Impaired value-based decision-making in Parkinson's disease apathy.

Apathy is a common and disabling complication of Parkinson's disease characterized by reduced goal-directed behaviour. Several studies have reported dysfunction within prefrontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision-making. Specifically, these neuromodulators have overlapping contributions to encoding the value of decisions, and influence whether to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesized that apathy in Parkinson's disease should be associated with an impairment in value-based learning. Using a four-armed restless bandit reinforcement learning task, we studied decision-making in 75 volunteers; 53 patients with Parkinson's disease, with and without clinical apathy, and 22 age-matched healthy control subjects. Patients with apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patient's apathy severity measured using the Lille Apathy Rating Scale (R = -0.46, P < 0.001). Computational modelling of the patient's choices confirmed the apathy group made decisions that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration, which also correlated with apathy scores (R = -0.5, P < 0.001). We went on to acquire functional MRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age-matched controls performing the Restless Bandit Task. Analysis of the functional MRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinson's disease, which was more marked in apathy, but not predictive of their individual apathy severity. Using a model-based categorization of choice type, decisions to explore lower value bandits in the apathy group activated prefrontal cortex to a similar degree to the age-matched controls. In contrast, Parkinson's patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched control subjects, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinson's disease.

Transferrin-Bearing, Zein-Based Hybrid Lipid Nanoparticles for Drug and Gene Delivery to Prostate Cancer Cells.

Gene therapy holds great promise for treating prostate cancer unresponsive to conventional therapies. However, the lack of delivery systems that can transport therapeutic DNA and drugs while targeting tumors without harming healthy tissues presents a significant challenge. This study aimed to explore the potential of novel hybrid lipid nanoparticles, composed of biocompatible zein and conjugated to the cancer-targeting ligand transferrin. These nanoparticles were designed to entrap the anti-cancer drug docetaxel and carry plasmid DNA, with the objective of improving the delivery of therapeutic payloads to prostate cancer cells, thereby enhancing their anti-proliferative efficacy and gene expression levels. These transferrin-bearing, zein-based hybrid lipid nanoparticles efficiently entrapped docetaxel, leading to increased uptake by PC-3 and LNCaP cancer cells and significantly enhancing anti-proliferative efficacy at docetaxel concentrations exceeding 1 µg/mL. Furthermore, they demonstrated proficient DNA condensation, exceeding 80% at polymer-DNA weight ratios of 1500:1 and 2000:1. This resulted in increased gene expression across all tested cell lines, with the highest transfection levels up to 11-fold higher than those observed with controls, in LNCaP cells. These novel transferrin-bearing, zein-based hybrid lipid nanoparticles therefore exhibit promising potential as drug and gene delivery systems for prostate cancer therapy.

Depression, anxiety, stress symptoms and their determinants among secondary students with vision impairment in rural Northwestern China during the COVID-19 pandemic.

Objective: The measures implemented to control the spread of Coronavirus disease 2019 (COVID-19) could affect children's mental and vision health. Youth particularly from minority and socioeconomically disadvantaged backgrounds were more likely to be impacted by these measures. This study aimed to examine the mental health of children with vision impairment and associated factors in North-western China during the COVID-19 pandemic. Methods: A cross-sectional study was conducted among 2,036 secondary school children living in Ningxia Hui Autonomous Region. Participants completed a survey on sociodemographic and lifestyle information and answered the Chinese version of the 21-item Depression Anxiety Stress Scales (DASS-21) questionnaire. Presenting visual acuity was measured by a trained enumerator. Multivariate logistic regression analysis was used to identify potential risk factors for mental health problems. Results: Responses from 1,992 (97.8%) children were included in the analysis after excluding those with incomplete mental health outcome data. The prevalence of depression, anxiety and stress symptoms within the dataset were 28.9, 46.4, and 22.3%, respectively. The distribution of children with different stress levels differed significantly between those with and without vision impairment (p = 0.03). Multivariable logistic regression analyses revealed that depression symptoms decreased with higher parental education (OR, 0.76, 95% confidence intervals (CI):0.63-0.96), longer sleep duration (OR, 0.90, 95% CI: 0.81-0.97) and longer study time (OR, 0.82, 95% CI: 0.74-0.91), whereas they increased with higher recreational screen time (OR, 1.19, 95% CI: 1.08-1.32). Anxiety symptoms decreased with higher parental education (OR, 0.80, 95% CI: 0.66-0.96) and increased with higher recreational screen time (OR, 1.15, 95% CI: 1.04-1.27) and being a left-behind child (OR, 1.26, 95% CI: 1.04-1.54). In addition, stress symptoms decreased with longer sleep duration (OR, 0.92, 95%CI: 0.85-0.99) and increased with higher number of siblings (OR, 1.10, 95% CI: 1.01-1.19), higher recreational screen time (OR, 1.15, 95% CI: 1.04-1.28) and older age (OR,1.12, 95% CI: 1.004-1.24). Conclusion: A considerable proportion of our sample experienced mental health problems during the pandemic. Healthcare planners in China should consider interventions such as reducing recreational screen time, ensuring sufficient sleep, and timely detection of mental health symptoms among socioeconomically disadvantaged groups.

