Investigation of a chondroitin sulfate-based bioactive coating for neural interface applications.

Invasive neural implants allow for high-resolution bidirectional communication with the nervous tissue and have demonstrated the ability to record neural activity, stimulate neurons, and sense neurochemical species with high spatial selectivity and resolution. However, upon implantation, they are exposed to a foreign body response which can disrupt the seamless integration of the device with the native tissue and lead to deterioration in device functionality for chronic implantation. Modifying the device surface by incorporating bioactive coatings has been a promising approach to camouflage the device and improve integration while maintaining device performance. In this work, we explored the novel application of a chondroitin sulfate (CS) based hydrophilic coating, with anti-fouling and neurite-growth promoting properties for neural recording electrodes. CS-coated samples exhibited significantly reduced protein-fouling in vitro which was maintained for up to 4-weeks. Cell culture studies revealed a significant increase in neurite attachment and outgrowth and a significant decrease in microglia attachment and activation for the CS group as compared to the control. After 1-week of in vivo implantation in the mouse cortex, the coated probes demonstrated significantly lower biofouling as compared to uncoated controls. Like the in vitro results, increased neuronal population (neuronal nuclei and neurofilament) and decreased microglial activation were observed. To assess the coating's effect on the recording performance of silicon microelectrodes, we implanted coated and uncoated electrodes in the mouse striatum for 1 week and performed impedance and recording measurements. We observed significantly lower impedance in the coated group, likely due to the increased wettability of the coated surface. The peak-to-peak amplitude and the noise floor levels were both lower in the CS group compared to the controls, which led to a comparable signal-to-noise ratio between the two groups. The overall single unit yield (% channels recording a single unit) was 74% for the CS and 67% for the control group on day 1. Taken together, this study demonstrates the effectiveness of the polysaccharide-based coating in reducing biofouling and improving biocompatibility for neural electrode devices.

Internal consistency reliability of the Revised Illness Perceptions Questionnaire: A systematic review and reliability generalization meta-analysis.

The Revised Illness Perception Questionnaire (IPQ-R) assesses patients' perspectives of their illnesses. Original psychometric testing occurred in limited populations. The purpose of this reliability generalization meta-analysis was to: (1) estimate internal consistency reliability of each IPQ-R subscale, and (2) test moderators of these estimates. Web of Science was searched in July 2022 for articles citing the original IPQ-R paper that reported IPQ-R reliability data. Cronbach's alphas (⍺) were pooled for each IPQ-R subscale using inverse variance weighting and DerSimonian and Laird estimation. Sixty-six studies met criteria. Overall pooled ⍺ estimates were acceptable: 0.71-0.87. Treatment control reliability was reduced among cardiac (⍺ = 0.68), diabetes/kidney disease (⍺ = 0.63), and mixed/other (⍺ = 0.66) samples; cyclical reliability was reduced in cancer (⍺ = 0.65) samples. Age, gender, and race were also significant moderators. Subscale reliability varied based on sample characteristics. Adapting IPQ-R subscales to account for sample variation could improve measurement of illness perception constructs.

COVID-19 vaccination in correctional systems in the United States.

Overcrowding and limited ability to social distance contribute to high rates of COVID-19 outbreaks in correctional facilities. Despite the Centers for Disease Controls' recommendations, incarcerated persons and correctional staff report a high prevalence of vaccine-hesitance. We sought to identify reasons underlying COVID-19 vaccine hesitation and refusal in correctional systems. We used Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines to design the review. We searched PubMed abstracts and reviewed literature relevant to COVID-19 vaccine uptake and hesitancy in correctional systems of the United States (n = 23). Reasons for vaccine hesitancy among incarcerated people and correctional staff include efficacy, safety concerns, lack of information, and distrust. Findings reveal higher vaccine hesitancy among young and Black residents whereas facilities in close collaborations with state health departments exhibited higher vaccination rates. Correctional facilities must prioritize communication and education to improve the current state of vaccine hesitancy.

