Examining the impact of a paediatric trauma family support service on the quality of life of injured children: A longitudinal cohort study.

PURPOSE: We describe and evaluate the introduction of a trauma family support service (TFSS) in an Australian tertiary paediatric hospital. DESIGN AND METHODS: A longitudinal mixed-methods cohort study evaluated the effectiveness of the TFSS on quality of life. PedsQL4.0 and EuroQol 5D-Y scores were collected at 6 and 12 months at intervention and non-intervention sites and outcomes were compared using a two-sample t-test. Qualitative data from field notes collected during the administration of the quality-of-life measures were analysed using inductive content analysis. Data were integrated during the interpretation of results to expand and strengthen findings. RESULTS: Data from 192 children were collected (intervention site: 104, control site: 88). Significant increases were seen in the PedsQL and EQ-5D-Y scores at the intervention site compared to the control site at both timepoints, indicating an increase in overall health related quality of life. Two main categories were generated from the qualitative analysis: "Psychosocial impact of trauma" and "Access to psychosocial services." CONCLUSIONS: The introduction of a dedicated family support service after paediatric injury improved well-being up to 12 months post injury. PRACTICE IMPLICATIONS: Healthcare providers should emphasise dedicated family support services for paediatric trauma patients, focusing on their psychosocial needs and ensuring access to suitable resources. Paediatric nurses are a major part of this service and should contribute to future research, co-designing and implementing these improved family support services to better serve families affected by paediatric trauma.

Investigating the efficacy of a Dialectical behaviour therapy-based universal intervention on adolescent social and emotional well-being outcomes.

There is increasing research interest as to whether Dialectical Behaviour Therapy (DBT), specifically the group skills training component, is an effective early intervention approach when delivered universally in schools. The current study aimed to provide the first large-scale examination of a universal DBT-based intervention and to also determine the extent to which home practice of DBT skills predicted changes in social and emotional outcomes over time. A non-randomised controlled trial design was employed whereby 1071 participants (51.30% Male; M age = 13.48 years) completed either an adapted eight-session DBT skills-training intervention ('WISE Teens) (n = 563) or class-as-per-usual (n = 508). On average, the 'WISE Teens' intervention did not improve outcomes with significant deteriorations or null effects observed across outcomes relative to class-as-per-usual immediately post-intervention. The largest deteriorations were observed for depressive (d = -0.22; 95% CI = -0.35, -0.08) and anxiety symptoms (d = -0.28; 95%CI - = -0.41, -0.14). Applying Bonferroni corrections, most group differences in outcomes had dissipated at follow-up, however, 'WISE Teens' participants continued to report significantly poorer quality of parent-child relationships relative to control (d = .16 for mother (95% CI = 0.01, 0.31); d = 0.17 for father (95% CI = 0.02, 0.33). While home practice was modest on average, further exploratory analyses nevertheless revealed that greater home practice was generally associated with more positive outcomes both immediately post-intervention and at follow-up. Based on these findings, the DBT-based 'WISE Teens' intervention is not recommended in its current format for universal dissemination amongst early adolescents in schools. Further research is needed to determine how to improve engagement and feasibility of delivery of DBT-based interventions universally in this context.

Emotion self-stigma as a unique predictor of help-seeking intentions: A comparative analysis of early adolescents and young adults.

OBJECTIVES: There has been limited consideration of the role emotion self-stigma (i.e. beliefs that experiencing and expressing so called 'negative' emotions are unacceptable) may play in help-seeking for emotional distress. This study is the first to investigate whether emotion self-stigma uniquely predicts help-seeking intentions across two key emotion vulnerability periods in development: (a) early adolescence and (b) young adulthood. METHODS AND DESIGN: Cross-sectional data were collected from secondary school (n = 510; M age = 13.96 years) and university students (n = 473; M age = 19.19 years) residing in Australia. Both samples completed measures online examining demographic characteristics, emotional competence, mental health and help-seeking stigma, emotion self-stigma, and help-seeking intentions. The Data were analysed using hierarchical multiple regression. RESULTS: Emotion self-stigma was a significant unique predictor of help-seeking intentions in young adults but not adolescents. The strength of the relationship between increased emotion self-stigma and lowered help-seeking intentions was similar for both males and females, regardless of developmental period. CONCLUSIONS: Addressing emotion self-stigma alongside mental illness and help-seeking stigma may be useful to improve help-seeking outcomes, particularly as young people transition into early adulthood.

The Pediatric Bougie for the First Tracheal Intubation Attempt in Critically Ill Children.