Preparation of Zein-Based Nanoparticles: Nanoprecipitation versus Microfluidic-Assisted Manufacture, Effects of PEGylation on Nanoparticle Characteristics and Cellular Uptake by Melanoma Cells.

Background: The manufacture of nanoparticles using manual methods is hampered by its challenging scale-up and poor reproducibility. To overcome this issue, the production of zein nanoparticles entrapping a lipophilic drug model, coumarin-6, by using a microfluidic system was assessed in this study. The influence of PEG density and chain length on zein nanoparticle characteristics, as well as their uptake efficacy in melanoma cancer cells, was also evaluated. Methods: Zein nanoparticles were prepared by both manual and microfluidic approaches to allow comparison between the two processes. PEGylated zein nanoparticles with various PEG densities and chain lengths were produced by nanoprecipitation and characterized. Their cellular uptake was evaluated on B16F10 melanoma cancer cells in vitro. Results: Zein nanoparticles have successfully been produced by both manual and microfluidic approaches. Parameters such as total flow rate and flow rate ratio of the aqueous and organic phases in microfluidic process, as well as the method preparation and aqueous to organic phase volume ratio during nanoprecipitation, have been shown to strongly influence the characteristics of the resulting nanoparticles. Continuous microfluidics led to the production of nanoparticles with low yield and drug entrapment, unlike nanoprecipitation, which resulted in zein nanoparticles with an appropriate size and an optimal drug entrapment efficiency of 64%. The surface modification of the nanoparticles produced by nanoprecipitation, with lower PEG density and shorter PEG chain length made mPEG5K-zein (0.5:1) the most favorable formulation in our study, resulting in enhanced stability and higher coumarin-6 uptake by melanoma cancer cells. Conclusion: mPEG5K-zein (0.5:1) nanoparticles prepared by nanoprecipitation were the most promising formulation in our study, exhibiting increased stability and enhancing coumarin-6 uptake by melanoma cancer cells.

Vision impairment and traffic safety outcomes in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Road traffic injuries are a major public health concern and their prevention requires concerted efforts. We aimed to systematically analyse the current evidence to establish whether any aspects of vision, and particularly interventions to improve vision function, are associated with traffic safety outcomes in low-income and middle-income countries (LMICs). METHODS: We did a systematic review and meta-analysis to assess the association between poor vision and traffic safety outcomes. We searched MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials in the Cochrane Library from database inception to April 2, 2020. We included any interventional or observational studies assessing whether vision is associated with traffic safety outcomes, studies describing prevalence of poor vision among drivers, and adherence to licensure regulations. We excluded studies done in high-income countries. We did a meta-analysis to explore the associations between vision function and traffic safety outcomes and a narrative synthesis to describe the prevalence of vision disorders and adherence to licensure requirements. We used random-effects models with residual maximum likelihood method. The systematic review protocol was registered on PROSPERO, CRD-42020180505. FINDINGS: We identified 49 (1·8%) eligible articles of 2653 assessed and included 29 (59·2%) in the various data syntheses. 15 394 participants (mean sample size n=530 [SD 824]; mean age of 39·3 years [SD 9·65]; 1167 [7·6%] of 15 279 female) were included. The prevalence of vision impairment among road users ranged from 1·2% to 26·4% (26 studies), colour vision defects from 0·5% to 17·1% (15 studies), and visual field defects from 2·0% to 37·3% (ten studies). A substantial proportion (range 10·6-85·4%) received licences without undergoing mandatory vision testing. The meta-analysis revealed a 46% greater risk of having a road traffic crash among those with central acuity visual impairment (risk ratio [RR] 1·46 [95% CI 1·20-1·78]; p=0·0002, 13 studies) and a greater risk among those with defects in colour vision (RR 1·36 [1·01-1·82]; p=0·041, seven studies) or the visual field (RR 1·36 [1·25-1·48]; p<0·0001, seven studies). The I2 value for overall statistical heterogeneity was 63·4%. INTERPRETATION: This systematic review shows a positive association between vision impairment and traffic crashes in LMICs. Our findings provide support for mandatory vision function assessment before issuing a driving licence. FUNDING: None.

