Investigation of metastable zones and induction times in glycine crystallisation across three different antisolvents

Experimental data on the effects that different antisolvents and antisolvent addition strategies have on nucleation behavior in antisolvent crystallization is very limited, and our understanding of these effects is sparse. In this work we measured the metastable zone width for the isothermal antisolvent crystallization of glycine from water utilizing methanol, ethanol, and dimethylformamide as antisolvents. We then investigated induction times for glycine crystallization across these metastable zones using the same three antisolvents. Supersaturated solutions were prepared by mixing of an antisolvent with undersaturated aqueous glycine solutions, either by batch rapid addition or using a continuous static mixer. Induction times were then recorded under agitated isothermal conditions in small vials with the use of webcam imaging and vary from apparently instant to thousands of seconds over a range of compositions and different mixing modes. Well-defined induction times were detected across most of the metastable zone, which shows that primary nucleation is significant at supersaturations much lower than those identified in conventional metastable zone width measurements. As supersaturation increases toward the metastable zone limit, crystal growth and secondary nucleation are likely to become rate-limiting factors in the observed induction times for antisolvent crystallization. Furthermore, the observed induction times were strongly dependent on the mode of mixing (batch rapid addition vs continuous static mixing), which demonstrates an interplay of antisolvent effects on nucleation with their effects on mixing, leading to crossover of mixing and nucleation time scales. This shows that appropriate mixing strategies are crucial for the rational development of robust scalable antisolvent crystallization processes

Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature

Introduction Since the frst description of gain of function (GOF) mutations in signal transducer and activator of transcrip tion (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefts in several reported cases, their indica tions, dosing, and monitoring remain to be established. Methods A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. Results Ten children (median age 8.5 years (3–18), receiving JAKinibs (ruxolitinib (n=9) and baricitinib (n=1)) with a median follow-up of 18 months (2–42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profle and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune defciency and dysregulation activity scores were 15.99 (5.2–40) pre and 7.55 (3–14.1) under therapy (p=0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. Conclusions Our study supports the potentially benefcial use of JAKinibs in patients with STAT1 GOF, in line with previ ously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitor ing, as well as defning biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries

Small vessel disease burden and functional brain connectivity in mild cognitive impairment

Background: The role of small vessel disease in the development of dementia is not yet completely understood. Functional brain connectivity has been shown to differ between individuals with and without cerebral small vessel disease. However, a comprehensive measure of small vessel disease quantifying the overall damage on the brain is not consistently used and studies using such measure in mild cognitive impairment individuals are missing.Method: Functional brain connectivity differences were analyzed between mild cognitive impairment individuals with absent or low (n = 34) and high (n = 34) small vessel disease burden using data from the Parelsnoer Institute, a Dutch multicenter study. Small vessel disease was characterized using an ordinal scale considering: lacunes, microbleeds, perivascular spaces in the basal ganglia, and white matter hyperintensities. Resting state functional MRI data using 3 Tesla scanners was analyzed with group-independent component analysis using the CONN toolbox.Results: Functional connectivity between areas of the cerebellum and between the cerebellum and the thalamus and caudate nucleus was higher in the absent or low small vessel disease group compared to the high small vessel disease group.Conclusion: These findings might suggest that functional connectivity of mild cognitive impairment individuals with low or absent small vessel disease burden is more intact than in mild cognitive impairment individuals with high small vessel disease. These brain areas are mainly responsible for motor, attentional and executive functions, domains which in previous studies were found to be mostly associated with small vessel disease markers. Our results support findings on the involvement of the cerebellum in cognitive functioning

Small vessel disease burden and functional brain connectivity in mild cognitive impairment

Background: The role of small vessel disease in the development of dementia is not yet completely understood. Functional brain connectivity has been shown to differ between individuals with and without cerebral small vessel disease. However, a comprehensive measure of small vessel disease quantifying the overall damage on the brain is not consistently used and studies using such measure in mild cognitive impairment individuals are missing.Method: Functional brain connectivity differences were analyzed between mild cognitive impairment individuals with absent or low (n = 34) and high (n = 34) small vessel disease burden using data from the Parelsnoer Institute, a Dutch multicenter study. Small vessel disease was characterized using an ordinal scale considering: lacunes, microbleeds, perivascular spaces in the basal ganglia, and white matter hyperintensities. Resting state functional MRI data using 3 Tesla scanners was analyzed with group-independent component analysis using the CONN toolbox.Results: Functional connectivity between areas of the cerebellum and between the cerebellum and the thalamus and caudate nucleus was higher in the absent or low small vessel disease group compared to the high small vessel disease group.Conclusion: These findings might suggest that functional connectivity of mild cognitive impairment individuals with low or absent small vessel disease burden is more intact than in mild cognitive impairment individuals with high small vessel disease. These brain areas are mainly responsible for motor, attentional and executive functions, domains which in previous studies were found to be mostly associated with small vessel disease markers. Our results support findings on the involvement of the cerebellum in cognitive functioning

An Interpretable Machine Learning Model with Deep Learning-based Imaging Biomarkers for Diagnosis of Alzheimer's Disease

Machine learning methods have shown large potential for the automatic early diagnosis of Alzheimer's Disease (AD). However, some machine learning methods based on imaging data have poor interpretability because it is usually unclear how they make their decisions. Explainable Boosting Machines (EBMs) are interpretable machine learning models based on the statistical framework of generalized additive modeling, but have so far only been used for tabular data. Therefore, we propose a framework that combines the strength of EBM with high-dimensional imaging data using deep learning-based feature extraction. The proposed framework is interpretable because it provides the importance of each feature. We validated the proposed framework on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, achieving accuracy of 0.883 and area-under-the-curve (AUC) of 0.970 on AD and control classification. Furthermore, we validated the proposed framework on an external testing set, achieving accuracy of 0.778 and AUC of 0.887 on AD and subjective cognitive decline (SCD) classification. The proposed framework significantly outperformed an EBM model using volume biomarkers instead of deep learning-based features, as well as an end-to-end convolutional neural network (CNN) with optimized architecture.Comment: 11 pages, 5 figure

Is it possible to assess the effects of dynamic arm supports on upper extremity range of motion during activities of daily living in the domestic setting using a portable motion capturing device? - A pilot study

BACKGROUND: Understanding how dynamic arm supports affect the ability to perform activities of daily living (ADL) in daily life situations is essential for improved prescription. OBJECTIVE: To determine whether the newly developed MMAAS is a useful tool to assess the RoM at home. Secondly, to investigate differences in RoM and ADL performance with and without dynamic arm support. METHODS: Five dynamic arm support users performed nine activities with and without dynamic arm support at home. A reference group of five participants was included. Shoulder and elbow RoM were assessed for the three most difficult tasks. RESULTS: The measurement of the elbow joint RoM appeared unreliable. In most participants shoulder RoM increased with dynamic arm support, but the magnitude of change differed. Variation was also found regarding whether people could perform ADL with and without support. CONCLUSIONS: In its current state the MMAAS is not regarded a useful tool for assessing the RoM in the domestic setting. The ability to perform ADL and RoM seem influenced by the environment, users' needs and abilities. Future studies investigating effects and benefits of dynamic arm supports should be conducted in a broader daily life context