Clinically relevant mouse models of Charcot-Marie-Tooth type 2S.

Charcot-Marie-Tooth disease is an inherited peripheral neuropathy that is clinically and genetically heterogenous. Mutations in IGHMBP2, a ubiquitously expressed DNA/RNA helicase, have been shown to cause the infantile motor neuron disease spinal muscular atrophy with respiratory distress type 1 (SMARD1), and, more recently, juvenile-onset Charcot-Marie-Tooth disease type 2S (CMT2S). Using CRISPR-cas9 mutagenesis, we developed the first mouse models of CMT2S [p.Glu365del (E365del) and p.Tyr918Cys (Y918C)]. E365del is the first CMT2S mouse model to be discovered and Y918C is the first human CMT2S allele knock-in model. Phenotypic characterization of the homozygous models found progressive peripheral motor and sensory axonal degeneration. Neuromuscular and locomotor assays indicate that both E365del and Y918C mice have motor deficits, while neurobehavioral characterization of sensory function found that E365del mutants have mechanical allodynia. Analysis of femoral motor and sensory nerves identified axonal degeneration, which does not impact nerve conduction velocities in E365del mice, but it does so in the Y918C model. Based on these results, the E365del mutant mouse, and the human allele knock-in, Y918C, represent mouse models with the hallmark phenotypes of CMT2S, which will be critical for understanding the pathogenic mechanisms of IGHMBP2. These mice will complement existing Ighmbp2 alleles modeling SMARD1 to help understand the complex phenotypic and genotypic heterogeneity that is observed in patients with IGHMBP2 variants.

Effects of grid spacing on high-frequency precipitation variance in coupled high-resolution global ocean-atmosphere models.

High-frequency precipitation variance is calculated in 12 different free-running (non-data-assimilative) coupled high resolution atmosphere-ocean model simulations, an assimilative coupled atmosphere-ocean weather forecast model, and an assimilative reanalysis. The results are compared with results from satellite estimates of precipitation and rain gauge observations. An analysis of irregular sub-daily fluctuations, which was applied by Covey et al. (Geophys Res Lett 45:12514-12522, 2018. 10.1029/2018GL078926) to satellite products and low-resolution climate models, is applied here to rain gauges and higher-resolution models. In contrast to lower-resolution climate simulations, which Covey et al. (2018) found to be lacking with respect to variance in irregular sub-daily fluctuations, the highest-resolution simulations examined here display an irregular sub-daily fluctuation variance that lies closer to that found in satellite products. Most of the simulations used here cannot be analyzed via the Covey et al. (2018) technique, because they do not output precipitation at sub-daily intervals. Thus the remainder of the paper focuses on frequency power spectral density of precipitation and on cumulative distribution functions over time scales (2-100 days) that are still relatively "high-frequency" in the context of climate modeling. Refined atmospheric or oceanic model grid spacing is generally found to increase high-frequency precipitation variance in simulations, approaching the values derived from observations. Mesoscale-eddy-rich ocean simulations significantly increase precipitation variance only when the atmosphere grid spacing is sufficiently fine (< 0.5°). Despite the improvements noted above, all of the simulations examined here suffer from the "drizzle effect", in which precipitation is not temporally intermittent to the extent found in observations.

Enhancing Satellite Oceanography-Driven Research in West Africa: a Case Study of Capacity Development in an Underserved Region.

