Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease

Mannitol, a natural alcoholic-sugar, was recently suggested as a potential disease-modifying agent in Parkinson's disease. In animal models of the disease, mannitol interferes with the formation of α-synuclein fibrils, inhibits the formation of α-synuclein oligomers and leads to phenotypic recovery of impaired motor functions. Parkinson's patients who consume mannitol report improvements of both motor and non-motor symptoms. Safety of long-term use of oral mannitol, tolerable dose and possible benefit, however, were never clinically studied. We studied the safety of oral mannitol in Parkinson's disease and assessed the maximal tolerable oral dose by conducting a phase IIa, randomized, double-blind, placebo-controlled, single-center, dose-escalating study (ClinicalTrials.gov Identifier: NCT03823638). The study lasted 36 weeks and included four dose escalations of oral mannitol or dextrose to a maximal dose of 18 g per day. The primary outcome was the safety of oral mannitol, as assessed by the number of adverse events and abnormal laboratory results. Clinical and biochemical efficacy measures were collected but were not statistically-powered. Fourteen patients receiving mannitol completed the trial (in addition to eight patients on placebo). Mannitol-related severe adverse events were not observed. Gastrointestinal symptoms limited dose escalation in 6/14 participants on mannitol. None of the clinical or biochemical efficacy secondary outcome measures significantly differed between groups. We concluded that long-term use of 18 g per day of oral mannitol is safe in Parkinson's disease patients but only two third of patients tolerate this maximal dose. These findings should be considered in the design of future efficacy trials.

Polyester 5-0 Suture for Porous Implant Placement After Retinoblastoma Enucleation: Analysis of 120 Sockets

Background: Techniques used to suture the rectus muscle to the implant can influence the implant-related complications which is still a major problem following retinoblastoma enucleation. The goals of this work were to report the efficacy among patients with retinoblastoma who underwent enucleation followed by porous implant placement with the rectus muscles sutured with 5-0 polyester suture.Methods: This was a retrospective study of consecutive patients with retinoblastoma who underwent primary enucleation and porous implant placement with the rectus muscles tagged and sutured to the implant with polyester 5-0 suture. All the patients were followed up for a minimum of 2 years. The main outcome measure was implant exposure. The secondary efficacy measures were other implant-related complications.Results: A total of 120 patients (120 eyes) underwent primary enucleation and porous implant placement were included. Postoperatively, 10/120 (8.3%) eyes developed exposure and conjunctival granuloma. Exposure was the most common postoperative complication (7/10, 70.0%). There were no cases of implant extrusion, migration, or infection.Conclusions:Polyester 5-0 sutures are successful in patients with retinoblastoma who underwent enucleation followed by porous implant placement. Complications are minimal. Polyester 5-0 sutures were not associated with unacceptable complications in this pediatric population.

Epidemiology for Monitoring and Evaluation

Monitoring involves continuous observation to see if plans are on track and evaluation determines the effectiveness of planned health interventions delivered by the health services and programmes. The systems approach uses indicators to measure delivery, access, quality, and coverage of services and programmes and their impact on health status indicators. Efficacy measures the impact of interventions in individual people. Measuring effectiveness in whole communities utilizes quasi-experimental population-based study designs with community controls. The importance of ethical principles and monitoring equity in health planning is presented and emphasised.

"A New Instrument for Assessment of Emotion Regulation: The Emotion Regulation Interview-Revised Form"

"The main purpose of the present study is to adapt the Emotion Regulation Interview (ERI) into Turkish and to examine its psychometric properties, while at the same time, to revise it by extending its scope in terms of emotions, emotion regulation (ER) strategies, and the efficacy measures related to ER strategies. For this purpose, various adjustments have been made to the original interview form, resulting in the Emotion Regulation Interview-Revised Form (ERI-RF). The ERI-RF evaluates the regulation of the emotions (i.e., anxiety, sadness, anger) experienced in romantic relationships, recognizing that emotions and ER mostly emerge in close relationships. A total of 138 participants in romantic relationships were interviewed using the ERI-RF, and second interviews were conducted with 31 of the participants for the assessment of test-retest reliability. Results showed that the ERI-RF had good validity results, and the use of some ER strategies to certain emotions demonstrated sufficient test-retest reliability. It was concluded that the ERI-RF, as an assessment tool for the evaluation of a wide range of ER strategies based on the most frequently experienced emotions, has sufficient psychometric properties, and that its use in different samples in feature studies may yield useful results."

