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A health-related (HR) profile is a set of multiple health-related items recording the status of the patient at different follow-up times post-stroke. In order to support clinicians in designing rehabilitation treatment programs, we propose a novel multi-task learning (MTL) strategy for predicting post-stroke patient HR profiles. The HR profile in this study is measured by the Barthel index (BI) assessment or by the EQ-5D-3L questionnaire. Three datasets are used in this work and for each dataset six neural network architectures are developed and tested. Results indicate that an MTL architecture combining a pre-trained network for all tasks with a concatenation strategy conditioned by a task grouping method is a promising approach for predicting the HR profile of a patient with stroke at different phases of the patient journey. These models obtained a mean F1-score of 0.434 (standard deviation 0.022, confidence interval at 95% [0.428, 0.44]) calculated across all the items when predicting BI at 3 months after stroke (MaS), 0.388 (standard deviation 0.029, confidence interval at 95% [0.38, 0.397]) when predicting EQ-5D-3L at 6MaS, and 0.462 (standard deviation 0.029, confidence interval at 95% [0.454, 0.47]) when predicting the EQ-5D-3L at 18MaS. Furthermore, our MTL architecture outperforms the reference single-task learning models and the classic MTL of all tasks in 8 out of 10 tasks when predicting BI at 3MaS and has better prediction performance than the reference models on all tasks when predicting EQ-5D-3L at 6 and 18MaS. The models we present in this paper are the first models to predict the components of the BI or the EQ-5D-3L, and our results demonstrate the potential benefits of using MTL in a health context to predict patient profiles., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nguyen, García-Rudolph, Saurí and Kelleher.)

After stroke rehabilitation, patients need to reintegrate back into their daily life, workplace and society. Reintegration involves complex processes depending on age, sex, stroke severity, cognitive, physical, as well as socioeconomic factors that impact long-term outcomes post-stroke. Moreover, post-stroke quality of life can be impacted by social risks of inadequate family, social, economic, housing and other supports needed by the patients. Social risks and barriers to successful reintegration are poorly understood yet critical for informing clinical or social interventions. Therefore, the aim of this work is to predict social risk at rehabilitation discharge using sociodemographic and clinical variables at rehabilitation admission and identify factors that contribute to this risk. A Gradient Boosting modelling methodology based on decision trees was applied to a Catalan 217-patient cohort of mostly young (mean age 52.7), male (66.4%), ischemic stroke survivors. The modelling task was to predict an individual's social risk upon discharge from rehabilitation based on 16 different demographic, diagnostic and social risk variables (family support, social support, economic status, cohabitation and home accessibility at admission). To correct for imbalance in patient sample numbers with high and low-risk levels (prediction target), five different datasets were prepared by varying the data subsampling methodology. For each of the five datasets a prediction model was trained and the analysis involves a comparison across these models. The training and validation results indicated that the models corrected for prediction target imbalance have similarly good performance (AUC 0.831-0.843) and validation (AUC 0.881 - 0.909). Furthermore, predictor variable importance ranked social support and economic status as the most important variables with the greatest contribution to social risk prediction, however, sex and age had a lesser, but still important, contribution. Due to the complex and multifactorial nature of social risk, factors in combination, including social support and economic status, drive social risk for individuals., (© 2024. The Author(s).)

Background: Low rates of participation and quality of life (QoL) and high rates of psychological distress are common in spinal cord injury (SCI) population. Research has supported the mediating role of self-efficacy and functionality in improving psychosocial outcomes. Furthermore, evidence supports the impact of physical activity (PA) on psychosocial variables, but little is known about the types and intensities of PA. The objective of this study was to determine whether functionality and/or general self-efficacy (GSE) mediate the relationships between the various types of PA: (1) lifestyle and (2) leisure-time physical activity (LTPA); and various intensities of PA: (1) mild, (2) moderate, and (3) heavy PA with participation, psychological distress, and perception of QoL., Methods: The Physical Activity Recall Assessment for SCI, and measures of functionality, GSE, participation, psychological distress, and perception of QoL were administered to 159 participants. Path analysis was performed using Jeffrey's Amazing Statistics Program., Results: GSE significantly mediated, and functionality partially significantly mediated, the relationship between LTPA and psychosocial outcomes. GSE and functionality did not mediate the relationship between lifestyle activity and psychosocial outcomes., Conclusions: It is recommended that people with SCI perform LTPA on a regular basis to achieve psychosocial benefits. These programs should be accompanied by strategies to improve GSE.