Marine business and resources play a major role in the economics and way of life in coastal West African countries. Such countries see great profitability from their marine resources while also facing challenges that come with a bordering sea. Despite this fact, there has been limited research into the optimal way for West African Coastal States to coexist with, and sustainably use their marine resources, a research deficit that is mainly due to a lack of infrastructure for in-situ work, lack of capacity development, and comprehensive datasets to undertake oceanographic research. The Coastal Ocean Environment Summer School in Ghana (COESSING; www.coessing.org) was developed to help meet some of these challenges. Each summer since 2015, ocean scientists (e.g., biologists, chemists, physicists, hydrologists) from the USA and Europe have collaborated with West African colleagues to lead a week-long intensive summer school in Accra, Ghana, alternating in location between the Regional Maritime University and the University of Ghana. The school receives in excess of 100 participants drawn from universities, government agencies, and the private sector organizations, mainly from Ghana and neighboring Liberia, Nigeria, Togo, and Benin, among others. The format of the school includes morning lectures, afternoon field trips, and hands-on laboratory exercises and one-on-one coaching of students. Important to the COESSING program is the satellite oceanography component which introduces participants to the extensive and often free, remotely sensed oceanographic datasets. Participants develop skills that allow them to access, process, and analyze these datasets in order to better understand regional oceanographic phenomena, such as upwelling, pollution, habitat characterization, sea level rise, and coastal erosion. Following the school, facilitators keep in touch with program participants, helping them acquire and analyze data for their studies, dissertations, and often graduate school applications, etc. In summary, schools such as COESSING are critical not only for science in the region but for the global ocean community as such training develops eager, bright minds while leading to improved regional observing and modeling strategies in severely under-sampled seas. Here, we describe a unique case in which satellite oceanography has led to such outcomes for countries bordering the Gulf of Guinea, West Africa.

Author Correction: NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease.

A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway-Ribosome-associated Quality Control (RQC)-by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF's role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.

Overlapping spectrums: The clinicogenetic commonalities between Charcot-Marie-Tooth and other neurodegenerative diseases.

Charcot-Marie-Tooth (CMT) disease is a progressive and heterogeneous inherited peripheral neuropathy. A myriad of genetic factors have been identified that contribute to the degeneration of motor and sensory axons in a length-dependent manner. Emerging biological themes underlying disease include defects in axonal trafficking, dysfunction in RNA metabolism and protein homeostasis, as well deficits in the cellular stress response. Moreover, genetic contributions to CMT can have overlap with other neuropathies, motor neuron diseases (MNDs) and neurodegenerative disorders. Recent progress in understanding the molecular biology of CMT and overlapping syndromes aids in the search for necessary therapeutic targets.

Modeling Spatiotemporal Factors Associated With Sentiment on Twitter: Synthesis and Suggestions for Improving the Identification of Localized Deviations.

BACKGROUND: Studies examining how sentiment on social media varies depending on timing and location appear to produce inconsistent results, making it hard to design systems that use sentiment to detect localized events for public health applications. OBJECTIVE: The aim of this study was to measure how common timing and location confounders explain variation in sentiment on Twitter. METHODS: Using a dataset of 16.54 million English-language tweets from 100 cities posted between July 13 and November 30, 2017, we estimated the positive and negative sentiment for each of the cities using a dictionary-based sentiment analysis and constructed models to explain the differences in sentiment using time of day, day of week, weather, city, and interaction type (conversations or broadcasting) as factors and found that all factors were independently associated with sentiment. RESULTS: In the full multivariable model of positive (Pearson r in test data 0.236; 95% CI 0.231-0.241) and negative (Pearson r in test data 0.306; 95% CI 0.301-0.310) sentiment, the city and time of day explained more of the variance than weather and day of week. Models that account for these confounders produce a different distribution and ranking of important events compared with models that do not account for these confounders. CONCLUSIONS: In public health applications that aim to detect localized events by aggregating sentiment across populations of Twitter users, it is worthwhile accounting for baseline differences before looking for unexpected changes.

Tumor M2-PK: A novel urine marker of bladder cancer.

