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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.

ObjectiveOlaparib 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.MethodsThe 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 aBRCA1/2mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network.ResultsThe myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwentBRCA1/2and 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 aBRCA1/2mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to beBRCA1/2wild-type (n=510) thanBRCA1/2 mutant (n=304). The distribution of GIS was bimodal, withBRCA1/2mutant tumors having a higher mean score thanBRCA1/2wild-type tumors (61 vs 33, respectively, χ2test pConclusionThis 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.

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 an individual’s risk of illness progression. The application of staging has been traditionally limited to trained clinicians, yet if digital technologies could be leveraged to apply clinical staging, then this could increase the scalability and utility of this model in services. OBJECTIVE The aim of this study is to validate a digital algorithm to accurately differentiate young people at lower and higher risk of developing mental disorders. METHODS The cohort comprised 131 young people, aged between 16 to 25 years, who presented to youth mental health services in Australia for the first time between November 2018 to March 2021. Clinical stages (either stage 1a or stage 1b+) were allocated independently by expert psychiatrists and compared to the digital algorithm based on a multidimensional self-report questionnaire. RESULTS Of the 131 participants, the mean (SD) age was 20.3 (2.4) years and 94 (71.8%) were female. Ninety-one percent of clinical stage ratings were concordant between the digital algorithm and the expert ratings with a substantial interrater agreement (κ=0.67, P 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 early stages of common anxiety and depressive disorders. Between 11% and 27% of young people presenting for care may be suitable for low intensity online or brief interventions, creating additional clinical capacity to be directed towards those who are in stage 1b+ for further assessment and intervention.

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 an individual’s risk of illness progression. The application of staging has been traditionally limited to trained clinicians, yet if digital technologies could be leveraged to apply clinical staging, then this could increase the scalability and utility of this model in services. OBJECTIVE The aim of this proof-of-concept study is to validate a digital algorithm to accurately differentiate young people at lower and higher risk of developing mental disorders. METHODS The cohort comprised 131 young people, aged between 16 to 25 years, who presented to youth mental health services in Australia for the first time between November 2018 to March 2021. Clinical stages (either stage 1a or stage 1b+) were allocated independently by expert psychiatrists and compared to the digital algorithm based on a multidimensional self-report questionnaire. RESULTS Of the 131 participants, the mean (SD) age was 20.3 (2.4) years and 94 (71.8%) were female. Ninety-one percent of clinical stage ratings were concordant between the digital algorithm and the expert ratings with a substantial interrater agreement (κ=0.67, P 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 early stages of common anxiety and depressive disorders. Between 11% and 27% of young people presenting for care may be suitable for low intensity online or brief interventions, creating additional clinical capacity to be directed towards those who are stage 1b+ for further assessment and intervention.

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).

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.

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.

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.

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 IL1β expression was significantly attenuated by both calcium chelation and calcineurin inhibition, a finding mediated by inhibition of degradation of the NFκB inhibitory protein IκBβ. In contrast, calcium ionophore exposure increased CpG‐induced IκBβ degradation and IL1α and IL1β expression. These results demonstrate that through its effect on IκBβ degradation, increased intracellular Ca(2+) 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.

The β-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 β-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 ±IκBβ 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, IκBβ and IκBα. There was no NFκB activation in MIN6 cell exposed to STZ (2 mM) alone. However, knocking down IκBβ 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 IκBβ−/− and WT mice were exposed to STZ and monitored for diabetes. The IκBβ−/− 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 IκBβ 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 β-cell injury and the development of diabetes.

Exposure-based writing interventions for posttraumatic stress disorder (PTSD) have shown promise when compared with waitlist conditions, placebo writing control conditions, and evidence-based, trauma-focused treatments. Recently, Dawson et al. (2020) conducted a systematic review and meta-analysis to examine existing published randomized controlled trials investigating exposure-based writing interventions. The findings were encouraging; however, the studies included in the meta-analysis had a high degree of methodological heterogeneity. Our own work examining exposure-based writing as an intervention for PTSD has demonstrated that methodological differences in the structure of exposure-based writing can have a meaningful impact on treatment outcome. Accordingly, we urge caution in interpreting the meta-analysis findings reported by Dawson and colleagues and encourage investigation into better understanding the mechanisms underlying exposure-based writing interventions to further propel this important area of work.

