Combining machine learning with structure-based protein design to predict and engineer post-translational modifications of proteins.

Post-translational modifications (PTMs) of proteins play a vital role in their function and stability. These modifications influence protein folding, signaling, protein-protein interactions, enzyme activity, binding affinity, aggregation, degradation, and much more. To date, over 400 types of PTMs have been described, representing chemical diversity well beyond the genetically encoded amino acids. Such modifications pose a challenge to the successful design of proteins, but also represent a major opportunity to diversify the protein engineering toolbox. To this end, we first trained artificial neural networks (ANNs) to predict eighteen of the most abundant PTMs, including protein glycosylation, phosphorylation, methylation, and deamidation. In a second step, these models were implemented inside the computational protein modeling suite Rosetta, which allows flexible combination with existing protocols to model the modified sites and understand their impact on protein stability as well as function. Lastly, we developed a new design protocol that either maximizes or minimizes the predicted probability of a particular site being modified. We find that this combination of ANN prediction and structure-based design can enable the modification of existing, as well as the introduction of novel, PTMs. The potential applications of our work include, but are not limited to, glycan masking of epitopes, strengthening protein-protein interactions through phosphorylation, as well as protecting proteins from deamidation liabilities. These applications are especially important for the design of new protein therapeutics where PTMs can drastically change the therapeutic properties of a protein. Our work adds novel tools to Rosetta's protein engineering toolbox that allow for the rational design of PTMs.

Contextual factors of child behavioral health across developmental stages.

This study examines the relative influence of environmental contexts (family, school, neighborhood) on child behavioral health at ages 3, 5, 9, and 15 years. Path analysis was conducted on a sample of 4,898 urban children from a longitudinal dataset called the Fragile Families and Child Wellbeing Study. Child physical abuse, emotional abuse, maternal depression, substance use, neighborhood social cohesion, neighborhood poverty, school connectedness, and peer bullying had concurrent relationships with child behavior problems at one or more developmental stages. Early childhood abuse (age 3) and school age environmental contexts (age 9) had lasting effects on later behavior problems. Findings underscore the importance of both multilevel contextual factors and developmental timing in determining behavioral health outcomes in children.

The moderating role of neighborhood social cohesion on the relationship between early mother-child attachment security and adolescent social skills: Brief report.

Background: Social skill is a critical asset for adolescents, and early mother-child attachment is an essential contributor to their development. While less secure mother-child attachment is a known risk factor for adolescent social development, the protective factor of neighborhood context in buffering this risk is still not well understood. Research Design: This study used longitudinal data from the Fragile Families and Child Wellbeing Study (n = 1,876). Adolescent social skills (at age 15) were examined as a function of early attachment security and neighborhood social cohesion (age 3). Results: Children with higher mother-child attachment security at age three had higher adolescent social skills at age 15. The findings show that there was an interaction effect such that neighborhood social cohesion buffered the relationship between mother-child attachment security and adolescent social skills. Conclusion: Our study highlights that early mother-child attachment security can be promotive for cultivating adolescent social skills. Furthermore, neighborhood social cohesion can be protective among children with lower mother-child attachment security.

Implementation and Mental Health Outcomes of a Service Cascade Linking Child Welfare and Children's Mental Health Systems: A Case Study of the Gateway CALL Demonstration.

The mental health needs of children and youth involved in the child welfare system remain largely unmet. Service cascades are an emerging approach to systematizing mental health screening, assessment, and treatment referral processes. However, evidence is minimal and inconsistent regarding the effectiveness of such approaches for improving mental health service access and outcomes. In an effort to address this gap, this study presents a case-study of the implementation fidelity and treatment outcomes of the Gateway CALL service cascade. Study analyses involved longitudinal data collected as part of a larger evaluation of Gateway CALL. Specifically, descriptive and linear mixed model analyses were conducted to assess the implementation of service cascade components, and changes in mental health outcomes (behavior problems) among 175 children placed out-of-home during the study. Study analyses found that although fidelity was strong early in the service cascade, implementation began to break down once components involved more than one service system (child welfare, mental health). However, results also indicated that parent-reported child behavior problems decreased significantly over time, despite later cascade components being implemented with poor fidelity to the Gateway CALL service model. For children and youth involved in child welfare systems, service cascades like Gateway CALL have the potential to significantly improve both mental health service receipt and outcomes. To maximize the effectiveness of such approaches, later phases of implementation may require increased attention and support, particularly regarding processes and outcomes that cross child welfare and mental health service systems.

XENet: Using a new graph convolution to accelerate the timeline for protein design on quantum computers.

