Staging 2·0: refining transdiagnostic clinical staging frameworks to enhance reliability and utility for youth mental health.

Globally, 75% of depressive, bipolar, and psychotic disorders emerge by age 25 years. However, these disorders are often preceded by non-specific symptoms or attenuated clinical syndromes. Difficulties in determining optimal treatment interventions for these emerging mental disorders, and uncertainties about accounting for co-occurring psychopathology and illness trajectories, have led many youth mental health services to adopt transdiagnostic clinical staging frameworks. In this Health Policy paper, an international working group highlights ongoing challenges in applying transdiagnostic staging frameworks in clinical research and practice, and proposes refinements to the transdiagnostic model to enhance its reliability, consistent recording, and clinical utility. We introduce the concept of within-stage heterogeneity and describe the advantages of defining stage in terms of clinical psychopathology and stage modifiers. Using examples from medicine, we discuss the utility of categorising stage modifiers into factors associated with progression (ie, potential predictors of stage transition) and extension (ie, factors associated with the current presentation that add complexity to treatment selection). Lastly, we suggest how it is possible to revise the currently used transdiagnostic staging approach to incorporate these key concepts, and how the revised framework could be applied in clinical and research practice.

EMPOWERED trial: protocol for a randomised control trial of digitally supported, highly personalised and measurement-based care to improve functional outcomes in young people with mood disorders.

OBJECTIVES: Many adolescents and young adults with emerging mood disorders do not achieve substantial improvements in education, employment, or social function after receiving standard youth mental health care. We have developed a new model of care referred to as 'highly personalised and measurement-based care' (HP&MBC). HP&MBC involves repeated assessment of multidimensional domains of morbidity to enable continuous and personalised clinical decision-making. Although measurement-based care is common in medical disease management, it is not a standard practice in mental health. This clinical effectiveness trial tests whether HP&MBC, supported by continuous digital feedback, delivers better functional improvements than standard care and digital support. METHOD AND ANALYSIS: This controlled implementation trial is a PROBE study (Prospective, Randomised, Open, Blinded End-point) that comprises a multisite 24-month, assessor-blinded, follow-up study of 1500 individuals aged 15-25 years who present for mental health treatment. Eligible participants will be individually randomised (1:1) to 12 months of HP&MBC or standardised clinical care. The primary outcome measure is social and occupational functioning 12 months after trial entry, assessed by the Social and Occupational Functioning Assessment Scale. Clinical and social outcomes for all participants will be monitored for a further 12 months after cessation of active care. ETHICS AND DISSEMINATION: This clinical trial has been reviewed and approved by the Human Research Ethics Committee of the Sydney Local Health District (HREC Approval Number: X22-0042 & 2022/ETH00725, Protocol ID: BMC-YMH-003-2018, protocol version: V.3, 03/08/2022). Research findings will be disseminated through peer-reviewed journals, presentations at scientific conferences, and to user and advocacy groups. Participant data will be deidentified. TRIAL REGISTRATION NUMBER: ACTRN12622000882729.

Childhood contact with social services and risk of suicide or sudden death in young adulthood: identifying hidden risk in a population-wide cohort study.

BACKGROUND: Childhood out-of-home care is associated with premature death in adulthood, in particular death by suicide, accidents and violence. However, little is known about the mortality risk in the much larger population of adults that had contact with social services in childhood but never entered out-of-home care. We determine the association between all tiers of contact with children's social services and risk of suicide and other sudden deaths in young adulthood. METHODS: This population-wide, longitudinal, record-linkage study of adults in Northern Ireland born between 1985 and 1997 (n=437 008) followed each individual from age 18 years to July 2021 (maximum age 36 years). Cox regression models estimated the association between level of contact with social services in childhood (no contact; referred but assessed as not in need (NIN); child in need (CIN) and child in care (CIC)) and risk of death by suicide and sudden death in young adulthood. RESULTS: Individuals with childhood social care contact (n=51 097) comprised 11.7% of the cohort yet accounted for 35.3% of sudden deaths and 39.7% of suicide deaths. Risk of suicide or sudden death increased stepwise with level of childhood contact and was highest in adults with a history of out-of-home care (suicide HR 8.85 (95% CI 6.83 to 11.4)). Individuals assessed as NIN, and those deemed a CIN, had four times the risk of death by suicide in young adulthood compared with unexposed peers (HR 4.25 (95% CI 3.26 to 5.53) and HR 4.49 (95% CI 3.75 to 5.39), respectively). CONCLUSION: Childhood contact with social services is a risk marker for death by suicide and sudden death in young adulthood. Risk is not confined to adults with a history of out-of-home care but extends to the much larger population that had contact with social services but never entered care.

