Temporal and spatial dynamics of Plasmodium falciparum clonal lineages in Guyana.

Plasmodium parasites, the causal agents of malaria, are eukaryotic organisms that obligately undergo sexual recombination within mosquitoes. However, in low transmission settings where most mosquitoes become infected with only a single parasite clone, parasites recombine with themselves, and the clonal lineage is propagated rather than broken up by outcrossing. We investigated whether stochastic/neutral factors drive the persistence and abundance of Plasmodium falciparum clonal lineages in Guyana, a country with relatively low malaria transmission, but the only setting in the Americas in which an important artemisinin resistance mutation (pfk13 C580Y) has been observed. To investigate whether this clonality was potentially associated with the persistence and spatial spread of the mutation, we performed whole genome sequencing on 1,727 Plasmodium falciparum samples collected from infected patients across a five-year period (2016-2021). We characterized the relatedness between each pair of monoclonal infections (n=1,409) through estimation of identity by descent (IBD) and also typed each sample for known or candidate drug resistance mutations. A total of 160 clones (mean IBD ≥ 0.90) were circulating in Guyana during the study period, comprising 13 highly related clusters (mean IBD ≥ 0.40). In the five-year study period, we observed a decrease in frequency of a mutation associated with artemisinin partner drug (piperaquine) resistance (pfcrt C350R) and limited co-occurence of pfcrt C350R with duplications of plasmepsin 2/3, an epistatic interaction associated with piperaquine resistance. We additionally report polymorphisms exhibiting evidence of selection for drug resistance or other phenotypes and reported a novel pfk13 mutation (G718S) as well as 61 nonsynonymous substitutions that increased markedly in frequency. However, P. falciparum clonal dynamics in Guyana appear to be largely driven by stochastic factors, in contrast to other geographic regions. The use of multiple artemisinin combination therapies in Guyana may have contributed to the disappearance of the pfk13 C580Y mutation.

The use of innovative approaches to strengthen health system resilience during the COVID-19 pandemic: case studies from selected Commonwealth countries.

This article is part of the Research Topic 'Health Systems Recovery in the Context of COVID-19 and Protracted Conflict'. The COVID-19 pandemic has exposed the vulnerabilities and limitations of many health systems and underscored the need for strengthening health system resilience to make and sustain progress toward Universal Health Coverage (UHC), global health security and healthier populations in tandem. In response to the COVID-19 pandemic, Commonwealth countries have been practicing a combination of innovative integrated approaches and actions to build health systems resilience. This includes utilizing digital tools, improvements in all-hazard emergency risk management, developing multisectoral partnerships, strengthening surveillance and community engagement. These interventions have been instrumental in strengthening national COVID-19 responses and can contribute to the evidence-base for increasing country investment into health systems resilience, particularly as we look toward COVID-19 recovery. This paper gives perspectives of five Commonwealth countries and their overall responses to the pandemic, highlighting practical firsthand experiences in the field. The countries included in this paper are Guyana, Malawi, Rwanda, Sri Lanka, and Tanzania. Given the diversity within the Commonwealth both in terms of geographical location and state of development, this publication can serve as a useful reference for countries as they prepare their health systems to better absorb the shocks that may emerge in future emergencies.

Automated radiosynthesis of 1-(2-[18 F]fluoroethyl)-L-tryptophan ([18 F]FETrp) for positron emission tomography (PET) imaging of cancer in humans.

The radiotracer 1-(2-[18 F]fluoroethyl)-L-tryptophan (L-[18 F]FETrp or [18 F]FETrp) is a substrate of indoleamine 2,3-dioxygenase, the initial and key enzyme of the kynurenine pathway associated with tumoral immune resistance. In preclinical positron emission tomography studies, [18 F]FETrp is highly accumulated in a wide range of primary and metastatic cancers, such as lung cancer, prostate cancer, and gliomas. However, the clinical translation of this radiotracer into the first-in-human trial has not been reported, partially due to its racemization during radiofluorination which renders the purification of the final product challenging. However, efficient purification is essential for human studies in order to assure radiochemical and enantiomeric purity. In this work, we report a fully automated radiosynthesis of [18 F]FETrp on a Synthra RNPlus research module, including a one-pot two steps radiosynthesis, dual independent chiral and reverse-phase semipreparative high-performance liquid chromatography purifications, and solid-phase extraction-assisted formulation. The presented approach has led to its Investigational New Drug application and approval that allows the testing of this tracer in humans.