Graph representations are traditionally used to represent protein structures in sequence design protocols in which the protein backbone conformation is known. This infrequently extends to machine learning projects: existing graph convolution algorithms have shortcomings when representing protein environments. One reason for this is the lack of emphasis on edge attributes during massage-passing operations. Another reason is the traditionally shallow nature of graph neural network architectures. Here we introduce an improved message-passing operation that is better equipped to model local kinematics problems such as protein design. Our approach, XENet, pays special attention to both incoming and outgoing edge attributes. We compare XENet against existing graph convolutions in an attempt to decrease rotamer sample counts in Rosetta's rotamer substitution protocol, used for protein side-chain optimization and sequence design. This use case is motivating because it both reduces the size of the search space for classical side-chain optimization algorithms, and allows larger protein design problems to be solved with quantum algorithms on near-term quantum computers with limited qubit counts. XENet outperformed competing models while also displaying a greater tolerance for deeper architectures. We found that XENet was able to decrease rotamer counts by 40% without loss in quality. This decreased the memory consumption for classical pre-computation of rotamer energies in our use case by more than a factor of 3, the qubit consumption for an existing sequence design quantum algorithm by 40%, and the size of the solution space by a factor of 165. Additionally, XENet displayed an ability to handle deeper architectures than competing convolutions.

Informal supports, housing insecurity, and adolescent outcomes: Implications for promoting resilience.

Adolescents in low-income, marginalized families are vulnerable to behavior problems that impede healthy functioning and threaten long-term well-being. Informal supports may fill an important gap for these households as they navigate financial and social stressors. Instrumental support from social networks and neighborhood cohesion may promote family stability and youth well-being; further, these informal supports may promote resilience to housing insecurity, which is linked with a range of adverse adolescent outcomes. The present study utilized data from a large sample of at-risk families with children (N = 2425) to investigate whether instrumental support and neighborhood cohesion predicted adolescent behavior problems over 10 years and whether these links were mediated by housing insecurity. Results of structural equation modeling with latent variables showed direct links from instrumental support to anxious/depressed behaviors and from neighborhood cohesion to aggressive behaviors, as well as an indirect link from instrumental support to aggressive behavior via housing insecurity. Findings suggest informal supports are an important source of resilience for low-income families who may be excluded from or are reluctant to engage with formal social systems. Further, stable, connected communities with highly embedded social networks can promote housing stability and youth well-being in a virtuous cycle.

Perturbing the energy landscape for improved packing during computational protein design.

The FastDesign protocol in the molecular modeling program Rosetta iterates between sequence optimization and structure refinement to stabilize de novo designed protein structures and complexes. FastDesign has been used previously to design novel protein folds and assemblies with important applications in research and medicine. To promote sampling of alternative conformations and sequences, FastDesign includes stages where the energy landscape is smoothened by reducing repulsive forces. Here, we discover that this process disfavors larger amino acids in the protein core because the protein compresses in the early stages of refinement. By testing alternative ramping strategies for the repulsive weight, we arrive at a scheme that produces lower energy designs with more native-like sequence composition in the protein core. We further validate the protocol by designing and experimentally characterizing over 4000 proteins and show that the new protocol produces higher stability proteins.

Enhancing Permanency in Children and Families (EPIC): a child welfare intervention for parental substance abuse.

BACKGROUND: Across Ohio, parental substance abuse has contributed to a marked increase in the number of children in foster care. Children exposed to parental substance use have a higher likelihood of physical abuse and neglect, and consequently a variety of physical, psychological and cognitive problems. The Enhancing Permanency in Children and Families (EPIC) program is a collaborative effort between the Ohio State University College of Social Work, two county offices of the Ohio Department of Job and Family Services, two juvenile courts and local behavioral health agencies. The goal of EPIC is to use three evidence-based and evidence-informed practices to reduce abusive and neglectful parenting, reduce addiction severity in parents, and improve permanency outcomes for families involved with the child welfare system due to substance abuse. METHODS: EPIC is a quasi-experimental study. Under the program, child welfare-involved adults who screen positive for substances are matched with a peer recovery supporter. Participants are also incentivized to participate in family treatment drug court, medications for opioid use disorders and home-based parenting supports. Participating adults (N = 250) are matched with comparison groups from counties participating in a separate intervention (Ohio START) and to those receiving treatment as usual, resulting in a final sample of 750 adults. Primary outcomes including addiction severity, child trauma symptoms, resilience, and attachment are assessed at baseline and at program completion. Additional outcomes include timely access to treatment services, length of placement in out-of-home care and recidivism into the child welfare system. DISCUSSION: This intervention formalizes cross-system collaboration between child welfare, behavioral health and juvenile courts to support families affected by addiction. The use of three evidence-based or evidence-informed strategies presents the opportunity to determine specific strategies that are most effective for reducing addiction severity. Lastly, the intervention combines several sources of funding to bolster sustainability beyond the life of the Regional Partnership Grant (RPG). TRIAL REGISTRATION: NCT04700696 . Registered January 7, 2021-retrospectively registered.