PURPOSE: Bladder cancer is a "Warburg-like" tumor characterized by a reliance on aerobic glycolysis and expression of pyruvate kinase M2 (PKM2). PKM2 oscillates between an active tetramer and an inactive dimer. We aim to further characterize PKM2, in particular PKM2 dimer, as a urinary biomarker of bladder cancer and a potential target for treatment. METHODS: HTB-9, HTB-5, and UM-UC3 bladder cancer cells were assessed for proliferation under differential glucose levels using the hexosaminidase assay. Western blot and Blue-native analysis was performed for protein expression of PKM2. Shikonin, an herb that is known to bind and inhibit PKM2, was utilized to determine if PKM2 has a role in glucose usage and cellular proliferation in bladder cancer cells by caspase activity assay. Institutional review board approval was obtained to collect healthy control and bladder cancer patient urine samples. The ScheBo M2-PK EDTA Plasma Test was performed on urine samples to assess urine Tumor M2-PK values. RESULTS: The three bladder cancer cell lines tested all demonstrate statistically significant increases in proliferation when exposed to higher level of glucose (200mg/dL). Similarly, low doses of glucose (25mg/dL) result in reduced proliferation. Increased cell growth in higher glucose concentration correlated with up-regulation of PKM2 protein expression. Shikonin, a PKM2 inhibitor, reduced cell proliferation and switched PKM2 isoforms from the dimer to tetramer. Lastly, dimer PKM2 (Tumor-M2PK) levels were assessed in the urine samples from bladder cancer (Bca) patients and healthy controls. Tumor M2-PK significantly correlated with the presence of BCa in our subjects. CONCLUSIONS: Our studies demonstrate the potential of PKM2, specifically the dimer (Tumor-M2PK) as a target of drug therapy and as a urinary marker for bladder cancer.

Context-Aware Systems for Chronic Disease Patients: Scoping Review.

BACKGROUND: Context-aware systems, also known as context-sensitive systems, are computing applications designed to capture, interpret, and use contextual information and provide adaptive services according to the current context of use. Context-aware systems have the potential to support patients with chronic conditions; however, little is known about how such systems have been utilized to facilitate patient work. OBJECTIVE: This study aimed to characterize the different tasks and contexts in which context-aware systems for patient work were used as well as to assess any existing evidence about the impact of such systems on health-related process or outcome measures. METHODS: A total of 6 databases (MEDLINE, EMBASE, CINAHL, ACM Digital, Web of Science, and Scopus) were scanned using a predefined search strategy. Studies were included in the review if they focused on patients with chronic conditions, involved the use of a context-aware system to support patients' health-related activities, and reported the evaluation of the systems by the users. Studies were screened by independent reviewers, and a narrative synthesis of included studies was conducted. RESULTS: The database search retrieved 1478 citations; 6 papers were included, all published from 2009 onwards. The majority of the papers were quasi-experimental and involved pilot and usability testing with a small number of users; there were no randomized controlled trials (RCTs) to evaluate the efficacy of a context-aware system. In the included studies, context was captured using sensors or self-reports, sometimes involving both. Most studies used a combination of sensor technology and mobile apps to deliver personalized feedback. A total of 3 studies examined the impact of interventions on health-related measures, showing positive results. CONCLUSIONS: The use of context-aware systems to support patient work is an emerging area of research. RCTs are needed to evaluate the effectiveness of context-aware systems in improving patient work, self-management practices, and health outcomes in chronic disease patients.

HPV vaccine coverage in Australia and associations with HPV vaccine information exposure among Australian Twitter users.

Introduction: Human papillomavirus (HPV) vaccine coverage in Australia is 80% for females and 76% for males. Attitudes may influence coverage but surveys measuring attitudes are resource-intensive. The aim of this study was to determine whether Twitter-derived estimates of HPV vaccine information exposure were associated with differences in coverage across regions in Australia. Methods: Regional differences in information exposure were estimated from 1,103,448 Australian Twitter users and 655,690 HPV vaccine related tweets posted between 6 September 2013 and 1 September 2017. Tweets about HPV vaccines were grouped using topic modelling; an algorithm for clustering text-based data. Proportional exposure to topics across 25 regions in Australia were used as factors to model HPV vaccine coverage in females and males, and compared to models using employment and education as factors. Results: Models using topic exposure measures were more closely correlated with HPV vaccine coverage (female: Pearson's R = 0.75 [0.49 to 0.88]; male: R = 0.76 [0.51 to 0.89]) than models using employment and education as factors (female: 0.39 [-0.02 to 0.68]; male: 0.36 [-0.04 to 0.66]). In Australia, positively-framed news tended to reach more Twitter users overall, but vaccine-critical information made up higher proportions of exposures among Twitter users in low coverage regions, where distorted characterisations of safety research and vaccine-critical blogs were popular. Conclusions: Twitter-derived models of information exposure were correlated with HPV vaccine coverage in Australia. Topic exposure measures may be useful for providing timely and localised reports of the information people access and share to inform the design of targeted vaccine promotion interventions.