An Assessment of Individuals’ Systems Thinking Skills via Immersive Virtual Reality Complex System Scenarios

This study utilized the application of authentic Virtual Reality (VR) to replicate the real-world complex system scenarios of a large retail supply chain. The proposed VR scenarios were developed based on an established systems thinking instrument that consists of seven dimensions: level of complexity, independence, interaction, change, uncertainty, systems’ worldview, and flexibility. However, in this study, we only developed the VR scenarios for the first dimension, level of complexity, to assess an individual’s Systems Thinking Skills (STS) when he or she engages in a turbulent virtual environment. The main objective of this study was to compare a student’s STS when using traditional ST instruments versus VR scenarios for the complexity dimension. The secondary aim was to investigate the efficacy of VR scenarios utilizing three measurements: Simulation Sickness Questionnaire (SSQ), System Usability Scale (SUS), and Presence Questionnaire (PQ). In addition to the three measures, NASA TLX assessment was also performed to assess the perceived workload with regards to performing the tasks in VR scenarios. The results show students’ preferences in the VR scenarios are not significantly different from their responses obtained using the traditional systems skills instrument. The efficacy measures confirmed that the developed VR scenarios are user friendly and lie in an acceptable region for users. Finally, the overall NASA TLX score suggests that users require 36% perceived work effort to perform the activities in VR scenarios.

A phase 1/2 open-label study of KY1044, an anti-ICOS antibody with dual mechanism of action, as single agent and in combination with atezolizumab, in adult patients with advanced malignancies.

2624 Background: KY1044, is a fully human IgG1 anti ICOS antibody designed to stimulate Teffs and to deplete ICOS high Tregs in the tumor microenvironment. Methods: Patients with advanced/metastatic malignancies received escalating doses of KY1044 as a single agent and in combination with atezolizumab 1200 mg by IV infusion every 3 weeks until disease progression or unacceptable toxicity. Dose escalation was guided by a modified toxicity probability interval design. The primary objective was to determine safety, tolerability, and maximum tolerated dose. Cohorts that were tolerated were later enriched with more subjects. AEs were classified according to CTCAE v5 and efficacy measures performed according to RECIST v1.1 every 8 weeks for the first 16 weeks and then every 12 weeks. Results: As of 16-Dec-2020, a total of 103 patients have been enrolled in the study (38 patients as monotherapy in 6 cohorts at doses ranging from 0.8 to 240 mg and 65 in combination with atezolizumab in 5 cohorts at doses 0.8 – 80 mg). 63% and 55% of patients received ≥4 prior anti-cancer therapies in the single agent and combination cohorts, respectively. All cohorts were completed without DLTs during the first 21 days of treatment. In the KY1044 single agent cohorts, 47.4% of patients experienced treatment-related AEs (TRAEs), all were grades 1 or 2. In the combination cohorts, TRAEs were observed in 58% of patients. Most of the TRAEs were grade 1 or 2 apart from 8 TRAEs that were ≥grade 3 occurring in <8% of patients. Infusion-related reactions, pyrexia and lymphopenia were the most commonly occurring TRAEs in ≥10% of patients. TRAE leading to dose interruptions occurred in 1 patient in the single agent cohort and in 4 patients in the combination cohort. Only 1 patient discontinued treatment due to myositis that was considered related to the combination. Preliminary KY1044 PK data from 69 patients agree with the PK model predictions. Median treatment duration for all enrolled patients was 9 weeks. Treatment duration ≥16 weeks was observed in 24% (9/38) and 27% (17/64) patients in the single agent and combination cohorts, respectively. Five objective responses, including 1 CR in triple negative breast cancer (TNBC) and 4 PRs in TNBC, head and neck squamous cell carcinoma, penile and pancreatic cancer were observed. Four of the 5 responding patients were still on treatment at the data cut, with 3 patients on treatment for >43 weeks (range 45 to 66 weeks). Conclusions: KY1044 is well tolerated as single agent and in combination with atezolizumab. Objective responses have been observed in this phase 1 part of the study. The phase 1 expansion and phase 2 part of the study is ongoing. Clinical trial information: NCT03829501.