Supportive supervisor behavior and helping behaviors in the hotel sector: assessing the mediating effect of employee engagement and moderating influence of perceived organizational obstruction.

While emerging studies pay much attention to the supervisory support-employee performance relationship, the supportive supervisor consequences on employees' attitudes and behaviors have attracted little attention in this relationship. In spite of the growing concern about employees' helping behaviors as a tool that directly benefit coworkers to be work-role focused and improve performance, supportive supervisor behavior that represents the psychological, physical, cognitive, and esteem assistance has also been deemed to be a catalyst of employees' helping behaviors. Also, it is worth noting that employees exhibit helping behaviors when they are highly engaged in work role focus, activation, and positive affect. However, little has been espoused on how supportive behaviors could enhance employees' loyalty to spark helping behaviors. Owing to this narrative, this study draws on social exchange theory and reciprocity norm to examine the mediating role of employee engagement in the effects of supportive supervisor behavior on hotel employees' helping behaviors. Also, this study examined the boundary role of perceived organizational obstruction based on perceived organizational support as proposed by organizational support theory. Using a time lag of six months, a two-wave data were gathered from 461 full‒time frontline employees working in 3-5 star hotels in Ghana. Hierarchical regression was used to analyze the hypothesized relationships. The results demonstrated that supportive supervisor behavior positively related to employees' helping behaviors. Besides, intellectual, social, and affective engagement partly mediated the relationship between supportive manager behavior and employees' helping behavior. Moreover, perceived organizational obstruction moderated the relationship between intellectual engagement and employees' helping behavior. However, failed to moderate social and affective engagement relationships with employees' helping behaviors.

Prognostic Impact of Early Treatment and Oxaliplatin Discontinuation in Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 11 Adjuvant Trials.

PURPOSE: Oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) for 6 months remains a standard in high-risk stage III patients. Data are lacking as to whether early discontinuation of all treatment (ETD) or early discontinuation of oxaliplatin (EOD) could worsen the prognosis. MATERIALS AND METHODS: We studied the prognostic impact of ETD and EOD in patients with stage III CC from the ACCENT/IDEA databases, where patients were planned to receive 6 months of infusional fluorouracil, leucovorin, and oxaliplatin or capecitabine plus oxaliplatin. ETD was defined as discontinuation of treatment and EOD as discontinuation of oxaliplatin only before patients had received a maximum of 75% of planned cycles. Association between ETD/EOD and overall survival and disease-free survival (DFS) were assessed by Cox models adjusted for established prognostic factors. RESULTS: Analysis of ETD and EOD included 10,447 (20.9% with ETD) and 7,243 (18.8% with EOD) patients, respectively. Compared with patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, with Eastern Cooperative Oncology Group performance status ≥ 1, and for ETD, older with a lower body mass index. In multivariable analyses, ETD was associated with a decrease in disease-free survival and overall survival (hazard ratio [HR], 1.61, P < .001 and HR, 1.73, P < .001), which was not the case for EOD (HR, 1.07, P = .3 and HR, 1.13, P = .1). However, patients who received < 50% of the planned cycles of oxaliplatin had poorer outcomes. CONCLUSION: In patients treated with 6 months of oxaliplatin-based chemotherapy for stage III CC, ETD was associated with poorer oncologic outcomes. However, this was not the case for EOD. These data favor discontinuing oxaliplatin while continuing fluoropyrimidine in individuals with significant neurotoxicity having received > 50% of the planned 6-month chemotherapy.

