Sulfation and Calcium Favor Compact Conformations of Chondroitin in Aqueous Solutions.

The effects of sulfation and calcium cations (Ca2+) on the atomic-resolution conformational properties of chondroitin carbohydrate polymers in aqueous solutions are not well studied owing to experimental challenges. Here, we compare all-atom explicit-solvent molecular dynamics simulations results for pairs of O-type (nonsulfated) and A-type (GlcNAc 4-O-sulfated) chondroitin 20-mers in 140 mM NaCl with and without Ca2+ and find that both sulfation and Ca2+ favor more compact polymer conformations. We also show that subtle differences in force-field parametrization can have dramatic effects on Ca2+ binding to chondroitin carboxylate and sulfate functional groups and thereby determine Ca2+-mediated intra- and interstrand association. In addition to providing an atomic-resolution picture of the interaction of Ca2+ with sulfated and nonsulfated chondroitin polymers, the molecular dynamics data emphasize the importance of careful force-field parametrization to balance ion-water and ion-chondroitin interactions and suggest additional parametrization efforts to tune interactions involving sulfate.

Constructing 3-Dimensional Atomic-Resolution Models of Nonsulfated Glycosaminoglycans with Arbitrary Lengths Using Conformations from Molecular Dynamics.

Glycosaminoglycans (GAGs) are the linear carbohydrate components of proteoglycans (PGs) and are key mediators in the bioactivity of PGs in animal tissue. GAGs are heterogeneous, conformationally complex, and polydisperse, containing up to 200 monosaccharide units. These complexities make studying GAG conformation a challenge for existing experimental and computational methods. We previously described an algorithm we developed that applies conformational parameters (i.e., all bond lengths, bond angles, and dihedral angles) from molecular dynamics (MD) simulations of nonsulfated chondroitin GAG 20-mers to construct 3-D atomic-resolution models of nonsulfated chondroitin GAGs of arbitrary length. In the current study, we applied our algorithm to other GAGs, including hyaluronan and nonsulfated forms of dermatan, keratan, and heparan and expanded our database of MD-generated GAG conformations. Here, we show that individual glycosidic linkages and monosaccharide rings in 10- and 20-mers of hyaluronan and nonsulfated dermatan, keratan, and heparan behave randomly and independently in MD simulation and, therefore, using a database of MD-generated 20-mer conformations, that our algorithm can construct conformational ensembles of 10- and 20-mers of various GAG types that accurately represent the backbone flexibility seen in MD simulations. Furthermore, our algorithm efficiently constructs conformational ensembles of GAG 200-mers that we would reasonably expect from MD simulations.

Efficient Construction of Atomic-Resolution Models of Non-Sulfated Chondroitin Glycosaminoglycan Using Molecular Dynamics Data.

Glycosaminoglycans (GAGs) are linear, structurally diverse, conformationally complex carbohydrate polymers that may contain up to 200 monosaccharides. These characteristics present a challenge for studying GAG conformational thermodynamics at atomic resolution using existing experimental methods. Molecular dynamics (MD) simulations can overcome this challenge but are only feasible for short GAG polymers. To address this problem, we developed an algorithm that applies all conformational parameters contributing to GAG backbone flexibility (i.e., bond lengths, bond angles, and dihedral angles) from unbiased all-atom explicit-solvent MD simulations of short GAG polymers to rapidly construct models of GAGs of arbitrary length. The algorithm was used to generate non-sulfated chondroitin 10- and 20-mer ensembles which were compared to MD-generated ensembles for internal validation. End-to-end distance distributions in constructed and MD-generated ensembles have minimal differences, suggesting that our algorithm produces conformational ensembles that mimic the backbone flexibility seen in simulation. Non-sulfated chondroitin 100- and 200-mer ensembles were constructed within a day, demonstrating the efficiency of the algorithm and reduction in time and computational cost compared to simulation.

Managing uncertainty in inherited cardiac pathologies-an international multidisciplinary survey.

