Local Delivery of Therapeutics to the Inner Ear: The State of the Science

BACKGROUND: Advances in the understanding of the genetic and molecular etiologies of inner ear disorders have enabled the identification of therapeutic targets and innovative delivery approaches to the inner ear. As this field grows, the need for knowledge about effective delivery of therapeutics to the inner ear has become a priority. This review maps all clinical and pre-clinical research published in English in the field to date, to guide both researchers and clinicians about local drug delivery methods in the context of novel therapeutics. METHODS: A systematic search was conducted using customized strategies in Cochrane, pubmed and EMBASE databases from inception to 30/09/2018. Two researchers undertook study selection and data extraction independently. RESULTS: Our search returned 12,200 articles, of which 837 articles met the inclusion criteria. 679 were original research and 158 were reviews. There has been a steady increase in the numbers of publications related to inner ear therapeutics delivery over the last three decades, with a sharp rise over the last 2 years. The intra-tympanic route accounts for over 70% of published articles. Less than one third of published research directly assesses delivery efficacy, with most papers using clinical efficacy as a surrogate marker. CONCLUSION: Research into local therapeutic delivery to the inner ear has undergone a recent surge, improving our understanding of how novel therapeutics can be delivered. Direct assessment of delivery efficacy is challenging, especially in humans, and progress in this area is key to understanding how to make decisions about delivery of novel hearing therapeutics

Inverse association between negative symptoms and body mass index in chronic schizophrenia.

BACKGROUND: We investigated whether negative symptoms, such as poor motivation or anhedonia, were associated with higher body mass index (BMI) in stable patients with schizophrenia chronically treated with antipsychotic medication. METHODS: 62 olanzapine- or clozapine-treated patients with illness duration of at least four years were selected from an international multicenter study on the characterization of negative symptoms. All participants completed the Brief Negative Symptom Scale (BNSS) and the Positive and Negative Syndrome Scale (PANSS). Bivariate correlations between BMI and negative symptoms (BNSS) were explored, as well as multiple regression analyses. We further explored the association of two principal component factors of the BNSS and BMI. Subsidiary analyses re-modeled the above using the negative symptoms subscale of the PANSS and the EMSLEY factor for negative symptoms for convergent validity. RESULTS: Lower negative symptoms (BNSS score) were associated with higher BMI (r=-0.31; p=0.015). A multiple regression analysis showed that negative symptoms (BNSS score) and age were significant predictors of BMI (p=0.037). This was mostly driven by the motivation/pleasure factor of the BNSS. Within this second factor, BMI was negatively associated with anhedonia (r=-0.254; p=0.046) and asociality (r=-0.253; p=0.048), but not avolition (r=-0.169; p=0.188). EMSLEY score was positively associated with BNSS (r=0.873, p<0.001), but negatively associated with BMI (r=-0.308; p=0.015). The association between PANSS and BMI did not reach significance (r=-224, p=0.080). CONCLUSIONS: We conclude that lower negative symptoms were associated with higher BMI (assessed using both the BNSS and EMSLEY) in chronic stable schizophrenia patients, mostly due to lower anhedonia and asociality levels

Contextualizing the teaching and assessment of engineering skills

We are frequently being informed that Engineering graduates are not 'work ready', but lacking in a broad range of generic skills, despite these being mandatory for professional body accreditation. In this case study we present a newly developed second year undergraduate module which explicitly integrates the practice and assessment of generic skills with realistic technical challenges in 'scenarios' (week long intensive group projects). It is intended that this format would demonstrate the relevance of the generic skills to the students and hence improve engagement and learning. Observations by staff and feedback from students confirmed the success of this approach

Visual dysfunction and its correlation with retinal changes in patients with Parkinson’ s disease: an observational cross-sectional study

Objectives: To evaluate visual dysfunction and its correlation with structural changes in the retina in patients with Parkinson’s disease (PD). Methods: Patients with PD (n=37) and controls (n=37) were included in an observational cross- sectional study, and underwent visual acuity (VA), colour vision (using the Farnsworth and Lanthony desaturated D15 colour tests) and contrast sensitivity vision (CSV; using the Pelli-Robson chart and CSV 1000E test) evaluation to measure visual dysfunction. Structural measurements of the retinal nerve fibre layer (RNFL), and macular and ganglion cell layer (GCL) thicknesses, were obtained using spectral domain optical coherence tomography (SD-OCT). Comparison of obtained data, and correlation analysis between functional and structural results were performed. Results: VA (in all different contrast levels) and all CSV spatial frequencies were significantly worse in patients with PD than in controls. Colour vision was significantly affected based on the Lanthony colour test. Significant GCL loss was observed in the minimum GCL+inner plexiform layer. A clear tendency towards a reduction in several macular sectors (central, outer inferior, outer temporal and superior (inner and outer)) and in the temporal quadrant of the RNFL thickness was observed, although the difference was not significant. CSV was the functional parameter most strongly correlated with structural measurements in PD. Colour vision was associated with most GCL measurements. Macular thickness was strongly correlated with macular volume and functional parameters (r>0.70, p<0.05). Conclusions: Patients with PD had visual dysfunction that correlated with structural changes evaluated by SD-OCT. GCL measurements may be reliable indicators of visual impairment in patients with PD