The discorhabdin natural products are a large subset of pyrroloiminoquinone alkaloids with a myriad of biological activities. Despite garnering much synthetic attention, few members have thus far been completed, particularly those featuring a bridging carbon-nitrogen bond that is found in numerous discorhabdins, including discorhabdin V. Herein we report the first total synthesis and full stereochemical assignment of (+)-discorhabdin V. To access the pyrroloiminoquinone we developed a convergent N-alkylation/oxidative aminocyclization/bromination cascade that joins two key components, which are both made on multigram scale. An intramolecular Heck reaction then forms the quaternary carbon center in an intermediate containing the carbon-nitrogen bridge, and a reductive N,O-acetal cyclization sequence introduces the final piperidine ring. Furthermore, we have established the relative configuration of (+)-discorhabdin V through experimental NOESY data and DP4 NMR probability calculations. The absolute configuration of the natural product has also been determined by circular dichroism and the use of an amino acid derived chiral starting material. Our work represents one of only two reports of a total synthesis of a nitrogen-bridged discorhabdin and paves the way for future biological evaluation of such compounds., (© 2023 Wiley-VCH GmbH.)

Background: In the field of disability and rehabilitation, participation in society has become an important therapeutic objective due to its potential impact on rehabilitation, prognosis, and patient's mid and long-term well-being. However, only a few studies have explored this issue in relation with the subjective perspective of individuals with disabilities about their decision-making capacity and satisfaction with the activities in which they participate., Objective: Our aim is to analyze the relationship between participation in society of people with disabilities and both emotional well-being and quality of life, including variables about subjective perspective of participation (satisfaction) and the ability to decide and pursue their own preferences., Method: The cross-sectional study presented here includes 424 participants with disabilities over 18-years-old from Spain. This research is part of a larger ongoing longitudinal cohort study called Participa (https://participa.guttmann.com/en/). Participants were asked to complete several on-line surveys to explore quality of life, emotional well-being, participation in society, self-determination, and independent living., Results: The results revealed an association between the dimensions of participation satisfaction, self-determination, and levels of independent living with both quality of life and emotional well-being. Mediation models indicated that satisfaction and self-determination partially mediated the relationship between independent living and both quality of life and emotional well-being., Conclusion: The level of independent living, self-determination, and satisfaction with participation are fundamental aspects for promoting a high quality of life and emotional well-being in people with disabilities. These findings carry significant implications for health and social services, as well as policies guidelines, highlighting the need to prioritize empowerment and self-determination in all interventions designed for people with disabilities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cegarra, Cattaneo, Ribes, Solana-Sánchez and Saurí.)

Introduction and Objective: We propose to assess the impact of educational level on cognitive tests at admission and discharge after a period of cognitive rehabilitation in young patients after ischaemic stroke., Materials and Methods: We considered secondary and higher education (group A) and less than 6 years of formal education (group B). We compared A and B using χ 2 and Kruskal-Wallis. We studied A and B as predictors of verbal and working memory at discharge. Verbal and working memories were assessed at admission and discharge using Rey Auditory Verbal Learning Test (RAVLT) and DIGITS of the Barcelona Test respectively., Results: We analysed n=277 patients (55% belonging to A, mean age of 51 years) admitted to a specialised centre in Spain between 2009 and 2019. We found significant differences (P<.05) at admission, all in favour of A in the assessments of attention, inhibition, visuoperception, visuoconstruction, verbal fluency and comprehension. In DIGITS and RAVLT-learning we found differences at admission. In Digits and RAVLT-recognition we found differences at discharge, all in favour of A. We found no differences in age, severity, time at admission, or length of stay in hospital. Nor did we find differences in cognitive gains or treatment efficiency in memory tests. The groups A and B did not predict RAVLT (R 2 =.53) or DIGITS (R 2 =.48)., Conclusions: A scores better in 63% of tests at admission and in 75% of tests at discharge, A and B are similar in gains and efficiency on memory tests., (Copyright © 2021 Sociedad Española de Rehabilitación y Medicina Física. Publicado por Elsevier España, S.L.U. All rights reserved.)

A novel, convergent synthesis of aminotriazoloquinazolines is reported. These heterocycles are reliably prepared via a "click-like" reaction between readily available aryl carbodiimides and acyl or aryl hydrazides. Such products are of particular interest with respect to their inhibitory activity against the A 2A and A 2B adenosine receptors, and the title two-component coupling reaction has greatly accelerated the discovery of potent/selective chemical matter in this space.