Multi-gene testing is useful in genetically heterogeneous conditions, including inherited cardiac pathologies. Increasing the number of genes analysed increases diagnostic yield of variants of certain, likely, or uncertain pathogenicity. Concerns exist regarding management of variants of uncertain/likely pathogenicity in conditions of oligogenic inheritance or variable expressivity. We surveyed a sample of colleagues across different specialties and departments internationally to compare management of patients with class 3 or class 4 variants in genes associated with non-syndromic cardiomyopathy or arrhythmia. An electronic survey regarding clinical management of variants ( www.surveymonkey.com/r/cardiacvariants ) was designed and distributed to colleagues internationally via professional bodies and direct email. 150 respondents (88 centres, 27 countries) completed the survey, most of whom were Clinical Geneticists or Genetic Counsellors. Most respondents offer pre-symptomatic testing to asymptomatic relatives of an individual with class 4 or class 5 variants. A minority of respondents offer pre-symptomatic testing for class 3 variants. Considering class 4 variants, 22 (15%) are fully reassuring that the patient with a negative predictive test would not develop the familial phenotype, while 123 (82%) counselled patients about the possibility of variant reclassification. Variability existed between and within centres and specialties. Multiple "free text" comments were provided. Recurring themes including need for multidisciplinary input, technical concerns, and concern regarding duty to review variants of uncertain significance. This study demonstrates that variability in management of likely pathogenic/uncertain variants exists. Close multi-disciplinary input is essential. The development of disorder or gene-specific evidence-based guidelines might ameliorate uncertainty in management.

First record of the Neotropical cladoceran Diaphanosoma fluviatile in the Great Lakes basin.

The ctenopod Diaphanosoma fluviatile has been reported primarily from the Neotropical region and occasionally from the southern United States. D. fluviatile was collected in the Great Lakes basin (the Maumee River, Western Lake Erie, and Lake Michigan) in 2015 and 2018, far north from its previously known distribution. The occurrence of this southern species in the Maumee River and Great Lakes may be the result of an anthropogenic introduction, although a natural range expansion cannot be excluded. This report documents the northernmost record of D. fluviatile in the Nearctic region, extending the known distribution of the species to 42°N, which is a notable increase of 11 degrees latitude. Our detection of D. fluviatile is the first record of this southern species from the Laurentian Great Lakes drainage.

Therapists' and Clients' Perceptions of Bonding as Predictors of Outcome in Multisystemic Therapy®.

This longitudinal study examined whether strength of and balance in self-reported caregiver, youth, and therapist emotional bonds in mid- and late treatment predicted outcomes in Multisystemic Therapy of adolescent behavior problems in a sample of 164 caregiver-youth dyads. Strength of and balance in bonds related to outcome in different ways, depending on the source of the report and time. Results showed a limited association between family members' emotional connection with the therapist and treatment outcome, whereas therapists' perceptions of bond with the caregiver showed highly significant associations across time. Caregiver-therapist agreement on emotional connection at both time points predicted therapist evaluation of treatment success and successful termination, but this was largely explained by therapists' level of alliance. Balance in bonds with the therapist between caregiver and youth had no significant associations with any outcome. The study major limitations such as examining only one component of alliance and possible implications are discussed.

Adolescent Physiological and Behavioral Patterns of Emotion Dysregulation Predict Multisystemic Therapy Response.

This study examined whether physiological and behavioral indicators of emotion dysregulation assessed over the course of Multisystemic Therapy (MST) were related to treatment response. Participants were 180 ethnically diverse adolescents (n=120 males), ranging in age from 12 to 17 years. Treatment response was assessed through therapist report and official arrest records. Changes in cortisol reactivity and changes in scores on a behavioral dysregulation subscale of the Child Behavior Checklist were used as indicators of emotion dysregulation. Hierarchical linear modeling analyses examined whether a less favorable treatment response was associated with cortisol reactivity measures (a) collected early in treatment and (b) over the course of treatment, as well as with behavioral reports of emotion dysregulation reported (c) early in treatment, and (d) over the course of treatment. Sex was explored as a moderator of these associations. Results indicated that both cortisol and behavioral indices of emotion dysregulation early in treatment and over the course of therapy predicted treatment responsiveness. This relationship was moderated by sex: girls were more likely to evidence a pattern of increasing emotion regulation prior to successful therapy response. The results lend further support to the notion of incorporating emotion regulation techniques into treatment protocols for delinquent behavior.