Digital Application of Clinical Staging to Support Stratification in Youth Mental Health Services: Validity and Reliability Study.

BACKGROUND: As the demand for youth mental health care continues to rise, managing wait times and reducing treatment delays are key challenges to delivering timely and quality care. Clinical staging is a heuristic model for youth mental health that can stratify care allocation according to individuals' risk of illness progression. The application of staging has been traditionally limited to trained clinicians yet leveraging digital technologies to apply clinical staging could increase the scalability and usability of this model in services. OBJECTIVE: The aim of this study was to validate a digital algorithm to accurately differentiate young people at lower and higher risk of developing mental disorders. METHODS: We conducted a study with a cohort comprising 131 young people, aged between 16 and 25 years, who presented to youth mental health services in Australia between November 2018 and March 2021. Expert psychiatrists independently assigned clinical stages (either stage 1a or stage 1b+), which were then compared to the digital algorithm's allocation based on a multidimensional self-report questionnaire. RESULTS: Of the 131 participants, the mean age was 20.3 (SD 2.4) years, and 72% (94/131) of them were female. Ninety-one percent of clinical stage ratings were concordant between the digital algorithm and the experts' ratings, with a substantial interrater agreement (κ=0.67; P<.001). The algorithm demonstrated an accuracy of 91% (95% CI 86%-95%; P=.03), a sensitivity of 80%, a specificity of 93%, and an F1-score of 73%. Of the concordant ratings, 16 young people were allocated to stage 1a, while 103 were assigned to stage 1b+. Among the 12 discordant cases, the digital algorithm allocated a lower stage (stage 1a) to 8 participants compared to the experts. These individuals had significantly milder symptoms of depression (P<.001) and anxiety (P<.001) compared to those with concordant stage 1b+ ratings. CONCLUSIONS: This novel digital algorithm is sufficiently robust to be used as an adjunctive decision support tool to stratify care and assist with demand management in youth mental health services. This work could transform care pathways and expedite care allocation for those in the early stages of common anxiety and depressive disorders. Between 11% and 27% of young people seeking care may benefit from low-intensity, self-directed, or brief interventions. Findings from this study suggest the possibility of redirecting clinical capacity to focus on individuals in stage 1b+ for further assessment and intervention.

The Polarization of Clinician and Service Staff Perspectives After the Use of Health Information Technology in Youth Mental Health Services: Implementation and Evaluation Study.

BACKGROUND: Highly personalized care is substantially improved by technology platforms that assess and track patient outcomes. However, evidence regarding how to successfully implement technology in real-world mental health settings is limited. OBJECTIVE: This study aimed to naturalistically monitor how a health information technology (HIT) platform was used within 2 real-world mental health service settings to gain practical insights into how HIT can be implemented and sustained to improve mental health service delivery. METHODS: An HIT (The Innowell Platform) was naturally implemented in 2 youth mental health services in Sydney, Australia. Web-based surveys (n=19) and implementation logs were used to investigate staff attitudes toward technology before and after implementation. Descriptive statistics were used to track staff attitudes over time, whereas qualitative thematic analysis was used to explore implementation log data to gain practical insights into useful implementation strategies in real-world settings. RESULTS: After the implementation, the staff were nearly 3 times more likely to agree that the HIT would improve care for their clients (3/12, 25% agreed before the implementation compared with 7/10, 70% after the implementation). Despite this, there was also an increase in the number of staff who disagreed that the HIT would improve care (from 1/12, 8% to 2/10, 20%). There was also decreased uncertainty (from 6/12, 50% to 3/10, 30%) about the willingness of the service to implement the technology for its intended purpose, with similar increases in the number of staff who agreed and disagreed with this statement. Staff were more likely to be uncertain about whether colleagues in my service are receptive to changes in clinical processes (not sure rose from 5/12, 42% to 7/10, 70%). They were also more likely to report that their service already provides the best mental health care (agreement rose from 7/12, 58% to 8/10, 80%). After the implementation, a greater proportion of participants reported that the HIT enabled shared or collaborative decision-making with young people (2/10, 20%, compared with 1/12, 8%), enabled clients to proactively work on their mental health care through digital technologies (3/10, 30%, compared with 2/12, 16%), and improved their response to suicidal risk (4/10, 40% compared with 3/12, 25%). CONCLUSIONS: This study raises important questions about why clinicians, who have the same training and support in using technology, develop more polarized opinions on its usefulness after implementation. It seems that the uptake of HIT is heavily influenced by a clinician's underlying beliefs and attitudes toward clinical practice in general as well as the role of technology, rather than their knowledge or the ease of use of the HIT in question.

