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.

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.

Sporadic Fatal Insomnia in Europe: Phenotypic Features and Diagnostic Challenges.

OBJECTIVE: Comprehensively describe the phenotypic spectrum of sporadic fatal insomnia (sFI) to facilitate diagnosis and management of this rare and peculiar prion disorder. METHODS: A survey among major prion disease reference centers in Europe identified 13 patients diagnosed with sFI in the past 20 years. We undertook a detailed analysis of clinical and histopathological features and the results of diagnostic investigations. RESULTS: Mean age at onset was 43 years, and mean disease duration 30 months. Early clinical findings included psychiatric, sleep, and oculomotor disturbances, followed by cognitive decline and postural instability. In all tested patients, video-polysomnography demonstrated a severe reduction of total sleep time and/or a disorganized sleep. Cerebrospinal fluid (CSF) levels of proteins 14-3-3 and t-tau were unrevealing, the concentration of neurofilament light protein (NfL) was more consistently increased, and the real-time quaking-induced conversion assay (RT-QuIC) revealed a positive prion seeding activity in 60% of cases. Electroencephalography and magnetic resonance imaging showed nonspecific findings, whereas fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrated a profound bilateral thalamic hypometabolism in 71% of cases. Molecular analyses revealed PrPSc type 2 and methionine homozygosity at PRNP codon 129 in all cases. INTERPRETATION: sFI is a disease of young or middle-aged adults, which is difficult to reconcile with the hypothesis of a spontaneous etiology related to stochastic, age-related PrP misfolding. The combination of psychiatric and/or sleep-related symptoms with oculomotor abnormalities represents an early peculiar clinical feature of sFI to be valued in the differential diagnosis. Video-polysomnography, FDG-PET, and especially CSF prion RT-QuIC and NfL constitute the most promising supportive diagnostic tests in vivo. Ann Neurol 2018;84:347-360.

Improving eye care in Rwanda.

PROBLEM: Visual impairment affects nearly 285 million people worldwide. Although there has been much progress in combating the burden of visual impairment through initiatives such as VISION 2020, barriers to progress, especially in African countries, remain high. APPROACH: The Rwandan Ministry of Health has formed partnerships with several nongovernmental organizations and has worked to integrate their efforts to prevent and treat visual impairment, including presbyopia. LOCAL SETTING: Rwanda, an eastern African country of approximately 11 million people. RELEVANT CHANGES: The Rwandan Ministry of Health developed a single national plan that allows key partners in vision care to coordinate more effectively in measuring eye disease, developing eye care infrastructure, building capacity, controlling disease, and delivering and evaluating services. LESSONS LEARNT: Collaboration between stakeholders under a single national plan has ensured that resources and efforts are complementary, optimizing the ability to provide eye care. Improved access to primary eye care and insurance coverage has increased demand for services at secondary and tertiary levels. A comprehensive strategy that includes prevention as well as a supply chain for glasses and lenses is needed.

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.

The child self-refraction study results from urban Chinese children in Guangzhou.

OBJECTIVE: To compare visual and refractive outcomes between self-refracting spectacles (Adaptive Eyecare, Ltd, Oxford, UK), noncycloplegic autorefraction, and cycloplegic subjective refraction. DESIGN: Cross-sectional study. PARTICIPANTS: Chinese school-children aged 12 to 17 years. METHODS: Children with uncorrected visual acuity ≤ 6/12 in either eye underwent measurement of the logarithm of the minimum angle of resolution visual acuity, habitual correction, self-refraction without cycloplegia, autorefraction with and without cycloplegia, and subjective refraction with cycloplegia. MAIN OUTCOME MEASURES: Proportion of children achieving corrected visual acuity ≥ 6/7.5 with each modality; difference in spherical equivalent refractive error between each of the modalities and cycloplegic subjective refractive error. RESULTS: Among 556 eligible children of consenting parents, 554 (99.6%) completed self-refraction (mean age, 13.8 years; 59.7% girls; 54.0% currently wearing glasses). The proportion of children with visual acuity ≥ 6/7.5 in the better eye with habitual correction, self-refraction, noncycloplegic autorefraction, and cycloplegic subjective refraction were 34.8%, 92.4%, 99.5% and 99.8%, respectively (self-refraction versus cycloplegic subjective refraction, P<0.001). The mean difference between cycloplegic subjective refraction and noncycloplegic autorefraction (which was more myopic) was significant (-0.328 diopter [D]; Wilcoxon signed-rank test P<0.001), whereas cycloplegic subjective refraction and self-refraction did not differ significantly (-0.009 D; Wilcoxon signed-rank test P = 0.33). Spherical equivalent differed by ≥ 1.0 D in either direction from cycloplegic subjective refraction more frequently among right eyes for self-refraction (11.2%) than noncycloplegic autorefraction (6.0%; P = 0.002). Self-refraction power that differed by ≥ 1.0 D from cycloplegic subjective refractive error (11.2%) was significantly associated with presenting without spectacles (P = 0.011) and with greater absolute power of both spherical (P = 0.025) and cylindrical (P = 0.022) refractive error. CONCLUSIONS: Self-refraction seems to be less prone to accommodative inaccuracy than noncycloplegic autorefraction, another modality appropriate for use in areas where access to eye care providers is limited. Visual results seem to be comparable. Greater cylindrical power is associated with less accurate results; the adjustable glasses used in this study cannot correct astigmatism. Further studies of the practical applications of this modality are warranted. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

