Parenting, Child Maltreatment, and Social Disadvantage: A Population-Based Implementation and Evaluation of the Triple P System of Evidence-Based Parenting Support.

Child Maltreatment (CM) is a widespread public health problem, with adverse outcomes for children, families, and communities. Evidence-based parenting support delivered via a public health approach may be an effective means to prevent CM. The Every Family 2 population trial applied a public health approach to delivering evidence-based parenting support to prevent CM in disadvantaged communities. Using a quasi-experimental design, 64 matched low socioeconomic communities in the Australian states of Queensland and New South Wales received either the full multi-level Triple P system (TPS) of parenting support, or Care as Usual (CAU). Two population indicators of CM, the number of substantiated cases of CM, and the number of notifications of CM to protective services were compared using Welch's t-test to evaluate intervention effectiveness. After two years of intervention, medium to large effect sizes favoring TPS communities were found for substantiations (d = 0.57, p < .05) and notifications (d = 1.86, p < .001). These findings show the value of the TPS, deployed using a public health approach, in efforts to prevent CM in socially disadvantaged communities. A number of uncontrolled contextual factors are described that may have contributed to some of the differences detected between TPS and CAU communities.

Unambiguous Characterization of Commercial Natural (Dihydro)phenanthrene Compounds Is Vital in the Discovery of AMPK Activators.

These days, easy access to commercially available (poly)phenolic compounds has expanded the scope of potential research beyond the field of chemistry, particularly in the area of their bioactivity. However, the quality of these compounds is often overlooked or not even considered. This issue is illustrated in this study through the example of (dihydro)phenanthrenes, a group of natural products present in yams, as AMP-activated protein kinase (AMPK) activators. A study conducted in our group on a series of compounds, fully characterized using a combination of chemical synthesis, NMR and MS techniques, provided evidence that the conclusions of a previous study were erroneous, likely due to the use of a misidentified commercial compound by its supplier. Furthermore, we demonstrated that additional representatives of the (dihydro)phenanthrene phytochemical classes were able to directly activate AMPK, avoiding the risk of misinterpretation of results based on analysis of a single compound alone.

Play Well Triple P: Developing and Evaluating a Program to Promote Positive Parental Involvement in Junior Sport.

Parents play a central role in children's ongoing participation and enjoyment of sport. Despite compelling evidence that parental behaviour can undermine the quality of children's experiences in sport, little research has examined whether strategies to support parents to engage in positive sports parenting behaviour are effective. In this paper, we report two studies that had the overall aim of developing, implementing and evaluating a program designed to promote positive parental involvement and improve spectator behaviour in junior rugby league in Australia. Study 1 involved the development of a prototype version of the program, named Play Well Triple P, which was qualitatively evaluated through interviews with 19 parents about their satisfaction with the program. In Study 2, we used feedback from Study 1 to refine the program and develop a pilot version, which was then evaluated in a quasi-experimental feasibility study with 101 parents (mean age = 38.42 years; 72% mothers) of junior rugby league players. The pilot version involved one interactive online module and text messages to reinforce content and prompt strategy implementation across the season. Participation in Play Well Triple P was associated with increased positive sports parenting behaviour and reduced controlling and intrusive sports parenting behaviour, with a trend towards reducing over-reactive parenting practices at home. These findings are discussed in relation to the feasibility of implementing a brief and engaging sports parenting intervention in the context of a broader integrated system designed to facilitate ongoing participation of children in sport.

Leveraging Triphenylphosphine-Containing Polymers to Explore Design Principles for Protein-Mimetic Catalysts.

Complex interactions between noncoordinating residues are significant yet commonly overlooked components of macromolecular catalyst function. While these interactions have been demonstrated to impact binding affinities and catalytic rates in metalloenzymes, the roles of similar structural elements in synthetic polymeric catalysts remain underexplored. Using a model Suzuki-Miyuara cross-coupling reaction, we performed a series of systematic studies to probe the interconnected effects of metal-ligand cross-links, electrostatic interactions, and local rigidity in polymer catalysts. To achieve this, a novel bifunctional triphenylphosphine acrylamide (BisTPPAm) monomer was synthesized and evaluated alongside an analogous monofunctional triphenylphosphine acrylamide (TPPAm). In model copolymer catalysts, increased initial reaction rates were observed for copolymers untethered by Pd complexation (BisTPPAm-containing) compared to Pd-cross-linked catalysts (TPPAm-containing). Further, incorporating local rigidity through secondary structure-like and electrostatic interactions revealed nonmonotonic relationships between composition and the reaction rate, demonstrating the potential for tunable behavior through secondary-sphere interactions. Finally, through rigorous cheminformatics featurization strategies and statistical modeling, we quantitated relationships between chemical descriptors of the substrate and reaction conditions on catalytic performance. Collectively, these results provide insights into relationships among the composition, structure, and function of protein-mimetic catalytic copolymers.