The mental health of all children in contact with social services: a population-wide record-linkage study in Northern Ireland.

AIMS: Children in contact with social services are at high risk for mental ill health, but it is not known what proportion of the child population has contact with social services or how risk varies within this group compared to unexposed peers. We aim to quantify the extent and nature of contact with social services within the child population in Northern Ireland (NI) and the association with mental ill health. We also examine which social care experiences identify those most at risk. METHODS: This is a population-based record-linkage study of 497,269 children (aged under 18 years) alive and resident in NI in 2015 using routinely collected health and social care data. Exposure was categorized as (1) no contact, (2) referred but assessed as not in need (NIN), (3) child in need (CIN) and (4) child in care (CIC). Multilevel logistic regression analyses estimated odds ratios (ORs) for mental ill health indicated by receipt of psychotropic medication (antidepressants, anxiolytics, antipsychotics and hypnotics), psychiatric hospital admission and hospital-presenting self-harm or ideation. RESULTS: Over one in six children (17.2%, n = 85,792) were currently or previously in contact with social services, and almost one child in every 20 (4.8%, n = 23,975) had contact in 2015. Likelihood of any mental ill health outcome increased incrementally with the level of contact with social services relative to unexposed peers: NIN (OR 5.90 [95% confidence interval (CI) 5.10-6.83]), CIN (OR 5.99 [95% CI 5.50-6.53]) and CIC (OR 12.60 [95% CI 10.63-14.95]). All tiers of contact, number of referrals, number of care episodes and placement type were strongly associated with the likelihood of mental ill health. CONCLUSION: Children who have contact with social services account for a large and disproportionate amount of mental ill health in the child population. Likelihood of poor mental health across indicators is highest in care experienced children but also extends to the much larger population of children in contact with social services but never in care. Findings suggest a need for targeted mental health screening and enhanced support for all children in contact with social services.

Strengthening mental health research outcomes through genuine partnerships with young people with lived or living experience: A pilot evaluation study.

BACKGROUND: Despite increasing support for stakeholder inclusion in research, there is limited evaluative research to guide safe (i.e., youth-friendly) and meaningful (i.e., non-tokenistic) partnerships with young people with lived experience of mental ill-health in research. This paper describes a pilot evaluation and iterative design of a Youth Lived Experience Working Group (LEWG) protocol that was established by the Youth Mental Health and Technology team at The University of Sydney's Brain and Mind Centre, based on the results of two studies. METHODS: Study one consisted of a pilot evaluation of the extent to which youth partners felt empowered to contribute, to qualitatively explore how LEWG processes could be improved. Youth partners completed online surveys, and results were shared over two LEWG meetings in 2021 to empower youth partners to collectively identify actions of positive change regarding LEWG processes. These meetings were audio-recorded and transcripts were subsequently coded using thematic analysis. Study two assessed whether LEWG processes and proposed improvements were acceptable and feasible from the perspective of academic researchers via an online survey in 2022. RESULTS: Quantitative and qualitative data collected from nine youth partners and 42 academic researchers uncovered initial learnings regarding facilitators, motivators, and barriers to partnering with young people with lived experience in research. Implementing clear processes for youth partners and academic researchers on effective partnership strategies, providing training opportunities for youth partners to develop research skills, and providing regular updates on how youth partner contributions led to research outcomes were identified as key facilitators. CONCLUSIONS: This pilot study provides insight into a growing international field on how to optimise participatory processes so that researchers and young people with lived experience can be better supported and engaged to make meaningful contributions to mental health research. We argue that more transparency is needed around participatory research processes so that partnerships with young people with lived experience are not merely tokenistic. CONSUMER CONTRIBUTIONS: Our study has also been approved by and reflects the concepts and priorities of our youth lived experience partners and lived experience researchers, all of whom are authors of this paper.