Context/objective: Compare community integration, quality of life, anxiety and depression of people with chronic spinal cord injury (SCI) living in the community before the outbreak of coronavirus SARS-CoV-2 disease (COVID-19) and during it., Design: Prospective observational cohort study., Setting: In-person follow-up visits (before COVID-19 outbreak) to a rehabilitation hospital in Spain and on-line during COVID-19., Participants: Community dwelling adults (≥ 18 years) with chronic SCI., Outcome Measures: Hospital Anxiety and Depression Scale (HADS), Community Integration Questionnaire (CIQ) and World Health Organization Quality of Life (WHOQOL-BREF) were compared using the Wilcoxon ranked test or paired t-test when appropriate., Results: One hundred and seventy five people with SCI assessed on-line between June 2020 and November 2020 were compared to their own assessments before COVID-19. Participants reported significantly decreased Social Integration during COVID-19 compared to pre-pandemic scores (P = 0.037), with a small effect size ( d  = -0.15). Depression (measured using HADS) was significantly higher than before COVID-19 (P < 0.001) with a moderate effect size ( d  = -0.29). No significant differences were found in any of the 4 WHOQOL-BREF dimensions (Physical, Psychological, Social and Environmental).Nevertheless, when all participants were stratified in two groups according to their age at on-line assessment, the younger group (19-54 years, N  = 85) scored lower during COVID-19 than before, in WHOQOL-BREF Physical (P = 0.004), ( d  = -0.30) and Psychological dimensions (P = 0.007) ( d  = -0.29). The older group (55-88 years, N  = 0) reported no significant differences in any dimension., Conclusions: COVID-19 impacted HADS' depression and CIQ's social integration. Participants younger than 55 years were impacted in WHOQOL-BREF's physical and psychological dimensions, meanwhile participants older than 55, were not.

Synthesis of medium-sized rings is known to be challenging due to high transannular strain especially for 9- and 10-membered rings. Herein we report design and synthesis of unprecedented 9- and 10-membered purine 8,5'-cyclonucleosides as the first cyclonucleoside PRMT5 inhibitors. The cocrystal structure of PRMT5:MEP50 in complex with the synthesized 9-membered cyclonucleoside 1 revealed its binding mode in the SAM binding pocket of PRMT5., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Abstract: Compare community integration of people with stroke or traumatic brain injury (TBI) living in the community before and during the coronavirus severe acute respiratory syndrome coronavirus 2 disease (COVID-19) when stratifying by injury: participants with stroke (G1) and with TBI (G2); by functional independence in activities of daily living: independent (G3) and dependent (G4); by age: participants younger than 54 (G5) and older than 54 (G6); and by gender: female (G7) and male (G8) participants.Prospective observational cohort studyIn-person follow-up visits (before COVID-19 outbreak) to a rehabilitation hospital in Spain and on-line during COVID-19.Community dwelling adults (≥18 years) with chronic stroke or TBI.Community integration questionnaire (CIQ) the total-CIQ as well as the subscale domains (ie, home-CIQ, social-CIQ, productivity CIQ) were compared before and during COVID-19 using the Wilcoxon ranked test or paired t test when appropriate reporting Cohen effect sizes (d). The functional independence measure was used to assess functional independence in activities of daily living.Two hundred four participants, 51.4% with stroke and 48.6% with TBI assessed on-line between June 2020 and April 2021 were compared to their own in-person assessments performed before COVID-19.When analyzing total-CIQ, G1 (d = -0.231), G2 (d = -0.240), G3 (d = -0.285), G5 (d = -0.276), G6 (d = -0.199), G7 (d = -0.245), and G8 (d = -0.210) significantly decreased their scores during COVID-19, meanwhile G4 was the only group with no significant differences before and during COVID-19.In productivity-CIQ, G1 (d = -0.197), G4 (d = -0.215), G6 (d = -0.300), and G8 (d = -0.210) significantly increased their scores, meanwhile no significant differences were observed in G2, G3, G5, and G7.In social-CIQ, all groups significantly decreased their scores: G1 (d = -0.348), G2 (d = -0.372), G3 (d = -0.437), G4 (d = -0.253), G5 (d = -0.394), G6 (d = -0.319), G7 (d = -0.355), and G8 (d = -0.365).In home-CIQ only G6 (d = -0.229) significantly decreased, no significant differences were observed in any of the other groups.The largest effect sizes were observed in total-CIQ for G3, in productivity-CIQ for G6, in social-CIQ for G3 and in home-CIQ for G6 (medium effect sizes).Stratifying participants by injury, functionality, age or gender allowed identifying specific CIQ subtotals where remote support may be provided addressing them., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Recent technological and synthetic advances have led to a resurgence in the exploration of peptides as potential therapeutics. Understanding peptide conformation in both free and protein-bound states remains one of the most critical areas for successful development of peptide drugs. In this study it was demonstrated that the combination of Size-Exclusion Chromatography with Hydrogen-Deuterium Exchange Mass Spectrometry (SEC-HDX-MS) and Circular Dichroism Spectroscopy (CD) can be used to guide the selection of peptides for further NMR analysis. Moreover, the insights from this workflow guide the choice of the best biologically relevant conditions for NMR conformational studies of peptide ligands in a free state in solution. Combined information about solution conformation character and stability across temperatures and co-solvent compositions greatly expedites selection of optimal conditions for NMR analysis. In total, the combination of SEC-HDX-MS, CD, and NMR into a single complementary workflow greatly accelerates conformational analysis of peptides in the drug discovery lead optimization process.

