Search Results (73)

Cutaneous leishmaniasis is a protozoan disease which is responsible for significant morbidity in humans. Currently, there is no clinically approved vaccine to prevent infections, and, therefore, treatments to cure skin lesions are required. Ideally, a treatment that can be self-administered to affected areas is desirable. In this study, the effect of violet-blue light, of wavelength in the region of 405 nm, on the survival of Leishmania major and Leishmania mexicana was determined using in vitro and in vivo models. Light treatment caused significant killing of both promastigotes and intracellular amastigotes (p < 0.001) of both species in vitro, and L. mexicana intracellular amastigotes were more resistant to light treatment than L. major intracellular amastigotes. Treatment with violet-blue light at a dose of 45 J/cm² (0.15 W/cm² for 5 min) per day on days 3–7 post-infection in an in vivo footpad model caused a significant reduction in L. major parasite burdens on day 5 post-infection (p < 0.05) in one of two experiments, though by day 10 post-infection, parasite numbers had recovered to those of controls. The results of this study clearly demonstrate that violet-blue light can kill both L. major and L. mexicana parasites, but application to infected cutaneous tissues requires refinement. Full article

In November 2024, a two-day meeting entitled “PBBM—Best Scientific Practices to Define Drug Product Performance: Latest Regulatory and Industry Perspectives” was organised by the Academy of Pharmaceutical Sciences Biopharmaceutics Focus group and hosted by MHRA in London, UK. Physiologically based biopharmaceutics modelling, referred to as PBBM, is used to inform drug product quality strategies and provide a more detailed understanding of how medicines can interact with the human body. Industrial, academic, regulatory, and software company scientists came together to discuss the latest developments in PBBM and to debate key topics relevant to the establishment of best practices and improved implementation. Case study presentations and breakout sessions highlighted how companies are using PBBM in their portfolio decision-making (early development through post-approval changes). Discussions highlighted how the exploration of drug product quality risks has evolved over time, moving from the more empirical BCS classification approach to a more detailed in vivo and mechanistic understanding, where sponsors have and continue to invest in building clinical drug product knowledge. Regulatory scientists shared how they are building experience in using PBBM to set clinically relevant drug product quality specifications, including how they would like to see the area grow in the future. Although significant progress has certainly been made in this field over the last 10 years, the need to continue to bring industry and regulators closer together in the future remains a key topic. Guideline evolution, training and continued dialogue will be essential in reaching a harmonised approach to the use of PBBM to develop drug product strategies and set quality specifications. Full article

Background/Objectives: Prostate cancer is the most commonly diagnosed cancer in men and a leading cause of cancer-related mortality, highlighting the need for delivery systems capable of efficiently transporting both chemotherapeutic drugs and therapeutic genes to tumor cells. Generation-3 diaminobutyric polypropylenimine (DAB) dendrimers display low toxicity, high drug loading capacity and efficient gene delivery, and can be engineered as camptothecin-bearing PEGylated carriers complexed with plasmid DNA. The aim of this study was to compare microfluidic processing with conventional hand mixing for the preparation of camptothecin-bearing PEGylated DAB dendriplexes and to evaluate the impact of formulation methods and microfluidic parameters on their physicochemical properties, cellular uptake and gene expression in prostate cancer cells. Methods: Camptothecin-bearing PEGylated DAB dendrimers were synthesized and complexed with plasmid DNA to form dendriplexes. Formulations were prepared either by microfluidics, using different total flow rates and aqueous: organic flow rate ratios, or by conventional hand mixing. The resulting dendriplexes were characterized for DNA condensation, particle size, polydispersity index and zeta potential. Morphology was assessed by transmission electron microscopy. Cellular uptake of fluorescein-labelled DNA and β-galactosidase reporter gene expression were evaluated in PC3-Luc and DU145 prostate cancer cells. Results: Both microfluidic and hand-mixed methods produced stable, nanosized, positively charged dendriplexes with efficient and sustained DNA condensation (more than 99% over 24 h). Microfluidic processing, particularly at an aqueous: organic flow rate ratio of 3:1, yielded dendriplexes with hydrodynamic diameters and zeta potentials comparable to or slightly improved over hand-mixed formulations. These microfluidic conditions significantly enhanced cellular uptake in both PC3-Luc and DU145 cells. In PC3-Luc cells, this translated into β-galactosidase expression levels comparable to hand-mixed dendriplexes and higher than naked DNA, whereas in DU145 cells, transfection efficiencies remained modest for all formulations despite increased uptake. Conclusions: Microfluidic processing enables the reproducible and scalable preparation of camptothecin-bearing PEGylated DAB dendriplexes with tunable physicochemical properties. Under selected conditions, in vitro cellular uptake and gene expression were comparable to conventional hand mixing, supporting microfluidics as a robust alternative platform for the manufacture of dendrimer-based systems for combined chemo–gene delivery in prostate cancer. Full article

