Neoblast-like stem cells of Fasciola hepatica.

The common liver fluke (Fasciola hepatica) causes the disease fasciolosis, which results in considerable losses within the global agri-food industry. There is a shortfall in the drugs that are effective against both the adult and juvenile life stages within the mammalian host, such that new drug targets are needed. Over the last decade the stem cells of parasitic flatworms have emerged as reservoirs of putative novel targets due to their role in development and homeostasis, including at host-parasite interfaces. Here, we investigate and characterise the proliferating cells that underpin development in F. hepatica. We provide evidence that these cells are capable of self-renewal, differentiation, and are sensitive to ionising radiation- all attributes of neoblasts in other flatworms. Changes in cell proliferation were also noted during the early stages of in vitro juvenile growth/development (around four to seven days post excystment), which coincided with a marked reduction in the nuclear area of proliferating cells. Furthermore, we generated transcriptomes from worms following irradiation-based ablation of neoblasts, identifying 124 significantly downregulated transcripts, including known stem cell markers such as fgfrA and plk1. Sixty-eight of these had homologues associated with neoblast-like cells in Schistosoma mansoni. Finally, RNA interference mediated knockdown of histone h2b (a marker of proliferating cells), ablated neoblast-like cells and impaired worm development in vitro. In summary, this work demonstrates that the proliferating cells of F. hepatica are equivalent to neoblasts of other flatworm species and demonstrate that they may serve as attractive targets for novel anthelmintics.

A Review of Meaningful Change Thresholds for EORTC QLQ-C30 and FACT-G Within Oncology.

OBJECTIVES: This literature review provides an overview of meaningful change thresholds for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and the Functional Assessment of Cancer Therapy - General (FACT-G) used across hematological cancers and solid tumors (melanoma, lung, bladder, and prostate). METHODS: Embase, MEDLINE, and PubMed were searched to identify relevant oncology publications from 2016 to 2021. Label claims from the US Food and Drug Administration and the European Medicines Agency for 7 recently approved drugs (pembrolizumab, atezolizumab, glasdegib, gilteritinib, tisagenlecleucel, axicabtagene ciloleucel, and daratumumab plus hyaluronidase-fihj) were reviewed. RESULTS: Publications providing guidance on meaningful change thresholds for the QLQ-C30 displayed a growing trend away from broad "legacy" thresholds of 10 points for all QLQ-C30 scales), toward deriving "contemporary" thresholds (eg, subscale specific, population specific). Contemporary publications generally provide guidance on selecting thresholds for specific scales that account for improved or worsening thresholds (eg, QLQ-C30 subscales). This trend was not clear for FACT-G, with less new guidance available. Most clinical trials used in regulatory label submissions have used thresholds of 10 points for the QLQ-C30 subscales and 3 to 7 points for the FACT-G total score. Despite the availability of more recent guidelines, contemporary meaningful change thresholds seem slow to emerge in the published literature and regulatory labels. CONCLUSIONS: Trialists should consider using contemporary thresholds, rather than legacy thresholds, for QLQ-C30 endpoints. Thresholds derived for a similar patient-population should be used where available. Further work is required to provide these across a broader range of cancer sites.

Big Data Confidentiality: An Approach Toward Corporate Compliance Using a Rule-Based System.

Organizations have been investing in analytics relying on internal and external data to gain a competitive advantage. However, the legal and regulatory acts imposed nationally and internationally have become a challenge, especially for highly regulated sectors such as health or finance/banking. Data handlers such as Facebook and Amazon have already sustained considerable fines or are under investigation due to violations of data governance. The era of big data has further intensified the challenges of minimizing the risk of data loss by introducing the dimensions of Volume, Velocity, and Variety into confidentiality. Although Volume and Velocity have been extensively researched, Variety, "the ugly duckling" of big data, is often neglected and difficult to solve, thus increasing the risk of data exposure and data loss. In mitigating the risk of data exposure and data loss in this article, a framework is proposed to utilize algorithmic classification and workflow capabilities to provide a consistent approach toward data evaluations across the organizations. A rule-based system, implementing the corporate data classification policy, will minimize the risk of exposure by facilitating users to identify the approved guidelines and enforce them quickly. The framework includes an exception handling process with appropriate approval for extenuating circumstances. The system was implemented in a proof of concept working prototype to showcase the capabilities and provide a hands-on experience. The information system was evaluated and accredited by a diverse audience of academics and senior business executives in the fields of security and data management. The audience had an average experience of ∼25 years and amasses a total experience of almost three centuries (294 years). The results confirmed that the 3Vs are of concern and that Variety, with a majority of 90% of the commentators, is the most troubling. In addition to that, with an approximate average of 60%, it was confirmed that appropriate policies, procedure, and prerequisites for classification are in place while implementation tools are lagging.