Background: Stroke is a major worldwide cause of serious long-term disability. Most previous studies addressing functional independence included only inpatients with limited follow-up., Objective: To identify novel classes of patients having similar temporal patterns in motor functional independence and relate them to baseline clinical features., Methods: Retrospective observational cohort study, data were obtained for n = 428 adult patients with ischemic stroke admitted to rehabilitation (March 2005-March 2020), including baseline clinical features and follow-ups of motor Functional Independence Measure (mFIM) categorized as poor, fair or good. Growth mixture models (GMMs) were fitted to identify classes of patients with similar mFIM trajectories., Results: GMM identified three classes of trajectories (1,664 mFIM assessments):C1 (11.2 %), 97.9% having poor admission mFIM, at 4.93 years 61.1% still poor, with the largest percentage of hypertension, neglect, dysphagia, diabetes and dyslipidemia of all three classes.C2 (23.1%), 99% had poor admission mFIM, 25% poor discharge mFIM, the largest percentage of aphasia and greatest mFIM gain, at 4.93 years only 6.2% still poor.C3 (65.7%) the youngest, lowest NIHSS, 37.7% poor admission mFIM, 73% good discharge mFIM, only 4.6% poor discharge mFIM, 90% good at 4.93 years., Conclusions: GMM identified novel motor functional classes characterized by baseline features.

Comprehensive synthetic strategies afforded a diverse set of structurally unique bicyclic proline-containing arginase inhibitors with a high degree of three-dimensionality. The analogs that favored the Cγ-exo conformation of the proline improved the arginase potency over the initial lead. The novel synthetic strategies reported here not only enable access to previously unknown stereochemically complex proline derivatives but also provide a foundation for the future synthesis of bicyclic proline analogs, which incorporate inherent three-dimensional character into building blocks, medicine, and catalysts and could have a profound impact on the conformation of proline-containing peptides and macrocycles., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Objectives: The aims of the study were (1) to identify relationships between functional and psychological aspects with community integration and quality of life assessments in people with chronic traumatic spinal cord injury and (2) to analyze clinical and demographic predictors of quality of life dimensions., Design: This is an observational cohort study, and correlation coefficients were calculated between the Functional Independence Measure, the Hospital Anxiety and Depression Scale, the Community Integration Questionnaire, and the World Health Organization Quality of Life-BREF dimensions (physical [D1], psychological [D2], social [D3], and environmental [D4]). Quality of life predictors were identified using multiple linear regression analyses., Results: Nine hundred seventy-five people with traumatic spinal cord injury assessed since 2007-2020 were included. The Community Integration Questionnaire home integration correlated strongly with the Functional Independence Measure self-care (r = 0.74) and transfers (r = 0.62) for participants with tetraplegia. The specific Hospital Anxiety and Depression Scale items (known as the anhedonia subscale) correlated strongly with D1 (r = -0.65), D2 (r = -0.69), D3 (r = -0.53), and D4 (r = -0.51) for participants with paraplegia and D1 (r = -0.53), D2 (r = -0.61), D3 (r = -0.47), and D4 (r = -0.53) for participants with tetraplegia. The Hospital Anxiety and Depression Scale-depression was the most relevant predictor of D1 (β = -0.61) and D2 (β = -0.76)., Conclusions: The Functional Independence Measure transfers and self-care were strongly associated with the Community Integration Questionnaire home integration (in participants with tetraplegia). Anhedonia was strongly related to all four World Health Organization Quality of Life-BREF Scale dimensions, being the Hospital Anxiety and Depression Scale-depression the most relevant predictor of D1 and D2., To Claim Cme Credits: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME., Cme Objectives: Upon completion of this article, the reader should be able to (1) Determine the associations between functional and psychological measures with community integration domains and quality of life from a multidimensional perspective (physical, psychological, social, and environmental) in persons with chronic traumatic paraplegia or tetraplegia living in the community; (2) Identify long-term clinical and demographic predictors of specific quality of life dimensions (e.g., physical and psychological) in persons with paraplegia or tetraplegia living in the community; and (3) Illustrate the strength of the identified associations and the impact of the quality of life predictors to suggest possible specific aspects to be addressed by professionals in clinical practice., Level: Advanced., Accreditation: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a , 18 , and 27 , demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Background: About one-third of adult stroke patients suffer from aphasia when they are discharged from hospital. Aphasia seems to be a negative predictive factor affecting post-stroke functional recovery after rehabilitation, but this association has been scarcely addressed in previous research., Objectives: We aim to evaluate the impact of aphasia in cognitive functional outcomes in working-age first-ever ischemic stroke adults., Methods: Retrospective observational cohort study. One hundred and thirty ischemic (≤ 64 years old) adult stroke patients (43.07% with aphasia) admitted to a rehabilitation center between 2007 and 2019 were analyzed. Univariate and multivariate linear regressions were performed using state-of-the-art variables (stroke severity, gender, age) extending them with potential confounders (e.g. diabetes, medication for depression). The cognitive subtest (C-FIM) of the Functional Independence Measure (FIM) at discharge and C-FIM gain were the dependent variables., Results: Patients with aphasia (PWA) had lower C-FIM scores at admission and at discharge. No significant differences were observed in relation to C-FIM gain, C-FIM efficiency, C-FIM effectiveness and length of stay (LOS).C-FIM gain was remarkably higher though non-significant ( p = .059) in PWA. Regression analysis identifies C-FIM at admission and aphasia as significant predictors of C-FIM at discharge (R 2  = 0.72). The same variables plus taking medication for depression predicted C-FIM gain (R 2  = 0.38)., Conclusions: We identified no significant differences in C-FIM outcomes (gain, efficiency and effectiveness) either in LOS between PWA and patients without aphasia, though C-FIM differences were significant at admission and discharge. Aphasia was a significant predictor of C-FIM gain and C-FIM at discharge.