Methods for making and observing model lipid droplets.

We present methods for making and testing the membrane biophysics of model lipid droplets (LDs). Methods are described for imaging LDs ranging in size from 0.1 to 40 µm in diameter with high-resolution microscopy and spectroscopy. With known LD compositions, membrane binding, sorting, diffusion, and tension were measured via fluorescence correlation spectroscopy (FCS), fluorescence recovery after photobleaching (FRAP), fluorescence lifetime imaging microscopy (FLIM), atomic force microscopy (AFM), and imaging flow cytometry. Additionally, a custom, small-volume pendant droplet tensiometer is described and used to measure the association of phospholipids to the LD surface. These complementary, cross-validating methods of measuring LD membrane behavior reveal the interplay of biophysical processes on lipid droplet monolayers.

Paediatric cerebellar glioblastoma - long-term survival following surgery and adjuvant chemoradiotherapy: A case report and literature review.

Introduction: Paediatric cerebellar glioblastoma is an exceptionally rare clinical entity, with very few cases described in the literature. In the majority of reported cases, prognosis is extremely poor, despite surgical and oncological management. The paucity of data results in lack of consensus as to the optimal management of these patients, with the objective of prolonging survival. Research question: Do patient or tumour characteristics suggest more favourable rates of progression-free survival in paediatric cerebellar glioblastoma? Material and methods: Tumour histopathology plus retrospective molecular analysis of archived samples, as well treatment strategy and patient characteristics of a six-year-old child with cerebellar glioblastoma and prolonged progression-free survival were assessed. Characteristics in the published literature that inferred prolonged survival were identified and compared. Results: Paediatric cerebellar glioblastoma is extremely rare, with only a handful of cases reported over several decades, during which time diagnostic and therapeutic techniques have evolved markedly. Consequently, the scarcity of data with sufficient granularity means that limited conclusions can be drawn. Specific clinical and histopathological factors (i.e. female sex, young age, EGFR negativity and surgical resection plus adjuvant chemoradiotherapy) may indicate a more favourable progression-free survival. Discussion and conclusion: Rates of progression-free survival in this rare condition are generally poor, however, several patient and tumour characteristics may infer more favourable prognosis. As increasingly refined means of diagnosis and characterisation are developed, particularly as a result of advances in molecular analyses, more adjuvant treatment options are likely to come on stream in future.

Supporting Families Affected by Adversity: An Open Feasibility Trial of Family Life Skills Triple P.

This pilot feasibility study examined the effects of a new trauma-informed parenting program, Family Life Skills Triple P (FLSTP), in an open uncontrolled trial conducted in a regular service delivery context via video conferencing. FLSTP was trialed as a group-delivered 10-session intervention. Program modules target positive parenting skills (4 sessions) and adult life skills including coping with emotions, taking care of relationships, self-care, dealing with the past, healthy living, and planning for the future. Participants were 50 parents with multiple vulnerabilities, due to social disadvantage or adverse childhood experiences, who had children aged 3-9 with early onset behavior problems. Outcomes were assessed across four data collection points: baseline, mid-intervention (after Session 4), post-intervention, and 3-month follow up. Findings show moderate to large intra-group effect sizes for changes in child behavior problems, parenting practices and risk of child maltreatment, and medium effect sizes for parental distress, emotion regulation and self-compassion. Parents and practitioners reported high levels of consumer satisfaction with the program. Parents with lower levels of parental self-efficacy, lower personal agency and higher baseline scores on a measure of child abuse potential were at greater risk of not completing the program. The strength of these preliminary findings indicates that a more rigorous evaluation using a randomized clinical trial is warranted.

Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.

The role of parenting self-efficacy on teacher-child relationships and parent-teacher communication: Evidence from an Australian national longitudinal study.

