Acquisition of aspect and aktionsart by children in croatian and french

Our results indicate some differences in the use of aspect between French and Croatian speaking children. In Croatian language children always manage to keep the appropriate aspect, unlike French children. However, the imperfective aspect seems to be better acquired in French children than the perfective aspect. The perfective aspect, the marked form both in French as well as in Croatian, is related to the lexical meaning of the verbs. The acquisition of the Aktionsart in both languages seems to be more a matter of semantics than of morphology. Furthermore, our data suggest the existence of a specific developmental trend in the use of Aktionsart (intensive, iterative and inchoative), which is similar for children speaking Slavic and Romanic languages

Development of Nanoparticles for Imaging Applications

Nanoparticles have attracted considerable recent research interest for a variety of applications and can be used to visualize and characterise biological processes at the molecular and cellular level. They can be exploited as contrast agents for imaging and functionalised to incorporate luminescent moieties to a provide multi-modal imaging capability. This thesis presents a detailed series of studies on a luminescently labelled gold and silica nanoparticles, with the use of optical and electron microscopies to examine their applications. Using surfactant and peptide pre-coatings gold nanoparticles were coated with an organic dye developed bind to the nanoparticle surface. The imaging potential of these novel nanoprobes is explored by examining uptake in vitro in cancer cells. Confocal laser scanning and transmission electron microscopies indicate significant cellular uptake. Nuclear uptake is also observed and possible methods of translocation to the nucleus are discussed. Cell cycle dysregulation is also assessed with no statistically significant perturbations observed. The cellular uptake of 13 nm and 100 nm gold nanoparticles coated with a luminescent ruthenium polypyridyl complex was also investigated. Microscopy studies demonstrated the imaging potential of luminescent nanoprobes upon cellular uptake which was not accompanied significant cytotoxicity. Finally an investigation in to the interaction of luminescent silica particles with dentine is presented. Confocal and scanning electron microscopies enable qualitative comparisons of the dentinal tubule occluding ability of particles coated with surfactants. The data indicate surfactant hydrophobicity is important factor in governing interactions with the dentine and illustrate the potential of luminescence imaging in dentistry

Randomized trial comparing proactive, high-dose versus reactive, low-dose intravenous iron supplementation in hemodialysis (PIVOTAL) : Study design and baseline data

Background: Intravenous (IV) iron supplementation is a standard maintenance treatment for hemodialysis (HD) patients, but the optimum dosing regimen is unknown. Methods: PIVOTAL (Proactive IV irOn Therapy in hemodiALysis patients) is a multicenter, open-label, blinded endpoint, randomized controlled (PROBE) trial. Incident HD adults with a serum ferritin 700 μg/L and/or TSAT ≥40%) or a reactive, low-dose IV iron arm (iron sucrose administered if ferritin <200 μg/L or TSAT < 20%). We hypothesized that proactive, high-dose IV iron would be noninferior to reactive, low-dose IV iron for the primary outcome of first occurrence of nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure or death from any cause. If noninferiority is confirmed with a noninferiority limit of 1.25 for the hazard ratio of the proactive strategy relative to the reactive strategy, a test for superiority will be carried out. Secondary outcomes include infection-related endpoints, ESA dose requirements, and quality-of-life measures. As an event-driven trial, the study will continue until at least 631 primary outcome events have accrued, but the expected duration of follow-up is 2-4 years. Results: Of the 2,589 patients screened across 50 UK sites, 2,141 (83%) were randomized. At baseline, 65.3% were male, the median age was 65 years, and 79% were white. According to eligibility criteria, all patients were on ESA at screening. Prior stroke and MI were present in 8 and 9% of the cohort, respectively, and 44% of patients had diabetes at baseline. Baseline data for the randomized cohort were generally concordant with recent data from the UK Renal Registry. Conclusions: PIVOTAL will provide important information about the optimum dosing of IV iron in HD patients representative of usual clinical practice. Trial Registration: EudraCT number: 2013-002267-25.Peer reviewedFinal Published versio

Cisplatin +/− rucaparib after preoperative chemotherapy in patients with triple-negative or BRCA mutated breast cancer

Patients with triple-negative breast cancer (TNBC) who have residual disease after neoadjuvant therapy have a high risk of recurrence. We tested the impact of DNA-damaging chemotherapy alone or with PARP inhibition in this high-risk population. Patients with TNBC or deleterious BRCA mutation (TNBC/BRCAmut) who had >2 cm of invasive disease in the breast or persistent lymph node (LN) involvement after neoadjuvant therapy were assigned 1:1 to cisplatin alone or with rucaparib. Germline mutations were identified with BROCA analysis. The primary endpoint was 2-year disease-free survival (DFS) with 80% power to detect an HR 0.5. From Feb 2010 to May 2013, 128 patients were enrolled. Median tumor size at surgery was 1.9 cm (0-11.5 cm) with 1 (0-38) involved LN; median Residual Cancer Burden (RCB) score was 2.6. Six patients had known deleterious BRCA1 or BRCA2 mutations at study entry, but BROCA identified deleterious mutations in 22% of patients with available samples. Toxicity was similar in both arms. Despite frequent dose reductions (21% of patients) and delays (43.8% of patients), 73% of patients completed planned cisplatin. Rucaparib exposure was limited with median concentration 275 (82-4694) ng/mL post-infusion on day 3. The addition of rucaparib to cisplatin did not increase 2-year DFS (54.2% cisplatin vs. 64.1% cisplatin + rucaparib; P = 0.29). In the high-risk post preoperative TNBC/BRCAmut setting, the addition of low-dose rucaparib did not improve 2-year DFS or increase the toxicity of cisplatin. Genetic testing was underutilized in this high-risk population