OP0154-HPR FEASIBILITY OF A WEB-BASED, PEER-SUPPORTED EXERCISE PROGRAM FOR PEOPLE WITH HIP OR KNEE OSTEOARTHRITIS

Background:Long-term physical activity (PA) and exercise is recommended as a cornerstone in the treatment of people with osteoarthritis (OA) (1), yet adherence to exercise is challenging (2). The treatment needs for this large group of patients cannot be fully managed within the health-care system, thus developing innovative and effective follow-up strategies is urgently needed.Objectives:To explore the feasibility and preliminary efficacy of a web-based, peer-supported exercise program for people with hip or knee OA.Methods:This study was a single-group, pre-post feasibility study. Patients aged 40-80 years with hip or knee OA who were not candidates for surgery were eligible. The 12-week intervention was delivered through a patient-organizations (The Norwegian Association for Rheumatic Diseases) web-based platforms, and included weekly exercise programs, weekly motivational messages, an OA and exercise website and assigned peer-supporters. Feasibility was evaluated by calculating the proportion of eligible patients who were enrolled and retained at follow-up, as well as time resources used on delivery of the intervention. Acceptability was evaluated by calculating proportion of patients who had valid baseline accelerometer data and completed the maximal cardiorespiratory exercise test according to protocol. Primary efficacy measures were change in PA assessed by accelerometers and change in exercise capacity (VO2peak) assessed by indirect maximal cardiorespiratory exercise test. Secondary efficacy measures were change in patient reported outcomes assessed by HOOS and KOOS (www.koos.nu) (a 10-point change in normalized scores was considered a minimally important change). Data was analysed using paired sample t-test, given as mean change (95% confidence interval) and p-values.Results:We identified 49 eligible patients of which 35 (71%) consented and were enrolled. Among those who consented, 22 (63%) were retained. Time resources used on delivery of the exercise programs and motivational messages were mean (SD) 7.3±1.1 min per week/patient. Compliance with wearing the accelerometer was mean (SD) 6.1±1.0 valid days (mean (SD) 13.8±1.3 hours/day). Twenty (67%) out of 30 patients who attended baseline testing performed the maximal cardiorespiratory exercise test, of which 18 completed according to protocol. Due to Covid-19 restrictions, follow-up testing of primary efficacy measures included only eight patients. For these patients there was a significant increase from baseline to follow-up on moderate-to-vigorous PA (mean change 16.4 minutes/day; 95% CI 6.9, 25.9, p=0.005) and VO2peak (mean change 1.83 ml/kg/min; 95% CI 0.29, 3.36, p=0.026). Across all secondary efficacy measures 30-52% of the patients (n=21) improved from baseline to follow-up (Figure 1).Figure 1.Proportion (%) of patients with Minimally Important Change (from baseline to follow-up) in normalized scores in subdomains of Hip disability and Osteoarthritis Outcome Score (HOOS) / Knee injury and Osteoarthritis Outcome Score (KOOS).Conclusion:Overall, the examined study processes were considered to be feasible and acceptable. Some minor amendments should be applied to improve the recruitment and retention rate before it can be carried out in a larger trial. The efficacy results should be interpreted with caution due the small sample size. However, if the positive results in this study are confirmed in a power-calculated randomised controlled trial, our novel follow-up strategy may be implemented and recommended for long-term management of hip and knee OA.References:[1]Kolasinski SL, Neogi T, Hochberg MC, Oatis C, Guyatt G, Block J, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol. 2020;72(2):220-33.[2]Williamson W, Kluzek S, Roberts N, Richards J, Arden N, Leeson P, et al. Behavioural physical activity interventions in participants with lower-limb osteoarthritis: a systematic review with meta-analysis. BMJ Open. 2015;5(8):e007642.Acknowledgements:The authors wish to acknowledge all patients for participating, the patient representative who gave invaluable input on interventional components and the peer-supporters for volunteering to provide interventional support.Disclosure of Interests:None declared

Career Adaptability and Career Decision Self-Efficacy: Meta-Analysis

The relationship between career adaptability and career decision self-efficacy was examined due to its importance for clients in the career development and career decision-making process. Multivariate meta-analyses using 18 studies with a total population of 6,339 participants were employed. Moderator variables important to this relationship were country of participants, mean age, and career adaptability measures. Estimated correlations between career adaptability subscales and career decision self-efficacy measures ranged from .36 to .44. Findings are discussed in relation to career research and counseling.

Correlates of Vaccine-Induced Protection against SARS-CoV-2

We are in the midst of a pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19). SARS-CoV-2 has caused more than two million deaths after one year of the pandemic. The world is experiencing a deep economic recession. Safe and effective vaccines are needed to prevent further morbidity and mortality. Vaccine candidates against COVID-19 have been developed at an unprecedented speed, with more than 200 vaccine candidates currently under investigation. Among those, 20 candidates have entered the clinical Phase 3 to evaluate efficacy, and three have been approved by the European Medicines Agency. The aim of immunization is to act against infection, disease and/or transmission. However, the measurement of vaccine efficacy is challenging, as efficacy trials need to include large cohorts with verum and placebo cohorts. In the future, this will be even more challenging as further vaccine candidates will receive approval, an increasing number of humans will receive vaccinations and incidence might decrease. To evaluate novel and second-generation vaccine candidates, randomized placebo-controlled trials might not be appropriate anymore. Correlates of protection (CoP) could be an important tool to evaluate novel vaccine candidates, but vaccine-induced CoP have not been clearly defined for SARS-CoV-2 vaccines. In this review, we report on immunogenicity against natural SARS-CoV-2 infection, vaccine-induced immune responses and discuss immunological markers that can be linked to protection. By discussing the immunogenicity and efficacy of forerunner vaccines, we aim to give a comprehensive overview of possible efficacy measures and CoP.