While there is extensive literature on the strengths of different supervisory models, we have limited understanding of how the relational capacity of front-line staff may impact how they receive and seek feedback from their supervisor. This study examines how mental health providers’ and front-line staff’s own rejection sensitivity may be associated with the supervisory relationship and the ways in which job feedback is sought and received in community-based mental health settings. Cross-sectional survey data were collected from 156 front-line staff of three mental health agencies. Staff were administered an original survey using validated measures related to supervision, feedback, and relational capacities. We found staff with a higher rejection sensitivity (RS) were less likely to actively seek feedback about their performance; and, when feedback was received, were more likely to rate its quality as poor. Staff with a higher RS were more likely to perceive their supervisor and their relationship negatively. This is the first study to examine whether workers’ relational capacities, as expressed through a higher RS, influence their perceptions of supervision and quality of feedback and their feedback-seeking behaviors. These findings build theory related to the important role that staff relational capacities play in influencing organizational dynamics and support. Full article

Background: Glioblastoma (GBM) is an aggressive brain tumor, with surgery being an integral part of treatment. Aggressive resections improve clinical outcomes but need to be balanced against potential functional impairment. Neuropsychological (NP) testing is an important tool neurosurgeons use to assess cognitive functioning. Importantly, associations between NP test scores and imaging biomarkers could enable a testable baseline by which to track patient outcomes over time and aid in presurgical counseling. Methods: We identified 44 patients diagnosed with primary GBM and who had detailed NP testing and presurgical imaging. Regression models for NP indices were created with tumor size, hemisphere, and lobar location as predictors. Lesion–symptom mapping (LSM) analyses were used to identify more detailed structure–function relationships. Results: Larger tumor volumes predicted worse attention, immediate memory, language, visuospatial, and overall NP performance (p < 0.05 for all). Left hemisphere involvement predicted worse attention, language, and immediate memory NP performance (p < 0.01 for all). Only visuospatial testing had lobar location significantly associated with worse scores (occipital lobe; p < 0.05). The LSM analyses identified areas around the left sagittal stratum as significantly associated with language performance (p < 0.05), with no other structure–function relationships being identified. Conclusions: These findings support the growing evidence that outside of a small number of truly critical regions, high-grade gliomas impair cognition generally, likely due to progressive tumor infiltration-associated neuroplasticity of complex parallel and interconnected networks. To investigate this, future studies should incorporate larger cohort sizes and should examine the relationship of glioma-induced network-level perturbations on cognitive decline. Full article

Elevated chloride (Cl⁻) concentrations in surface water and groundwater are an increasing concern in cold region urban environments, largely due to long-term road salt application. This study investigates the Cl⁻ distribution across southern Ontario, Canada, using geospatial methods to identify contamination hot spots and assess groundwater vulnerability at both regional and watershed scales. Chloride data from 2001 to 2010 and 2011 to 2020 were compiled from public sources and interpolated using inverse distance weighting. A regional-scale vulnerability index was developed using slope (SL), surficial geology (SG), and land use (LU) (SL-SG-LU), and compared it to a more detailed DRASTIC-LU index within the Credit River watershed. Results show that Cl⁻ hot spots are concentrated in urbanized areas, including the Greater Toronto Area and Golden Horseshoe, with some rural zones also exhibiting elevated concentrations. Vulnerability mapping corresponded well with the observed Cl⁻ patterns and highlighted areas at risk for groundwater discharge to surface waters. While the DRASTIC-LU method offered finer resolution, the simplified SL-SG-LU index effectively captured broad vulnerability trends and is suitable for data-limited regions. This work provides a transferable framework for identifying Cl⁻ risk areas and supports long-term monitoring and management strategies in cold climate watersheds. Full article

