Conversation Analysis of Repair in Interaction with Adults who Have Acquired HI

“Copyright 2009, Sonova. Published version of the paper reproduced here with permission from the publisher."This chapter presents a summary of some recent re-search which has been undertaken to address the pat-terns of conversational behaviour in interaction involv-ing adults who have post-lingual hearing impairment (HI). The purpose behind this research is to develop a clinical assessment and intervention protocol for assist-ing HI adults and their conversation partners in reduc-ing the impact of conversation breakdown and its repair in everyday talk. Lind (this volume) lists various conversational be-haviours which arise in the conversation of HI adults and which have been identified by the authors as being mal-adaptive . Each of these behaviours may evolve to be a genuine target for intervention. However, at this point, the patterns of most of these behaviours as they are in-fluenced by one person’s HI are not yet well enough un-derstood nor are they yet clearly distinguished from the same behaviours as they occur in conversations not in-fluenced by HI. Until evidence of their patterns of occur-rence and their sequential consequences is established they cannot readily be translated into goals for assess-ment or intervention. Amongst these behaviours, conversation repair has been the most commonly identified therapy target, for two reasons. First, it is the only one of these behaviours that can be identified a priori as a problem for conversa-tional fluency. Repair is by its very nature the result of a breakdown in mutual understanding in the conversa-tion. Participants’ attempts to resolve the breakdown inhe immediate environment in which it occurred speaks to the importance to the talkers of re-instating mutual understanding. Second, there is now a growing body of research that identifies the patterns of repair as they may be influenced by post-lingual HI. The common se-quential behaviours in one particular type of repair were outlined briefly in Lind (this volume). Two additional ex-amples are provided here also. This series of projects from our recent research has been designed as the early stages in an attempt to ad-dress the foundation issues in conversation-based ther-apy; a model of therapy in which clinical tasks directly address conversation difficulties arising as a result of one participant having a post-lingual hearing impair-ment. The studies have been designed to address key questions about the clinical patterns of repair behaviour, including: • Can we reliably sample conversation repair? • Is repair behaviour consistent over time? • Is repair influenced by intervention? and • Does repair in conversationally-oriented clinical tasks mirror repair in conversation sampling

FGF4 retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs.

Chondrodystrophy in dogs is defined by dysplastic, shortened long bones and premature degeneration and calcification of intervertebral discs. Independent genome-wide association analyses for skeletal dysplasia (short limbs) within a single breed (PBonferroni = 0.01) and intervertebral disc disease (IVDD) across breeds (PBonferroni = 4.0 × 10-10) both identified a significant association to the same region on CFA12. Whole genome sequencing identified a highly expressed FGF4 retrogene within this shared region. The FGF4 retrogene segregated with limb length and had an odds ratio of 51.23 (95% CI = 46.69, 56.20) for IVDD. Long bone length in dogs is a unique example of multiple disease-causing retrocopies of the same parental gene in a mammalian species. FGF signaling abnormalities have been associated with skeletal dysplasia in humans, and our findings present opportunities for both selective elimination of a medically and financially devastating disease in dogs and further understanding of the ever-growing complexity of retrogene biology

Oxytocin receptor antagonists as a novel pharmacological agent for reducing smooth muscle tone in the human prostate