The role of bank financing in economic growth and environmental outcomes of sub-Saharan Africa: evidence from novel quantile regression and panel vector autoregressive models.

In sub-Saharan Africa, economic expansion and its environmental implications have become major problems. The banking system has been described as a mechanism for decoupling economic expansion from environmental implications. However, the function of bank financing in the growth-environmental consequences in SSA remains undeveloped. This study investigated the role of bank financing in economic growth and environmental outcomes in SSA over the period 1990-2018. We implemented the novel panel quantile regression and panel vector autoregressive models in a generalized method of moments' framework to investigate the influence of bank financing on economic growth and carbon emissions, and the moderating effect of bank financing in growth-environmental consequences among the four regional economies in SSA. The empirical results revealed that bank financing (1) increases economic growth and carbon emissions across quantiles; (2) positively influences economic growth and carbon emissions of East and Central African regions but negatively influences economic growth and carbon emissions of the West African region; (3) mitigates growth-emissions outcomes of low-emission countries but worsens growth-emissions outcomes of median and high emission countries; and (4) worsens growth-emissions outcomes of East and Central African regions but mitigates growth-emissions outcomes of Southern and West African sub-regions. The variance decomposition and impulse response results discovered that the role of bank financing in growth-environmental challenges varies in terms of magnitude and elasticities across the sub-regions over the sampled period. The study also revealed mixed findings regarding the existence of the EKC hypothesis for the sub-regional economies in SSA.

Molecular characteristics and clinical outcomes of patients with Neurofibromin 1-altered metastatic colorectal cancer.

Loss-of-function alterations of Neurofibromin 1 (NF1) activate RAS, a driver of colorectal cancer. However, the clinical implications of NF1 alterations are largely unknown. We performed a comprehensive molecular profiling of NF1-mutant colorectal cancer using data from 8150 patients included in a dataset of commercial CLIA-certified laboratory (Caris Life Sciences). In addition, NF1 expression levels were tested for associations with clinical outcomes using data from 431 patients in the CALGB/SWOG 80405 trial. In the Caris dataset, 2.2% of patients had pathogenic or presumed pathogenic NF1 mutations. NF1-mutant tumors more frequently harbored PIK3CA (25.0% vs. 16.7%) and PTEN mutations (24.0% vs. 4.2%) than wild type tumors. Gene set enrichment analysis revealed that MAPK and PI3K pathway signatures were enriched in NF1-mutant tumors. In the CALGB/SWOG 80405 cohort, low NF1 expression was associated with poor prognosis, and high NF1 expression was associated with better efficacy of cetuximab than bevacizumab. Together, we revealed concurrent genetic alterations in the PI3K pathways in NF1-mutant tumors, suggesting the need to simultaneously block MAPK and PI3K pathways in treatment. The potential of NF1 alteration as a novel biomarker for targeted therapy was highlighted, warranting further investigations in clinical settings.

Investigating the Effects of Role Demands, Psychosocial Stress Symptoms and Safety Leadership on Mineworkers' Safety Performance.

PURPOSE: This study aimed to investigate the effects of role demands on safety performance in mining companies under the mediating role of psychosocial stress symptoms. Three dimensions of safety leadership were also tested as moderators on the relationship between psychosocial stress symptoms and safety performance. METHODS: To collect data to analyze the hypothesized relationships in the present study, a total of 850 questionnaires were distributed to mineworkers in Ghana. Hierarchical regression analysis was employed as the main statistical technique in analyzing the data using SPSS version 21 software. FINDINGS: Results from hierarchical regression analysis showed that psychosocial stress symptoms fully mediated the relationship between role demands and safety compliance but showed no mediation on role demands and safety participation. Also, only safety coaching from safety leadership demonstrated to have a moderating effect on the relationship between psychosocial stress symptoms and safety compliance of safety performance. CONCLUSION: The study proposes that it is important to examine the effects of role demands on specific job performance. The importance of safety coaching as a key element of planning to improve safety performance should not be underestimated.