Development and validation of a high performance liquid chromatography-tandem mass spectrometry method for the absolute analysis of 17 alpha D-amino acids in cooked meals

In the nutrition field, there is a lack of understanding about the impact that dietary chiral composition may have on health, especially regarding cooked meals. Chiral amino acids (AAs) are naturally present in food and their proportion may vary quite a lot. Besides, the D-amino acids (D-AAs) are present in very low concentration compared to L-AAs, so very sensitive methods are required for their accurate quantitation. Moreover, some of them have been described as indicators of quality and different food processes. In this research, we propose a robust method for the absolute quantitation and enantiomeric ratio of 17 D-AAs in cooked meals. The AAs were extracted from 1 g of the homogenised meal with methanol, derivatised with (S)-N-(4-nitrophenoxycarbonyl) phenylalanine methoxyethyl ester ((S)-NIFE) and analysed by RP-LC-MS/MS. The separation was carried out with an Acquity BEH C18 (100 mm x 2.1 mm, 1.7 µm) column at 70 ºC, with 10 mmol/L ammonium bicarbonate in water as eluent A and acetonitrile as eluent B at a 0.3 mL/min flow rate in gradient elution. The MS operated in positive electrospray ionisation method in multiple reaction monitoring (MRM) mode. Isotopically labelled AAs were used as internal standards for the quantitation. The method was validated for 17 D-AAs in the cooked food samples in terms of specificity, linearity, precision, accuracy, matrix effect and stability. LLOQ are 2.0 ng/mL for most of them. Additionally, linearity was also studied for L-AAs. After optimization and validation, the method was applied to real breakfast, lunch and dinner samples of cooked meals (n = 18) that were part of a diet with a very high concordance with WHO dietary guidelines. Level of concentration of major and minor D-AAs have been described per total daily intake and within each of the three main meals. This method can be used for quality control purposes as well as to investigate the role of chiral composition in food and clinical outcomes

Os efeitos do cigarro e do consumo de café sobre a formação óssea e a integração óssea de implantes de hidroxiapatita

The present study aims to assess the effects of cigarette smoke inhalation and/or coffee consumption on bone formation and osseous integration of a dense hydroxyapatite (DHA) implant in rats. For this study, 20 male rats were divided into four groups (n = 5): CT (control) group, CE (coffee) group, CI (cigarette) group and CC (coffee + cigarette) group. During 16 weeks, animals in the CI group were exposed to cigarette smoke inhalation equivalent to 6 cigarettes per day; specimens in the CE group drank coffee as liquid diet; and rats in the CC group were submitted to both substances. In the 6th week a 5 mm slit in the parietal bone and a 4 mm slit in the tibia were performed on the left side: the former was left open while the latter received a DHA implant. As soon as surgeries were finished, the animals returned to their original protocols and after 10 weeks of exposure they were euthanised (ethically sacrificed) and the mentioned bones collected for histological processing. Data showed that exposure to cigarette smoke inhalation and coffee consumption did not interfere in weight gain and that solid and liquid diet consumption was satisfactory. Rats in the CC group showed a decrease in bone neoformation around the tibial DHA implant (31.8 ± 2.8) as well as in bone formation in the parietal slit (28.6 ± 2.2). On their own, cigarette smoke inhalation or coffee consumption also led to diminished bone neoformation around the implant and delayed the bone repair process in relation to the CT group. However, reduction in the bone repair process was accentuated with exposure to both cigarette smoke inhalation and coffee consumption in this study.O presente estudo teve como objetivo avaliar os efeitos do tabagismo e do consumo de café, isolada ou concomitantemente, sobre a formação óssea e a osseointegração de implantes hidroxiapatita densa. Foram utilizados 20 ratos machos, divididos em quatro grupos (n = 5): grupo CT (controle); grupo CA (café); grupo CI (cigarro), e grupo CC (cigarro + café). Durante 16 semanas, os animais do grupo CI foram expostos à fumaça de seis cigarros/dia; os animais do grupo CA consumiram café como dieta líquida, e os animais do grupo CC, ambas as substâncias. Após seis semanas de exposição, uma falha óssea de 5 mm foi produzida no osso parietal esquerdo e de 4 mm, na tíbia esquerda dos animais. A falha do parietal foi mantida aberta, enquanto na tíbia corpos cerâmicos de hidroxiapatita densa (HAD) foram implantados em cavidade produzida cirurgicamente. Após as cirurgias, os animais retornaram aos protocolos experimentais e, ao término de dez semanas, foram eutanasiados, sendo as tíbias e os parietais coletados para processamento histológico. A exposição à fumaça do cigarro e o consumo de café não interferiram no ganho de peso dos animais, e os consumos de dieta líquida e sólida foram satisfatórios entre os grupos. Os animais do grupo CC apresentaram menor volume de osso neoformado ao redor do implante de HAD na tíbia (31,8 ± 2,8) e menor osteogênese na falha produzida no osso parietal (28,6 ± 2,2). O café e o cigarro consumidos isoladamente provocam a diminuição do volume de osso ao redor do implante e o atraso no processo de reparação óssea. Observou-se que o consumo de café associado à exposição à fumaça do cigarro reduziu de forma acentuada o processo de reparação óssea, no presente estudo.17317