Pharmacotherapies for the treatment of Benign Prostatic Hyperplasia (BPH) are targeted at reducing cellular proliferation (static component) or reducing smooth muscle tone (dynamic component), but response is unpredictable and many patients fail to respond. An impediment to identifying novel pharmacotherapies is the incomplete understanding of paracrine signalling. Oxytocin has been highlighted as a potential paracrine mediator of BPH. To better understand oxytocin signalling, we investigated the effects of exogenous oxytocin on both stromal cell proliferation, and inherent spontaneous prostate contractions using primary models derived from human prostate tissue. We show that the Oxytocin Receptor (OXTR) is widely expressed in the human prostate, and co-localises to contractile cells within the prostate stroma. Exogenous oxytocin did not modulate prostatic fibroblast proliferation, but did significantly (p < 0.05) upregulate the frequency of spontaneous contractions in prostate tissue, indicating a role in generating smooth muscle tone. Application of atosiban, an OXTR antagonist, significantly (p < 0.05) reduced spontaneous contractions. Individual tissue responsiveness to both exogenous oxytocin (R2 = 0.697, p < 0.01) and atosiban (R2 = 0.472,p < 0.05) was greater in tissue collected from older men. Overall, our data suggest that oxytocin is a key regulator of inherent spontaneous prostate contractions, and targeting of the OXTR and associated downstream signalling is an attractive prospect in the development of novel BPH pharmacotherapies

The care of older cancer patients in the United Kingdom

The ageing population poses new challenges globally. Cancer care for older patients is one of these challenges, and it has a significant impact on societies. In the United Kingdom (UK), as the number of older cancer patients increases, the management of this group has become part of daily practice for most oncology teams in every geographical area. Older cancer patients are at a higher risk of both under- and over-treatment. Therefore, the assessment of a patient’s biological age and effective organ functional reserve becomes paramount. This may then guide treatment decisions by better estimating a prognosis and the risk-to-benefit ratio of a given therapy to anticipate and mitigate against potential toxicities/difficulties. Moreover, older cancer patients are often affected by geriatric syndromes and other issues that impact their overall health, function and quality of life. Comprehensive geriatric assessments offer an opportunity to identify and address health problems which may then optimise one’s fitness and well-being. Whilst it is widely accepted that older cancer patients may benefit from such an approach, resources are often scarce, and access to dedicated services and research remains limited to specific centres across the UK. The aim of this project is to map the current services and projects in the UK to learn from each other and shape the future direction of care of older patients with cancer

Omega-6 Fatty Acid Biomarkers and Incident Type 2 Diabetes: Pooled Analysis of Individual-Level Data for 39 740 Adults from 20 Prospective Cohort Studies

Background: The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes. Methods: We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes. We analysed data from 20 prospective cohort studies from ten countries (Iceland, the Netherlands, the USA, Taiwan, the UK, Germany, Finland, Australia, Sweden, and France), with biomarkers sampled between 1970 and 2010. Participants included in the analyses were aged 18 years or older and had data available for linoleic acid and arachidonic acid biomarkers at baseline. We excluded participants with type 2 diabetes at baseline. The main outcome was the association between omega-6 PUFA biomarkers and incident type 2 diabetes. We assessed the relative risk of type 2 diabetes prospectively for each cohort and lipid compartment separately using a prespecified analytic plan for exposures, covariates, effect modifiers, and analysis, and the findings were then pooled using inverse-variance weighted meta-analysis. Findings: Participants were 39 740 adults, aged (range of cohort means) 49-76 years with a BMI (range of cohort means) of 23·3-28·4 kg/m(2), who did not have type 2 diabetes at baseline. During a follow-up of 366 073 person-years, we identified 4347 cases of incident type 2 diabetes. In multivariable-adjusted pooled analyses, higher proportions of linoleic acid biomarkers as percentages of total fatty acid were associated with a lower risk of type 2 diabetes overall (risk ratio [RR] per interquintile range 0·65, 95% CI 0·60-0·72,

Vocal learning-associated convergent evolution in mammalian proteins and regulatory elements.