Background: The average fibre consumption of 4–10-year-old children in the UK is 14.6 g per day, with only 14% of these children reaching the 20 g recommended by the SACN (UK Scientific Advisory Committee on Nutrition), and this ‘fibre gap’ may be most pronounced in communities with the lowest socioeconomic status. School breakfast clubs target children from disadvantaged communities, but their provision may favour lower-fibre foods, due to perceptions that children will reject higher-fibre foods. Our research programme aims to increase the fibre density, digestive-metabolic quality and acceptability of school breakfast provision. Methods: In Study 1, we examined the in vitro digestion of four novel bread products, to determine the relationship between fibre content and glucose release profile, and assess their suitability for sustaining school activity. In Study 2, we introduced the Prograins breads, alongside higher-fibre breakfast cereals and fresh fruit, to primary school breakfast clubs. Results: The Prograins bread products yielded lower peaks and more sustained glucose release curves than the ‘standard’ white bread control. Many children liked and chose the intervention foods, and the average fibre content of children’s breakfasts increased. Conclusions: We conclude from this study that nutritious, fibre-rich bread products can be acceptable to children and that higher-fibre breakfast provision is feasible, and we recommend larger-scale intervention and assessment to validate these real-world findings. Full article

This study examines how Ibn Arabi’s metaphysics can address key challenges in the contemporary philosophical debate on the problem of evil. John Mackie famously argues that the existence of an omnibenevolent and omnipotent God is logically incompatible with the existence of evil, suggesting that theism must relinquish one of these divine attributes to resolve this contradiction. Alvin Plantinga, through his Free Will Defense, demonstrates that no logical contradiction undermines the coherence of the theistic conception of God. Although Mackie concedes this point, he contends that Plantinga’s defense does not sufficiently explain why God permits evil. With the resolution of the logical problem of evil, the evidential problem has gained prominence in the theistic debate, where Plantinga’s defense remains inadequate. While Plantinga invites theists to explore potential theological reasons for God’s allowance of evil, he acknowledges that this approach may not yield strong philosophical results. In contrast, Ibn Arabi’s metaphysical framework offers a more comprehensive solution. By integrating ontology, epistemology, and metaphysics to establish a coherent relationship between God, the universe, and humanity, Ibn Arabi renders Mackie’s logical critique irrelevant. Furthermore, his approach fills the gaps left by Plantinga’s defense, offering a more nuanced understanding of the relationship between God and evil. Full article

Increasing testing is key to achieving hepatitis C elimination. This retrospective study aimed to assess the testing cascade of patients at a regional hospital in Victoria, Australia, who inject drugs or are living with hepatitis C, to identify missed opportunities for hepatitis C care. Adult hospital inpatients and emergency department (ED) attendees from 2018 to 2021 with indications for intravenous drug use (IDU) or hepatitis C on their discharge or ED summary were included. Data sources: hospital admissions, pathology, hospital pharmacy, and outpatients. We assessed progression through the testing cascade and performed logistic regression analysis for predictors of hepatitis C care, including testing and treatment. Of 79,923 adults admitted, 1345 (1.7%) had IDU-coded separations and 628 (0.8%) had hepatitis C-coded separations (N = 1892). Hepatitis C virus (HCV) status at the end of the study was unknown for 1569 (82.9%). ED admissions were associated with increased odds of not providing hepatitis C care (odds ratio 3.29, 95% confidence interval 2.42–4.48). More than 2% of inpatients at our hospital have an indication for testing, however, most are not being tested despite their hospital contact. As we work toward HCV elimination in our region, we need to incorporate testing and linkage strategies within hospital departments with a higher prevalence of people at risk of infection. Full article

