Digital Devices for Assessing Motor Functions in Mobility-Impaired and Healthy Populations: Systematic Literature Review.

BACKGROUND: With the advent of smart sensing technology, mobile and wearable devices can provide continuous and objective monitoring and assessment of motor function outcomes. OBJECTIVE: We aimed to describe the existing scientific literature on wearable and mobile technologies that are being used or tested for assessing motor functions in mobility-impaired and healthy adults and to evaluate the degree to which these devices provide clinically valid measures of motor function in these populations. METHODS: A systematic literature review was conducted by searching Embase, MEDLINE, CENTRAL (January 1, 2015, to June 24, 2020), the United States and European Union clinical trial registries, and the United States Food and Drug Administration website using predefined study selection criteria. Study selection, data extraction, and quality assessment were performed by 2 independent reviewers. RESULTS: A total of 91 publications representing 87 unique studies were included. The most represented clinical conditions were Parkinson disease (n=51 studies), followed by stroke (n=5), Huntington disease (n=5), and multiple sclerosis (n=2). A total of 42 motion-detecting devices were identified, and the majority (n=27, 64%) were created for the purpose of health care-related data collection, although approximately 25% were personal electronic devices (eg, smartphones and watches) and 11% were entertainment consoles (eg, Microsoft Kinect or Xbox and Nintendo Wii). The primary motion outcomes were related to gait (n=30), gross motor movements (n=25), and fine motor movements (n=23). As a group, sensor-derived motion data showed a mean sensitivity of 0.83 (SD 7.27), a mean specificity of 0.84 (SD 15.40), a mean accuracy of 0.90 (SD 5.87) in discriminating between diseased individuals and healthy controls, and a mean Pearson r validity coefficient of 0.52 (SD 0.22) relative to clinical measures. We did not find significant differences in the degree of validity between in-laboratory and at-home sensor-based assessments nor between device class (ie, health care-related device, personal electronic devices, and entertainment consoles). CONCLUSIONS: Sensor-derived motion data can be leveraged to classify and quantify disease status for a variety of neurological conditions. However, most of the recent research on digital clinical measures is derived from proof-of-concept studies with considerable variation in methodological approaches, and much of the reviewed literature has focused on clinical validation, with less than one-quarter of the studies performing analytical validation. Overall, future research is crucially needed to further consolidate that sensor-derived motion data may lead to the development of robust and transformative digital measurements intended to predict, diagnose, and quantify neurological disease state and its longitudinal change.

Intergenerational Continuity in Adverse Childhood Experiences and Rural Community Environments.

OBJECTIVES: To understand the role of the community environment on intergenerational continuity in adverse childhood experiences (ACEs) among a rural White sample. METHODS: Parents in 12 counties in rural Iowa reported retrospectively on their own ACEs in 1989. We measured their child's ACEs retrospectively and prospectively across adolescence (n = 451 families). We measured structural and social process-related measures of community environment (i.e., community socioeconomic status, parents' perception of community services, perceived community social cohesion, and neighborhood alcohol vendor density) on multiple occasions during the child's adolescence. RESULTS: The 4 measures of community environment were all correlated with the child's ACEs, but only alcohol vendor density predicted ACEs after inclusion of covariates. Intergenerational continuity in ACEs was moderated by both social cohesion (b = -0.11; SE = 0.04) and alcohol vendor density (b = -0.11; SE = 0.05). CONCLUSIONS: Efforts to increase community social cohesion and manage alcohol vendor density may assist families in breaking the cycle of maltreatment across generations.

Disrupting intergenerational continuity in harsh parenting: Self-control and a supportive partner.

Harsh, abusive, and rejecting behavior by parents toward their children is associated with increased risk for many developmental problems for youth. Children raised by harsh parents are also more likely to treat their own children harshly. The present study addresses conditions that would break this intergenerational cycle of harsh parenting. Data come from a three-generation study of a cohort of 290 adolescents (Generation 2 [G2], 52% female) grown to adulthood and their parents (Generation 1 [G1]). During adolescence, observers rated G1 harsh parenting to G2. Several years later observers rated G2 harsh parenting toward their oldest child (Generation 3 [G3]). Several adaptive systems fundamental to human resilience attenuate intergenerational continuity in harshness. G2 parents were relatively less harsh to G3 children (notwithstanding a history of harshness from G1) when G2's romantic partner (a) communicated positively with G2 and (b) had a good relationship with G3, and (c) when G2 was high on self-control. Interventions that target all of these protective factors may not only break but also reverse the intergenerational cycle of child maltreatment.