Characterising variability in youth mental health service populations: A detailed and scalable approach using digital technology.

OBJECTIVE: This study utilised digital technology to assess the clinical needs of young people presenting for care at headspace centres across Australia. METHOD: 1490 young people (12-25 years) who presented to one of 11 headspace services from four geographical locations (urban New South Wales, urban South Australia, regional New South Wales, and regional Queensland) completed a digital multidimensional assessment at initial presentation. Characteristics were compared between services and geographical locations. RESULTS: We identified major variation in the demographics, and the type and severity of needs across different services. Individuals from regional services were more likely to be younger, of Aboriginal and Torres Strait Islander origin, and present with psychotic-like symptoms and suicidality, while those in urban areas were more likely to have previously sought help and have problematic alcohol use. Further differences in age, distress, depressive symptoms, psychotic-like experiences, trauma, family history, alcohol use, education/employment engagement, and days out of role were identified between different urban sites. CONCLUSIONS: The variability between services provides insight into the heterogeneity of youth mental health populations which has implications for appropriate early intervention and prevention service provisions. We propose that integrating digital technologies has the potential to provide insights for smarter service planning and evaluation.

Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: a multi-national observational study.

OBJECTIVE: Olaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022. METHODS: The Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with a BRCA1/2 mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network. RESULTS: The myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwent BRCA1/2 and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained a BRCA1/2 mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to be BRCA1/2 wild-type (n=510) than BRCA1/2 mutant (n=304). The distribution of GIS was bimodal, with BRCA1/2 mutant tumors having a higher mean score than BRCA1/2 wild-type tumors (61 vs 33, respectively, χ2 test p<0.0001). CONCLUSION: This is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specialization, and the NHS Genomic Laboratory Hub network.

The burden of nonalcoholic steatohepatitis (NASH) in the United States.

BACKGROUND: There is limited data on the comparative economic and humanistic burden of non-alcoholic steatohepatitis (NASH) in the United States. The objective was to examine the burden of disease comparing NASH to a representative sample of the general population and separately to a type 2 diabetes mellitus (T2DM) cohort by assessing health-related quality of life (HRQoL) measures, healthcare resource use (HRU) and work productivity and activity impairment (WPAI). METHODS: Data came from the 2016 National Health and Wellness Survey, a nationally representative patient-reported outcomes survey conducted in the United States. Respondents with physician-diagnosed NASH, physician-diagnosed T2DM, and respondents from the general population were compared. Humanistic burden was examined with mental (MCS) and physical (PCS) component summary scores from the Short-Form (SF)-36v2, concomitant diagnosis of anxiety, depression, and sleep difficulties. Economic burden was analysed based on healthcare professional (HCP) and emergency room (ER) visits, hospitalizations in the past six months; absenteeism, presenteeism, overall work impairment, and activity impairment scores on WPAI questionnaire. Bivariate and multivariable analysis were conducted for each outcome and matched comparative group. RESULTS: After adjusting for baseline demographics and characteristics, NASH (N = 136) compared to the matched general population cohort (N = 544), reported significantly lower (worse) mental (MCS 43.19 vs. 46.22, p = 0.010) and physical (PCS 42.04 vs. 47.10, p < 0.001) status, higher % with anxiety (37.5% vs 25.5%, p = 0.006) and depression (43.4% vs 30.1%, p = 0.004), more HCP visits (8.43 vs. 5.17), ER visits (0.73 vs. 0.38), and hospitalizations (0.43 vs. 0.2) all p's < 0.05, and higher WPAI scores (e.g. overall work impairment 39.64% vs. 26.19%, p = 0.011). NASH cohort did not differ from matched T2DM cohort (N = 272) on mental or work-related WPAI scores, but had significantly worse physical status (PCS 40.52 vs. 44.58, p = 0.001), higher % with anxiety (39.9% vs 27.8%, p = 0.043), more HCP visits (8.63 vs. 5.68, p = 0.003) and greater activity impairment (47.14% vs. 36.07%, p = 0.010). CONCLUSION: This real-world study suggests that burden of disease is higher for all outcomes assessed among NASH compared to matched general controls. When comparing to T2DM, NASH cohort has comparable mental and work-related impairment but worse physical status, daily activities impairment and more HRU.