How Do Evaluators Differentiate Successful From Less-Than-Successful Experiences With Collaborative Approaches to Evaluation?

OBJECTIVES: In this exploratory study, we wanted to know how evaluators differentiate collaborative approaches to evaluation (CAE) perceived to be successful from those perceived to be less-than-successful. METHOD: In an online questionnaire survey, we obtained 320 responses from evaluators who practice CAE (i.e., evaluations on which program stakeholders coproduce evaluation knowledge). Respondents identified two specific CAE projects from their own experience-one they believed to be "highly successful" and another they considered "far less successful than [they] had hoped."-and offered their comments and reflections about them. They rated the respective evaluations on 5-point opinion and frequency scales about (i) antecedent stakeholder perspectives, (ii) the purposes and justifications for collaborative inquiry, and (iii) the form such inquiry takes. FINDINGS: The results showed that successful evaluations, relative to their less-than-successful counterparts, tended to reflect higher levels of agreement among stakeholders about the focal program; higher intentionality estimates of evaluation justification and espoused purposes; and wider ranges and deeper levels of stakeholder participation. No differences were found for control of technical decision-making, and evaluators tended to lead evaluation decision making, regardless of success condition. DISCUSSION: The results are discussed in terms of implications for ongoing research on CAE.

Therapist perception of treatment outcome: Evaluating treatment outcomes among youth with antisocial behavior problems.

Effective evaluation of treatment requires the use of measurement tools producing reliable scores that can be used to make valid decisions about the outcomes of interest. Therapist-rated treatment outcome scores that are obtained within the context of empirically supported treatments (ESTs) could provide clinicians and researchers with data that are easily accessible and complimentary to existing instrumentation. We examined the psychometric properties of scores from the Therapist Perception of Treatment Outcome: Youth Antisocial Behavior (TPTO:YAB), an instrument developed to assess therapist judgments of treatment success among families participating in an EST, Multisystemic Therapy (MST), for youth with antisocial behavior problems. Data were drawn from a longitudinal study of MST. The initial 20-item TPTO:YAB was completed by therapists of 111 families at midtreatment and 163 families at treatment termination. Rasch model dimensionality analyses provided evidence for 2 dimensions reflecting youth- and caregiver-related aspects of treatment outcome, although a bifactor analyses suggested that these dimensions reflected a single more general construct. Rasch analyses were also used to assess item and rating scale characteristics and refine the number of items. These analyses suggested items performed similarly across time and that scores reflect treatment outcome in similar ways at mid and posttreatment. Multilevel and zero-order analyses provided evidence for the validity of TPTO:YAB scores. TPTO:YAB scores were moderately correlated with scores of youth and caregiver behaviors targeted in treatment, adding support to its use as a treatment outcome measurement instrument.

Social context, parental monitoring, and multisystemic therapy outcomes.

Multisystemic therapy (MST) and other evidence-based treatments targeting juvenile delinquency have been well substantiated in the literature. Although these treatments have been demonstrated to be effective overall at reducing juvenile delinquency, it is well known that they do not benefit all treated youth. Research has yet to examine the potential influence of contextual factors, such as socioeconomic status (SES) and neighborhood characteristics, on treatment outcomes, particularly as they influence parental monitoring, which is often a focus of interventions targeting juvenile delinquency. A primary goal of these treatments is to help parents develop the requisite skills to adequately monitor and discipline their children; however, this goal may be compromised by contextual factors affecting parental effectiveness and, ultimately, treatment efficacy. The objective of this study was to explore the role of SES and neighborhood factors in moderating the effects of parental monitoring across treatment. Using hierarchical linear modeling (HLM), we analyzed these contextual and family predictors of response to MST treatment within a sample of 185 youth (65.4% male) ages 12-18 (M = 15.35; SD = 1.28). Neighborhood factors interacted with parental monitoring, such that monitoring predicted decreases in externalizing behavior only for youth residing in better neighborhoods. In contrast, SES was unrelated to changes in externalizing behaviors in response to MST. Taken together, these results demonstrate a need for further understanding the potential role of the youth's larger social context in predicting MST outcomes.