Mother-Adolescent Proficiency in a Common Language Facilitates Socialization Among Mexican-Origin Families.

The primary goal of this study was to test how mother and adolescent proficiency in a common language moderates the link from parenting to adolescent development. A sample of Mexican-origin fifth-grade adolescents (N = 674, 50% female) was measured longitudinally on self-control and aggression. Mothers were rated on observed positive discipline, warmth, and harsh discipline. Positive discipline and warm parenting predicted increases in self-control and decreases in aggression, but only among mother-adolescent dyads who were proficient in a common language. Harsh parenting predicted decreases in self-control and increases in aggression, but only among dyads who were not proficient in a common language. Similar results were found in a conceptual replication among a second sample of 167 Mexican-origin adolescents.

Unsupervised self-care predicts conduct problems: The moderating roles of hostile aggression and gender.

Despite widespread speculation about the detrimental effect of unsupervised self-care on adolescent outcomes, little is known about which children are particularly prone to problem behaviors when left at home without adult supervision. The present research used data from a longitudinal study of 674 Mexican-origin children residing in the United States to examine the prospective effect of unsupervised self-care on conduct problems, and the moderating roles of hostile aggression and gender. Results showed that unsupervised self-care was related to increases over time in conduct problems such as lying, stealing, and bullying. However, unsupervised self-care only led to conduct problems for boys and for children with an aggressive temperament. The main and interactive effects held for both mother-reported and observational-rated hostile aggression and after controlling for potential confounds.

The asymmetric syntheses of pyrrolizidines, indolizidines and quinolizidines via two sequential tandem ring-closure/N-debenzylation processes.

Concise asymmetric syntheses of (-)-lupinine, (+)-isoretronecanol, (+)-5-epi-tashiromine and (R,R)-1-(hydroxymethyl)octahydroindolizine (the azabicyclic core within stellettamides A-C) have been achieved in 8 steps or fewer from commercially available starting materials. The key steps in these syntheses involved the preparation of enantiopure ß-amino esters, upon conjugate addition of lithium (R)-N-(p-methoxybenzyl)-N-(α-methyl-p-methoxybenzyl)amide to either ζ-chloro or ζ-hydroxy substituted tert-butyl (E)-hept-2-enoate, or ε-chloro or ε-hydroxy substituted tert-butyl (E)-hex-2-enoate. Activation of the ω-substituent as a leaving group led to SN2-type ring-closure, which occurred with concomitant N-debenzylation via an E1-type deprotection step, to give the corresponding pyrrolidine or piperidine in good yield. Subsequent alkylation of these enantiopure azacycles, followed by a second ring-closure/concomitant N-debenzylation step formed the pyrrolizidine, indolizidine or quinolizidine motif, and reduction with LiAlH4 gave the target compounds in diastereoisomerically and enantiomerically pure form.

ETD001: A novel inhaled ENaC blocker with an extended duration of action in vivo.

BACKGROUND: Inhibiting ENaC in the airways of people with cystic fibrosis (pwCF) is hypothesized to enhance mucociliary clearance (MCC) and provide clinical benefit. Historically, inhaled ENaC blockers have failed to show benefit in pwCF challenging this hypothesis. It is however unknown whether the clinical doses were sufficient to provide the required long duration of action in the lungs and questions whether a novel candidate could offer advantages where others have failed? METHODS: Dose-responses with the failed ENaC blockers (VX-371, BI 1265162, AZD5634, QBW276) together with ETD001 (a novel long acting inhaled ENaC blocker) were established in a sheep model of MCC and were used to predict clinically relevant doses that would provide a long-lasting enhancement of MCC in pwCF. In each case, dose predictions were compared with the selected clinical dose. RESULTS: Each of the failed candidates enhanced MCC in the sheep model. Translating these dose-response data to human equivalent doses, predicted that substantially larger doses of each candidate, than were evaluated in clinical studies, would likely have been required to achieve a prolonged enhancement of MCC in pwCF. In contrast, ETD001 displayed a long duration of action (≥16 h) at a dose level that was well tolerated in Phase 1 clinical studies. CONCLUSIONS: These data support that the ENaC blocker hypothesis is yet to be appropriately tested in pwCF. ETD001 has a profile that enables dosing at a level sufficient to provide a long duration of action in a Phase 2 clinical study in pwCF scheduled for 2024.