STUDY OBJECTIVE: Bougie use during emergency tracheal intubation has not been well studied in children. METHODS: This was a 10-year observational study of pediatric intubations (<18 years of age) in the emergency department (ED) of an academic institution. Bougie training and use are standard in our ED, including for emergency medicine residents. Study data were collected by a combination of charts and video reviews. We compare first-attempt intubation success and procedural complications between pediatric patients with and without bougie use during tracheal intubation in the ED. In addition, we evaluate the independent association of bougie use with first-attempt intubation success using multivariable logistic regression. RESULTS: We collected data on intubation success and bougie use for 195 pediatric patients over more than 10 years. On the first tracheal intubation attempt, a pediatric bougie was used in 126 patients (65%). Median patient age was 5 years (interquartile range 1.7 to 9) in the bougie group and 1.7 years (interquartile range 0.2 to 5) in the no bougie group. Intubation was successful on the first attempt in 72% of intubations with a bougie versus 78% without a bougie (absolute difference -6%, 95% confidence interval [CI] -19 to 6%); the adjusted odds of first-attempt success with a bougie were 0.54 (95% CI 0.24 to 1.19). A procedural complication occurred for 38% of patients in the bougie group versus 51% in the no bougie group (-13%, 95% CI -27% to 2%). Two neonates, one in each group, experienced a potential injury to the airway or lower respiratory tract. CONCLUSION: In an academic ED where the bougie is commonly used, bougie use in children was not associated with procedural success or complications. Our study suggests that a randomized clinical trial is needed to determine the effect of bougie use during emergency pediatric intubation.

Cardiovascular Disease and Migraine: Are the New Treatments Safe?

PURPOSE OF REVIEW: The authors present data on cardiovascular safety for the new acute and preventive migraine treatments including ditans, gepants, and calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) alongside older medications like triptans and ergotamines. RECENT FINDINGS: The authors conclude that there are no cardiovascular safety concerns for lasmiditan, and that it could be used in those with cardiovascular disease. In fact, the literature even suggests that triptans are safer in cardiovascular disease than their contraindications may suggest. At this time, there is insufficient evidence that gepants and CGRP mAbs should be contraindicated in those with cardiovascular disease including stroke or myocardial infarction, though erenumab has now been associated with hypertension. Vasodilation may be an important CGRP-mediated mechanism mid-ischemia especially in patients with small vessel disease; hence, CGRP antagonists should be use with caution in this context. Long-term data is still needed, and prescribers should ensure patients are aware of the limitations of our knowledge at this time, while still offering these effective and well-tolerated treatment options.

Depression predicts emotion acceptance beliefs in early adolescence: A longitudinal investigation.

OBJECTIVES: Adolescence is a time period which confers significant risk for the development of psychopathology. There is increasing consensus within the literature that beliefs about one's emotional experience are important and may present a unique risk factor during this time period. However, to date, there has been no longitudinal examination of the relationship between depression and specific beliefs regarding the acceptability of experiencing and expressing emotion in young people. DESIGN: The present study used a cross-lagged longitudinal design with questionnaires completed at two waves spaced 8 months apart. METHODS: 506 participants (50.60% female) aged 12-15 years completed the Beliefs about Emotion questionnaire to assess for beliefs regarding the acceptability of experiencing and expressing emotions, and the depression subscale of the DASS-21 to measure depressive symptoms. RESULTS: Greater depressive symptoms were associated with more negative beliefs about emotion at both time points. More negative beliefs about emotion at T1 did not significantly predict greater depressive symptoms at T2. However, greater depressive symptoms at T1 predicted significantly more negative beliefs about emotions at T2. CONCLUSIONS: Greater beliefs about the unacceptability of experiencing or expressing emotions do not appear to predispose young people to depression. Rather, these beliefs appear to emerge following earlier experiences of depressive symptoms. Further research is needed over multiple measurement waves to further elucidate the relationship between emotion acceptance beliefs and depressive symptoms across adolescence into adulthood and whether such beliefs may predict future depressive episodes indirectly via difficulties in emotion regulation. PRACTITIONER POINTS: Current findings suggest that more negative beliefs about emotion, specifically, beliefs about the unacceptability of experiencing or expressing emotions do not represent a key risk factor for the onset of depressive symptoms in early adolescence. Rather, current evidence suggests these beliefs emerge following depressive symptoms. Given these findings, universal prevention programmes targeting valuation beliefs regarding emotion acceptability are less likely to be effective for this developmental age group. It is important to assess for beliefs that an individual may hold regarding their emotional states alongside symptoms, as these beliefs are associated with greater clinical severity of depressive symptoms. Further research, over multiple measurement waves, is needed to clarify whether emotion acceptability beliefs may predict future depressive episodes indirectly via difficulties in emotion regulation.