High-quality teacher-child relationships and parent-teacher communications have substantial benefits to children's well-being and school functioning. However, more research is needed to understand how parenting self-efficacy influences these relationships. This cross-sequential study investigated the direct associations of parenting self-efficacy with the teacher-child relationship and parent-teacher communication, as well as potential mediation pathways. The present study included a sample of 8152 children who participated in the Longitudinal Study of Australian Children (LSAC), a large study with a nationally representative sample of children from two cohorts who were 4 years apart. We used data collected in three waves when participating children were ages 6 years, 8 years, and 10 years. Structural equation modeling was used to test a panel model with parent-reported parenting self-efficacy and parent-teacher communication quality, as well as teacher-reported teacher-child relationship, child behavior difficulties, and child prosocial behaviors at school. Cross-lagged regressions demonstrated that baseline parenting self-efficacy directly and positively linked with the quality of teacher-child relationship and parent-teacher communication 2 years later. Child behavior at school was identified as a mediation pathway between parenting self-efficacy and teacher-child relationship. The same patterns were identified in two waves (Waves 6-8 and Waves 8-10). Limited child gender, parent gender, or cohort differences were observed. The current findings provide initial support that parenting self-efficacy may have spillover effects on school-related factors. The findings have implications both for parenting and school researchers and for child mental health practitioners because one important way to promote parenting self-efficacy is through evidence-based parenting programs.

Giving the cells what they need when they need it: Biosensor-based feeding control.

"Giving the cells exactly what they need, when they need it" is the core idea behind the proposed bioprocess control strategy: operating bioprocess based on the physiological behavior of the microbial population rather than exclusive monitoring of environmental parameters. We are envisioning to achieve this through the use of genetically encoded biosensors combined with online flow cytometry (FCM) to obtain a time-dependent "physiological fingerprint" of the population. We developed a biosensor based on the glnA promoter (glnAp) and applied it for monitoring the nitrogen-related nutritional state of Escherichia coli. The functionality of the biosensor was demonstrated through multiple cultivation runs performed at various scales-from microplate to 20 L bioreactor. We also developed a fully automated bioreactor-FCM interface for on-line monitoring of the microbial population. Finally, we validated the proposed strategy by performing a fed-batch experiment where the biosensor signal is used as the actuator for a nitrogen feeding feedback control. This new generation of process control, -based on the specific needs of the cells, -opens the possibility of improving process development on a short timescale and therewith, the robustness and performance of fermentation processes.

Piloting a one-day parent-only intervention in the treatment of youth with anxiety disorders: child and family-level outcomes.

OBJECTIVE: Parent-only cognitive-behavioural therapy (CBT) interventions have promise for youth with anxiety disorders. Fear-Less Triple P (FLTP) is one such intervention that has been found comparable to child-focused CBT. Although traditionally administered in six sessions, a one-day workshop format of FLTP was developed to improve accessibility. The current study compared the effectiveness of the six-session and one-day workshop formats. METHOD: Seventy-three youth (mean age, 8.4 years; 74% male) were randomized to traditional FLTP (6-week group) or the one-day workshop format. Anxiety diagnostic status, self- and parent-reported anxiety symptoms scores, independent evaluator-rated improvement, treatment satisfaction, and measures of family functioning were included to assess treatment outcome. Data were collected prior to treatment, and 1-week, 6-months, and 12-months following treatment. RESULTS: Both conditions resulted in significant improvement in child anxiety symptom scores per parent report (on both questionnaire and diagnostic interview measures). Furthermore, significant decreases in sibling anxiety were observed in both treatment conditions. There were no statistically significant differences between conditions on any outcome measure. CONCLUSIONS: Results of this study add to the growing evidence that brief, low-intensity, parent-only interventions can effectively target child psychopathology. These brief interventions are ideal for families for whom the resources and time required to commit to a standard multi-week intervention are prohibitive. REGISTRATION OF CLINICAL TRIALS: This trial was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN 12615001284550).

The thriving kids and parents schools project: protocol of an incomplete stepped wedged cluster randomised trial evaluating the effectiveness of a Triple P seminar series.

BACKGROUND: The COVID-19 pandemic disrupted the normality of daily life for many children, their families, and schools, resulting in heightened levels of anxiety, depression, social isolation, and loneliness among young people. An integrated public health model of interventions is needed to address the problem and to safeguard the mental health and wellbeing of children. The Triple P - Positive Parenting Program is one system of parenting support with a strong evidence-base and wide international reach. When implemented as a public health approach, Triple P has demonstrated population level positive effects on child wellbeing. This study will be the first large-scale, multi-site randomised controlled trial of a newly developed, low-intensity variant of Triple P, a school-based seminar series, as a response to the impacts of the pandemic. METHODS: The evaluation will employ an Incomplete Batched Stepped Wedge Cluster Randomised Trial Design. At least 300 Australian primary schools, from South Australia, Queensland, and Victoria will be recruited and randomised in three batches. Within each batch, schools will be randomly assigned to either start the intervention immediately or start in six weeks. Parents will be recruited from participating schools. The Triple P seminar series includes three seminars titled: "The Power of Positive Parenting", "Helping Your Child to Manage Anxiety", and "Keeping your Child Safe from Bullying". Parents will complete measures about child wellbeing, parenting, parenting self-regulation and other key intervention targets at baseline, six weeks after baseline, and 12 weeks after baseline. Intervention effectiveness will be evaluated with a Multilevel Piecewise Latent Growth Curve Modelling approach. Data collection is currently underway, and the current phase of the project is anticipated to be completed in January 2024. DISCUSSION: The findings from this study will extend the current knowledge of the effects of evidence-based parenting support delivered through brief, universally offered, low intensity, school-based parenting seminars in a post pandemic world. TRIAL REGISTRATION: The trial is registered at the Australian New Zealand Clinical Trials Registry (Trial Registration Number: ACTRN12623000852651).