Guidelines for Specialized Epilepsy Centers: Executive Summary of the Report of the National Association of Epilepsy Centers Guideline Panel.

The National Association of Epilepsy Centers first published the guidelines for epilepsy centers in 1990, which were last updated in 2010. Since that update, epilepsy care and the science of guideline development have advanced significantly, including the importance of incorporating a diversity of stakeholder perspectives such as those of patients and their caregivers. Currently, despite extensive published data examining the efficacy of treatments and diagnostic testing for epilepsy, there remain significant gaps in data identifying the essential services needed for a comprehensive epilepsy center and the optimal manner for their delivery. The trustworthy consensus-based statements (TCBS) process produces unbiased, scientifically valid guidelines through a transparent process that incorporates available evidence and expert opinion. A systematic literature search returned 5937 relevant studies from which 197 articles were retained for data extraction. A panel of 41 stakeholders with diverse expertise evaluated this evidence and drafted recommendations following the TCBS process. The panel reached consensus on 52 recommendations covering services provided by specialized epilepsy centers in both the inpatient and outpatient settings in major topic areas including epilepsy monitoring unit care, surgery, neuroimaging, neuropsychology, genetics, and outpatient care. Recommendations were informed by the evidence review and reflect the consensus of a broad panel of expert opinions.

Changes in auditory feedback connections determine the severity of speech processing deficits after stroke.

We compared brain structure and function in two subgroups of 21 stroke patients with either moderate or severe chronic speech comprehension impairment. Both groups had damage to the supratemporal plane; however, the severe group suffered greater damage to two unimodal auditory areas: primary auditory cortex and the planum temporale. The effects of this damage were investigated using fMRI while patients listened to speech and speech-like sounds. Pronounced changes in connectivity were found in both groups in undamaged parts of the auditory hierarchy. Compared to controls, moderate patients had significantly stronger feedback connections from planum temporale to primary auditory cortex bilaterally, while in severe patients this connection was significantly weaker in the undamaged right hemisphere. This suggests that predictive feedback mechanisms compensate in moderately affected patients but not in severely affected patients. The key pathomechanism in humans with persistent speech comprehension impairments may be impaired feedback connectivity to unimodal auditory areas.

Understanding adolescent and family influences on intimate partner psychological violence during emerging adulthood and adulthood.

The intergenerational transmission of violence directed toward intimate partners has been documented for the past three decades. Overall, the literature shows that violence in the family of origin leads to violence in the family of destination. However, this predominately cross-sectional or retrospective literature is limited by self-selection, endogeneity, and reporter biases as it has not been able to assess how individual and family behaviors simultaneously experienced during adolescence influence intimate partner violence throughout adulthood. The present study used data from the Iowa Youth and Families Project (IYFP; N = 392; 52 % Female), a multi-method, multi-trait prospective approach, to overcome this limitation. We focused on psychological intimate partner violence in both emerging adulthood (19-23 years) and adulthood (27-31 years), and include self and partner ratings of violence as well as observational data in a sample of rural non-Hispanic white families. Controlling for a host of individual risk factors as well as interparental psychological violence from adolescence (14-15 years), the results show that exposure to parent-to-child psychological violence during adolescence is a key predictor of intimate partner violence throughout adulthood. In addition, negative emotionality and the number of sexual partners in adolescence predicted intimate partner violence in both emerging adulthood and adulthood. Exposure to family stress was associated positively with intimate partner violence in adulthood but not in emerging adulthood, whereas academic difficulties were found to increase violence in emerging adulthood only. Unlike previous research, results did not support a direct effect of interparental psychological violence on psychological violence in the next generation. Gender differences were found only in emerging adulthood. Implications of these findings are discussed in light of the current literature and future directions.

Neighborhood selection by parent personality, depression, and coparent support: A two-study replication.

This study addresses the degree to which three selection factors (parent personality, depression, and coparent support) drive movement into neighborhoods and predict changes in youth externalizing behavior. Two studies followed children from birth to age 15 (N = 1,364 for Study 1; N = 4,898 for Study 2). Neighborhood socioeconomic disadvantage, family income, and youth externalizing behavior were consistently and significantly correlated cross sectionally and longitudinally. Selection factors predicted changes in youth externalizing behavior. Higher family income, mother agreeableness, and perceived support from a coparent predicted movement over time into less disadvantaged neighborhoods. Lower levels of mother impulsivity, neuroticism, and depression also predicted movement over time into less disadvantaged neighborhoods. Neighborhood disadvantage did not predict change in youth externalizing behavior when any of the above selection factors were included in the model. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Generative embedding for model-based classification of fMRI data.