While the opioid crisis has justifiably occupied news headlines, emergency rooms are seeing many thousands of visits for another cause: cannabinoid toxicity. This is partly due to the spread of cheap and extremely potent synthetic cannabinoids that can cause serious neurological and cardiovascular complications—and deaths—every year. While an opioid overdose can be reversed by naloxone, there is no analogous treatment for cannabis toxicity. Without an antidote, doctors rely on sedatives, with their own risks, or ‘waiting it out’ to treat these patients. We have shown that the canonical synthetic ‘designer’ cannabinoids are highly potent CB1 receptor agonists and, as a result, competitive antagonists may struggle to rapidly reverse an overdose due to synthetic cannabinoids. Negative allosteric modulators (NAMs) have the potential to attenuate the effects of synthetic cannabinoids without having to directly compete for binding. We tested a group of CB1 NAMs for their ability to reverse the effects of the canonical synthetic designer cannabinoid JWH018 in vitro in a neuronal model of endogenous cannabinoid signaling and also in vivo. We tested ABD1085, RTICBM189, and PSNCBAM1 in autaptic hippocampal neurons that endogenously express a retrograde CB1-dependent circuit that inhibits neurotransmission. We found that all of these compounds blocked/reversed JWH018, though some proved more potent than others. We then tested whether these compounds could block the effects of JWH018 in vivo, using a test of nociception in mice. We found that only two of these compounds—RTICBM189 and PSNCBAM1—blocked JWH018 when applied in advance. The in vitro potency of a compound did not predict its in vivo potency. PSNCBAM1 proved to be the more potent of the compounds and also reversed the effects of JWH018 when applied afterward, a condition that more closely mimics an overdose situation. Lastly, we found that PSNCBAM1 did not elicit withdrawal after chronic JWH018 treatment. In summary, CB1 NAMs can, in principle, reverse the effects of the canonical synthetic designer cannabinoid JWH018 both in vitro and in vivo, without inducing withdrawal. These findings suggest a novel pharmacological approach to at last provide a tool to counter cannabinoid toxicity. Full article

The current investigation delved into the utilization of cattle and municipal sanitary inocula for anaerobic digestion of poultry wastes, addressing a crucial and pragmatic challenge in waste management. The emphasis on poultry waste is pertinent due to its well-documented impediments in anaerobic digestion, attributed to heightened levels of ammonia and volatile fatty acids (VFAs). The strategic selection of cattle and municipal sanitary inocula suggests an approach aimed at bolstering the anaerobic digestion process. In this study, we evaluated the use of cattle and municipal sanitary inocula for the anaerobic digestion of various poultry wastes, which is often challenged by high levels of ammonia and volatile fatty acids (VFAs). The substrates tested included belt waste (Poultry A), poultry litter plus feed residues (Poultry B), tray hatchery ©, and stillage. These substrates were processed in two continuous stirred tank reactors (CSTRs), R-1 (with antibiotic monensin) and R-2 (without monensin). Initially, both reactors operated with the same hydraulic retention time (HRT), using a substrate ratio of stillage: belt: tray hatchery (S:B:T) of 70:15:15. On the 41st day, the HRT was adjusted to 20 days, and the substrate ratio was changed to S:A:T 70:40:40. The specific methane yield for R-1 started at 10.768 L g⁻¹ COD, but decreased to 2.65 L g⁻¹ COD by the end of the experiment. For R-2, the specific methane yield varied between 0.45 L g⁻¹ COD and 0.243 L g⁻¹ COD. Microbial composition in the reactors changed over time. In R-1, bacteroides were consistently dominant, while firmicutes were less abundant compared to R-2. Proteobacteria were initially low in abundance, but spirochetes were found in both reactors throughout the experiment. The study concluded that Poultry B substrates, due to their rich nutrient and trace element composition, are suitable for biogas plants. Municipal sanitary inocula also showed promise due to their resilience in high ammonia concentrations. Further research into biofilm interactions is recommended to better understand microbial responses to high ammonia concentrations, which can lead to propionate production in anaerobic digestion (AD). Full article

