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.

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).

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.

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.

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 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.

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.

Family health and income: A two-sample replication.

The current study examined psychological and family health predictors of change over time in household income, using data from longitudinal studies of African American (N = 889, 93.5% female) and Mexican origin (N = 674, 100% female) families. Participants self-reported their household income, as well as their emotional, personality, and cognitive resources. Participant behavioral and physical resources were coded from observed family interactions. Although income did not predict change in any personal resources, all five classes of personal resources (i.e., emotional, personality, cognitive, behavioral, physical) predicted change in income across a 10-year span (Study 1) and a 6-year span (Study 2). Income is potentially caused by these personal resources, or both income and these personal resources share a common cause. The dominant approach of assuming income causes personal and family health needs stronger support. (PsycINFO Database Record

Breastfeeding duration predicts greater maternal sensitivity over the next decade.

The current study represents the first longitudinal investigation of the potential effects of breastfeeding duration on maternal sensitivity over the following decade. This study also examined whether infant attachment security at 24 months would mediate longitudinal relations between breastfeeding duration and changes in maternal sensitivity over time. Using data from 1,272 families from the National Institute of Child Health and Human Development's Study of Early Child Care and Youth Development, we found that longer breastfeeding duration (assessed up to age 3) predicted increases in observed maternal sensitivity up to child age 11, after accounting for maternal neuroticism, parenting attitudes, ethnicity, maternal years of education, and presence of a romantic partner. Additionally, secure attachment at 24 months was predicted by breastfeeding duration, but it did not act as a mediator of the link from breastfeeding duration to maternal sensitivity in this study. Generating a more specific understanding of how breastfeeding impacts the mother-child dyad beyond infancy will inform recommendations for best practices regarding breastfeeding. (PsycINFO Database Record

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.

Parenting and later substance use among Mexican-origin youth: Moderation by preference for a common language.

The primary goal of the current study was to test whether parent and adolescent preference for a common language moderates the association between parenting and rank-order change over time in offspring substance use. A sample of Mexican-origin 7th-grade adolescents (Mage = 12.5 years, N = 194, 52% female) was measured longitudinally on use of tobacco, alcohol, and marijuana. Mothers, fathers, and adolescents all reported on consistent discipline and monitoring of adolescents. Both consistent discipline and monitoring predicted relative decreases in substance use into early adulthood but only among parent-offspring dyads who expressed preference for the same language (either English or Spanish). This moderation held after controlling for parent substance use, family structure, having completed schooling in Mexico, years lived in the United States, family income, and cultural values. An unintended consequence of the immigration process may be the loss of parenting effectiveness that is normally present when parents and adolescents prefer to communicate in a common language. (PsycINFO Database Record

Intergenerational continuity in attitudes: A latent variable family fixed-effects approach.

Attitudes are associated with behavior. Adolescents raised by parents who endorse particular attitudes are relatively more likely to endorse those same attitudes. The present study addresses conditions that would moderate intergenerational continuity in attitudes across 6 domains: authoritative parenting, conventional life goals, gender egalitarianism, deviancy, abortion, and sexual permissiveness. Hypothesized moderators included the attitudes of the other parent, and adolescent sex. Data come from a 2-generation study of a cohort of 451 adolescents (52% female), a close-aged sibling, and their parents. After employing a novel specification in which family fixed-effect models partitioned out variation at the between-family level, hypotheses were tested on the within-family variance. Unlike typical family fixed-effect models, this specification accounted for measurement error. Intergenerational continuity was not significant (deviancy), negative (sexual permissiveness), and conditional on the attitudes of the coparent (authoritative parenting, conventional life goals, and gender egalitarianism). Adolescent age, sex, and conscientiousness were accounted for in all analyses. (PsycINFO Database Record

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.

Harsh parenting, physical health, and the protective role of positive parent-adolescent relationships.