Decoding models, such as those underlying multivariate classification algorithms, have been increasingly used to infer cognitive or clinical brain states from measures of brain activity obtained by functional magnetic resonance imaging (fMRI). The practicality of current classifiers, however, is restricted by two major challenges. First, due to the high data dimensionality and low sample size, algorithms struggle to separate informative from uninformative features, resulting in poor generalization performance. Second, popular discriminative methods such as support vector machines (SVMs) rarely afford mechanistic interpretability. In this paper, we address these issues by proposing a novel generative-embedding approach that incorporates neurobiologically interpretable generative models into discriminative classifiers. Our approach extends previous work on trial-by-trial classification for electrophysiological recordings to subject-by-subject classification for fMRI and offers two key advantages over conventional methods: it may provide more accurate predictions by exploiting discriminative information encoded in 'hidden' physiological quantities such as synaptic connection strengths; and it affords mechanistic interpretability of clinical classifications. Here, we introduce generative embedding for fMRI using a combination of dynamic causal models (DCMs) and SVMs. We propose a general procedure of DCM-based generative embedding for subject-wise classification, provide a concrete implementation, and suggest good-practice guidelines for unbiased application of generative embedding in the context of fMRI. We illustrate the utility of our approach by a clinical example in which we classify moderately aphasic patients and healthy controls using a DCM of thalamo-temporal regions during speech processing. Generative embedding achieves a near-perfect balanced classification accuracy of 98% and significantly outperforms conventional activation-based and correlation-based methods. This example demonstrates how disease states can be detected with very high accuracy and, at the same time, be interpreted mechanistically in terms of abnormalities in connectivity. We envisage that future applications of generative embedding may provide crucial advances in dissecting spectrum disorders into physiologically more well-defined subgroups.

Neighborhood disorder and children's antisocial behavior: the protective effect of family support among Mexican American and African American Families.

Using data from a sample of 673 Mexican Origin families, the current investigation examined the degree to which family supportiveness acted as a protective buffer between neighborhood disorder and antisocial behavior during late childhood (i.e. intent to use controlled substances, externalizing, and association with deviant peers). Children's perceptions of neighborhood disorder fully mediated associations between census and observer measures of neighborhood disorder and their antisocial behavior. Family support buffered children from the higher rates of antisocial behavior generally associated with living in disorderly neighborhoods. An additional goal of the current study was to replicate these findings in a second sample of 897 African American families, and that replication was successful. These findings suggest that family support may play a protective role for children living in dangerous or disadvantaged neighborhoods. They also suggest that neighborhood interventions should consider several points of entry including structural changes, resident perceptions of their neighborhood and family support.

Novel Functional, Health, and Genetic Determinants of Cognitive Terminal Decline: Kuakini Honolulu Heart Program/Honolulu-Asia Aging Study.

To investigate interindividual differences in cognitive terminal decline and identify determinants including functional, health, and genetic risk and protective factors, data from the Honolulu Heart Program/Honolulu-Asia Aging Study, a prospective cohort study of Japanese American men, were analyzed. The sample was recruited in 1965-1968 (ages 45-68 years). Longitudinal performance of cognitive abilities and mortality status were assessed from Exam 4 (1991-1993) through June 2014. Latent class analysis revealed 2 groups: maintainers retained relatively high levels of cognitive functioning until death and decliners demonstrated significant cognitive waning several years prior to death. Maintainers were more likely to have greater education, diagnosed coronary heart disease, and presence of the apolipoprotein E (APOE) ε2 allele and FOXO3 G allele (SNP rs2802292). Decliners were more likely to be older and have prior stroke, Parkinson's disease, dementia, and greater depressive symptoms at Exam 4, and the APOE ε4 allele. Findings support terminal decline using distance to death as the basis for modeling change. Significant differences were observed between maintainers and decliners 15 years prior to death, a finding much earlier compared to the majority of previous investigations.

Comparing families of dynamic causal models.

Mathematical models of scientific data can be formally compared using Bayesian model evidence. Previous applications in the biological sciences have mainly focussed on model selection in which one first selects the model with the highest evidence and then makes inferences based on the parameters of that model. This "best model" approach is very useful but can become brittle if there are a large number of models to compare, and if different subjects use different models. To overcome this shortcoming we propose the combination of two further approaches: (i) family level inference and (ii) Bayesian model averaging within families. Family level inference removes uncertainty about aspects of model structure other than the characteristic of interest. For example: What are the inputs to the system? Is processing serial or parallel? Is it linear or nonlinear? Is it mediated by a single, crucial connection? We apply Bayesian model averaging within families to provide inferences about parameters that are independent of further assumptions about model structure. We illustrate the methods using Dynamic Causal Models of brain imaging data.