Cardiac rehabilitation to improve health-related quality of life following trans-catheter aortic valve implantation: a randomised controlled feasibility study: RECOVER-TAVI Pilot, ORCA 4, for the Optimal Restoration of Cardiac Activity Group

Objectives: Transcatheter aortic valve implantation (TAVI) is often undertaken in the oldest frailest cohort of patients undergoing cardiac interventions. We plan to investigate the potential benefit of cardiac rehabilitation (CR) in this vulnerable population. Design: We undertook a pilot randomised trial of CR following TAVI to inform the feasibility and design of a future randomised clinical trial (RCT). Participants: We screened patients undergoing TAVI at a single institution between June 2016 and February 2017. Interventions: Participants were randomised post-TAVI to standard of care (control group) or standard of care plus exercise-based CR (intervention group). Outcomes: We assessed recruitment and attrition rates, uptake of CR, and explored changes in 6-min walk test, Nottingham Activities of Daily Living, Fried and Edmonton Frailty scores and Hospital Anxiety and Depression Score, from baseline (30 days post TAVI) to 3 and 6 months post randomisation. We also undertook a parallel study to assess the use of the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the post-TAVI population. Results: Of 82 patients screened, 52 met the inclusion criteria and 27 were recruited (3 patients/month). In the intervention group, 10/13 (77%) completed the prescribed course of 6 sessions of CR (mean number of sessions attended 7.5, SD 4.25) over 6 weeks. At 6 months, all participants were retained for follow-up. There was apparent improvement in outcome scores at 3 and 6 months in control and CR groups. There were no recorded adverse events associated with the intervention of CR. The KCCQ was well accepted in 38 post-TAVI patients: mean summary score 72.6 (SD 22.6). Conclusions: We have demonstrated the feasibility of recruiting post-TAVI patients into a randomised trial of CR. We will use the findings of this pilot trial to design a fully powered multicentre RCT to inform the provision of CR and support guideline development to optimise health-related quality of life outcomes in this vulnerable population. Retrospectively registered 3rd October 2016 clinicaltrials.gov NCT02921880. Trial registration: Clinicaltrials.Gov identifier NCT0292188

Effective bridging therapy can improve CD19 CAR-T outcomes while maintaining safety in patients with large B-cell lymphoma

The impact of bridging therapy (BT) on CD19-directed chimeric antigen receptor T-cell (CD19CAR-T) outcomes in large B-cell lymphoma (LBCL) is poorly characterised. Current practice is guided by physician preference rather than established evidence. Identification of effective BT modalities and factors predictive of response could improve CAR-T intention to treat and clinical outcomes. We assessed BT modality and response in 375 adult LBCL patients in relation to outcomes following axicabtagene ciloleucel (Axi-cel) or tisagenlecleucel (Tisa-cel). The majority of patients received BT with chemotherapy (57%) or radiotherapy (17%). We observed that BT was safe for patients, with minimal morbidity/mortality. We showed that complete or partial response to BT conferred a 42% reduction in disease progression and death following CD19CAR-T therapy. Multivariate analysis identified several factors associated with likelihood of response to BT, including response to last line therapy, the absence of bulky disease, and the use of Polatuzumab-containing chemotherapy regimens. Our data suggested that complete/partial response to BT may be more important for Tisa-cel than Axi-cel, as all Tisa-cel patients with less than partial response to BT experienced frank relapse within 12 months of CD19CAR-T infusion. In summary, BT in LBCL should be carefully planned towards optimal response and disease debulking, to improve CD19CAR-T patient outcomes. Polatuzumab-containing regimens should be strongly considered for all suitable patients, and failure to achieve complete/partial response to BT pre-Tisa-cel may prompt consideration of further lines of BT where possible

The PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease trial:study design and baseline data for a multicentre randomized controlled trial

Background: Exercise interventions designed to improve physical function and reduce sedentary behaviour in haemodialysis (HD) patients might improve exercise capacity, reduce fatigue and lead to improved quality of life (QOL). The PEDAL study aimed to evaluate the effectiveness of a 6-month intradialytic exercise programme on quality of life (QOL) and physical function, compared to usual care for patients on HD in the UK.Methods: We conducted a prospective, pragmatic multicentre randomised controlled trial (RCT) in 335 HD patients and randomly (1:1) assigned them to either, i) intradialytic exercise training plus usual care maintenance HD, or ii) usual care maintenance HD. The primary outcome of the study was the change in Kidney Disease Quality of Life (KDQOL-SF 1.3) Physical Component Score between baseline and 6 months. Additional secondary outcomes included changes in: peak aerobic capacity, physical fitness, habitual physical activity levels and falls (International Physical Activity Questionnaire, Duke’s Activity Status Index and Tinetti Falls Efficacy Scale), quality of life and symptom burden assessments (EQ5D), arterial stiffness (pulse wave velocity), anthropometric measures, resting blood pressure, clinical chemistry, safety and harms associated with the intervention, hospitalisations, and cost-effectiveness. A nested qualitative study investigated the experience and acceptability of the intervention for both participants and members of the renal healthcare team.Results: At baseline assessment, 62.4% of the randomised cohort were male, the median age was 59.3 years, and 50.4% were White. Prior cerebrovascular events and myocardial infarction (MI) were present in 8 and 12% of the cohort, respectively, 77.9% of patients had 3hypertension and 39.4% had diabetes. Baseline clinical characteristic and laboratory data for the randomised cohort were generally concordant with data from the UK Renal Registry.Conclusion: The results from this study will address a significant knowledge gap in the prescription of exercise interventions for patients receiving maintenance HD therapy and inform the development of intradialytic exercise programmes both nationally and internationally.Trial Registration: ISRCTN N83508514; registered on 17th December 2014.</p