Efficacy of a Mobile Social Networking Intervention in Promoting Physical Activity: Quasi-Experimental Study.

BACKGROUND: Technological interventions such as mobile apps, Web-based social networks, and wearable trackers have the potential to influence physical activity; yet, only a few studies have examined the efficacy of an intervention bundle combining these different technologies. OBJECTIVE: This study aimed to pilot test an intervention composed of a social networking mobile app, connected with a wearable tracker, and investigate its efficacy in improving physical activity, as well as explore participant engagement and the usability of the app. METHODS: This was a pre-post quasi-experimental study with 1 arm, where participants were subjected to the intervention for a 6-month period. The primary outcome measure was the difference in daily step count between baseline and 6 months. Secondary outcome measures included engagement with the intervention and system usability. Descriptive and inferential statistical tests were conducted; posthoc subgroup analyses were carried out for participants with different levels of steps at baseline, app usage, and social features usage. RESULTS: A total of 55 participants were enrolled in the study; the mean age was 23.6 years and 28 (51%) were female. There was a nonstatistically significant increase in the average daily step count between baseline and 6 months (mean change=14.5 steps/day, P=.98, 95% CI -1136.5 to 1107.5). Subgroup analysis comparing the higher and lower physical activity groups at baseline showed that the latter had a statistically significantly higher increase in their daily step count (group difference in mean change from baseline to 6 months=3025 steps per day, P=.008, 95% CI 837.9-5211.8). At 6 months, the retention rate was 82% (45/55); app usage decreased over time. The mean system usability score was 60.1 (SD 19.2). CONCLUSIONS: This study showed the preliminary efficacy of a mobile social networking intervention, integrated with a wearable tracker to promote physical activity, particularly for less physically active subgroups of the population. Future research should explore how to address challenges faced by physically inactive people to provide tailored advices. In addition, users' perspectives should be explored to shed light on factors that might influence their engagement with the intervention.

Trial2rev: Combining machine learning and crowd-sourcing to create a shared space for updating systematic reviews.

OBJECTIVES: Systematic reviews of clinical trials could be updated faster by automatically monitoring relevant trials as they are registered, completed, and reported. Our aim was to provide a public interface to a database of curated links between systematic reviews and trial registrations. MATERIALS AND METHODS: We developed the server-side system components in Python, connected them to a PostgreSQL database, and implemented the web-based user interface using Javascript, HTML, and CSS. All code is available on GitHub under an open source MIT license and registered users can access and download all available data. RESULTS: The trial2rev system is a web-based interface to a database that collates and augments information from multiple sources including bibliographic databases, the ClinicalTrials.gov registry, and the actions of registered users. Users interact with the system by browsing, searching, or adding systematic reviews, verifying links to trials included in the review, and adding or voting on trials that they would expect to include in an update of the systematic review. The system can trigger the actions of software agents that add or vote on included and relevant trials, in response to user interactions or by scheduling updates from external resources. DISCUSSION AND CONCLUSION: We designed a publicly-accessible resource to help systematic reviewers make decisions about systematic review updates. Where previous approaches have sought to reactively filter published reports of trials for inclusion in systematic reviews, our approach is to proactively monitor for relevant trials as they are registered and completed.

mHealth App Patient Testing and Review of Educational Materials Designed for Self-Management of Gout Patients: Descriptive Qualitative Studies.