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.

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.

Regression of prostate tumors after intravenous administration of lactoferrin-bearing polypropylenimine dendriplexes encoding TNF-α, TRAIL, and interleukin-12.

The possibility of using gene therapy for the treatment of prostate cancer is limited by the lack of intravenously administered delivery systems able to safely and selectively deliver therapeutic genes to tumors. Given that lactoferrin (Lf) receptors are overexpressed on prostate cancer cells, we hypothesized that the conjugation of Lf to generation 3-diaminobutyric polypropylenimine dendrimer would improve its transfection and therapeutic efficacy in prostate cancer cells. In this study, we demonstrated that the intravenous administration of Lf-bearing DAB dendriplexes encoding TNFα resulted in the complete suppression of 70% of PC-3 and 50% of DU145 tumors over one month. Treatment with DAB-Lf dendriplex encoding TRAIL led to tumor suppression of 40% of PC-3 tumors and 20% of DU145 tumors. The treatment was well tolerated by the animals. Lf-bearing generation 3-polypropylenimine dendrimer is therefore a highly promising delivery system for non-viral gene therapy of prostate cancer.

Effect of providing near glasses on productivity among rural Indian tea workers with presbyopia (PROSPER): a randomised trial.

BACKGROUND: Presbyopia, age-related decline in near vision, is the most common cause of vision impairment globally, but no trials have assessed its workplace effects. We aimed to study the effect of near glasses on the productivity of tea workers with presbyopia. METHODS: This randomised trial was done in tea pickers aged 40 years or older in Assam, India, with unaided near visual acuity (NVA) lower than 6/12 in both eyes, correctable to 6/7·5 with near glasses; unaided distance vision 6/7·5 or greater; and no eye disease. Participants were randomly assigned (1:1) to receive free glasses optimising NVA at working distance (cost including delivery US$10·20 per person), either immediately (intervention group) or at closeout (control group). Participants were stratified by age, sex, and productivity. The primary outcome (investigator-masked) was the difference between groups in the change in mean daily weight of tea picked (productivity), between the 4-week baseline period (June, 2017) and the 11-week evaluation period (July 24, 2017, to Oct 7, 2017). Workers' income was tied to their productivity. Compliance with study glasses was assessed at seven unannounced visits. Results were analysed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT03228199. FINDINGS: Between July 3, 2017, and July 15, 2017, 1297 (48·1%) of 2699 permanent workers met the age criteria and consented for eye examinations. 751 (57·9%) fulfilled vision criteria and were randomly assigned to the intervention (n=376) or control (n=375) groups. Groups did not differ substantially in baseline characteristics. No participants owned glasses at baseline, 707 (94·1%) received the allocated intervention, and all were followed up and analysed. Between the baseline and evaluation periods, mean productivity in the intervention group increased from 25·0 kg per day to 34·8 kg per day (an increase of 9·84 kg per day), a significantly higher increase than in the control group (from 26·0 kg per day to 30·6 kg per day; an increase of 4·59 kg per day), corresponding to a between-group difference of 5·25 kg per day (95% CI 4·50-5·99; 21·7% relative productivity increase; effect size 1·01 [95% CI 0·86-1·16]; p<0·0001). Intervention-group compliance with study glasses reached 84·5% by closeout. Regression model predictors of greater productivity increase included intervention group membership (5·25 kg per day [95% CI 4·60-5·91], p<0·0001) and, among intervention participants, older age (p=0·039) and better compliance with the intervention (p<0·0001). INTERPRETATION: A substantial productivity increase was achieved in this rural cohort by providing glasses to correct presbyopia, with little cost and high intervention uptake. FUNDING: Clearly.