Background Research consistently suggests that children in care have higher rates of mental ill-health compared to their peers in the community, however, studies exploring the long-term adult mental health outcomes have shown mixed results. The proliferation of research in this area is challenging and to date no comprehensive overview exists. This study synthesised the literature on the mental health outcomes of adults with a history of child welfare involvement. Methods A systematic scoping review methodology was used to search five electronic databases (MEDLINE, EMBASE, PsychINFO, IBSS, Social Policy and Practice). Two reviewers screened all papers independently. Studies were included if they examined any child welfare exposure (including being known to social services and remaining at home or being removed from the home and placed in foster care or residential care) and adult mental health status. Results In total 4,591 records were retrieved, of which 53 met the eligibility criteria. Four major themes of child welfare and adult mental health research were identified based broadly on service type: 35 studies examined out-of-home care (OHC) without specifying outcomes by placement type; eleven studies of OHC examined specific placement types; four studies examined both in-home care (IHC) and OHC; and three studies examined IHC services only. Overall, both OHC and IHC were associated with an increased risk of adult mental ill-health, suicide attempt and completed suicide. Potential moderating factors such as gender and care related experiences have been explored but produced conflicting results. Reason for becoming known to child welfare services and experience of abuse or neglect have not been widely explored, nor have outcomes in those who received child welfare services but remained in their own home. Mental health was defined and measured heterogeneously and detail on welfare services received was lacking. Conclusion This is the first review to systematically map the available evidence on child welfare exposure and adult mental health. There is a need for detailed, longitudinal studies to better understand the aetiology of mental ill health amongst adults with a childhood history of welfare service exposure, with more standardised measures of mental ill-health and more detail from authors on specific care exposure.

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.

Background The pro-inflammatory consequences of IL1β expression contribute to the pathogenesis of BPD. Selectively targeting LPS-induced IκBβ/NFκB signaling attenuates IL1β mRNA expression in macrophages. Whether targeting IκBβ/NFκB signaling affects anti-apoptotic gene expression, a known consequence of global LPS-induced NFκB inhibition, is unknown. Methods Macrophages (RAW 264.7, BMDM) were assessed for LPS-induced IL1β mRNA/protein expression, anti-apoptotic gene expression, cell viability (trypan blue exclusion) and activation of apoptosis (caspase-3 and PARP cleavage) following pharmacologic and genetic attenuation of IκBβ/NFκB signaling. Expression of IL1β and anti-apoptotic genes were assessed in endotoxemic newborn mice (P0) with intact (WT), absent (IκBβ KO) and attenuated (IκBβ overexpressing) IκBβ/NFκB signaling. Results In cultured macrophages, pharmacologic and genetic inhibition of LPS-induced IκBβ/NFκB signaling significantly attenuated IL1β mRNA and protein expression. Importantly, targeting IκBβ/NFκB signaling did not attenuate LPS-induced expression of anti-apoptotic genes or result in cell death. In endotoxemic neonatal mice, targeting LPS-induced IκBβ/NFκB signaling significantly attenuated pulmonary IL1β expression without affecting anti-apoptotic gene expression. Conclusion Targeting IκBβ/NFκB signaling prevents LPS-induced IL1β expression without inducing apoptosis in cultured macrophages and in the lungs of endotoxemic newborn mice. Inhibiting this pathway may prevent inflammatory injury without affecting the protective role of NFκB activity in the developing lung., Graphical Abstract