Vocal production learning (vocal learning) is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat (Rousettus aegyptiacus) with analyses of the genomes of 215 placental mammals. First, we identified a set of proteins evolving more slowly in vocal learners. Then, we discovered a vocal motor cortical region in the Egyptian fruit bat, an emergent vocal learner, and leveraged that knowledge to identify active cis-regulatory elements in the motor cortex of vocal learners. Machine learning methods applied to motor cortex open chromatin revealed 50 enhancers robustly associated with vocal learning whose activity tended to be lower in vocal learners. Our research implicates convergent losses of motor cortex regulatory elements in mammalian vocal learning evolution

Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality: An Individual-Level Pooled Analysis of 30 Cohort Studies

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88–0.99), 0.78 (0.70–0.85), and 0.88 (0.79–0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88–1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86–0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Opetusvideoiden hyödyntäminen oppimisessa - teoriatiedon siirtäminen käytäntöön

Kliiniseen hoitoharjoitteluun siirryttäessä hammaslääketieteellisen teoriatiedon ohella opiskelijan on omaksuttava ja hallittava runsaasti erilaisia kädentaitoja sekä sosiaalisia tilanteita. Muutosvaiheen alussa sisäistettävän tietotaidon määrä sekä oppimisympäristön vaihdos voivat aiheuttaa myös jännitystä tai stressiä ja siten lisätä opiskelusta koettua kuormitusta. Hankkeen tarkoituksena oli opetusvideoiden avulla kehittää hoitoharjoitteluun liittyvää valmentavaa opintojaksoa ja samalla havainnoida opetusvideoiden hyödyllisyyttä yhtenä oppimismuotona. Lisätavoitteena oli selvittää, voidaanko opetusvideoiden avulla vähentää opiskelijoiden kokemaa stressiä kliiniseen vaiheeseen siirryttäessä. Syyslukukausien 2016 ja 2017 alussa kahdelle samassa opiskeluvaiheessa olevalle kandiryhmälle (ryhmät 1 ja 2; yhteensä 86 opiskelijaa) kohdennettiin kysely, jonka avulla selvitettiin heidän hoitoharjoitteluun liittyviä tuntemuksiaan sekä käsityksiään. Lukuvuoden 2016-2017 aikana laadittiin myös neljä opetusvideota, joilla demonstroitiin Turun kaupungin opetushammashoitolan toimintaympäristössä edellytettäviä ja kliinisen hoitoharjoittelun aloittavan hammaslääketieteen kandin näkökulmasta tarpeellisia toimintamalleja. Ryhmä 2 sai mahdollisuuden katsoa nämä videot valmentavan opintojakson yhteydessä, joten heidän kyselyssään selvitettiin myös kunkin videon osalta katselukerrat sekä tiedusteltiin yleisiä mielipiteitä videoiden käyttökelpoisuudesta / hyödyllisyydestä lisäoppimateriaalina. Kyselyn vastausprosentti oli kattava; 83,7 % ryhmän 1 ja 62,8 % ryhmän 2 kandeista osallistui kyselyyn. Valtaosa vastanneista koki klinikkaan siirtymisen jännittävänä tai jokseenkin jännittävänä. Koetun stressin osalta ryhmät eivät juuri poikenneet toisistaan (p>0.05), joskin hieman suurempi osa ryhmän 2 vastaajista koki olevansa valmis tai jokseenkin valmis siirtymään klinikkaan (p>0.05). Merkittävimmät erot ryhmien välillä liittyivät tietouteen alkutarkastuskäynnin sisällöstä (p=0,024) ja sen toteutuksesta (p=0,003); ts. ryhmän 2 opiskelijat olivat selvästi tietoisempia, miten toimia em. kliinisissä tilanteissa. Kyseiset vastaukset korreloivat hyvin opetusvideoiden katselukertojen kanssa. Opetusvideot koettiin yleisesti mielekkäiksi ja hyödyllisiksi, sillä niiden avulla on mahdollista selventää perehdytyksessä epäselväksi jääneitä ja/tai unohtuneita asioita. Siten videomateriaalin avulla on ilmeisesti mahdollista selkeyttää opiskelijoiden käsityksiä kliinisten toimenpiteiden toteutustavoista, mikä osaltaan ainakin epäsuorasti saattaa vähentää myös klinikkavaiheeseen liittyvää jännitystä