Nitrogenous heterocycles are ubiquitous in pharmaceuticals and drug-like compounds; however, regioselective synthesis has proved challenging. Herein we report our efforts to develop a regioselective method for the synthesis of pyrazolo[1,5- a ]pyridines and the serendipitous discovery of a protocol for the regioselective formation of imidazo[1,5- a ]pyridines. Together, these transformations allow for the rapid and selective formation of two important heterocyclic motifs from a common intermediate.

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections.

In the context of a PRMT5 inhibitor program, we describe our efforts to develop a flexible and robust strategy to access tetrahydrofuro[3,4- b ]furan nucleoside analogues. Ultimately, it was found that a Wolfe type carboetherification from an alkenol derived from d-glucofuranose diacetonide was capable of furnishing the B-ring and installing the desired heteroaryl group in a single step. Using this approach, key intermediate 1.3-A was delivered on a gram scale in a 62% yield and 9.1:1 dr in favor of the desired S -isomer. After deprotection of 1.3-A , a late-stage glycosylation was performed under Mitsunobu conditions to install the pyrrolopyrimidine base. This provided serviceable yields of nucleoside analogues in the range of 31-48% yield. Compound 1.1-C was profiled in biochemical and cellular assays and was demonstrated to be a potent and cellularly active PRMT5 inhibitor, with a PRMT5-MEP50 biochemical IC 50 of 0.8 nM, a MCF-7 target engagement EC 50 of 3 nM, and a Z138 cell proliferation EC 50 of 15 nM. This work sets the stage for the development of new inhibitors of PRMT5 and novel nucleoside chemical matter for alternate drug discovery programs.