Background: Tumour lysis syndrome (TLS) occurs when lysis of malignant cells causes electrolyte disturbances and potentially organ dysfunction. Guidelines recommending preventive therapy according to TLS risk are based on low-quality evidence.Objectives: The primary objective was to characterize utilization of TLS preventive strategies through comprehensive description of current practice. Secondary objectives were to determine TLS incidence, to compare use of preventive strategies among intermediate- and high-risk patients, and to describe TLS treatment strategies.Methods: This retrospective chart review examined data for patients with newly diagnosed hematologic malignancy who were admitted to an oncology centre and/or affiliated intensive care unit between October 2015 and September 2016 in Toronto, Ontario, Canada. Results: Fifty-eight patients (29 at intermediate risk, 29 at high risk) were eligible for inclusion. Use of preventive allopurinol, IV bicarbonate, and furosemide was similar between groups. Rasburicase was more frequently used for high-risk patients (3% [1/29] of intermediate-risk patients versus 36% [9/25] of high-risk patients; p = 0.003). In 4 (14%) of the intermediate-risk patients and 2 (8%) of the high-risk patients, TLS developed during the admission. TLS was observed in 10% (1/10) of patients who received preventive rasburicase and 11% (5/44) of those who did not (p > 0.99), and in 9% (4/45) of patients who received preventive IV bicarbonate and 25% (2/8) of those who did not (p = 0.22). Treatment strategies included rasburicase, IV bicarbonate, furosemide, and renal replacement therapy.Conclusions: In this retrospective chart review, rasburicase was more commonly used for high-risk patients, whereas the use of other agents was similar between risk groups. This pattern of use is inconsistent with guidelines, which recommend that all high-risk patients receive rasburicase. There was no difference in TLS incidence between patients who did and did not receive preventive rasburicase or IV bicarbonate. Further prospective studies are needed to inform management of patients with malignancies who are at intermediate or high risk of TLS.RÉSUMÉContexte : Le syndrome de lyse tumorale (SLT) se produit lorsque la lyse de cellules malignes provoque des perturbations électrolytiques et la dysfonction potentielle d’un organe. Les lignes directrices préconisant une thérapie préventive basée sur le risque de SLT se fondent sur des éléments de preuve de piètre qualité.Objectifs : L’objectif principal consistait à décrire l’adoption des stratégies de prévention du SLT en décrivant précisément la pratique actuelle. Les objectifs secondaires consistaient, quant à eux, à déterminer l’incidence du SLT, à comparer l’utilisation des stratégies de prévention pour les patients présentant un risque élevé et moyen et à décrire les stratégies de traitement du SLT.Méthodes : Cet examen rétrospectif a permis d’examiner les données de patients ayant récemment reçu un diagnostic d’hémopathie maligne et ayant été admis dans un centre d’oncologie ou une unité de soins intensifs affiliée, entre octobre 2015 et septembre 2016 à Toronto (Ontario), au Canada.Résultats : Cinquante-huit patients (29 présentant un risque moyen et 29 un risque élevé) étaient admissibles. L’utilisation d’allopurinol à titre préventif, de bicarbonate par voie intraveineuse et de furosémide était similaire d’un groupe à l’autre. Le rasburicase était plus fréquemment utilisé pour les patients présentant un risque élevé (3 % [1/29] de patients présentant un risque moyen contre 36 % [9/25] de patients présentant un risque élevé; p = 0.003). Quatre (14 %) patients présentant un risque moyen et deux (8 %) présentant un risque élevé ont développé un SLT pendant l’admission. Le SLT a été observé chez 10 % (1/10) des patients ayant reçu du rasburicase à titre préventif et chez 11 % (5/44) des patients qui n’en avaient pas reçu (p > 0,99); il a aussi été observé chez 9 % (4/45) des patients ayant reçu du bicarbonate par voie intraveineuse à titre préventif et chez 25 % (2/8) des patients qui n’en avaient pas reçu (p = 0.22). Les stratégies de traitement comprenaient le rasburicase, le bicarbonate par voie intraveineuse, le furosémide et la thérapie de remplacement rénal.Conclusions : Dans cet examen rétrospectif des dossiers, l’usage du rasburicase était plus fréquent pour les patients présentant un risque élevé, tandis que celui d’autres agents était similaire entre les groupes à risque. Ce schéma d’utilisation n’est pas conforme aux lignes directrices, qui recommandent que tous les patients présentant un risque élevé reçoivent du rasburicase. Aucune différence n’est apparue dans l’incidence du SLT parmi les patients ayant reçu du rasburicase ou du bicarbonate par voie intraveineuse à titre préventif et parmi ceux qui n’en avaient pas reçu. Davantage d’études prospectives sont nécessaires pour mieux connaitre la gestion des patients à haut risque ou ceux qui présentent des risques moyens de SLT, mais qui ont des malignités.

