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Background The leucine-rich repeat kinase 2 gene ( LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab–Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab–Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15–1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35–3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab–Berber series (combined odds ratio 0·82, 0·72–0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20–2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36–1·07; p=0·087). In the Arab–Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33–15·09; p=0·012). The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. Michael J Fox Foundation and National Institutes of Health.

ObjectiveTranscranial sonography (TCS) shows characteristic hyperechogenicity of the substantia nigra (SN) in patients with Parkinson's disease (PD). Although this feature is well established, sufficient observer reliability and diagnostic accuracy are prerequisites for advancements of this method.MethodsThe authors investigated both aspects in a cross-sectional study with four blinded TCS raters in 22 PD patients and 10 healthy controls.ResultsAs expected, the authors found significant bilateral SN hyperechogenicity in PD patients. Quantitative computerised SN planimetry had a substantial intra- (intraclass correlation coefficient (ICC) 0.97 and 0.93 respectively for both hemispheres) and inter-rater reliability (ICC 0.84 and 0.89), while visual semiquantitative echogenicity grading of the SN revealed a moderate intrarater (weighted kappa 0.80 ipsilateral and 0.74 contralateral) and slight (0.33) to fair (0.51) inter-rater reliability only. Diagnostic accuracy measured as the area under the curve of receiver-operating characteristics plots was highest in TCS of the SN opposite the clinically most affected body side (planimetry 0.821, echogenicity grading 0.792) with a hyperechogenic area of 0.24 cm2 as the optimum cut-off value for the differentiation between PD and controls (sensitivity 79%, specificity 81%).ConclusionsThe data demonstrate that the observer variability of SN planimetry is low in the hands of experienced investigators. This approach also offers adequate diagnostic accuracy. The authors conclude that reliable SN TCS data on PD can be achieved in clinical routine and multicentre trials when standardised analysis protocols and certain quality criteria of brain parenchyma sonography are met.

Organoids are engineered 3D miniature tissues that are defined by their organ-like structures, which drive a fundamental understanding of human development. However, current organoid generation methods are associated with low production throughputs and poor control over size and function including due to organoid merging, which limits their clinical and industrial translation. Here, we present a microfluidic platform for the mass production of lumenogenic embryoid bodies and functional cardiospheres. Specifically, we apply triple-jet in-air microfluidics for the ultra-high-throughput generation of hollow, thin-shelled, hydrogel microcapsules that can act as spheroid-forming bioreactors in a cytocompatible, oil-free, surfactant-free, and size-controlled manner. Uniquely, we show that microcapsules generated by in-air microfluidics provide a lumenogenic microenvironment with near 100% efficient cavitation of spheroids. We demonstrate that upon chemical stimulation, human pluripotent stem cell-derived spheroids undergo cardiomyogenic differentiation, effectively resulting in the mass production of homogeneous and functional cardiospheres that are responsive to external electrical stimulation. These findings drive clinical and industrial adaption of stem cell technology in tissue engineering and drug testing. Current methods to generate spheroids are associated with low production throughputs, limiting clinical and industrial translation. Here the authors present a clean ultra-high-throughput in-air microfluidic platform for mass production of lumenogenic embryoid bodies and functional cardiospheres.

Background A healthy lifestyle is indispensable for the prevention of noncommunicable diseases. However, lifestyle medicine is hampered by time constraints and competing priorities of treating physicians. A dedicated lifestyle front office (LFO) in secondary/tertiary care may provide an important contribution to optimize patient-centred lifestyle care and connect to lifestyle initiatives from the community. The LOFIT study aims to gain insight into the (cost-)effectiveness of the LFO. Methods Two parallel pragmatic randomized controlled trials will be conducted for (cardio)vascular disorders (i.e. (at risk of) (cardio)vascular disease, diabetes) and musculoskeletal disorders (i.e. osteoarthritis, hip or knee prosthesis). Patients from three outpatient clinics in the Netherlands will be invited to participate in the study. Inclusion criteria are body mass index (BMI) ≥25 (kg/m 2 ) and/or smoking. Participants will be randomly allocated to either the intervention group or a usual care control group. In total, we aim to include 552 patients, 276 in each trial divided over both treatment arms. Patients allocated to the intervention group will participate in a face-to-face motivational interviewing (MI) coaching session with a so-called lifestyle broker. The patient will be supported and guided towards suitable community-based lifestyle initiatives. A network communication platform will be used to communicate between the lifestyle broker, patient, referred community-based lifestyle initiative and/or other relevant stakeholders (e.g. general practitioner). The primary outcome measure is the adapted Fuster-BEWAT, a composite health risk and lifestyle score consisting of resting systolic and diastolic blood pressure, objectively measured physical activity and sitting time, BMI, fruit and vegetable consumption and smoking behaviour. Secondary outcomes include cardiometabolic markers, anthropometrics, health behaviours, psychological factors, patient-reported outcome measures (PROMs), cost-effectiveness measures and a mixed-method process evaluation. Data collection will be conducted at baseline, 3, 6, 9 and 12 months follow-up. Discussion This study will gain insight into the (cost-)effectiveness of a novel care model in which patients under treatment in secondary or tertiary care are referred to community-based lifestyle initiatives to change their lifestyle. Trial registration ISRCTN ISRCTN13046877 . Registered 21 April 2022.