Predicting Clinical Remission of Chronic Urticaria Using Random Survival Forests: Machine Learning Applied to Real-World Data.

INTRODUCTION: The time required to reach clinical remission varies in patients with chronic urticaria (CU). The objective of this study is to develop a predictive model using a machine learning methodology to predict time to clinical remission for patients with CU. METHODS: Adults with ≥ 2 ICD-9/10 relevant CU diagnosis codes/CU-related treatment > 6 weeks apart were identified in the Optum deidentified electronic health record dataset (January 2007 to June 2019). Clinical remission was defined as ≥ 12 months without CU diagnosis/CU-related treatment. A random survival forest was used to predict time from diagnosis to clinical remission for each patient based on clinical and demographic features available at diagnosis. Model performance was assessed using concordance, which indicates the degree of agreement between observed and predicted time to remission. To characterize clinically relevant groups, features were summarized among cohorts that were defined based on quartiles of predicted time to remission. RESULTS: Among 112,443 patients, 73.5% reached clinical remission, with a median of 336 days from diagnosis. From 1876 initial features, 176 were retained in the final model, which predicted a median of 318 days to remission. The model showed good performance with a concordance of 0.62. Patients with predicted longer time to remission tended to be older with delayed CU diagnosis, and have more comorbidities, more laboratory tests, higher body mass index, and polypharmacy during the 12-month period before the first CU diagnosis. CONCLUSIONS: Applying machine learning to real-world data enabled accurate prediction of time to clinical remission and identified multiple relevant demographic and clinical variables with predictive value. Ongoing work aims to further validate and integrate these findings into clinical applications for CU management.

Racing against time: leveraging preclinical models to understand pulmonary susceptibility to perinatal acetaminophen exposures.

Over the past decade, clinicians have increasingly prescribed acetaminophen (APAP) for patients in the neonatal intensive care unit (NICU). Acetaminophen has been shown to reduce postoperative opiate burden, and may provide similar efficacy for closure of the patent ductus arteriosus (PDA) as nonsteroidal anti-inflammatory drugs (NSAIDs). Despite these potential benefits, APAP exposures have spread to increasingly less mature infants, a highly vulnerable population for whom robust pharmacokinetic and pharmacodynamic data for APAP are lacking. Concerningly, preclinical studies suggest that perinatal APAP exposures may result in unanticipated adverse effects that are unique to the developing lung. In this review, we discuss the clinical observations linking APAP exposures to adverse respiratory outcomes and the preclinical data demonstrating a developmental susceptibility to APAP-induced lung injury. We show how clinical observations linking perinatal APAP exposures to pulmonary injury have been taken to the bench to produce important insights into the potential mechanisms underlying these findings. We argue that the available data support a more cautious approach to APAP use in the NICU until large randomized controlled trials provide appropriate safety and efficacy data.

Understanding Strengths in Adolescent-Parent Relationships: A Qualitative Analysis of Adolescent Speech Samples.

Although adolescents' perspective on the parent-adolescent relationship uniquely predicts their mental health and wellbeing, there is limited research using qualitative methodologies to explore rich descriptions of adolescents' expectations, attitudes, and beliefs towards parents. The current study qualitatively analyzed adolescent narratives regarding their relationships with their parents. Seventy-two adolescents (68% female; M age = 16.56) provided three-minute speech samples that were examined using thematic analysis to understand key themes in adolescent-parent relationships from adolescents' perspectives. Overall, adolescents valued positive relationships with parents (involving emotional support and companionship), respected their authority, and looked to parents to role-model-valued traits. Mentions of negative interactions were mostly absent or justified as normal. Thus, normative adolescent-parent relationships are largely positive and valued by adolescents.

Lower threshold to NFκB activity sensitizes murine ß-cells to streptozotocin.