Predicting early positive change in multisystemic therapy with youth exhibiting antisocial behaviors.

This study examined individual and family characteristics that predicted early positive change in the context of Multisystemic Therapy (MST). Families (n = 185; 65% male; average youth age 15 years) receiving MST in community settings completed assessments at the outset of treatment and 6-12 weeks into treatment. Early positive changes in youth antisocial behavior were assessed using the caregiver report on the Child Behavior Checklist Externalizing Behaviors subscale and youth report on the Self-Report Delinquency Scale. Overall, families showed significant positive changes by 6-12 weeks into treatment; these early changes were maintained into midtreatment 6-12 weeks later. Families who exhibited clinically significant gains early in treatment were more likely to terminate treatment successfully compared with those who did not show these gains. Low youth internalizing behaviors and absence of youth drug use predicted early positive changes in MST. High levels of parental monitoring and low levels of affiliation with deviant peers (mechanisms known to be associated with MST success) were also associated with early positive change.

Biosocial processes predicting multisystemic therapy treatment response.

This study examined biological (testosterone) and social (deviant peer affiliation) factors early in treatment as predictors of treatment outcome among adolescent boys receiving Multisystemic Therapy (MST) in community settings. Outcome variables included changes in youth aggression and delinquency as reported by the primary caregiver. Testosterone and deviant peer affiliation were assessed at treatment onset; and outcome variables (aggression and delinquency) were assessed at treatment onset, mid-treatment and end-of-treatment. Participants were 112 adolescent boys (M age=15.42, SD=1.31) and their caregivers. Growth curve analyses revealed that the combination of high testosterone and high deviant peer affiliation early in treatment were significantly associated with less of a decline in aggression and delinquency over the course of treatment. Results provide novel evidence for the role of testosterone in the prediction of future externalizing behaviors. Clinical and theoretical implications are discussed.

Predictors of Therapist Adherence and Emotional Bond in Multisystemic Therapy: Testing Ethnicity as a Moderator.

This study examined the interaction between problem severity and race\ethnicity as a predictor of therapist adherence and family-therapist emotional bond. Data for this study came from a longitudinal evaluation of Multisystemic Therapy (MST) provided by licensed MST provider organizations in community settings. Outcome variables included mid-treatment levels of caregiver report of therapist adherence, changes in caregiver report of therapist adherence over the course of treatment, and overall levels of caregiver-therapist and youth-therapist emotional bond. Hypothesized predictors included race\ethnicity and levels of poly-substance use, externalizing behavior, and youth self-report of delinquency early in treatment as well as pre-treatment number of arrests. Participants were 185 adolescents (M age = 15.35, SD = 1.29) and their caregivers. Of the participating youth, 48 % self-identified as Caucasian, 20 % as African-American, 28 % as Hispanic\Latino, and 4 % as "other." Two-level Hierarchical Linear Modeling analyses revealed that for Caucasian youth, lower rates of self-reported delinquency were associated with greater increases in caregiver report of therapist adherence over the course of MST. For His-panic\Latino caregivers, higher externalizing behavior and poly-substance use were associated with reports of lower therapist adherence at mid-treatment and poorer overall levels of emotional bonding with therapists. In contrast, for African-American participants, higher levels of youth externalizing behavior and poly-substance use were associated with higher overall levels of caregiver and youth report of emotional bonding with therapists, respectively. Results provide evidence that race\ethnicity interacts with problem severity in predicting therapist adherence and family-therapist emotional bond within real-world practice settings and suggest possible therapeutic process differences across race.

Stress, cortisol, and externalizing behavior in adolescent males: an examination in the context of multisystemic therapy.