Conventionally, methanol is the solvent of choice in the synthesis of gamma-cyclodextrin metal-organic frameworks (γ-CD-MOFs), but using ethanol as a replacement could allow for a more food-grade synthesis condition. Therefore, the aim of the study was to compare the γ-CD-MOFs synthesised with both methanol and ethanol. The γ-CD-MOFs were characterised by scanning electron microscopy (SEM), surface area and pore measurement, Fourier transform infrared spectroscopy (FTIR) and powder X-ray diffraction (PXRD). The encapsulation efficiency (EE) and loading capacity (LC) of the γ-CD-MOFs were also determined for curcumin, using methanol, ethanol and a mixture of the two as encapsulation solvent. It was found that γ-CD-MOFs synthesised by methanol and ethanol do not differ greatly, the most significant difference being the larger crystal size of γ-CD-MOFs crystallised from ethanol. However, the change in solvent significantly influenced the EE and LC of the crystals. The higher solubility of curcumin in ethanol reduced interactions with the γ-CD-MOFs and resulted in lowered EE and LC. This suggests that different solvents should be used to deliberately manipulate the EE and LC of target compounds for better use of γ-CD-MOFs as their encapsulating and delivery agents. Full article

Red beetroot is a well-recognized and established source of bioactive compounds (e.g., betalains and polyphenols) with anti-inflammatory and antimicrobial properties. It is proposed as a potential alternative to zinc oxide with a focus on gut microbiota modulation and metabolite production. In this study, weaned pigs aged 28 days were fed either a control diet, a diet supplemented with zinc oxide (3000 mg/kg), or 2% and 4% pulverized whole red beetroot (CON, ZNO, RB2, and RB4; respectively) for 14 days. After pigs were euthanized, blood and digesta samples were collected for microbial composition and metabolite analyses. The results showed that the diet supplemented with red beetroot at 2% improved the gut microbial richness relative to other diets but marginally influenced the cecal microbial diversity compared to a zinc-oxide-supplemented diet. A further increase in red beetroot levels (4%—RB4) led to loss in cecal diversity and decreased short chain fatty acids and secondary bile acid concentrations. Also, an increased Proteobacteria abundance, presumably due to increased lactate/lactic-acid-producing bacteria was observed. In summary, red beetroot contains several components conceived to improve the gut microbiota and metabolite output of weaned pigs. Future studies investigating individual components of red beetroot will better elucidate their contributions to gut microbiota modulation and pig health. Full article

Young people have emerged as one of the most impacted groups from the COVID-19 pandemic and related restrictions to daily activities, with disruptions to schooling, social interactions, and connections. Simultaneously, students’ access to school mental health professionals were restricted or modified. The aim of this paper was to identify how school mental health professionals supported and addressed the mental health needs of young people during COVID-19 restrictions in Australia. School mental health professionals were surveyed during the 2020 lockdowns using a questionnaire designed by researchers in the United States of America. The innovations school mental health staff adopted to support students during lockdowns and remote learning were presented, including telehealth services, digital resources, and the online training and support they received/provided. The barriers and facilitators to providing counselling and assessment services during lockdowns were identified, including issues with providing psychometric assessments during remote learning, and ethical concerns when delivering remote counselling to students. Recommendations have been included, which address how school mental health professionals could be supported to assess and treat young people during future pandemics and school restrictions. Full article

The microbiological quality of water is usually assessed by fecal coliform bacteria, and the presence of E. coli as an indicator of fecal contamination is widely recommended by international guidelines. This study aimed to assess the prevalence of diarrheagenic pathogens, in both public and personal domain water sources and examine the reliance on the WHO drinking water risk assessment guidelines. This study was conducted in a low-income urban community in Dhaka, Bangladesh between September 2014 and October 2015. Polymerase chain reaction (PCR) was used to detect the marker and virulence genes of Escherichia coli, Vibrio cholerae, Salmonella species, and Campylobacter species, and the culture method was employed for the quantitative assessment of E. coli. According to the WHO guidelines, 48% of the public domain source water and 21% of the personal domain point-of-drinking water were classified in the low-risk group, i.e., 0 CFU of E. coli/100 mL. However, when using PCR, we detected pathogens in 39% (14/36) of the point-of-drinking water samples and 65% (74/114) of the public domain water source samples classified in the low-risk group. Our study showed that relying solely on E. coli detection as a measure of water quality may overlook the presence of other pathogens in the drinking water. In addition to the culture-based method, the detection of virulence genes by PCR should also be considered to add more scrutiny to the detection of diverse types of pathogens. Full article