The ß-cell response to injury may be as critical for the development of diabetes as the specific insult. In the current study, we used streptozotocin (STZ) to injure the ß-cell in order to study the response with a focus on NFκB. MIN6 cells were exposed to STZ (0.5-8 mM, 0-24h) ±TNFα (100 ng/mL) and ±IκBß siRNA to lower the threshold to NFκB activation. Cell viability was determined by trypan blue exclusion. NFκB activation was determined by the expression of the target genes Nos2 and Cxcl10, localization of the NFκB proteins p65 and p50, and expression and localization of the NFκB inhibitors, IκBß and IκBα. There was no NFκB activation in MIN6 cell exposed to STZ (2 mM) alone. However, knocking down IκBß expression using siRNA resulted in STZ-induced expression of NFκB target genes and increased cell death, while co-incubation with STZ and TNFα enhanced cell death compared to either exposure alone. Adult male IκBß-/- and WT mice were exposed to STZ and monitored for diabetes. The IκBß-/- mice developed hyperglycemia and diabetes more frequently than controls following STZ exposure. Based on these results we conclude that STZ exposure alone does not induce NFκB activity. However, lowering the threshold to NFκB activation by co-incubation with TNFα or lowering IκBß levels by siRNA sensitizes the NFκB response to STZ and results in a higher likelihood of developing diabetes in vivo. Therefore, increasing the threshold to NFκB activation through stabilizing NFκB inhibitory proteins may prevent ß-cell injury and the development of diabetes.

Experience of child welfare services and long-term adult mental health outcomes: a scoping review.

PURPOSE: This is the first comprehensive review of empirical research that investigated the association between receipt of child welfare services and adult mental health outcomes. The review summarised the results of studies about mental health outcomes of adults with a history of child welfare involvement. METHODS: A scoping review methodology was used to search five electronic databases (MEDLINE, EMBASE, PsychINFO, IBSS, Social Policy and Practice). Studies were included if they examined any child welfare exposure (including receipt of services while remaining at home/being placed in care) and adult mental health status. RESULTS: In total 4591 records were retrieved, of which 55 met the eligibility criteria. Overall, receipt of child welfare services was associated with an increased risk of adult mental ill-health, suicide attempt and completed suicide. Results regarding potential moderating factors, such as gender and care-related experiences, were mixed. Relatively few studies investigated the reasons for requiring child welfare services, the experience of abuse or neglect or the adult outcomes of child welfare service users who remained in their own homes. Mental ill-health was defined and measured heterogeneously and details about the nature and type of welfare service utilisation were lacking. CONCLUSION: There is a need for detailed, longitudinal studies to better understand the relative contribution of pre-existing adversity versus experiences during and after exposure to child welfare services on adult mental health outcomes. More standardised measures of mental ill-health and greater detail from authors on specific care exposure are also needed.

The Emerging Literature on Exposure-Based Writing Therapies for Subthreshold and Clinical Posttraumatic Stress Disorder: A Response to Thompson-Hollands et al.'s (2020) Commentary on Dawson et al. (2020).

Thompson-Hollands et al.'s (2020) commentary on our systematic review of exposure-based writing therapies for subthreshold and clinical posttraumatic stress symptoms (Dawson et al., 2020) emphasizes important questions about the impact of heterogeneity in drawing inferences from evidence reviews. In this reply, we discuss (a) our rationale for undertaking a systematic review that was broad rather than narrow in scope and (b) provide clarifications on how heterogeneity was considered in the meta-analyses that were conducted. We also strongly agree with Thompson-Hollands et al.'s recommendation that future research should focus on better understanding the mechanisms by which exposure-based writing therapies help reduce posttraumatic stress symptoms.

Exposure-Based Writing Therapies for Subthreshold and Clinical Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis.

We undertook a systematic review to assess the efficacy of exposure-based writing therapies (WTs) for trauma-exposed adults with subthreshold or clinical levels of posttraumatic stress disorder. Four databases (PsycINFO, Medline, Wiley Online, PILOTS) were searched for randomized controlled trials (RCTs) of exposure-based WTs. A total of 13 RCTs that reported on results from 17 WT versus control comparisons were included. The primary outcomes were posttraumatic stress symptom severity at posttreatment and/or clinical response. An overall unclear or high risk of bias was identified in 84.6% of studies. In comparison to both waitlist k = 3, Hedges' g = -0.97, 95% CI [-1.20, -0.73], and placebo writing conditions, k = 9, Hedges' g = -0.48, 95% CI [-0.87, -0.08], WTs were more beneficial to participants. There was no evidence of a difference between WTs that were longer in duration compared to other psychotherapy, k = 2; pooled OR = 1.42; 95% CI [0.83, 2.43]. These findings indicate that exposure-based WTs are effective when compared to waitlist and placebo writing control conditions. The evidence needs to be considered in the context of the modest number of studies conducted to date, the high methodological heterogeneity between the studies, and the high or unclear risk of bias across many studies. Further research is needed to increase the evidence base regarding the efficacy of WTs for posttraumatic stress. Future research should also measure the mediators and predictors of outcomes to further develop protocols and understand which variants of WTs work for different populations or individuals.