Stress and hypothalamic-pituitary-adrenal (HPA) axis dysregulation have been associated with externalizing behavior in adolescence, but few studies have examined these factors in a treatment context. This study investigated the relationship between stress, cortisol, and externalizing behavior among 120 adolescent males (mean age = 15) receiving Multisystemic Therapy (MST). To examine the differential relationship of cortisol with various types of stressors, self-report measures assessed lifetime stress, current episodic stress, and daily hassles. Morning and afternoon cortisol samples were collected to examine whether the relationship between stress and treatment outcome depended on the youth's biological stress levels. Regression analyses indicated that awakening cortisol levels moderated the relationship between daily hassles and externalizing behaviors at post-treatment. More specifically, higher levels of daily hassles predicted worse outcomes only among adolescents with high levels of morning cortisol. In addition, lifetime stressors and afternoon measures of cortisol interacted to predict changes in caretaker reports of externalizing problems and youth arrests following treatment; lifetime stressors were positively associated with externalizing behavior when adolescents had low levels of afternoon cortisol. Implications for theory and future directions for evidence-based treatment are discussed.

Examining therapist comfort in delivering family therapy in home and community settings: development and evaluation of the Therapist Comfort Scale.

This study reports on the development and psychometric properties of a new measure assessing therapist comfort in the home treatment context and the relationship between therapist comfort, related process variables, and therapist characteristics. Data were drawn from a longitudinal evaluation of 185 families treated by 51 therapists using Multisystemic Therapy (MST). Therapist comfort was measured at four time points. Psychometric evaluation indicated that the measure was internally and temporally consistent. Examination of the measure's validity indicated that therapists' feelings of safety and comfort during the provision of home-based treatment were associated with family neighborhood characteristics and family socioeconomic factors. Furthermore, the therapist's reported level of alliance (as measured by the Emotional Bonding subscale of the Working Alliance Inventory) was related to her/his feeling of comfort. Analyses also indicated that therapists with greater belief in the clinical utility of the MST model felt more comfortable when delivering MST. Together the results suggest that economically disadvantaged families treated in home and community settings may be most at risk for erosions in the therapeutic relationship over time as a function of lower therapist comfort. Because therapist comfort was associated with therapeutic alliance-a factor found to be associated with clinical outcomes across studies and treatment models-findings imply that psychotherapists should regularly examine their own level of comfort, especially when providing services in nontraditional settings, and that therapist comfort should be routinely assessed as part of clinical supervision and training.

Randomized controlled trial of osmotic-release methylphenidate with cognitive-behavioral therapy in adolescents with attention-deficit/hyperactivity disorder and substance use disorders.

OBJECTIVE: To evaluate the efficacy and safety of osmotic-release methylphenidate (OROS-MPH) compared with placebo for attention-deficit/hyperactivity disorder (ADHD), and the impact on substance treatment outcomes in adolescents concurrently receiving cognitive-behavioral therapy (CBT) for substance use disorders (SUD). METHOD: This was a 16-week, randomized, controlled, multi-site trial of OROS-MPH + CBT versus placebo + CBT in 303 adolescents (aged 13 through 18 years) meeting DSM-IV diagnostic criteria for ADHD and SUD. Primary outcome measures included the following: for ADHD, clinician-administered ADHD Rating Scale (ADHD-RS), adolescent informant; for substance use, adolescent-reported days of use in the past 28 days. Secondary outcome measures included parent ADHD-RS and weekly urine drug screens (UDS). RESULTS: There were no group differences on reduction in ADHD-RS scores (OROS-MPH: -19.2, 95% confidence interval [CI], -17.1 to -21.2; placebo, -21.2, 95% CI, -19.1 to -23.2) or reduction in days of substance use (OROS-MPH: -5.7 days, 95% CI, 4.0-7.4; placebo: -5.2 days, 95% CI, 3.5-7.0). Some secondary outcomes favored OROS-MPH, including lower parent ADHD-RS scores at 8 (mean difference = 4.4, 95% CI, 0.8-7.9) and 16 weeks (mean difference =6.9; 95% CI, 2.9-10.9) and more negative UDS in OROS-MPH (mean = 3.8) compared with placebo (mean = 2.8; p = .04). CONCLUSIONS: OROS-MPH did not show greater efficacy than placebo for ADHD or on reduction in substance use in adolescents concurrently receiving individual CBT for co-occurring SUD. However, OROS-MPH was relatively well tolerated and was associated with modestly greater clinical improvement on some secondary ADHD and substance outcome measures. Clinical Trial Registration Information-Attention Deficit Hyperactivity Disorder (ADHD) in Adolescents with Substance Use Disorders (SUD); http://www.clinicaltrials.gov; NCT00264797.

