The effect of limited English proficiency and interpreter service use on clinical outcomes in psychiatric inpatient units.

OBJECTIVE: The effects of limited English and interpreter use on clinical outcomes in mental health are poorly understood. This paper describes an exploratory study examining those effects across three adult inpatient psychiatric units, predicting it would lead to increased length of stay. METHODS: Forty-seven patients with limited English proficiency (LEP) were retrospectively identified and compared with 47 patients with proficient English. Length of stay, number of consultant reviews and discharge diagnosis were recorded and compared. RESULTS: An increased length of stay for those with LEP was not statistically significant (p=0.155). The LEP group did undergo more consultant reviews (p=0.036), however, and attracted different discharge diagnoses, with no primary discharge diagnoses of personality disorder made (p=0.018). CONCLUSIONS: This study provides evidence of significant effects of limited English on both service burden and outcome.

Brain-Derived Neurotrophic Factor as a Treatment Option for Retinal Degeneration.

This review discusses the therapeutic potential of brain-derived neurotrophic factor (BDNF) for retinal degeneration. BDNF, nerve growth factor (NGF), neurotrophin 3 (NT-3) and NT-4/NT-5 belong to the neurotrophin family. These neuronal modulators activate a common receptor and a specific tropomyosin-related kinase (Trk) receptor. BDNF was identified as a photoreceptor protectant in models of retinal degeneration as early as 1992. However, development of effective therapeutics that exploit this pathway has been difficult due to challenges in sustaining therapeutic levels in the retina.

Histone Deacetylase: Therapeutic Targets in Retinal Degeneration.

Previous studies report that retinitis pigmentosa (RP) patients treated with the histone deacetylase inhibitor (HDACi) valproic acid (VPA) present with improved visual fields and delayed vision loss. However, other studies report poor efficacy and safety of HDACi in other cohorts of retinal degeneration patients. Furthermore, the molecular mechanisms by which HDACi can improve visual function is unknown, albeit HDACi can attenuate pro-apoptotic stimuli and induce expression of neuroprotective factors. Thus, further analysis of HDACi is warranted in pre-clinical models of retinal degeneration including zebrafish. Analysis of HDAC expression in developing zebrafish reveals diverse temporal expression patterns during development and maturation of visual function.

Elexacaftor/tezacaftor/ivacaftor projected survival and long-term health outcomes in people with cystic fibrosis homozygous for F508del.

BACKGROUND: A series of phase 3 clinical trials have demonstrated that elexacaftor plus tezacaftor plus ivacaftor (ELX/TEZ/IVA) is safe and efficacious in people with cystic fibrosis (pwCF) aged ≥12 years with ≥1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The impact of this treatment on lifetime clinical outcomes and survival, however, has yet to be assessed. METHODS: We used a person-level microsimulation model to estimate the survival and lifetime clinical benefits of ELX/TEZ/IVA treatment versus other CFTR modulator combinations (tezacaftor plus ivacaftor [TEZ/IVA] or lumacaftor plus ivacaftor [LUM/IVA]) or best supportive care (BSC) alone in pwCF aged ≥12 years who are homozygous for F508del-CFTR. Disease progression inputs were derived from published literature; clinical efficacy inputs were derived from an indirect treatment comparison conducted using relevant phase 3 clinical trial data and extrapolations of clinical data. RESULTS: The median projected survival for pwCF homozygous for F508del-CFTR treated with ELX/TEZ/IVA was 71.6 years. This was an increase of 23.2 years versus TEZ/IVA, 26.2 years versus LUM/IVA, and 33.5 years versus BSC alone. Treatment with ELX/TEZ/IVA also reduced disease severity as well as the number of pulmonary exacerbations and lung transplants. In a scenario analysis, the median projected survival for pwCF initiating ELX/TEZ/IVA between the ages of 12 and 17 years was 82.5 years, an increase of 45.4 years compared with BSC alone. CONCLUSIONS: The results from our model suggest ELX/TEZ/IVA treatment may substantially increase survival for pwCF, with early initiation potentially allowing pwCF to achieve near-normal life expectancy.

Caregiver burden in cystic fibrosis: a systematic literature review.

