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Background The aim of this study was to develop and validate a functional ability index (FAI) that incorporates aspects of intrinsic capacity and environmental factors of older individuals based on the World Health Organization framework of healthy ageing. Methods Data of 7016 participants ≥60 years participating in the baseline survey of China Health and Retirement Longitudinal Study was used for the development and internal validation of the FAI. External validation was performed in a separate cohort of 1295 older individuals aged ≥60 years. Functional independency was considered the primary outcome and additional proxies of healthy ageing were considered as secondary outcomes. Cluster dendrogram was used to identify the distinct hierarchical clusters of all included variables for inclusion in the FAI. Backward elimination logistic regression model was implemented to identify the most significant variables associated with independency to be included in the FAI. Results The FAI score ranged from 0 to 19 and individuals having FAI ≥ 12 were more likely to be independent and at lower risk of negative outcomes. For each unit increase in the FAI the risk of having independency increased by 30%–58% cross-sectionally in the two cohorts, whilst the 2-year risk of independency increased by 20%. The FAI demonstrated a C-statistic of 0.73 (95% confidence interval, 0.72 and 0.75) for the primary outcome. Conclusions The FAI we developed effectively measured the functional ability status of community dwelling older individuals. FAI could serve as a tool for evaluating older individual's functional ability in routine health assessment. [ABSTRACT FROM AUTHOR]

Autosomal recessive spinocerebellar ataxias (SCARs) are a heterogeneous group of neurodegenerative disorders. VPS13D gene is currently the only gene associated with autosomal recessive spinocerebellar ataxia type 4 (SCAR4), also known as VPS13D dyskinesia. SCAR4 is a rare inherited disease, with only 34 reported cases reported worldwide. In this study, we reported three independent SCAR4 cases with adolescent onsets caused by five novel variants of the VPS13D gene. Each patient carried one frameshift and one missense variant: Patient 1 with c.10474del and c.9734C > A (p.Leu3492Tyrfs*43 and p.Thr3245Asn), Patient 2 with c.6094_6107delGTTCTCTTGATCCC and c.9734C > A (p.Val2032Argfs*7 and p.Thr3245Asn), and Patient 3 with c.11954_11963del and c.9833 T > G (p.Phe3985Serfs*10 and p.Ile3278Ser). Two of the three patients shared nystagmus with an identical variant c.9734C > A. Magnetic resonance imaging indicated thoracic spinal atrophy in all three patients and corpus callosum atrophy in one patient, along with other typical manifestations of white matter degradation, cerebral atrophy, and cerebellar atrophy. These findings expanded the genetic, clinical, and neuroimaging spectrum of SCAR4, and provided new insights into the genetic counseling, molecular mechanisms, and differential diagnosis of the disease. [ABSTRACT FROM AUTHOR]

The generation of alkyl radical from C(sp3)−H substrates via hydrogen atom abstraction represents a desirable yet underexplored strategy in alkylation reaction since involving common concerns remain adequately unaddressed, such as the harsh reaction conditions, limited substrate scope, and the employment of noble metal- or photo-catalysts and stoichiometric oxidants. Here, we utilize the synergistic strategy of photoredox and hydrogen atom transfer (HAT) catalysis to accomplish a general and practical functionalization of unactived C(sp3)−H centers with broad reaction scope, high functional group compatibility, and operational simplicity. A combination of validation experiments and density functional theory reveals that the N-centered radicals, generated from free N − H bond in a stepwise electron/proton transfer event, are the key intermediates that enable an intramolecular 1,5-HAT or intermolecular HAT process for nucleophilic carbon-centered radicals formation to achieve heteroarylation, alkylation, amination, cyanation, azidation, trifluoromethylthiolation, halogenation and deuteration. The practical value of this protocol is further demonstrated by the gram-scale synthesis and the late-stage functionalization of natural products and drug derivatives. Hydrogen atom abstraction from C(sp3)−H substrates for the generation of alkyl radical represents an underexplored strategy in alkylation reactions. Here the authors describe the synergistic utilization of photoredox and hydrogen atom transfer catalysis to accomplish a general and practical functionalization of unactived C(sp3)−H centers. [ABSTRACT FROM AUTHOR]