Rationale Suicide is a major public health concern and Northern Ireland (NI) has the highest rate of both self-harm and suicide in the UK and Ireland. In order to target prevention strategies effectively it is vital to understand who is most at risk. Those who present with self-harm offer a prime opportunity for intervention. The aim of this study is to examine the risk factors for completed suicide following presentation with self-harm. Data The Northern Ireland Registry of Self-Harm (NIRSH) collects information on all self-harm and suicide ideation presentations to all Emergency Departments in NI. NIRSH data for the four years 2012–2015 was linked to centralised electronic data relating to primary care, social services and prescribed medication and mortality records. Methods Initial analyses describing the profile of those who present with self-harm was followed by logistic regression to quantify the likelihood of mortality with adjustment for factors associated with mental ill health and suicide risk. Results The cohort consisted of all 1,483,435 individuals born or resident in NI from 1st January 1970 until 31st December 2015 (maximum age in 2015, 45 years). During the follow-up period, 11,371 (0.8%) individuals presented with self-harm and 1,719 (0.1%) died by suicide. Rates of self-harm were equivalent for males and females with highest rates observed in the 18–24 years age group, and more common in deprived than affluent areas (OR=3.34, 95%CI 3.12, 3.57). Rates of self-harm was highest among those who were (or ever had been) in the care of social services (OR=12.06, 95%CI 11.26, 12.93). Most individuals self-harm via self-poisoning with psychotropic medications (70.9%), followed by self-injury with a sharp object (21.6%). Although only 142 (1.3%) of those who presented with self-harm went on to die by suicide, in the unadjusted model those who self-harmed were almost 12 times more likely to die by suicide compared to those who did not present with self-harm (OR=11.79, 95%CI 9.92,14.01). Suicide was more likely in individuals who self-harmed with more violent methods such as strangulation or drowning. After full adjustment for gender, age, social services care, area of residence and deprivation individuals who self-harm are still 7 times more likely to die by suicide (OR=7.05, 95%CI 5.88,8.45). Further analysis is underway to explore which particular traits and characteristics of those who self-harm are most associated with risk of suicide using cox regression in order in inform intervention targeting.

Objective. There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT.Methods. We established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3-4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS).Results. 877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5-65) and 28 months (IQR 7-92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0.55 (95% CI, 0.45-0.66; P < 0.001) and 0.65 (95% CI 0.50-0.85, P = 0.002) respectively; no heterogeneity was identified (PFS: Q = 6.42, P = 0.698, I2 = 0.0%; OS: Q = 6.89, P = 0 648, I2 = 0.0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0.027).Conclusions. CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical trial design. (C) 2019 The Authors. Published by Elsevier Inc.

Being of the male sex has been identified as a risk factor for multiple morbidities associated with preterm birth, including bronchopulmonary dysplasia (BPD). Exposure to inflammatory stress is a well-recognized risk factor for developing BPD. Whether there is a sex difference in pulmonary innate immune TLR4 signaling, lung injury and subsequent abnormal lung development is unknown. Neonatal (P0) male and female mice (ICR) were exposed to systemic LPS (5 mg/kg, IP) and innate immune signaling, and the transcriptional response were assessed (1 and 5 hours), along with lung development (P7). Male and female mice demonstrated a similar degree of impaired lung development with decreased radial alveolar counts, increased surface area, increased airspace area and increased mean linear intercept. We found no differences between male and female mice in the baseline pulmonary expression of key components of TLR4-NFκB signaling, or in the LPS-induced pulmonary expression of key mediators of neonatal lung injury. Finally, we found no difference in the kinetics of LPS-induced pulmonary NFκB activation between male and female mice. Together, these data support the conclusion that the innate immune response to early postnatal LPS exposure and resulting pulmonary sequelae is similar in male and female mice.

The liver plays a central role in the innate immune response to endotoxemia. While previous studies have demonstrated lobe-specific transcriptional responses to various insults, whether this is true in response to endotoxemia is unknown. We sought to assess whether there were significant intra- and inter-lobe differences in the murine hepatic innate immune transcriptional response to endotoxemia. Adult male ICR mice were exposed to i.p. LPS (5 mg/kg, 30 min, 60 min, 5 h) and primary ( Tnf, Cxcl1, Nfkbia, Tnfiap3) and secondary ( Il6, Nos2) innate immune response gene expression was assessed in the left medial, right medial, left lateral, and right lateral lobes, and the papillary and caudate processes. The expression of all innate immune response genes increased following i.p. LPS challenge. When tested at the early time points (30 and 60 min), the left medial lobe and caudate process consistently demonstrated the highest induction of gene expression. Most inter-lobe differences were attenuated at later time points (5 h). To improve reproducibility of the study of endotoxemia induced by i.p. LPS challenge, inclusion of appropriate methodological details regarding collection of hepatic tissue should be included when reporting scientific results in published manuscripts.