BACKGROUND: Cystic fibrosis (CF) affects more than 80,000 people worldwide, having a considerable impact on the quality of life of patients and their caregivers, who assist patients with time-consuming treatment regimens. Despite this, a review of the available evidence has not been previously undertaken. This systematic literature review aimed to identify the humanistic and economic burdens of CF on caregivers. METHODS: A systematic literature review was conducted, in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Publications reporting outcomes for the caregivers of people with CF, including utility data, health status, and occupational impact, were reviewed. Sources searched were Embase (OvidSP), Medline (PubMed), the Cochrane Database of Systematic Reviews, and the Epistemonikos database, from 2010 to March 2020. A subsequent search with updated terms identified articles up to April 2020. Electronic searches were supplemented by hand searches to capture all relevant literature. RESULTS: A total of 889 articles reporting humanistic burden and 310 reporting economic burden were identified. Following full-text screening by two independent reviewers, 72 articles were included in the review, of which 65 and 17 reported data on humanistic and economic burdens, respectively, with 10 reporting on both. The reviewed literature covered several outcomes and identified multiple key findings: greater disease severity is associated with the reporting of greater caregiver burden and lower utility scores of quality of life; reduced patient lung function is associated with increased caregiver depression and anxiety; and caregiving causes significant occupational impact, with pulmonary exacerbations decreasing caregiver productivity by up to a third compared with the patient being in a 'well' state. CONCLUSION: Findings from this systematic literature review highlight the substantial humanistic and economic burdens borne by the caregivers of people with CF. Future research would help to further inform on the link between disease severity and caregiver burden.

HDAC6 inhibition by tubastatin A is protective against oxidative stress in a photoreceptor cell line and restores visual function in a zebrafish model of inherited blindness.

Retinal diseases, such as hereditary retinitis pigmentosa and age-related macular degeneration, are characterized by the progressive loss of photoreceptors. Histone deacetylase 6 (HDAC6) is considered as a stress surveillance factor and a potential target for neuroprotection and regeneration. Overexpression of HDAC6 has been connected to neurodegenerative disorders, and its suppression may provide protection. Here we show that HDAC6 is constitutively present in the mouse retina, and in the cone-like mouse cell line 661W. In 661W cells HDAC6 inhibition by the specific inhibitor tubastatin A (TST) led to the acetylation of α-tubulin, which is a major substrate for HDAC6. After oxidative stress, exerted by hydrogen peroxide, TST promoted cell survival and the upregulation of heat-shock proteins HSP70 and HSP25 by activation of heat-shock transcription factor 1. Furthermore, in response to oxidative stress the redox regulatory protein peroxiredoxin 1 (Prx1) was modulated in 661W cells by HDAC6 inhibition. The peroxide reducing activity of Prx1 is dependent on its acetylation, which is mediated by HDAC6. Pre-incubation with TST prevented the inactivation of Prx1 and its preserved activity may exert protective effects in photoreceptor cells. To determine whether TST treatment has a therapeutic effect on visual function, the dyeucd6 zebrafish model of inherited sight loss was utilized. Zebrafish have developed as a suitable model system for pharmacological testing. In vivo application of TST caused the hyperacetylation of α-tubulin, indicating that HDAC6 is active in this model. Furthermore, TST was sufficient to rescue visual function and retinal morphology. Hence, HDAC6 inhibition and the regulation of peroxiredoxin activity may play a significant role in protecting retinal cells and in particular photoreceptors, which are exposed to high levels of reactive oxygen species derived from oxidative stress-induced injuries.

A Brain-Derived Neurotrophic Factor Mimetic Is Sufficient to Restore Cone Photoreceptor Visual Function in an Inherited Blindness Model.

Controversially, histone deacetylase inhibitors (HDACi) are in clinical trial for the treatment of inherited retinal degeneration. Utilizing the zebrafish dye ucd6 model, we determined if treatment with HDACi can rescue cone photoreceptor-mediated visual function. dye exhibit defective visual behaviour and retinal morphology including ciliary marginal zone (CMZ) cell death and decreased photoreceptor outer segment (OS) length, as well as gross morphological defects including hypopigmentation and pericardial oedema. HDACi treatment of dye results in significantly improved optokinetic (OKR) (~43 fold, p < 0.001) and visualmotor (VMR) (~3 fold, p < 0.05) responses. HDACi treatment rescued gross morphological defects and reduced CMZ cell death by 80%. Proteomic analysis of dye eye extracts suggested BDNF-TrkB and Akt signaling as mediators of HDACi rescue in our dataset. Co-treatment with the TrkB antagonist ANA-12 blocked HDACi rescue of visual function and associated Akt phosphorylation. Notably, sole treatment with a BDNF mimetic, 7,8-dihydroxyflavone hydrate, significantly rescued dye visual function (~58 fold increase in OKR, p < 0.001, ~3 fold increase in VMR, p < 0.05). In summary, HDACi and a BDNF mimetic are sufficient to rescue retinal cell death and visual function in a vertebrate model of inherited blindness.