Intergenerational transmission of adaptive functioning: a test of the interactionist model of SES and human development.

The interactionist model (IM) of human development (R. D. Conger & M. B. Donellan, 2007) proposes that the association between socioeconomic status (SES) and human development involves a dynamic interplay that includes both social causation (SES influences human development) and social selection (individual characteristics affect SES). Using a multigenerational data set involving 271 families, the current study finds empirical support for the IM. Adolescent personality characteristics indicative of social competence, goal-setting, hard work, and emotional stability predicted later SES, parenting, and family characteristics that were related to the positive development of a third-generation child. Processes of both social selection and social causation appear to account for the association between SES and dimensions of human development indicative of healthy functioning across multiple generations.

Characterisation of a tripartite α-pore forming toxin from Serratia marcescens.

Tripartite members of the ClyA family of α-PFTs have recently been identified in a number of pathogenic Gram-negative bacteria, including the human pathogen Serratia marcescens. Structures of a Gram-negative A component and a tripartite α-PFT complete pore are unknown and a mechanism for pore formation is still uncertain. Here we characterise the tripartite SmhABC toxin from S. marcescens and propose a mechanism of pore assembly. We present the structure of soluble SmhA, as well as the soluble and pore forms of SmhB. We show that the ß-tongue soluble structure is well conserved in the family and propose two conserved latches between the head and tail domains that are broken on the soluble to pore conformational change. Using the structures of individual components, sequence analysis and docking predictions we illustrate how the A, B and C protomers would assemble on the membrane to produce a complete tripartite α-PFT pore.

The left superior temporal gyrus is a shared substrate for auditory short-term memory and speech comprehension: evidence from 210 patients with stroke.

Competing theories of short-term memory function make specific predictions about the functional anatomy of auditory short-term memory and its role in language comprehension. We analysed high-resolution structural magnetic resonance images from 210 stroke patients and employed a novel voxel based analysis to test the relationship between auditory short-term memory and speech comprehension. Using digit span as an index of auditory short-term memory capacity we found that the structural integrity of a posterior region of the superior temporal gyrus and sulcus predicted auditory short-term memory capacity, even when performance on a range of other measures was factored out. We show that the integrity of this region also predicts the ability to comprehend spoken sentences. Our results therefore support cognitive models that posit a shared substrate between auditory short-term memory capacity and speech comprehension ability. The method applied here will be particularly useful for modelling structure-function relationships within other complex cognitive domains.

Evaluation of the interactionist model of socioeconomic status and problem behavior: a developmental cascade across generations.

The current multigenerational study evaluates the utility of the interactionist model of socioeconomic influence on human development (IMSI) in explaining problem behaviors across generations. The IMSI proposes that the association between socioeconomic status (SES) and human development involves a dynamic interplay that includes both social causation (SES influences human development) and social selection (individual characteristics affect SES). As part of the developmental cascade proposed by the IMSI, the findings from this investigation showed that Generation 1 (G1) adolescent problem behavior predicted later G1 SES, family stress, and parental emotional investments, as well as the next generation of children's problem behavior. These results are consistent with a social selection view. Consistent with the social causation perspective, we found a significant relation between G1 SES and family stress, and in turn, family stress predicted Generation 2 (G2) problem behavior. Finally, G1 adult SES predicted both material and emotional investments in the G2 child. In turn, emotional investments predicted G2 problem behavior, as did material investments. Some of the predicted pathways varied by G1 parent gender. The results are consistent with the view that processes of both social selection and social causation account for the association between SES and human development.

The A component (SmhA) of a tripartite pore-forming toxin from Serratia marcescens: expression, purification and crystallographic analysis.

Tripartite α-pore-forming toxins are constructed of three proteins (A, B and C) and are found in many bacterial pathogens. While structures of the B and C components from Gram-negative bacteria have been described, the structure of the A component of a Gram-negative α-pore-forming toxin has so far proved elusive. SmhA, the A component from the opportunistic human pathogen Serratia marcescens, has been cloned, overexpressed and purified. Crystals were grown of selenomethionine-derivatized protein and anomalous data were collected. Phases were calculated and an initial electron-density map was produced.