Methods for making and observing model lipid droplets.

The mechanisms by which the lipid droplet (LD) membrane is remodeled in concert with the activation of lipolysis incorporate a complex interplay of proteins, phospholipids, and neutral lipids. Model LDs (mLDs) provide an isolated, purified system for testing the mechanisms by which the droplet composition, size, shape, and tension affects triglyceride metabolism. Described here are methods of making and testing mLDs ranging from 0.1 to 40 µm diameter with known composition. Methods are described for imaging mLDs with high-resolution microscopy during buffer exchanges for the measurement of membrane binding, diffusion, and tension via fluorescence correlation spectroscopy (FCS), fluorescence recovery after photobleaching (FRAP), fluorescence lifetime imaging microscopy (FLIM), atomic force microscopy (AFM), pendant droplet tensiometry, and imaging flow cytometry. These complementary, cross-validating methods of measuring LD membrane behavior reveal the interplay of biophysical processes in triglyceride metabolism.

The Triple P System of Evidence-Based Parenting Support: Past, Present, and Future Directions.

Triple P is an integrated, multi-level system of evidence-based parenting support designed to promote the well-being of children and families to reduce prevalence rates of social, emotional, and behavioral problems in children and adolescents and to prevent child maltreatment. The system developed gradually over four decades to address the complex needs of parents and children from diverse family, socioeconomic and cultural backgrounds. It blends universal and targeted programs, a focus on developing parental self-regulation capabilities, and adopts a life span perspective with a population health framework. The Triple P system is used as a case example to discuss the past, present and future challenges, and opportunities involved in developing, evaluating, adapting, scaling and maintaining a sustainable system of evidence-based parenting intervention. Seven stages of program development are outlined from initial theory building and development of the core parenting program through to the sustained deployment of the intervention system delivered at scale. The importance of ongoing research and evaluation is highlighted so that different programs within the system evolve and adapt to address the contemporary concerns and priorities of families in diverse cultural contexts. A well-trained workforce is essential to deliver evidence-based programs, in a need-responsive manner that blends both fidelity of delivery and flexibility and is tailored to respond to the needs of individual families and local context. Programs need to be gender-sensitive, culturally informed, and attuned to the local context including relevant policies, resources, cultural factors, funding, workforce availability and their capacity to implement programs.

Four-color fluorescence cross-correlation spectroscopy with one laser and one camera.

The diffusion and reorganization of phospholipids and membrane-associated proteins are fundamental for cellular function. Fluorescence cross-correlation spectroscopy (FCCS) measures diffusion and molecular interactions at nanomolar concentration in biological systems. We have developed an economical method to simultaneously monitor diffusion and complexation with the use of super-continuum laser and spectral deconvolution from a single detector. Customizable excitation wavelengths were chosen from the wide-band source and spectral fitting of the emitted light revealed the interactions for up to four chromatically overlapping fluorophores simultaneously. This method was applied to perform four-color FCCS that we demonstrated with polystyrene nanoparticles, lipid vesicles, and membrane-bound molecules. Up to four individually customizable excitation channels were selected from the broad-spectrum fiber laser to excite the diffusers within a diffraction-limited spot. The fluorescence emission passed through a cleanup filter and a dispersive prism prior to being collected by a sCMOS or EMCCD camera with up to 1.8 kHz frame rates. The emission intensity versus time of each fluorophore was extracted through a linear least-square fitting of each camera frame and temporally correlated via custom software. Auto- and cross-correlation functions enabled the measurement of the diffusion rates and binding partners. We have measured the induced aggregation of nanobeads and lipid vesicles in solution upon increasing the buffer salinity. Because of the adaptability of investigating four fluorophores simultaneously with a cost-effective method, this technique will have wide application for examining macromolecular complex formation in model and living systems.

Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

The role of implementation organizations in scaling evidence-based psychosocial interventions.