Adverse Childhood Experiences and Child Health Outcomes: Comparing Cumulative Risk and Latent Class Approaches.

Objectives This study seeks to further the work exploring adverse childhood experiences (ACEs) by proposing a novel approach to understanding the impact of ACEs through applying advanced analytical methods to examine whether combinations of ACEs differentially impact child health outcomes. Methods Using National Survey of Children's Health data, we use latent class analysis to estimate associations between classes of ACEs and child health outcomes. Results Class membership predicts child poor health, with differences found for specific ACE combinations. A subgroup of children exposed to poverty and parental mental illness are at higher risk for special healthcare needs than all other groups, including children exposed to 3 or more ACEs. Conclusions Different combinations of ACEs carry different risk for child health. Interventions tailored to specific ACEs and ACE combinations are likely to have a greater effect on improving child health. Our findings suggest children who experience specific ACE combinations (e.g., poverty and parental mental illness) are at particularly high risk for poor health outcomes. Therefore, clinicians should routinely assess for ACEs to identify children exposed to the most problematic ACE combinations; once identified, these children should be given priority for supportive interventions tailored to their specific ACE exposure and needs.

A Nationally Representative Study of Early Childhood Home Visiting Service Use in the United States.

Early childhood home visiting (HV) services are expanding broadly across the United States. Supported by federal policy, HV is now an integral part of maternal and child health services. However, no nationally representative estimate of HV use is available and no research has compared HV use across states. The 2011/12 National Survey on Children's Health was used to estimate the national and state prevalence of HV use for children 0-3 years. Generalized linear mixed modeling was used to predict HV use. An estimated 2,137,044 US children and families received HV during pregnancy and up to child age of 3 years. State HV prevalence range was 3.7-30.6 %. Nationally, 19.1 % of children below the federal poverty line received HV services. Although family poverty increased the odds of receiving HV services, higher rates of child poverty at the state level predicted less use of HV services. Important predictors of HV use include infant/child need factors (health risk, adverse experiences), predisposing factors (family size), and enabling factors (insurance type). This study provides the first estimates of national and state HV service use. Although findings indicate HV services are targeted to children at elevated risk for poor physical or developmental outcomes, our estimates show the vast majority of at-risk children did not receive HV services, including more than 80 % of low-income children, 76 % of preterm infants, and 57 % of very low birth weight infants. Increasing HV service availability could decrease negative health outcomes for young children.

Association between longitudinal patterns of child maltreatment experiences and adolescent substance use.

BACKGROUND: Although there is a well-established link between child maltreatment and adolescent substance use, it remains unclear if and how longitudinal patterns of maltreatment experiences are associated with substance use in adolescence. OBJECTIVE: The purpose of the study was to examine how distinct patterns of longitudinal maltreatment experiences are associated with adolescent substance use. PARTICIPANTS AND SETTING: The participants were 899 adolescents from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN). METHODS: We conducted repeated measures latent class analysis (RMLCA) to identify patterns of physical abuse, sexual abuse, and neglect from birth to age 17 and their relations to tobacco, alcohol, and marijuana use at age 18. RESULTS: RMLCA identified three physical abuse classes (Stable low physical abuse; School age peak physical abuse; Physical abuse primarily in infancy/toddlerhood), two sexual abuse classes (Stable no/low sexual abuse; School age peak sexual abuse), and three neglect classes (High neglect in childhood; Neglect primarily in infancy/toddlerhood; Neglect primarily at school age). Adolescents in the school age peak physical abuse class showed greater alcohol, cigarette, and marijuana use, compared to other physical abuse classes. Similarly, adolescents in the school age peak sexual abuse class showed greater substance use than those in the stable no/low sexual abuse class. Lastly, adolescents in the neglect primarily in infancy/toddlerhood class showed significantly less substance use than those in the other two neglect classes. CONCLUSIONS: Findings highlight the importance of early intervention and ongoing maltreatment prevention.

What was missed in child protection responses during COVID-19? Perceptions of professionals from various countries.