Clinical studies have demonstrated a strong association between both acute toxic exposure and the repetitive, chronic exposure to acetaminophen (APAP) with pulmonary dysfunction. However, the mechanisms underlying this association are unknown. Preclinical reports have demonstrated that significant bronchiolar injury occurs with toxic APAP exposure, but very little information exists on how the distal lung is affected. However, cells in the alveolar space, including the pulmonary epithelium and resident macrophages, express the APAP-metabolizing enzyme CYP2E1 and are a potential source of toxic metabolites and subsequent distal lung injury. Thus, we hypothesized that distal lung injury would occur in a murine model of toxic APAP exposure. Following exposure of APAP (280 mg/kg, IP), adult male mice were found to have significant proximal lung histopathology as well as distal lung inflammation and emphysematous changes. Toxic APAP exposure was associated with increased CYP2E1 expression in the distal lung and accumulation of APAP-protein adducts. This injury was associated with distal lung activation of oxidant stress, endoplasmic reticulum stress, and inflammatory stress response pathways. Our findings confirm that following toxic APAP exposure, distal lung CYP2E1 expression is associated with APAP metabolism, tissue injury, and oxidant, inflammatory, and endoplasmic reticulum signaling. This previously unrecognized injury may help improve our understanding of the relationship between APAP and pulmonary-related morbidity.

Elevated serum concentrations of the vasoactive protein endothelin-1 (ET-1) occur in the setting of systemic inflammatory response syndrome and contribute to distal organ hypoperfusion and pulmonary hypertension. Thus, understanding the cellular source and transcriptional regulation of systemic inflammatory stress-induced ET-1 expression may reveal therapeutic targets. Using a murine model of LPS-induced septic shock, we demonstrate that the hepatic macrophage is the primary source of elevated circulating ET-1, rather than the endothelium as previously proposed. Using pharmacologic inhibitors, ET-1 promoter luciferase assays, and by silencing and overexpressing NF-κB inhibitory protein IκB expression, we demonstrate that LPS-induced ET-1 expression occurs via an NF-κB–dependent pathway. Finally, the specific role of the cRel/p65 inhibitory protein IκBβ was evaluated. Although cytoplasmic IκBβ inhibits activity of cRel-containing NF-κB dimers, nuclear IκBβ stabilizes NF-κB/DNA binding and enhances gene expression. Using targeted pharmacologic therapies to specifically prevent IκBβ/NF-κB signaling, as well as mice genetically modified to overexpress IκBβ, we show that nuclear IκBβ is both necessary and sufficient to drive LPS-induced ET-1 expression. Together, these results mechanistically link the innate immune response mediated by IκBβ/NF-κB to ET-1 expression and potentially reveal therapeutic targets for patients with Gram-negative septic shock.

Multiple mediators of septic shock are regulated by the transcription factor nuclear factor κB (NFκB). However, complete NFκB inhibition can exacerbate disease, necessitating evaluation of targeted strategies to attenuate the pro-inflammatory response. Here, we demonstrate that in murine macrophages, low-dose NFκB inhibitors specifically attenuates lipopolysaccharide (LPS)-induced IκBβ degradation and the expression of a select subset of target genes (encoding IL1β, IL6, IL12β). Gain- and loss-of-function experiments demonstrate the necessary and sufficient role of inhibitor of NFκB family member IκBβ (also known as NFKBIB) in the expression of these genes. Furthermore, both fibroblasts and macrophages isolated from IκBβ overexpressing mice demonstrate attenuated LPS-induced IκBβ–NFκB signaling and IL1β, IL6 and IL12β expression. Further confirming the role of IκBβ and its NFκB subunit binding partner cRel in LPS-induced gene expression, pre-treatment of wild-type mouse embryonic fibroblasts with a cell-permeable peptide containing the cRel nuclear localization sequence attenuated IL6 expression. We prove that LPS-induced IκBβ–NFκB signaling can be selectively modulated to attenuate the expression of select pro-inflammatory target genes, thus providing therapeutic insights for patients exposed to systemic inflammatory stress.

Previous research has demonstrated that there is a negative relationship between ethnic diversity in a local community and social cohesion. Often the way social cohesion is assessed, though, varies across studies and only some aspects of the construct are included (e.g., trust). The current research explores the relationship between diversity and social cohesion across a number of indicators of social cohesion including neighbourhood social capital, safety, belonging, generalized trust, and volunteering. Furthermore, social psychological theories concerning the role of positive contact and its impact on feelings of threat are investigated. Using a sample of 1070 third generation 'majority' Australians and structural equation modelling (SEM), findings suggest ethnic diversity is related to positive intergroup contact, and that contact showed beneficial impacts for some indicators of social cohesion both directly and indirectly through reducing perceived threat. When interethnic contact and perceived threat are included in the model there is no direct negative effect between diversity and social cohesion. The theoretical implications of these findings are outlined including the importance of facilitating opportunities for positive contact in diverse communities.