The STRAT-PARK cohort: A personalized initiative to stratify Parkinson's disease.

The STRAT-PARK initiative aims to provide a platform for stratifying Parkinson's disease (PD) into biological subtypes, using a bottom-up, multidisciplinary biomarker-based and data-driven approach. PD is a heterogeneous entity, exhibiting high interindividual clinicopathological variability. This diversity suggests that PD may encompass multiple distinct biological entities, each driven by different molecular mechanisms. Molecular stratification and identification of disease subtypes is therefore a key priority for understanding and treating PD. STRAT-PARK is a multi-center longitudinal cohort aiming to recruit a total of 2000 individuals with PD and neurologically healthy controls from Norway and Canada, for the purpose of identifying molecular disease subtypes. Clinical assessment is performed annually, whereas biosampling, imaging, and digital and neurophysiological phenotyping occur every second year. The unique feature of STRAT-PARK is the diversity of collected biological material, including muscle biopsies and platelets, tissues particularly useful for mitochondrial biomarker research. Recruitment rate is ∼150 participants per year. By March 2023, 252 participants were included, comprising 204 cases and 48 controls. STRAT-PARK is a powerful stratification initiative anticipated to become a global research resource, contributing to personalized care in PD.

NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease.

Nicotinamide adenine dinucleotide (NAD) replenishment therapy using nicotinamide riboside (NR) shows promise for Parkinson's disease (PD) and other neurodegenerative disorders. However, the optimal dose of NR remains unknown, and doses exceeding 2000 mg daily have not been tested in humans. To evaluate the safety of high-dose NR therapy, we conducted a single-center, randomized, placebo-controlled, double-blind, phase I trial on 20 individuals with PD, randomized 1:1 on NR 1500 mg twice daily (n = 10) or placebo (n = 10) for four weeks. The trial was conducted at the Department of Neurology, Haukeland University Hospital, Bergen, Norway. The primary outcome was safety, defined as the frequency of moderate and severe adverse events. Secondary outcomes were tolerability defined as frequency of mild adverse events, change in the whole blood and urine NAD metabolome, and change in the clinical severity of PD, measured by MDS-UPDRS. All 20 participants completed the trial. The trial met all prespecified outcomes. NR therapy was well tolerated with no moderate or severe adverse events, and no significant difference in mild adverse events. NR therapy was associated with clinical improvement of total MDS-UPDRS scores. However, this change was also associated with a shorter interval since the last levodopa dose. NR greatly augmented the blood NAD metabolome with up to 5-fold increase in blood NAD+ levels. While NR-recipients exhibited a slight initial rise in serum homocysteine levels, the integrity of the methyl donor pool remained intact. Our results support extending the dose range of NR in phase II clinical trials to 3000 mg per day, with appropriate safety monitoring. Clinicaltrials.gov identifier: NCT05344404.

Comparing case-control study for treatment of proximal tibia fractures with a complete metaphyseal component in two centers with different distinct strategies: fixation with Ilizarov frame or locking plates.

BACKGROUND: The purpose of this study was to compare two methods of stabilization for proximal tibia fractures (AO 41) with a complete metaphyseal component, external fixation with the Ilizarov wire frame, and internal fixation with locking plates. METHODS: Patients from two level 1 trauma centers treated between 2009 and 2015 were included in a retrospective comparing cohort study. The first center stabilized the non-pathological, proximal tibia fractures exclusively with external fixation and the second with internal plating. Combined clinically and radiologically evaluated, bone healing was the primary outcome. The secondary outcomes included complications, range of motion (ROM) and axial alignment of the knee, the reoperation rate within 6 months, heterotopic ossifications (HTO), and signs of posttraumatic osteoarthritis (PTOA). A logistic regression analysis corrected for uneven distributed parameters. RESULTS: The 62 patients treated with Ilizarov frame and the 68 patients treated with plate fixation were comparable regarding epidemiological parameters, injury characteristics, and comorbidity except for injury severity score (ISS) and smoking behavior. The time of healing was shorter in the group undergoing plate fixation (p = 0.041); however, the incidence of non-unions was equal. Furthermore, there was no difference regarding the rate of deep infections, thrombosis, alignment, reoperations, PTOA, and ROM. Heterotopic ossifications were more prevalent following plate fixation (13.2 vs 1.6%, p = .013). External fixation was associated with a higher rate of superficial infections (40.4 vs 2.9%, p = .000). The initial displacement, the incidence of deep infections, and the classification significantly influenced the incidence of non-unions in both groups (p < 0.02). CONCLUSIONS: Fixation of proximal tibia fractures with plates resulted in a slightly shorter healing time compared to Ilizarov frame stabilization. Furthermore, the complication profiles differ with more heterotopic ossifications and less superficial infections following internal plating. TRIAL REGISTRATION: DRKS, DRKS00013275 , Registered 11/2/2017, Retrospectively registered.

Tales from an academic RNAi screening facility; FAQs.

RNAi technology is now a well-established and widely employed research technique that has been adopted by many researchers for use in large-scale screening campaigns. Here, we offer our experience of genome-wide siRNA screening from the perspective of a facility providing screening as a service to a wide range of researchers with diverse interests and approaches. We have experienced the emotional rollercoaster of screening from the exuberant early promise of a screen, the messy reality of the data through to the recognition of screen data as a potential information goldmine. Here, we use some of the questions we most frequently encounter to highlight the initial concerns of many researchers embarking on a siRNA screen and conclude that an informed view of what can be reasonably expected from a screen is essential to the most effective implementation of the technology. Along the way, we suggest that for this area of research at least, either centralization of the resources or close and open collaboration between interested parties offers distinct advantages.