BACKGROUND: The COVID-19 pandemic increased the likelihood of child maltreatment and made already difficult circumstances for children and their families much worse. This increased the significance of the child protection system's role in responding to child maltreatment and ensuring children's rights, including their right to a safe life without violence. Unfortunately, accumulating evidence has indicated that the rates of child maltreatment increased during the pandemic. OBJECTIVE: The current study sought to identify the gaps within child protection responses in various countries during the COVID-19 pandemic and to discover how we can respond to crises in the future while preserving children's rights, including their right to protection from maltreatment. METHOD: Five focus groups with a total of 47 professionals working with children from various countries were conducted via Zoom and analyzed using a thematic approach. RESULTS: Three main themes were identified: 1) gaps in policies, 2) gaps in practice, and 3) professionals' messages to improve policy and practice. CONCLUSIONS: This study emphasizes what was missed in child protection policy and practice, highlighting the continuous neglect of children's needs and voices within policies, practices and guidelines worldwide during the pandemic. Professionals' recommendations for policy and practice are also discussed.

Examining resilience among child protection professionals during COVID-19: A global comparison across 57 countries.

BACKGROUND: The COVID-19 pandemic led to numerous challenges for child protection professionals (CPPs). However, limited research has investigated the interwoven concepts of coping, resilience, and mental distress among CPPs during COVID-19 on a global scale. OBJECTIVES: This study aimed to explore CPPs' practice, resilience, and mental distress during COVID-19, the relationship between their resilience and mental distress, the global stability of the Multi-System Model of Resilience (MSMR), and how CPPs' resilience varied according to the Human Development Index (HDI). METHODS: Data were collected from 420 CPPs in 57 countries across five continents between July and September 2021. Participants completed an online questionnaire on demographics, resilience, mental distress, coping, and perceptions of child protection during the pandemic in their native languages. The analyses compared the countries grouped according to HDI using means comparisons, correlations, and multiple linear regressions. A two-path analysis was also performed to identify variables associated with behavioral resilience engagement and mental distress. RESULTS: The findings indicated that CPPs' perceptions of COVID-19's impact on child maltreatment varied in correlation with their country's HDI. There were also significant HDI-based differences regarding the perceived opportunity to engage in resilient behavior and its helpfulness. Years of professional experience, internal resilience, and external resilience were shown to be significant predictors of mental distress among CPPs during the pandemic, and resilience mediated how years of experience predicted mental distress. CONCLUSIONS: This study emphasized the importance of experience and internal resilience for CPPs' psychological well-being. It also provides empirical evidence to support the MSMR theory on a global scale. Additionally, it demonstrates how the perceived changes in child maltreatment during COVID-19 may be associated with regional HDI. Lastly, the opportunities CPPs had to engage in resilient behavior and how much this helped them was associated with regional HDI, but not in the way originally predicted. Study results also hold implications for how practice and policy may be altered to help CPPs cope better during times of crisis and generally.

Experiences and responses of child protection professionals during COVID-19: Lessons learned from professionals around the globe.

BACKGROUND: COVID-19 significantly worsened already challenging circumstances for children and their families and globally increased the likelihood of child maltreatment. This risk heightened the urgency of child protection professionals in preventing child maltreatment and defending children's rights. The vast and growing body of research on protecting children from child maltreatment during COVID-19 has emphasized practitioners' tremendous difficulty in this arena. OBJECTIVE: The current international study sought to identify the experiences and responses of child protection professionals to child maltreatment during COVID-19. PARTICIPANTS AND SETTING: Five real-time, virtual focus groups were conducted among professionals who work with children from countries around the globe. METHOD: Reflexive thematic analysis was employed to analyze the focus group transcripts. RESULTS: The participants identified their experiences and challenges in performing their role of protecting children. Additionally, they shared context-adapted and innovative responses to child maltreatment, while emphasizing self-care and their mental health. CONCLUSIONS: The results highlighted that child protection was significantly more challenging during the COVID-19 pandemic. Furthermore, they underlined the importance of establishing practices and policies for child protection in crisis times as well as ensuring both children's and professionals' well-being and mental health.

The remote work of child protection professionals during COVID-19: A scoping review and thematic analysis.

BACKGROUND: The COVID-19 pandemic created new challenges and barriers for the work of child protection professionals (CPPs) and intensified existing hardships for families and children, increasing the risk of child maltreatment. As new restrictions and precautions were implemented by governments worldwide to stop the virus from spreading, CPPs had to adapt to a new reality of working remotely. However, limited research has investigated how remote work impacted CPPs and child protection work and how CPPs handled this alternative work style. OBJECTIVE: This review aims to address gaps in the research to reveal the creative and effective approaches CPPs developed to overcome the challenges presented by COVID-19, defined as the 'positive legacy' of CPPs, particularly in adapting to remote work challenges. METHOD: This review was conducted using a scoping review, followed by two rounds of thematic analysis. The scoping review was conducted in six languages: Hebrew, Arabic, French, Portuguese, Spanish, and English. RESULTS: The first round of thematic analysis found 18 articles relevant to this review. The second round extracted two main themes: 1) the challenges of remote work and 2) overcoming the challenges of no contact. CONCLUSIONS: The findings of this review may be used to inform future strategies for child protection during a pandemic. They also provide an opportunity to rethink the relationship child protection work has with technology to systematically reform current and future protection policies and practices, including outside of a pandemic.