Site-Specific Conjugation of the Indolinobenzodiazepine DGN549 to Antibodies Affords Antibody-Drug Conjugates with an Improved Therapeutic Index as Compared with Lysine Conjugation.

Antibody-drug conjugates have elicited great interest recently as targeted chemotherapies for cancer. Recent preclinical and clinical data have continued to raise questions about optimizing the design of these complex therapeutics. Biochemical methods for site-specific antibody conjugation have been a design feature of recent clinical ADCs, and preclinical reports suggest that site-specifically conjugated ADCs generically offer improved therapeutic indices (i.e., the fold difference between efficacious and maximum tolerated doses). Here we present the results of a systematic preclinical comparison of ADCs embodying the DNA-alkylating linker-payload DGN549 generated with both heterogeneous lysine-directed and site-specific cysteine-directed conjugation chemistries. Importantly, the catabolites generated by each ADC are the same regardless of the conjugation format. In two different model systems evaluated, the site-specific ADC showed a therapeutic index benefit. However, the therapeutic index benefit is different in each case: both show evidence of improved tolerability, though with different magnitudes, and in one case significant efficacy improvement is also observed. These results support our contention that conjugation chemistry of ADCs is best evaluated in the context of a particular antibody, target, and linker-payload, and ideally across multiple disease models.

A review of children with severe trauma admitted to pediatric intensive care in Queensland, Australia.

BACKGROUND: The aim of this study is to review patient characteristics, injury patterns, and outcomes of trauma cases admitted to pediatric intensive care in Children's Health Queensland, Brisbane, Queensland, Australia. METHODS: Routinely recorded data collected prospectively from the Children's Health Queensland Trauma Service registry from November 2008 to October 2015 were reviewed. Demographic and clinical characteristics of trauma cases in children under 16 years of age are described, and their association with age and mortality analyzed. RESULTS: There were 542 cases of pediatric trauma identified and 66.4% were male. The overall mortality since January 2012 was 11.1%. The median injury severity score (ISS) was 11 (IQR = 9-22), 48.2% (n = 261) had an ISS > 12 and 41.7% (n = 226) patients had an ISS > 15. The most common injury patterns were isolated head injury (29.7%; n = 161) and multiple trauma (31.2%; n = 169). In 28.4% of cases (n = 154) surgery was required. The home was reported to be the most common place of injury (37.6%; n = 204). Children aged 0-4 years were least likely to survive their injury (15.3% mortality) compared with the 5-9 (5.6% mortality) and 10-15 (9.0% mortality) age groups. Higher mortality was associated with more severe injuries, abdomen/spine/thorax injuries, inflicted injuries, drowning and hanging. CONCLUSION: This description of major pediatric trauma cases admitted to pediatric intensive care in Children's Health Queensland, Australia, will inform future pediatric major trauma service requirements as it identifies injury patterns and profiles, injury severity, management and mortality across different age groups.

A CD123-targeting antibody-drug conjugate, IMGN632, designed to eradicate AML while sparing normal bone marrow cells.

The outlook for patients with refractory/relapsed acute myeloid leukemia (AML) remains poor, with conventional chemotherapeutic treatments often associated with unacceptable toxicities, including severe infections due to profound myelosuppression. Thus there exists an urgent need for more effective agents to treat AML that confer high therapeutic indices and favorable tolerability profiles. Because of its high expression on leukemic blast and stem cells compared with normal hematopoietic stem cells and progenitors, CD123 has emerged as a rational candidate for molecularly targeted therapeutic approaches in this disease. Here we describe the development and preclinical characterization of a CD123-targeting antibody-drug conjugate (ADC), IMGN632, that comprises a novel humanized anti-CD123 antibody G4723A linked to a recently reported DNA mono-alkylating payload of the indolinobenzodiazepine pseudodimer (IGN) class of cytotoxic compounds. The activity of IMGN632 was compared with X-ADC, the ADC utilizing the G4723A antibody linked to a DNA crosslinking IGN payload. With low picomolar potency, both ADCs reduced viability in AML cell lines and patient-derived samples in culture, irrespective of their multidrug resistance or disease status. However, X-ADC exposure was >40-fold more cytotoxic to the normal myeloid progenitors than IMGN632. Of particular note, IMGN632 demonstrated potent activity in all AML samples at concentrations well below levels that impacted normal bone marrow progenitors, suggesting the potential for efficacy in AML patients in the absence of or with limited myelosuppression. Furthermore, IMGN632 demonstrated robust antitumor efficacy in multiple AML xenograft models. Overall, these findings identify IMGN632 as a promising candidate for evaluation as a novel therapy in AML.