Effects of PGF2alpha on human melanocytes and regulation of the FP receptor by ultraviolet radiation.

Prostaglandins are potent lipid hormones that activate multiple signaling pathways resulting in regulation of cellular growth, differentiation, and apoptosis. In the skin, prostaglandins are rapidly released by keratinocytes following ultraviolet radiation and are chronically present in inflammatory skin lesions. We have shown previously that melanocytes, which provide photoprotection to keratinocytes through the production of melanin, express several receptors for prostaglandins, including the PGE2 receptors EP1 and EP3 and the PGF2alpha receptor FP, and that PGF2alpha stimulates melanocyte dendricity. We now show that PGF2alpha stimulates the activity and expression of tyrosinase, the rate-limiting enzyme in melanin synthesis. Analysis of FP receptor regulation showed that the FP receptor is regulated by ultraviolet radiation in melanocytes in vitro and in human skin in vivo. We also show that ultraviolet irradiation stimulates production of PGF2alpha by melanocytes. These results show that PGF2alpha binding to the FP receptor activates signals that stimulate a differentiated phenotype (dendricity and pigmentation) in melanocytes. The regulation of the FP receptor and the stimulation of production of PGF2alpha in melanocytes in response to ultraviolet radiation suggest that PGF2alpha could act as an autocrine factor for melanocyte differentiation.

Experimental and Theoretical Evidence for a Concerted Catalysis by Water Clusters in the Hydrolysis of Isocyanates.

A kinetic and mechanistic investigation of the catalyzed hydration of isocyanates was undertaken. Both experimental and theoretical results showed that the hydrolysis reaction involves a chain of water molecules. The detailed hydration mechanism by water and water clusters (H-N=C=O + n(H(2)O) --> H(2)NCOOH + (n - 1)H(2)O, n = 1-3) has been modeled by ab initio methods, both in the gas phase and in aqueous solution. While two water molecules in the form of a dimer seem to play the key role in hydrating the isocyanate, a third water molecule may be needed to bridge the gap from the point of attack on the isocyanate to the water dimer and to facilitate further the hydration. In accordance with these facts, experimental results imply a second-order dependence on water during its nucleophilic addition to phenyl isocyanate, over a wide concentration range. In this specific case, water oligomers higher than the dimer seem to make no appreciable contribution to the rate of the hydrolysis reaction. The nucleophilic addition occurs in a concerted way across the N=C bond of the isocyanate rather than across the C=O bond. This preferential reaction mechanism could be rationalized in terms of Fukui functions for both nucleophilic and electrophilic attacks. Although a charge separation occurs in the transition state, electrostatic solvent effects are not quite important in reducing only marginally the energy barriers.

The Alcoholysis Reaction of Isocyanates Giving Urethanes: Evidence for a Multimolecular Mechanism.

A kinetic and mechanistic investigation of the catalyzed alcoholysis of isocyanates was undertaken. Both experimental and theoretical results showed that the alcoholysis should be understood by a multimolecular intervention of the alcohols. The alcoholysis of isocyanate was examined experimentally for 2-propanol and cyclohexanol in low and high concentrations. It is suggested that either two or three molecules of the alcohol are implicated from the kinetic study, while the reaction with trimers becomes dominant at high alcohol concentrations. In accordance with these results, theoretical study suggests an active participation of at least three alcohol molecules in a reacting supersystem, giving rise to a genuine effect. The detailed reaction mechanism for the alcoholysis reaction by methanol and methanol clusters (HN=C=O + n(CH(3)OH), n = 1-3) was modeled by ab initio methods, both in the gas phase and in solution. The nucleophilic addition occurs in a concerted way across the N=C bond of the isocyanate rather than across the C=O, similar to the isocyanate hydrolysis. The bulk solvent effect, which is treated by a polarizable continuum model (PCM), does not affect the preference of the alcohol to attack across the N=C bond as pointed out by the gas-phase values.