BACKGROUND: Gout is a form of chronic arthritis caused by elevated serum uric acid (SUA) and culminates in painful gout attacks. Although effective uric acid-lowering therapies exist, adherence is low. This is partly due to the lack of support for patients to self-manage their disease. Mobile health apps have been used in the self-management of chronic conditions. However, not all are developed with patients, limiting their effectiveness. OBJECTIVE: The objective of our study was to collect feedback from gout patients to design an effective gout self-management app. METHODS: Two descriptive qualitative studies were conducted. In Study 1, researchers developed a short educational video and written materials about gout management, designed to be embedded into an app; 6 interviews and 1 focus group were held with gout patients to gather feedback on these materials. Usability testing in Study 2 involved additional gout patients using a pilot version of Healthy.me Gout, a gout self-management app, for 2 weeks. Following the trial, patients participated in an interview about their experiences using the app. RESULTS: Patients viewed the gout educational material positively, appreciating the combined use of video, text, and images. Patients were receptive to using a mobile app to self-manage their gout. Feedback about Healthy.me Gout was generally positive with patients reporting that the tracking and diary features were most useful. Patients also provided suggestions for improving the app and educational materials. CONCLUSIONS: These studies involved patients in the development of a gout self-management app. Patients provided insight to improve the app's presentation and usability and general lessons on useful features for chronic disease apps. Gout patients enjoyed tracking their SUA concentrations and gout attack triggers. These capabilities can be translated into self-management apps for chronic diseases that require monitoring of pathological values, medication adherence, or symptoms. Future health app design should integrate patient input and be developed iteratively to address concerns identified by patients.

Challenges During Implementation of a Patient-Facing Mobile App for Surgical Rehabilitation: Feasibility Study.

BACKGROUND: Translating research into practice, especially the implementation of digital health technologies in routine care, is increasingly important. Yet, there are few studies examining the challenges of implementing patient-facing digital technologies in health care settings. OBJECTIVE: The aim of this study was to report challenges experienced when implementing mobile apps for patients to support their postsurgical rehabilitation in an orthopedic setting. METHODS: A mobile app was tailored to the needs of patients undergoing rotator cuff repair. A 30-min usability session and a 12-week feasibility study were conducted with patients to evaluate the app in routine care. Implementation records (observation reports, issues log, and email correspondence) explored factors that hindered or facilitated patient acceptance. Interviews with clinicians explored factors that influenced app integration in routine care. RESULTS: Participant completion was low (47%, 9/19). Factors that affected patient acceptance included digital literacy, health status, information technology (IT) infrastructure at home, privacy concerns, time limitations, the role of a caregiver, inconsistencies in instruction received from clinicians and the app, and app advice not reflective of patient progress over time. Factors that negatively influenced app integration in routine care included competing demands among clinicians, IT infrastructure in health care settings, identifying the right time to introduce the app to patients, user interface complexity for older patients, lack of coordination among multidisciplinary clinicians, and technical issues with app installation. CONCLUSIONS: Three insights were identified for mobile app implementation in routine care: (1) apps for patients need to reflect their journey over time and in particular, postoperative apps ought to be introduced as part of preoperative care with opportunities for patients to learn and adopt the app during their postoperative journey; (2) strategies to address digital literacy issues among patients and clinicians are essential; and (3) impact of the app on patient outcomes and clinician workflow needs to be communicated, monitored, and reviewed. Lastly, digital health interventions should supplement but not replace patient interaction with clinicians.

Use of a mobile social networking intervention for weight management: a mixed-methods study protocol.