The executive disruption model of tinnitus distress: Model validation in two independent datasets using factor score regression.

This study presents the executive disruption model (EDM) of tinnitus distress and subsequently validates it statistically using two independent datasets (the Construction Dataset: n = 96 and the Validation Dataset: n = 200). The conceptual EDM was first operationalised as a structural causal model (construction phase). Then multiple regression was used to examine the effect of executive functioning on tinnitus-related distress (validation phase), adjusting for the additional contributions of hearing threshold and psychological distress. For both datasets, executive functioning negatively predicted tinnitus distress score by a similar amount (the Construction Dataset: ß = -3.50, p = 0.13 and the Validation Dataset: ß = -3.71, p = 0.02). Theoretical implications and applications of the EDM are subsequently discussed; these include the predictive nature of executive functioning in the development of distressing tinnitus, and the clinical utility of the EDM.

Transcriptomic analysis supports a role for the nervous system in regulating growth and development of Fasciola hepatica juveniles.

Fasciola spp. liver flukes have significant impacts in veterinary and human medicine. The absence of a vaccine and increasing anthelmintic resistance threaten sustainable control and underscore the need for novel flukicides. Functional genomic approaches underpinned by in vitro culture of juvenile Fasciola hepatica facilitate control target validation in the most pathogenic life stage. Comparative transcriptomics of in vitro and in vivo maintained 21 day old F. hepatica finds that 86% of genes are expressed at similar levels across maintenance treatments suggesting commonality in core biological functioning within these juveniles. Phenotypic comparisons revealed higher cell proliferation and growth rates in the in vivo juveniles compared to their in vitro counterparts. These phenotypic differences were consistent with the upregulation of neoblast-like stem cell and cell-cycle associated genes in in vivo maintained worms. The more rapid growth/development of in vivo juveniles was further evidenced by a switch in cathepsin protease expression profiles, dominated by cathepsin B in in vitro juveniles and by cathepsin L in in vivo juveniles. Coincident with more rapid growth/development was the marked downregulation of both classical and peptidergic neuronal signalling components in in vivo maintained juveniles, supporting a role for the nervous system in regulating liver fluke growth and development. Differences in the miRNA complements of in vivo and in vitro juveniles identified 31 differentially expressed miRNAs, including fhe-let-7a-5p, fhe-mir-124-3p and miRNAs predicted to target Wnt-signalling, which supports a key role for miRNAs in driving the growth/developmental differences in the in vitro and in vivo maintained juvenile liver fluke. Widespread differences in the expression of neuronal genes in juvenile fluke grown in vitro and in vivo expose significant interplay between neuronal signalling and the rate of growth/development, encouraging consideration of neuronal targets in efforts to dysregulate growth/development for parasite control.

RNA interference dynamics in juvenile Fasciola hepatica are altered during in vitro growth and development.

For over a decade RNA interference (RNAi) has been an important molecular tool for functional genomics studies in parasitic flatworms. Despite this, our understanding of RNAi dynamics in many flatworm parasites, such as the temperate liver fluke (Fasciola hepatica), remains rudimentary. The ability to maintain developing juvenile fluke in vitro provides the opportunity to perform functional studies during development of the key pathogenic life stage. Here, we investigate the RNAi competence of developing juvenile liver fluke. Firstly, all life stages examined possess, and express, core candidate RNAi effectors encouraging the hypothesis that all life stages of F. hepatica are RNAi competent. RNAi effector analyses supported growing evidence that parasitic flatworms have evolved a separate clade of RNAi effectors with unknown function. Secondly, we assessed the impact of growth/development during in vitro culture on RNAi in F. hepatica juveniles and found that during the first week post-excystment liver fluke juveniles exhibit quantitatively lower RNAi mediated transcript knockdown when maintained in growth inducing media. This did not appear to occur in older in vitro juveniles, suggesting that rapidly shifting transcript dynamics over the first week following excystment alters RNAi efficacy after a single 24 h exposure to double stranded (ds)RNA. Finally, RNAi efficiency was found to be improved through use of a repeated dsRNA exposure methodology that has facilitated silencing of genes in a range of tissues, thereby increasing the utility of RNAi as a functional genomics tool in F. hepatica.