Decisions about transferring nursing home residents to hospital: highlighting the roles of advance care planning and support from local hospital and community health services.

AIMS AND OBJECTIVES: To explore current practice and opportunities to improve practice in decision-making about transfer of nursing home residents to hospital. BACKGROUND: Nursing home staff are often faced with the decision of whether to send a resident to hospital for medical treatment. While many residents will benefit from going to hospital, there are also several risks associated with this. This study sought to add to the existing body of research on this issue by seeking the views of nursing home managers, who are the persons most frequently involved in making these decisions. DESIGN: Qualitative design using purposive, quota sampling. METHOD: Qualitative interviews with 41 nursing home managers from south-western Sydney, Australia. RESULTS: Factors affecting the decision to transfer a resident to hospital include acuteness of their condition; level and style of medical care available; role of family members; numbers, qualifications and skills mix of staff; and concern about criticism for not transferring to hospital. Two factors that have not featured as strongly in previous research are the roles of advance care planning and support from local hospital and community health services. CONCLUSION: While transferring a nursing home resident to hospital is often necessary, there are many situations where they could be cared for in the nursing home; therefore, avoid complications associated with being in hospital. Apart from a range of factors already identified in the literature, this study has highlighted the important role that advance care planning and support from local health services can play in reducing unnecessary transfers to hospital. RELEVANCE TO CLINICAL PRACTICE: There are several strategies that nursing homes and local health authorities can adopt to promote advance care planning and build better support systems between the two sectors, thereby reducing the numbers of residents who need to be transferred to hospital for their health care.

Understanding how advance care planning is approached in the residential aged care setting: a continuum model of practice as an explanatory device.

OBJECTIVE: To gain an understanding of how advance care planning (ACP) is understood and approached by managers of residential aged care facilities. METHODS: Qualitative interviews with managers from 41 residential aged care facilities from South Western Sydney, Australia. Content and thematic analysis of interview transcripts. RESULTS: The majority of facilities do not have a systematic approach to ACP, but tend to initiate discussions about end-of-life treatments late in a resident's illness. There are varying degrees to which these discussions are used in ongoing care planning or made explicit if the resident is transferred to hospital. A number of factors are identified that support the implementation of ACP. CONCLUSION: A continuum model of practice is proposed that describes four broad approaches to practice under the domains of initiation, scope, follow-up and documentation of ACP as well as the organisational leadership adopted around ACP.

Increasing the profile of the care of the older person in the ED: a contemporary nursing challenge.

The numbers of frail older persons using emergency departments are already considerable and will continue to increase over time. There are a number of issues related to the assessment and care of older patients that are significantly different to other patient groups. The traditional emergency department (ED) model focusing on rapid triage, treatment and throughput does not meet the needs of many older patients, who have complex presentations, and require comprehensive assessment and referral. In response to this, there are already a number of appropriate and innovative approaches to the care of the older patient demonstrated in the literature. Nurses have a crucial role in contributing to these approaches and in raising the profile of quality care of the older person. Some specific areas that ED nurses can focus on include a more comprehensive approach to assessment and discharge planning, improved communication with the patient and their personal carers, attention to basic nursing care, and making the physical environment safer and less stressful for the older patient. While developing collaborations with their aged care nursing colleagues is important, emergency nurses need to view care of the older person as a central part of their own core business.