Wisconsin's Community Response Program for families that have been reported for child maltreatment.

In 2006, the Wisconsin Children's Trust Fund launched a pilot initiative called "Community Response," a program targeted to families reported for maltreatment but not served by child protective services due to insufficient child safety concerns. This article presents general information on the program, including the variation in models used by sites across the state, information on the families that were served by the program, and lessons learned from the experience that may guide practical decisions around the implementation of similar models elsewhere.

QI initiative to reduce the number of inpatient falls in an acute hospital Trust.

Inpatient falls are one of the most frequent concerns to patient safety within the acute hospital environment, equating to 1700 falls per year in an 800-bed general hospital. They are predicted to cost approximately £2600 per patient, however, this estimate does not capture the costs and impact that inpatient falls have on the wider health and social care system. It also does not take into the account loss of confidence and delays in functional recovery.This report shares the learning from a quality improvement (QI) initiative that took place in a District General Hospital (DGH) in the UK. The initiative started in February 2020, was paused November 2020 due to wave 2 of the pandemic and restarted in March 2021. Improvement was achieved in January 2021.Data for falls within the Trust identified that falls were within common cause variation. A system change was needed to achieve an improvement.A QI project was commenced with the aim to achieve a 5% reduction in falls per 1000 bed days in a care of the elderly ward.Two primary drivers were identified: recognising patients at high risk of falls and preventing them from falling. Change ideas to address these primary drivers were tested using Plan Do Study Act (PDSA) cycles. Changes tested included: the development of an assessment tool to identify patients at high risk of falls, use of a wristband to identify patients at high risk of a fall, and increased observation.Change ideas achieved some success with the process measures but did not achieve an improvement with the outcome measures. A Trust wide change idea relating to the falls prevention service did lead to a sustained improvement in falls reduction.The barriers to the improvement included changing Trust priorities during the pandemic, and limited opportunities to fully engage the ward-based team with systems thinking and changing mental models.

Neighborhood Poverty, Family Economic Well-Being, and Child Maltreatment.

This study sought to understand the relationships between neighborhood poverty, family monetary well-being, and child maltreatment. The specific research questions were as follows: (1) Is neighborhood poverty at age 1 related to child physical abuse, psychological abuse, and neglect at age 5? (2) Are these relationships mediated by family monetary well-being? The study relied on data from three waves (child ages 1, 3, and 5) of the Fragile Families and Child Wellbeing Study, a longitudinal birth-cohort study of 4,898 children from 20 large U.S. cities. Structural equation modeling was employed to examine mediational effects. The study found a lasting impact of neighborhood poverty on child neglect only, and this relationship was fully mediated by family monetary well-being. There was not a significant longitudinal relationship between neighborhood poverty and physical abuse or psychological abuse. Implications from the study suggest that neighborhood disadvantage impacts a families' economic well-being, and that individual-level economic supports may interrupt the pathway from neighborhood poverty to child neglect.

Neighborhoods and child abuse: Multiple informant perspectives.

INTRODUCTION: Using data from the nationally representative longitudinal Future of Families and Child Wellbeing Study, the current study sought to examine associations between neighborhood disorder and physical characteristics of the neighborhood at child age three with the likelihood of experiencing physical and psychological abuse and neglect at age five. METHODS: Negative binomial regression and zero inflated negative binomial regression models were used to estimate the associations. RESULTS: Resident perceptions of neighborhood disorder and outside observation of neighborhood physical characteristics were both found to be independently related to the likelihood of physical assault. Resident perceptions were related to psychological aggression. A more positive perception of the neighborhood environment for children (lack of neighborhood disorder) and physical characteristics of the neighborhood were protective against maltreatment. These relationships were not significant for neglect. DISCUSSION: Neighborhood environment is a crucial contributor to maltreatment risk. Findings from the present study showed that multiple perceptions of neighborhood quality were associated with lower risk for child physical assault and psychological aggression. Mothers' perceptions of a more positive neighborhood environment were associated with significantly lower physical assault and psychological aggression scores.