BACKGROUND: To bring evidence-based interventions (EBIs) to individuals with behavioral health needs, psychosocial interventions must be delivered at scale. Despite an increasing effort to implement effective treatments in communities, most individuals with mental health and behavioral problems do not receive EBIs. We posit that organizations that commercialize EBIs play an important role in disseminating EBIs, particularly in the USA. The behavioral health and implementation industry is growing, bringing the implementation field to an important inflection point: how to scale interventions to improve access while maintaining EBI effectiveness and minimizing inequities in access to psychosocial intervention. MAIN BODY: We offer a first-hand examination of five illustrative organizations specializing in EBI implementation: Beck Institute for Cognitive Behavioral Therapy; Incredible Years, Inc.; the PAXIS Institute; PracticeWise, LLC; and Triple P International. We use the Five Stages of Small Business Growth framework to organize themes. We discuss practical structures (e.g., corporate structures, intellectual property agreements, and business models) and considerations that arise when trying to scale EBIs including balancing fidelity and reach of the intervention. Business models consider who will pay for EBI implementation and allow organizations to scale EBIs. CONCLUSION: We propose research questions to guide scaling: understanding the level of fidelity needed to maintain efficacy, optimizing training outcomes, and researching business models to enable organizations to scale EBIs.

The Change of Practitioner's Self-Efficacy in Triple P Professional Training: Moderating Role of Practitioner Characteristics, Country, and Delivery Mode.

Two studies examined the change in self-efficacy of practitioners after attending Triple P training and the moderators that affect training outcomes. Study 1 used a large multidisciplinary sample of health, education, and welfare practitioners (N = 37,235) came from 30 countries around the world, which all participate in a Triple P professional training course during 2012-2019. This study assessed practitioners' overall self-efficacy and their consultation skills efficacy prior to training, immediately following training, and at six- to eight-weeks follow-up. Participants reported significant improvements of their overall self-efficacy and their consultation skills self-efficacy. There were significantly small differences based on practitioners' gender, disciplines, education levels, and country location. Study 2 examined the training outcomes of videoconference-based training (following the COVID-19 pandemic) compared to in-person training (N = 6867). No significant differences were found between videoconference and in-person training on any outcome measure. Implications for the global dissemination of evidence-based parenting programs as part of a comprehensive public health response to COVID-19 was discussed.

Melanoma and Human Leukocyte Antigen (HLA): Immunogenicity of 69 HLA Class I Alleles With 11 Antigens Expressed in Melanoma Tumors.

Host immunogenetics play a critical role in the human immune response to melanoma, influencing both melanoma prevalence and immunotherapy outcomes. Beneficial outcomes that stimulate T cell response hinge on binding affinity and immunogenicity of human leukocyte antigen (HLA) with melanoma antigen epitopes. Here, we use an in silico approach to characterize binding affinity and immunogenicity of 69 HLA Class I human leukocyte antigen alleles to epitopes of 11 known melanoma antigens. The findings document a significant proportion of positively immunogenic epitope-allele combinations, with the highest proportions of positive immunogenicity found for the Q13072/BAGE1 melanoma antigen and alleles of the HLA B and C genes. The findings are discussed in terms of a personalized precision HLA-mediated adjunct to immune checkpoint blockade immunotherapy to maximize tumor elimination.

Procedural anxiety among children and adolescents with cystic fibrosis and their parents.

BACKGROUND: Procedural anxiety involves acute distress around medical procedures and may lead to avoidance or resistance behaviors that interfere with effective cystic fibrosis (CF) care and health outcomes. While individuals with CF commonly endure uncomfortable and/or distressing medical procedures, procedural anxiety among children and adolescents with CF has received little research attention. This study investigated the prevalence and correlates of procedural anxiety among individuals with CF aged 6-18 and their parents. METHOD: Eighty-nine parents of children with CF completed surveys examining child procedural anxiety, anxiety, and health behaviors (including treatment adherence); and parent vicarious procedural anxiety. RESULTS: Seventy-five percent of participants rated at least one CF-related procedure as "extremely" anxiety-inducing for their child. Parental vicarious procedural anxiety was reported in 80.9% of participants. Procedural anxiety significantly correlated with child anxiety, treatment-resistive behaviors, and parent-vicarious procedural anxiety. Procedural anxiety was associated with younger age and frequency of distressing procedures, but not with forced expiratory volume in 1 s, body mass index, hospitalizations, or exposure to general anesthesia. CONCLUSION: Procedural anxiety is common among children, adolescents, and caregivers, and is associated with child anxiety and treatment resistance, emphasizing the importance of screening and interventions for procedural anxiety as part of routine CF care from early childhood. Implications for screening and intervention are discussed.