the squat, jack, and corkscrew exercises, respectively) between the predicted fatigue levels and self-reported fatigue levels. Predictions using force plate data achieved similar performance as those with IMU data; the best results in both cases were achieved with a convolutional neural network. The displacement of the center of pressure (COP) was found to be correlated with fatigue compared to other commonly used features of the force plate. Bland–Altman analysis also confirmed that the predicted fatigue levels were close to the true values. These results contribute to the field of human motion recognition by proposing a deep neural network model that can detect fairly small changes of motion data in a continuous process and quantify the movement. Based on the successful findings with three different exercises, the general nature of the methodology is potentially applicable to a variety of other forms of exercises, thereby contributing to the future adaptation of exercise programs and prevention of over-training and injury as a result of excessive fatigue.