Background: Many efforts have been devoted to identify predictors of functional outcomes after stroke rehabilitation. Though extensively recommended, there are very few external validation studies., Objective: To externally validate two predictive models (Maugeri model 1 and model 2) and to develop a new model (model 3) that estimate the probability of achieving improvement in physical functioning (primary outcome) and a level of independence requiring no more than supervision (secondary outcome) after stroke rehabilitation., Methods: We used multivariable logistic regression analysis for validation and development. Main outcome measures were: Functional Independence Measure (FIM) (primary outcome), Functional Independence Staging (FIS) (secondary outcome) and Minimal Clinically Important Difference (MCID)., Results: Patients with stroke admitted to a rehabilitation center from 2006 to 2019 were retrospectively studied (N = 710). Validation of Maugeri models confirmed very good discrimination: for model 1 AUC = 0.873 (0.833-0.915) and model 2 AUC = 0.803 (0.749-0.857). The Hosmer-Lemeshow χ2 was 6.07(p = 0.63) and 8.91(p = 0.34) respectively. Model 3 yielded an AUC = 0.894 (0.857-0.929) (primary outcome) and an AUC = 0.769 (0.714-0.825) (MCID)., Conclusions: Discriminative power of both Maugeri models was externally confirmed (in a 20 years younger population) and a new model (incorporating aphasia) was developed outperforming Maugeri models in primary outcome and MCID.

Background: The World Health Organization's International Classification of Functioning Disability and Health (ICF) conceptualizes disability not solely as a problem that resides in the individual, but as a health experience that occurs in a context. Word embeddings build on the idea that words that occur in similar contexts tend to have similar meanings. In spite of both sharing "context" as a key component, word embeddings have been scarcely applied in disability. In this work, we propose social media (particularly, Reddit) to link them., Objective: The objective of our study is to train a model for generating word associations using a small dataset (a subreddit on disability) able to retrieve meaningful content. This content will be formally validated and applied to the discovery of related terms in the corpus of the disability subreddit that represent the physical, social, and attitudinal environment (as defined by a formal framework like the ICF) of people with disabilities., Methods: Reddit data were collected from pushshift.io with the pushshiftr R package as a wrapper. A word2vec model was trained with the wordVectors R package using the disability subreddit comments, and a preliminary validation was performed using a subset of Mikolov analogies. We used Van Overschelde's updated and expanded version of the Battig and Montague norms to perform a semantic categories test. Silhouette coefficients were calculated using cosine distance from the wordVectors R package. For each of the 5 ICF environmental factors (EF), we selected representative subcategories addressing different aspects of daily living (ADLs); then, for each subcategory, we identified specific terms extracted from their formal ICF definition and ran the word2vec model to generate their nearest semantic terms, validating the obtained nearest semantic terms using public evidence. Finally, we applied the model to a specific subcategory of an EF involved in a relevant use case in the field of rehabilitation., Results: We analyzed 96,314 comments posted between February 2009 and December 2019, by 10,411 Redditors. We trained word2vec and identified more than 30 analogies (eg, breakfast - 8 am + 8 pm = dinner). The semantic categorization test showed promising results over 60 categories; for example, s(A relative)=0.562, s(A sport)=0.475 provided remarkable explanations for low s values. We mapped the representative subcategories of all EF chapters and obtained the closest terms for each, which we confirmed with publications. This allowed immediate access (≤ 2 seconds) to the terms related to ADLs, ranging from apps "to know accessibility before you go" to adapted sports (boccia). For example, for the support and relationships EF subcategory, the closest term discovered by our model was "resilience," recently regarded as a key feature of rehabilitation, not yet having one unified definition. Our model discovered 10 closest terms, which we validated with publications, contributing to the "resilience" definition., Conclusions: This study opens up interesting opportunities for the exploration and discovery of the use of a word2vec model that has been trained with a small disability dataset, leading to immediate, accurate, and often unknown (for authors, in many cases) terms related to ADLs within the ICF framework., (©Alejandro Garcia-Rudolph, Joan Saurí, Blanca Cegarra, Montserrat Bernabeu Guitart. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 20.11.2020.)

Three new aryl alkaloids named suberitamides A-C ( 1 - 3 ), were isolated from an extract of the marine sponge Pseudosuberites sp. collected along the coast of North Carolina. Their planar structures were established by extensive nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis. To assign the challenging relative configuration of the saturated five-membered ring in suberitamide A ( 1 ), a simple and efficient NMR protocol was applied that is based on the analysis of 2- and 3-bond 1 H- 13 C spin-spin coupling constants using a PIP (pure in-phase) HSQMBC (heteronuclear single quantum multiple bond correlation) IPAP (in-phase and anti-phase) experiment. Suberitamides A ( 1 ) and B ( 2 ) inhibited Cbl-b, an E3 ubiquitin ligase that is an important modulator of immune cell function, with IC 50 values of approximately 11 μM.