IMGN779, a Novel CD33-Targeting Antibody-Drug Conjugate with DNA-Alkylating Activity, Exhibits Potent Antitumor Activity in Models of AML.

The myeloid differentiation antigen CD33 has long been exploited as a target for antibody-based therapeutic approaches in acute myeloid leukemia (AML). Validation of this strategy was provided with the approval of the CD33-targeting antibody-drug conjugate (ADC) gemtuzumab ozogamicin in 2000; the clinical utility of this agent, however, has been hampered by safety concerns. Thus, the full potential of CD33-directed therapy in AML remains to be realized, and considerable interest exists in the design and development of more effective ADCs that confer high therapeutic indices and favorable tolerability profiles. Here, we describe the preclinical characterization of a novel CD33-targeting ADC, IMGN779, which utilizes a unique DNA-alkylating payload to achieve potent antitumor effects with good tolerability. The payload, DGN462, is prototypical of a novel class of purpose-created indolinobenzodiazeprine pseudodimers, termed IGNs. With low picomolar potency, IMGN779 reduced viability in a panel of AML cell lines in vitro Mechanistically, the cytotoxic activity of IMGN779 involved DNA damage, cell-cycle arrest, and apoptosis consistent with the mode of action of DGN462. Moreover, IMGN779 was highly active against patient-derived AML cells, including those with adverse molecular abnormalities, and sensitivity correlated to CD33 expression levels. In vivo, IMGN779 displayed robust antitumor efficacy in multiple AML xenograft and disseminated disease models, as evidenced by durable tumor regressions and prolonged survival. Taken together, these findings identify IMGN779 as a promising new candidate for evaluation as a novel therapeutic in AML. Mol Cancer Ther; 17(6); 1271-9. ©2018 AACR.

A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody-Drug Conjugates (ADCs).

Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared with those of the cross-linker. Thus, the improved in vivo tolerability and antitumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment. Mol Cancer Ther; 17(3); 650-60. ©2018 AACR.

Chemical discrimination of lubricant marketing types using direct analysis in real time time-of-flight mass spectrometry.

RATIONALE: In comparison to other violent crimes, sexual assaults suffer from very low prosecution and conviction rates especially in the absence of DNA evidence. As a result, the forensic community needs to utilize other forms of trace contact evidence, like lubricant evidence, in order to provide a link between the victim and the assailant. METHODS: In this study, 90 personal bottled and condom lubricants from the three main marketing types, silicone-based, water-based and condoms, were characterized by direct analysis in real time time of flight mass spectrometry (DART-TOFMS). The instrumental data was analyzed by multivariate statistics including hierarchal cluster analysis, principal component analysis, and linear discriminant analysis. RESULTS: By interpreting the mass spectral data with multivariate statistics, 12 discrete groupings were identified, indicating inherent chemical diversity not only between but within the three main marketing groups. A number of unique chemical markers, both major and minor, were identified, other than the three main chemical components (i.e. PEG, PDMS and nonoxynol-9) currently used for lubricant classification. The data was validated by a stratified 20% withheld cross-validation which demonstrated that there was minimal overlap between the groupings. CONCLUSIONS: Based on the groupings identified and unique features of each group, a highly discriminating statistical model was then developed that aims to provide the foundation for the development of a forensic lubricant database that may eventually be applied to casework. Copyright © 2017 John Wiley & Sons, Ltd.

Defensin DEFB103 bidirectionally regulates chemokine and cytokine responses to a pro-inflammatory stimulus.

Human ß defensin DEFB103 acts as both a stimulant and an attenuator of chemokine and cytokine responses: a dichotomy that is not entirely understood. Our predicted results using an in silico simulation model of dendritic cells and our observed results in human myeloid dendritic cells, show that DEFB103 significantly (p < 0.05) enhanced 6 responses, attenuated 7 responses, and both enhanced/attenuated the CXCL1 and TNF responses to Porphyromonas gingivalis hemagglutinin B (HagB). In murine JAWSII dendritic cells, DEFB103 significantly attenuated, yet rarely enhanced, the Cxcl2, Il6, and Csf3 responses to HagB; and in C57/BL6 mice, DEFB103 significantly enhanced, yet rarely attenuated, the Cxcl1, Csf1, and Csf3 responses. Thus, DEFB103 influences pro-inflammatory activities with the concentration of DEFB103 and order of timing of DEFB103 exposure to dendritic cells, with respect to microbial antigen exposure to cells, being paramount in orchestrating the onset, magnitude, and composition of the chemokine and cytokine response.