Intraputamenal Cerebral Dopamine Neurotrophic Factor in Parkinson's Disease: A Randomized, Double-Blind, Multicenter Phase 1 Trial.

BACKGROUND: Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD). OBJECTIVE: The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity. METHODS: We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone-anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo-controlled, double-blind, 6-month main study followed by an active-treatment 6-month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [18 F]FE-PE2I. RESULTS: Drug-related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies. CONCLUSIONS: Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Single-arm Phase II Trial of Neoadjuvant Cabazitaxel and Cisplatin Chemotherapy for Muscle-Invasive Transitional Cell Carcinoma of the Urinary Bladder.

INTRODUCTION: Neoadjuvant cisplatin-based combination chemotherapy improves survival in muscle-invasive bladder cancer. However, response rates and survival remain suboptimal. We evaluated the efficacy, safety, and tolerability of cisplatin plus cabazitaxel. METHODS: A phase II single-arm trial was designed to recruit at least 26 evaluable patients. This would give 80% power to detect the primary endpoint, an objective response rate defined as a pathologic complete response plus partial response (pathologic downstaging), measured by pathologic staging at cystectomy (p0 = 0.35 and p1 = 0.60, α = 0.05). RESULTS: Objective response was seen in 15 of 26 evaluable patients (57.7%) and more than one- third of patients achieved a pathologic complete response (9/26; 34.6%). Seventy-eight percent of the patients (21/27) completed all cycles of treatment, with only 6.7% of the reported adverse events being graded 3 or 4. There were 6 treatment-related serious adverse event reported, but no suspected unexpected serious adverse reactions. In the patients who achieved an objective response, the median progression-free survival and overall survival were not reached (median follow-up of 41.5 months). In contrast, the median progression-free survival (7.2 months) and overall survival (16.9 months) were significantly worse (P = .001, log-rank) in patients who did not achieve an objective response. CONCLUSION: Cabazitaxel plus cisplatin for neoadjuvant treatment of muscle-invasive bladder cancer can be considered a well-tolerated and effective regimen before definitive therapy with higher rates (57.7%) of objective response, comparing favorably to that with of cisplatin/gemcitabine (23%-26%). These results warrant further evaluation in a phase III study.

Adolescent self-harm in the community: an update on prevalence using a self-report survey of adolescents aged 13-18 in England.

Background: To establish an estimate of prevalence in a nationally representative sample of community adolescents. To examine associations between self-harm and wellbeing. Methods: An anonymous self-report survey completed by 2000 adolescents aged 13-18 years across England. Wellbeing was measured using the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS). Results: In total 15.5% (n = 309) of participants reported ever having self-harmed (95% confidence intervals 13.9-17.1). The median age of onset was 13.0 years. Females aged 13-15 years reported the highest incidence of self-harm within the past year (54.9%). Cutting elsewhere (other than on the arms) was more prevalent amongst females (56.4%). The mean wellbeing score for the whole sample (45.6) was lower than the WEMWBS validation score (48.8). Self-harm was associated with a significantly lower wellbeing score, with mean scores of 38.7 (ever self-harmed) and 46.8 (never self-harmed). Conclusions: Self-harm remains prevalent amongst adolescents aged 13-18 years in England. An awareness of the age of peak incidence and risks associated with preferred harming behaviours is crucial during assessment and intervention. The promotion of wellbeing is important for all young people. Further study is needed on the ways in which wellbeing may prevent, or ameliorate, the distress associated with self-harm.

The safety of general anaesthesia in paediatric patients undergoing the application of Biobrane® for small scalds.

BACKGROUND: Each year more than 5000 children present to English and Welsh hospitals for the management of scalds; 60% of these are small scalds of less than 10% body surface area. There are no agreed UK care pathways for this injury. One method of management is to use a biosynthetic wound dressing after thorough wound cleaning. In children, this usually utilises general anaesthesia. This study investigates the incidence of adverse events during anaesthesia for the application of biosynthetic dressings in children with small-area scalds. METHODS: The medical records of 500 consecutive admissions to a tertiary care paediatric burn centre between July 1st 2007 and June 30th 2012 were analysed. The primary outcome was any patient-related adverse event incurred as a result of the general anaesthesia. Secondary outcomes included delays in discharge and any recovery sequelae to the adverse events. RESULTS: There were 21 (4.2%) documented adverse events associated with 500 episodes of anaesthesia. Of these, the majority (52%) were documented as self-resolving laryngospasm. All episodes were temporary with no recovery sequelae and did not delay discharge from the post-anaesthetic recovery area. CONCLUSIONS: The use of general anaesthesia in this setting for the application of biosynthetic dressings in children with small-area scalds has a low incidence of anaesthesia-related complications with no associated long-term sequelae. This incidence is similar to that quoted for adverse events related to anaesthesia for other procedures and is lower than that reported for procedures using sedation.

Personal birth preferences and actual mode of delivery outcomes of obstetricians and gynaecologists in South West England; with comparison to regional and national birth statistics.

OBJECTIVE: To determine personal birth preferences of obstetricians in various clinical scenarios, in particular elective caesarean section for maternal request. To determine actual rates of modes of deliveries amongst the same group. To compare the obstetrician's mode of delivery rates, to the general population. STUDY DESIGN: Following ethical approval, a piloted online survey link was sent via email to 242 current obstetricians and gynaecologists, (consultants and trainees) in South West England. Mode of delivery results were compared to regional and national population data, using Hospital Episode Statistics and subjected to statistical analysis. RESULTS: The response rate was 68%. 90% would hypothetically plan a vaginal delivery, 10% would consider a caesarean section in an otherwise uncomplicated primiparous pregnancy. Of the 94/165 (60%) respondents with children (201 children), mode of delivery for the first born child; normal vaginal delivery 48%, caesarean section 26.5% (elective 8.5%, emergency 18%), instrumental 24.5% and vaginal breech 1%. Only one chose an elective caesarean for maternal request. During 2006-2011 obstetricians have the same overall actual modes of birth as the population (p=0.9). CONCLUSIONS: Ten percent of obstetricians report they would consider requesting caesarean section for themselves/their partner, which is the lowest rate reported within UK studies. However only 1% actually had a caesarean solely for maternal choice. When compared to regional/national statistics obstetricians currently have modes of delivery that are not significantly different than the population and suggests that they choose non interventional delivery if possible.