Severe stroke patients are known to be associated with larger rehabilitation length of stay (LOS) but other factors besides severity may be contributing. We aim to identify LOS predictors within a population of mostly severe patients and analyze the impact of socioeconomic situation in functionality at admission.A retrospective observational cohort study was conducted including 172 inpatients admitted to a rehabilitation center between 2007 and 2019. Associations with LOS were examined among 30 potential predictor variables using bivariate correlations. Significantly correlated (P < .002, Bonferroni adjustment) variables were entered into 9 different multiple linear regression models.No mild participants were included, 63.37% severe and 36.63% moderate. Most significant LOS determinants were: 1) total functional independence measure (FIM) (P < .001) and hemiparesis (P = .0108) (adjusted R = 0.24), 2) cognitive FIM (P = .002) and severity (P = .001) (adjusted R = 0.22), and 3) home accessibility (P = .043) and hemiparesis (P = 0.032) (adjusted R = 0.19).Known LOS predictors (e.g., depression, ataxia) within the full stroke severities were not found significant in our dataset.Socioeconomic situation was found moderately correlated with total FIM (r = -0.32, P < .0001).When stratifying the patients' socioeconomic situation into mild, important, and severe social risk, their respective median total FIM at admission were 61.5, 50, and 41, with significant differences between the mild and important group (P < .001); also significant differences were found between mild and severe groups (P < .001).A few of the variables identified in the literature as significant predictors of LOS within the full stroke population were also significant for our dataset (National Institutes of Health Stroke Scale, FIM, home accessibility) explaining less than 25% of the LOS variance. Most of the 30 analyzed known predictors were not significant (e.g., depression, age, recurrent stroke, ataxia, orientation, verbal communication, etc) suggesting that factors outside functional, socioeconomic, medical, and demographics not included in this study (e.g., rehabilitation sessions intensity) have important influences on LOS for severe patients.Patients at mild social risk obtained significantly higher total FIM at admission than patients at important and severe social risk. The importance of socioeconomic situation has been scarcely studied in the literature in relation to functionality at admission; our results suggest that it requires to be considered.

Heteronuclear long-range scalar coupling constants ( n J CH ) are a valuable tool for solving problems in organic chemistry and are especially suited for stereochemical and configurational analyses of small molecules and natural products. This tutorial will focus on the step-by-step implementation of several 2D 1 H frequency selective HSQMBC experiments for the easy and accurate measurement of either the magnitude or both the magnitude and the sign of long-range n J CH couplings. The performance of these experiments will be showcased with several scenarios in a range of different experimental conditions., (© 2019 John Wiley & Sons, Ltd.)

The detection of ultra-long-range ( 4 J CH and higher) heteronuclear connectivities can complement the conventional use of HMBC/HSQMBC data in structure elucidation NMR studies of proton-deficient natural products, where two-bond and three-bond correlations are usually observed. The performance of the selHSQMBC experiment with respect to its broadband HSQMBC counterpart is evaluated. Despite its frequency-selectivity nature, selHSQMBC efficiently prevents any unwanted signal phase and intensity modulations due to passive proton-proton coupling constants typically involved in HSQMBC. As a result, selHSQMBC offers a significant sensitivity enhancement and provides pure in-phase multiplets, improving the detection levels for short- and long-range cross-peaks corresponding to small heteronuclear coupling values. This is particularly relevant for experiments optimized to small n J CH values (2-3 Hz), referred to as LR-selHSQMBC, where key cross-peaks that are not visible in the equivalent broadband LR-HSQMBC spectrum can become observable in optimum conditions.

The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme-inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3 , when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Saturated cyclic amines (aza-cycles) are ubiquitous structural motifs found in pharmaceuticals, agrochemicals, and bioactive natural products. Given their importance, methods that directly functionalize aza-cycles are in high demand. Herein, we disclose a fundamentally different approach to functionalizing cyclic amines which relies on C─C cleavage and attendant cross-coupling. The initial functionalization step is the generation of underexplored N-fused bicyclo α -hydroxy- β -lactams under mild, visible light conditions using a Norrish-Yang process to affect α -functionalization of saturated cyclic amines. This approach is complementary to previous methods for the C─H functionalization of aza-cycles and provides unique access to various cross-coupling adducts. In the course of these studies, we have also uncovered an orthogonal, base-promoted opening of the N-fused bicyclo α -hydroxy- β -lactams. Computational studies have provided insight into the origin of the complementary C─C cleavage processes.