Associations Between Subjective Tinnitus and Cognitive Performance: Systematic Review and Meta-Analyses.

Tinnitus is the perception of sound in the absence of a corresponding external sound source, and bothersome tinnitus has been linked to poorer cognitive performance. This review comprehensively quantifies the association between tinnitus and different domains of cognitive performance. The review protocol was preregistered and published in a peer-reviewed journal. The review and analyses were reported according to Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. Peer-reviewed literature was searched using electronic databases to find studies featuring participants with tinnitus who had undertaken measures of cognitive performance. Studies were assessed for quality and categorized according to an established cognitive framework. Random-effects meta-analyses were performed on various cognitive domains with potential moderator variables assessed where possible. Thirty-eight records were included in the analysis from a total of 1,863 participants. Analyses showed that tinnitus is associated with poorer executive function, processing speed, general short-term memory, and general learning and retrieval. Narrow cognitive domains of Inhibition and Shifting (within executive function) and learning and retrieval (within general learning and retrieval) were also associated with tinnitus.

Evidence for an Association Between Hearing Impairment and Disrupted Sleep: Scoping Review.

Purpose Hearing impairment (HI) is the most common sensory impairment and may negatively impact sleep through reduced auditory input. Factors associated with HI such as anxiety regarding communication in daily life may also adversely impact an individual's sleep. Here, research on the relationship between HI and sleep disruption was catalogued using scoping review methodology. Method A systematic strategy was employed to search various electronic databases. This review is reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses Scoping Review Extension. Results Sixteen records met inclusion criteria. Studies have investigated sleep in HI as a primary aim in noise-exposed workers or large surveys in older participants. Experimental and quasi-experimental studies report alterations to sleep architecture of potential neuroplastic origins. Studies reporting sleep as a secondary aim generally report poorer sleep in HI participants. Conclusions This scoping review has catalogued evidence that altered or negatively impacted sleep may be associated with HI. Potential confounding factors, mechanisms, and considerations for future research are discussed. Supplemental Material https://doi.org/10.23641/asha.9968369.

Association between subjective tinnitus and cognitive performance: protocol for systematic review and meta-analysis.

INTRODUCTION: Subjective tinnitus is very common and has a number of comorbid associations including depression, sleep disturbance and concentration difficulties. Concentration difficulties may be observable in people with tinnitus through poorer behavioural performance in tasks thought to measure specific cognitive domains such as attention and memory (ie, cognitive performance). Several reviews have discussed the association between tinnitus and cognition; however, none to date have investigated the association between tinnitus and cognitive performance through meta-analysis with reference to an established theoretical taxonomy. Furthermore, there has been little overlap between sets of studies that have been included in previous reviews, potentially contributing to the typically mixed findings that are reported. METHODS AND ANALYSIS: This systematic review aims to comprehensively review the literature using an established theoretical taxonomy and quantitatively synthesise relevant data to determine associations between subjective tinnitus and cognitive performance. Methods are reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. All study designs will be eligible for inclusion with no date restrictions on searches. Studies eligible for inclusion must contain adult participants (≥18 years) with subjective tinnitus and a behavioural measure of cognitive performance. Meta-analysis will be reported via correlation for the association between tinnitus and cognitive performance. ETHICS AND DISSEMINATION: No ethical issues are foreseen. Findings will be reported in a student thesis, at national and international , ear, nose and throat/audiology conferences and by peer-reviewed publication. PROSPERO REGISTRATION NUMBER: CRD42018085528.

Ester-prodrugs of ethambutol control its antibacterial activity and provide rapid screening for mycobacterial hydrolase activity.

M. tuberculosis contains an unusually high number of serine hydrolases by proteome percentage compared to other common bacteria or humans. This letter describes a method to probe the global substrate specificity of mycobacterial serine hydrolases with ester-protected prodrugs of ethambutol, a first-line antibiotic treatment for TB. These compounds were synthesized directly from ethambutol using a selective o-acylation to yield products in high yield and purity with minimal workup. A library of derivatives was screened against M. smegmatis, a non-infectious model for M. tuberculosis, which displayed significantly lowered biological activity compared to ethambutol. Incubation with a general serine hydrolase reactivated each derivative to near-ethambutol levels, demonstrating that esterification of ethambutol should provide a simple screen for mycobacterial hydrolase activity.