RATIONALE: Harsh, abusive and rejecting behavior by parents toward their adolescents is associated with increased risk of many developmental problems for youth. OBJECTIVE: In the present study we address behaviors of co-parents that might help disrupt the hypothesized health risk of harsh parenting. METHOD: Data come from a community study of 451 early adolescents followed into adulthood. During early adolescence, observers rated both parents separately on harshness towards the adolescent. Adolescents reported on their physical health at multiple assessments from age 12 through age 20, and on parental warmth. RESULTS: Harsh parenting predicted declines in adolescent self-reported physical health and increases in adolescent body mass index (BMI). Although the health risk associated with harshness from one parent was buffered by warmth from the other parent, warmth from the second parent augmented the association between harshness from the first parent and change over time in adolescent BMI. CONCLUSION: As appropriate, preventive interventions should include a focus on spousal or partner behaviors in their educational or treatment programs. Additional research is needed on the association between self-reported physical health and BMI in adolescence.

Optimal assessment of parenting, or how I learned to stop worrying and love reporter disagreement.

The purpose of this study was to examine differences and similarities across ratings of parenting by preadolescents, parents, and observers. Two hundred forty-one preadolescents rated their parents on warmth and harshness. Both mothers and fathers self-reported on these same dimensions, and observers rated each parents' warmth and harshness during a 10 min interaction task with the preadolescent. For the majority of outcomes assessed, the differences between preadolescent, parent, and observer ratings accounted for significant amounts of variance, beyond the levels accounted for by the average of their reports. A replication sample of 929 mother-child dyads provided a similar pattern of results. This methodology can help standardize the study of reporter differences, supports modeling of rater-specific variance as true score, and illustrates the benefits of collecting parenting data from multiple reporters. (PsycINFO Database Record

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.

Democratic parenting beliefs and observed parental sensitivity: Reciprocal influences between coparents.

Three hundred sixty-five 2-parent families from the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development were rated by trained observers on their parenting behavior at 6 assessments ranging from 6 months after the child's birth to when the child was in fifth grade (M = 10.4 years old at fifth grade). Across assessments, parents reported on their parenting beliefs and mothers reported on the child's externalizing behavior problems. Parenting beliefs predicted change in parenting behavior, and to a lesser degree parenting behavior predicted change in parenting beliefs. Parenting behavior and parenting beliefs both showed reciprocal effects between coparents, after controlling for child externalizing behavior and parent education. (PsycINFO Database Record

Early adolescent substance use in Mexican origin families: Peer selection, peer influence, and parental monitoring.

BACKGROUND: Because adolescents vary in their susceptibility to peer influence, the current study addresses potential reciprocal effects between associating with deviant peers and use of alcohol, tobacco and other drugs (ATOD), as well as the potential buffering role of parental monitoring on these reciprocal effects. METHOD: 674 children of Mexican origin reported at fifth and seventh grade (10.4 years old at fifth grade) on the degree to which they associated with deviant peers, intended to use alcohol, tobacco or other drugs (ATOD) in the future, and had used controlled substances during the past year. Trained observers rated parental monitoring from video-recorded family interactions at the first assessment. RESULTS: Youth who intended to use ATODs during fifth grade experienced a relative increase in number of deviant peers by seventh grade, and youth with more deviant peers in fifth grade were more likely to use ATODs by seventh grade. Parental monitoring buffered (i.e., moderated) the reciprocal association between involvement with deviant peers and both intent to use ATODs and actual use of ATODs. CONCLUSIONS: Parental monitoring can disrupt the reciprocal associations between deviant peers and ATOD use during the transition from childhood to adolescence.

The Impact of Economic Pressure on Parent Positivity, Parenting, and Adolescent Positivity into Emerging Adulthood.

The current study describes how positivity can be incorporated into the Family Stress Model to explain resilience to disrupted family processes in the face of economic distress. Prospective, longitudinal data came from 451 mothers, fathers, and youth participating from their adolescence through early adulthood. Assessments included observational and self-report measures. Information regarding economic pressure, parental positivity, and parenting were collected during early adolescence, positivity was collected in late adolescence and emerging adulthood. Results indicated that economic pressure was indirectly associated with adolescent positivity through parental positivity. Economic pressure was negatively associated with parent positivity, whereas parental positivity was positively associated with parenting. Moreover, parental positivity and parenting were both related to positivity in adolescence. Results suggest that personal resources linked to a positive outlook can foster nurturant parenting, even in times of economic strain. Such parenting seems to positively influence adolescent development into emerging adulthood.