Real-World Burden of Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is associated with an increase in healthcare resource use and poor health-related quality of life (HRQoL). We assessed the humanistic and economic burden of NASH, disease management, and patient journey. METHODS: We performed a cross-sectional analysis of data, collected from July through November 2017, from the Growth from Knowledge Disease Atlas Real-World Evidence program, reported by physicians in United States, France, and Germany. We extracted demographic and medical data from medical records. Some patients voluntarily completed a survey that provided information on disease history, treatment satisfaction, and patient-reported outcomes. RESULTS: We analyzed data from 1216 patients (mean age, 54.9±12.3 years; 57.5% male; mean body mass index, 31.7±6.9); 64.6% had biopsy-confirmed NASH and comorbidities were recorded for 41.3%. Treatments included lifestyle modification (64.6%) or use of statins (25.0%), vitamin E (23.5%), or metformin (20.2%). Patients with biopsy-confirmed NASH reported more physician (4.5 vs 3.7) and outpatient visits (1.8 vs1.4) than patients with suspected NASH not confirmed by biopsy. Among the 299 patients who completed the survey, 47.8% reported various symptoms associated to their NASH. Symptomatic patients reported significantly lower HRQoL than patients without symptoms. CONCLUSIONS: In an analysis of data from 3 countries, we found NASH to be associated with regular use of medical resources; patients with symptoms of NASH had reduced HRQoL. The burden of NASH appears to be underestimated. Studies are needed to determine the burden of NASH by fibrosis stage and disease severity.

Gaining a new perspective on the quality of parent-adolescent relationships from adolescent speech samples.

Although the quality of the parent-teen relationship is key to understanding both psychopathology and well-being in adolescence, there are limited assessments of adolescents' underlying attitudes regarding their parents. This study aimed to evaluate a novel and brief method of coding adolescents' 3-min speech samples regarding their affective attitudes (e.g., thoughts and feelings) toward their parent. A community sample of 72 adolescents (M age = 16 years) completed a 3-min speech sample and several questionnaire measures of the quality of the parent-teen relationship and adolescents' psychosocial outcomes. Speech samples were coded for critical and warm affective attitudes toward the parent using the Family Affective Attitude Rating Scale (FAARS). Results showed that FAARS negative relational schemas (NRS) and positive relational schemas (PRS) scales were reliable and converged with questionnaire assessments of attachment and relationship quality, antisocial outcomes, and pro-social behavior. When included in the same model, adolescents' NRS, but not the questionnaire measures, was uniquely associated with externalizing behavior and prosocial behavior. Furthermore, adolescents' PRS, but not the questionnaires, was uniquely associated with callous-unemotional traits. Results suggest that the FAARS coding scheme can reliably assess adolescents' affective attitudes toward their parents and that this information is relevant to understanding adolescents' psychosocial outcomes. The implications of these findings for multimethod clinical assessments, large cohort research, and adolescents' therapeutic outcomes are discussed. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

CpG-ODN-mediated TLR9 innate immune signalling and calcium dyshomeostasis converge on the NFκB inhibitory protein IκBß to drive IL1α and IL1ß expression.

Sterile inflammation contributes to many pathological states associated with mitochondrial injury. Mitochondrial injury disrupts calcium homeostasis and results in the release of CpG-rich mitochondrial DNA. The role of CpG-stimulated TLR9 innate immune signalling and sterile inflammation is well studied; however, how calcium dyshomeostasis affects this signalling is unknown. Therefore, we interrogated the relationship beτween intracellular calcium and CpG-induced TLR9 signalling in murine macrophages. We found that CpG-ODN-induced NFκB-dependent IL1α and IL1ß expression was significantly attenuated by both calcium chelation and calcineurin inhibition, a finding mediated by inhibition of degradation of the NFκB inhibitory protein IκBß. In contrast, calcium ionophore exposure increased CpG-induced IκBß degradation and IL1α and IL1ß expression. These results demonstrate that through its effect on IκBß degradation, increased intracellular Ca2+ drives a pro-inflammatory TLR9-mediated innate immune response. These results have implications for the study of innate immune signalling downstream of mitochondrial stress and injury.