The thyroid hormone system disrupting potential of resorcinol in fish.

Environmental pollutants capable of interfering with the thyroid hormone (TH) system increasingly raise concern for both human and environmental health. Recently, resorcinol has received attention as a compound of concern due to its endocrine disrupting properties. It is a known inhibitor of thyroperoxidase (TPO), an enzyme required in TH synthesis, and therapeutic use of resorcinol exposure has led to hypothyroidism in humans. There is limited evidence concerning ecotoxicologically relevant effects of resorcinol in fish. A set of adverse outcome pathways (AOPs) has recently been developed linking thyroid hormone system disruption (THSD) to impaired swim bladder inflation and eye development in fish. In the present study, these AOPs were used to provide the background for testing potential THSD effects of resorcinol in zebrafish eleutheroembryos. We exposed zebrafish eleutheroembryos to resorcinol and assessed TH levels, swim bladder inflation and eye morphology. As a TPO inhibitor, resorcinol is expected to affect TH levels and eye morphology but not swim bladder inflation during embryonic development. Indeed, thyroxine (T4) levels were significantly decreased following resorcinol exposure. In contrast to our hypothesis, swim bladder inflation was impaired at 5 days post fertilization (dpf) and no effects on eye morphology were detected. Therefore, in vitro assays were performed to identify potential additional thyroid hormone system disruption-related mechanisms through which resorcinol may act. Two new mechanisms were identified: TH receptor (TR) antagonism and transthyretin (TTR) binding inhibition. Both of these mechanisms can plausibly be linked to impaired swim bladder inflation and could, therefore, explain the observed effect. Overall, our study contributes to the knowledge of the THSD potential of resorcinol both in vivo in the zebrafish model as well as in vitro.

DNAfusion: an R/Bioconductor package for increased sensitivity of detecting gene fusions in liquid biopsies.

BACKGROUND: EML4-ALK gene fusions are oncogenic drivers in non-small cell lung cancer (NSCLC), and liquid biopsies containing EML4-ALK fragments can be used to study tumor dynamics using next-generation sequencing (NGS). However, the sensitivity of EML4-ALK detection varies between pipelines and analysis tools. RESULTS: We developed an R/Bioconductor package, DNAfusion, which can be applied to BAM files generated by commercially available NGS pipelines, such as AVENIO. Forty-eight blood samples from a training cohort consisting of 41 stage IV EML4-ALK-positive NSCLC patients and seven healthy controls were used to develop DNAfusion. DNAfusion detected EML4-ALK in significantly more samples (sensitivity = 61.0%) compared to AVENIO (sensitivity = 36.6%). The newly identified EML4-ALK-positive patients were verified using droplet digital PCR. DNAfusion was subsequently validated in a blinded validation cohort comprising 24 EML4-ALK-positive and 24 EML4-ALK-negative stage IV NSCLC patients. DNAfusion detected significantly more EML4-ALK individuals in the validation cohort (sensitivity = 62.5%) compared to AVENIO (sensitivity = 29.2%). DNAfusion demonstrated a specificity of 100% in both the training and validation cohorts. CONCLUSION: Here we present DNAfusion, which increases the sensitivity of EML4-ALK detection in liquid biopsies and can be implemented downstream of commercially available NGS pipelines. The simplistic method of operating the R package makes it easy to implement in the clinical setting, enabling wider expansion of NGS-based diagnostics.

Barriers and facilitators to return to work following cardiovascular disease: a systematic review and meta-synthesis of qualitative research.

OBJECTIVES: Return to work is a key rehabilitation goal, however, people recovering from cardiovascular disease (CVD) often struggle with returning to work. The aim of this study was to conduct a systematic review and meta-synthesis of the existing qualitative evidence on barriers and facilitators to return to work experienced by people with CVD. METHODS: A systematic literature search was conducted in PubMed, Embase, Web of Science, PsycINFO, Scopus and CINAHL in August 2022. The reference lists of the included articles were searched. The Critical Appraisal Skills Programme was used for quality appraisal and a meta-synthesis was employed. FINDINGS: This review includes 15 studies of overall high methodological quality. Barriers covered four themes: physical limitations, psychological and relational factors, the working context and support within health and social care systems. Facilitators were related to five themes: return to normality, enhancing well-being, financial concerns, the working context and support within health and social care systems. CONCLUSION: Our findings highlight that return to work following CVD is a complex process influenced by individual factors, as well as work-related factors, factors in the health and social care systems and social security policies and regulations. To improve return to work, this review illustrates a need for individualised, multidisciplinary and coordinated vocational rehabilitation programmes that accommodate potential barriers to re-employment. Similarly, this review highlights how vocational rehabilitation programmes should ensure individualised information and support early in the rehabilitation process, as well as the importance of engaging relevant stakeholders, such as employers, in making individualised return-to-work plans.