INTRODUCTION: Obesity and physical inactivity are major societal challenges and significant contributors to the global burden of disease and healthcare costs. Information and communication technologies are increasingly being used in interventions to promote behaviour change in diet and physical activity. In particular, social networking platforms seem promising for the delivery of weight control interventions.We intend to pilot test an intervention involving the use of a social networking mobile application and tracking devices (Fitbit Flex 2 and Fitbit Aria scale) to promote the social comparison of weight and physical activity, in order to evaluate whether mechanisms of social influence lead to changes in those outcomes over the course of the study. METHODS AND ANALYSIS: Mixed-methods study involving semi-structured interviews and a pre-post quasi-experimental pilot with one arm, where healthy participants in different body mass index (BMI) categories, aged between 19 and 35 years old, will be subjected to a social networking intervention over a 6-month period. The primary outcome is the average difference in weight before and after the intervention. Secondary outcomes include BMI, number of steps per day, engagement with the intervention, social support and system usability. Semi-structured interviews will assess participants' expectations and perceptions regarding the intervention. ETHICS AND DISSEMINATION: Ethics approval was granted by Macquarie University's Human Research Ethics Committee for Medical Sciences on 3 November 2016 (ethics reference number 5201600716).The social network will be moderated by a researcher with clinical expertise, who will monitor and respond to concerns raised by participants. Monitoring will involve daily observation of measures collected by the fitness tracker and the wireless scale, as well as continuous supervision of forum interactions and posts. Additionally, a protocol is in place to monitor for participant misbehaviour and direct participants-in-need to appropriate sources of help.

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish.

Paclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in cancer treatment and in a number of curative and palliative regimens. Despite its beneficial effects on cancer, paclitaxel also damages healthy tissues, most prominently the peripheral sensory nervous system. The mechanisms leading to paclitaxel-induced peripheral neuropathy remain elusive, and therapies that prevent or alleviate this condition are not available. We established a zebrafish in vivo model to study the underlying mechanisms and to identify pharmacological agents that may be developed into therapeutics. Both adult and larval zebrafish displayed signs of paclitaxel neurotoxicity, including sensory axon degeneration and the loss of touch response in the distal caudal fin. Intriguingly, studies in zebrafish larvae showed that paclitaxel rapidly promotes epithelial damage and decreased mechanical stress resistance of the skin before induction of axon degeneration. Moreover, injured paclitaxel-treated zebrafish skin and scratch-wounded human keratinocytes (HEK001) display reduced healing capacity. Epithelial damage correlated with rapid accumulation of fluorescein-conjugated paclitaxel in epidermal basal keratinocytes, but not axons, and up-regulation of matrix-metalloproteinase 13 (MMP-13, collagenase 3) in the skin. Pharmacological inhibition of MMP-13, in contrast, largely rescued paclitaxel-induced epithelial damage and neurotoxicity, whereas MMP-13 overexpression in zebrafish embryos rendered the skin vulnerable to injury under mechanical stress conditions. Thus, our studies provide evidence that the epidermis plays a critical role in this condition, and we provide a previously unidentified candidate for therapeutic interventions.

Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio.

PURPOSE: The blood-brain barrier (BBB) essentially restricts therapeutic drugs from entering into the brain. This study tests the hypothesis that brain endothelial cell derived exosomes can deliver anticancer drug across the BBB for the treatment of brain cancer in a zebrafish (Danio rerio) model. MATERIALS AND METHODS: Four types of exosomes were isolated from brain cell culture media and characterized by particle size, morphology, total protein, and transmembrane protein markers. Transport mechanism, cell uptake, and cytotoxicity of optimized exosome delivery system were tested. Brain distribution of exosome delivered anticancer drugs was evaluated using transgenic zebrafish TG (fli1: GFP) embryos and efficacies of optimized formations were examined in a xenotransplanted zebrafish model of brain cancer model. RESULTS: Four exosomes in 30-100 diameters showed different morphologies and exosomes derived from brain endothelial cells expressed more CD63 tetraspanins transmembrane proteins. Optimized exosomes increased the uptake of fluorescent marker via receptor mediated endocytosis and cytotoxicity of anticancer drugs in cancer cells. Images of the zebrafish showed exosome delivered anticancer drugs crossed the BBB and entered into the brain. In the brain cancer model, exosome delivered anticancer drugs significantly decreased fluorescent intensity of xenotransplanted cancer cells and tumor growth marker. CONCLUSIONS: Brain endothelial cell derived exosomes could be potentially used as a carrier for brain delivery of anticancer drug for the treatment of brain cancer.