The optimum detection and accurate measurement of longer-range ( 4 J and higher) heteronuclear NMR correlations is described. The magnitude and/or the sign of a wide range of large and small long-range couplings can be simultaneously determined for protonated and non-protonated 13 C and 15 N nuclei using the LR-selHSQMBC experiment., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new general de novo synthesis of pharmaceutically important N-(hetero)aryl piperidines is reported. This protocol uses a robustly diastereoselective reductive amination/aza-Michael reaction sequence to achieve rapid construction of complex polysubstituted ring systems starting from widely available heterocyclic amine nucleophiles and carbonyl electrophiles. Notably, the diastereoselectivity of this process is enhanced by the presence of water, and DFT calculations support a stereochemical model involving a facially selective protonation of a water-coordinated enol intermediate.

Introduction: Stroke is a leading cause of long-term disabilities worldwide. A great deal of meta-analyses of randomized controlled trials (RCTs) address rehabilitation in chronic stroke, several of them with focus on activities and participation, considered critical outcomes of successful rehabilitation. Nevertheless, substantial heterogeneity might exist between studies, the reported associations may be causal, but they might also be flawed, as inherent study biases such as residual confounding and selective reporting of positive results may exaggerate the effect of interventions in chronic phase. Furthermore, most RCTs might focus on specific rehabilitation domains, not paying the same attention to others., Evidence Acqusition: Formal evaluation of published systematic reviews of meta-analyses (January 2008 to November 2018) of rehabilitation in chronic phase to 1) assess the strength of evidence: participants, publication biases, heterogeneity, prediction intervals (PIs) 2) grade the evidence to perform qualitative analysis on effects sizes and heterogeneity, 3) perform meta-regressions and sensitivity analysis on relevant covariates 4) map outcomes to activities and participation domain of the World Health Organization's International Classification of Functioning, Disability and Health (ICF). Systematic review on meta-analyses of RCTs addressing activities and participation will be performed in Medline, Web of Science, Scopus, Cochrane and Google Scholar., Evidence Synthesis: A total of 97 meta-analyses on 31 different rehabilitation interventions involving 25,275 participants were included. Thirty-nine meta-analyses (40.74%) reported statistically significant findings (P<0.05) in both fixed and random effects sizes. Their magnitude was small in 62.96% cases, moderate in 19.75% and large in 17.28%. Heterogeneity was low in 48,48%, moderate and high in 21.2%. The mean number of participants is 815, far away from the convincing, highly suggestive, or suggestive required evidence levels. All PIs include the null value. Mobility is addressed by 87% of the identified meta-analyses, with 75% of them focusing exclusively in mobility., Conclusions: The findings of this study show a clear need for high quality RCTs examining the effectiveness of rehabilitation interventions addressing activities and participation. The ICF framework may contribute to a holistic approach in chronic stroke rehabilitation, including not only motor functioning but also the ability to participate in everyday life activities.

Bacterial symbionts frequently provide chemical defenses for their hosts, and such systems can provide discovery pathways to new antifungals and structurally intriguing metabolites. This report describes a small family of naturally occurring small molecules with chimeric structures and a mixed biosynthesis that features an unexpected but key nonenzymatic step. An insect-associated Pseudomonas protegens strain's activity in an in vivo murine candidiasis assay led to the discovery of a family of highly hydrogen-deficient metabolites. Bioactivity- and mass-guided fractionation led to the pyonitrins, highly complex aromatic metabolites in which 10 of the 20 carbons are quaternary, and 7 of them are contiguous. The P. protegens genome revealed that the production of the pyonitrins is the result of a spontaneous reaction between biosynthetic intermediates of two well-studied Pseudomonas metabolites, pyochelin and pyrrolnitrin. The combined discovery of the pyonitrins and identification of the responsible biosynthetic gene clusters revealed an unexpected biosynthetic route that would have prevented the discovery of these metabolites by bioinformatic analysis alone.

The challenging structural motif of dictyospiromide ( 1 ), a spirosuccinimide alkaloid with antioxidant properties that are associated with activation of the Nrf2/ARE signaling pathway, was assigned using contemporary NMR experiments complemented with anisotropic NMR, chiroptical, and computational methodologies. Anisotropic NMR parameters provided critical orthogonal verification of the configuration of the difficult to assign spiro carbon and the other stereogenic centers in  1 .

Ceftolozane is MSD's 5th generation cephalosporin antibiotic with broad-spectrum gram-negative activity. While refining the synthetic route to the drug substance, a dimeric impurity was observed in the final active pharmaceutical ingredient (API) of ceftolozane. Through impurity enrichment and preparative isolation, the structure of the impurity was subsequently established through LC/HRMS, HRMSMS, H/D exchange and 2D-NMR studies. A kinetic study of the impurity formation was conducted to determine the best conditions to control it in the final chemical process., (Copyright © 2019 Elsevier B.V. All rights reserved.)