The prevalence and correlates of vision impairment and glasses ownership among ethnic minority and Han schoolchildren in rural China.

PURPOSE: To determine the prevalence of visual impairment and glasses ownership among Han Chinese and Hui minority junior high school children in Ningxia Hui Autonomous Region, China. DESIGN: Population-based cross-sectional study. METHODS: Vision screening was conducted on 20,376 children (age 12-15 years) in all 124 rural junior high schools in Ningxia. Personal and family characteristics, glasses ownership, and academic performance were assessed through a survey questionnaire and standardized mathematics test, respectively. RESULTS: The prevalence of visual acuity (VA) ≤6/12 in either eye was significantly higher among Han (54.5%) than Hui (45.2%) children (P<0.001), and was significantly positively associated with age, female sex, Han ethnicity, parental outmigration for work, shorter time spent outside during recess, shorter time spent watching television and higher time spent studying. Among children with VA≤6/12 in both eyes, only 56.8% of Han and 41.5% of Hui children had glasses (P<0.001). Glasses ownership was significantly associated with worse vision, greater family wealth, female sex, higher test scores, age, parental outmigration for work, understanding of myopia and glasses, higher time spent studying and Han ethnicity. CONCLUSION: One of the first of its kind, this report on Han and Hui ethnic schoolchildren confirms a high prevalence of visual impairment among both populations, but slightly higher among the Han. Both groups, especially the Hui, have low rates of glasses ownership. Future interventions and policies designed to improve glasses usage should focus on populations with lower incomes and seek to correct erroneous beliefs about the safety of glasses and efficacy of traditional eye exercises.

No Adaptation of the Prion Strain in a Heterozygous Case of Variant Creutzfeldt-Jakob Disease.

We investigated a clinical case of variant Creutzfeldt-Jakob Disease in a person heterozygous for methionine/valine at codon 129 of the prion protein gene and identified the same strain properties in variant Creutzfeldt-Jakob disease in methionine homozygous persons and in bovine spongiform encephalopathy. These results indicate no adaptation of the agent in a different genetic background.

Biological Performance of Electrospun Polymer Fibres.

The evaluation of biological responses to polymeric scaffolds are important, given that the ideal scaffold should be biocompatible, biodegradable, promote cell adhesion and aid cell proliferation. The primary goal of this research was to measure the biological responses of cells against various polymeric and collagen electrospun scaffolds (polycaprolactone (PCL) and polylactic acid (PLA) polymers: PCL⁻drug, PCL⁻collagen⁻drug, PLA⁻drug and PLA⁻collagen⁻drug); cell proliferation was measured with a cell adhesion assay and cell viability using 5-bromo-2'-deoxyuridine (BrdU) and resazurin assays. The results demonstrated that there is a distinct lack of growth of cells against any irgasan (IRG) loaded scaffolds and far greater adhesion of cells against levofloxacin (LEVO) loaded scaffolds. Fourteen-day studies revealed a significant increase in cell growth after a 7-day period. The addition of collagen in the formulations did not promote greater cell adhesion. Cell viability studies revealed the levels of IRG used in scaffolds were toxic to cells, with the concentration used 475 times higher than the EC50 value for IRG. It was concluded that the negatively charged carboxylic acid group found in LEVO is attracting positively charged fibronectin, which in turn is attracting the cell to adhere to the adsorbed proteins on the surface of the scaffold. Overall, the biological studies examined in this paper are valuable as preliminary data for potential further studies into more complex aspects of cell behaviour with polymeric scaffolds.

Impact of Presbyopia and Its Correction in Low- and Middle-Income Countries.

Presbyopia affects more than 1 billion people worldwide, and the number is growing rapidly due to the aging global population. Uncorrected presbyopia is the world's leading cause of vision impairment, and as with other causes. The burden falls unfairly on low- and middle-income countries (LMICs), in which rates of presbyopic correction are as low as 10%. The importance of presbyopia as a cause of vision impairment is further underscored by the fact that it strikes at the heart of the productive working years, although it can be safely and effectively treated with a pair of inexpensive glasses. To galvanize action for programs to address uncorrected presbyopia in the workplace and beyond LMICs, it is crucial to build a solid evidence base detailing the impact of presbyopia and its correction in important areas such as work productivity, activities of daily living, visual function, and quality of life. The aim of this review was to provide an up-to-date reference for program planners and policymakers seeking to build support for programs of presbyopia correction, particularly in low-resource settings.