An efficient and mild multicomponent reaction (MCR) for the preparation of vinyl sulfone is reported, which is achieved by the hydrogenation/difunctional sulfonylation of an alkynyl ester with the corresponding N-allyl bromodifluoroacetamide, DABSO and H2O under visible light conditions without the need for any metal catalysts or additives. This transformation is the first example of a conversion using H2O as the hydrogen source to interact with DABCO to form [DABCO-H]+, which ultimately reacts with the vinyl group, with the advantage of high chemoselectivity and step economy. Notably, the method produces different sulfonylation products with the same substrate regulated by the presence or absence of H2O, which greatly reduces the cost of the chemical reaction and exhibits good functional group tolerance and substrate range. In addition, gram-scale experiments proceeded smoothly, proving the practicality of the methodology. [ABSTRACT FROM AUTHOR]

Background: Accurate diagnosis of Parkinson's disease (PD) is challenging due to its diverse manifestations. Machine learning (ML) algorithms can improve diagnostic precision, but their generalizability across medical centers in China is underexplored. Objective: To assess the accuracy of an ML algorithm for PD diagnosis, trained and tested on data from different medical centers in China. Methods: A total of 1656 participants were included, with 1028 from Beijing (training set) and 628 from Fuzhou (external validation set). Models were trained using the least absolute shrinkage and selection operator–logistic regression (LASSO-LR), decision tree (DT), random forest (RF), eXtreme gradient boosting (XGboost), support vector machine (SVM), and k-nearest neighbor (KNN) techniques. Hyperparameters were optimized using five-fold cross-validation and grid search techniques. Model performance was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve, accuracy, sensitivity (recall), specificity, precision, and F1 score. Variable importance was assessed for all models. Results: SVM demonstrated the best differentiation between healthy controls (HCs) and PD patients (AUC: 0.928, 95% CI: 0.908–0.947; accuracy: 0.844, 95% CI: 0.814–0.871; sensitivity: 0.826, 95% CI: 0.786–0.866; specificity: 0.861, 95% CI: 0.820–0.898; precision: 0.849, 95% CI: 0.807–0.891; F1 score: 0.837, 95% CI: 0.803–0.868) in the validation set. Constipation, olfactory decline, and daytime somnolence significantly influenced predictability. Conclusion: We identified multiple pivotal variables and SVM as a precise and clinician-friendly ML algorithm for prediction of PD in Chinese patients. [ABSTRACT FROM AUTHOR]

Background: Epilepsy (EP) is a common neurological disease in which 70–80% are thought to have a genetic cause. In patients with epilepsy, neurodevelopmental delay (NDD) was prevalent. Next generation of sequencing has been widely used in diagnosing EP/NDD. However, the diagnostic yield remains to be 40%–50%. Many reanalysis pipelines and software have been developed for automated reanalysis and decision making for the diseases. Nevertheless, it is a highly challenging task for smaller genetic centers or a routine pediatric practice. To address the clinical and genetic "diagnostic odyssey," we organized a Multidisciplinary Molecular Consultation (MMC) team for molecular consultation for 202 children with EP/NDD patients referred by lower level hospitals. Methods: All the patients had undergone an aligned and sequential consultations and discussions by a "triple reanalysis" procedure by clinical, genetic specialists, and researchers. Results: Among the 202 cases for MMC, we totally identified 47 cases (23%) harboring causative variants in 24 genes and 15 chromosomal regions after the MMC. In the 15 cases with positive CNVs, 3 cases harbor the deletions or duplications in 16p11.2, and 2 cases for 1p36. The bioinformatical reanalysis revealed 47 positive cases, in which 12 (26%) were reported to be negative, VUS or incorrectly positive in pre‐MMC reports. Additionally, among 87 cases with negative cases, 4 (5%) were reported to be positive in pre‐MMC reports. Conclusion: We established a workflow allowing for a "one‐stop" collaborative assessments by experts of multiple fields and helps for correct the diagnosis of cases with falsenegative and −positive and VUS genetic reports and may have significant influences for intervention, prevention and genetic counseling of pediatric epilepsy and neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]