Hospital Research Foundation

Chorioamnionitis or infection of the amniotic fluid and membranes surrounding the fetus can cause fetal systemic inflammation and adverse neurological outcomes. To investigate the pathogenesis of chorioamnionitis-induced neurological injury, we developed a non-human primate model by infusion of live Escherichia coli. A micro-osmotic pump was placed in pregnant Rhesus macaques at ~ 85% term gestation via hysterotomy. Live E. coli (105 CFU/h, 1µL/h, n = 7) or sterile broth (Controls, 1µL/h, n = 7) infusions were given over 72 h followed by necropsy. A third group of pregnant macaques received microbicidal antibiotics 24 h after the start of E. coli infusion (n = 5). Amniotic fluid, cord plasma, and fetal brain regions were carefully preserved for comparative analysis of fetal systemic and brain inflammation. E. coli exposure caused fetal systemic inflammation without bacteremia and induced pro-inflammatory cytokines in the periventricular white matter (PVWM) and thalamus. A diffuse inflammation characterized by aberrant proliferation and activation of IBA1+ microglia and GFAP+ astrocytes was observed in multiple brain regions. There was a selective vulnerability of the DCX expressing immature neurons with relative sparing of cortical mature neurons expressing MAP2 or NeuN. Periventricular and entorhinal white matter regions were particularly vulnerable with relative sparing of the cortex. These pathogenic changes of fetal brain injury were observed after 72 h exposure. Maternal antibiotics cleared the bacteremia but did not decrease neuroinflammation or neuropathology. These results highlight the potential need for anti-inflammatory adjunctive therapy in addition to antibiotics for optimal outcomes in chorioamnionitis.

Fragile X Syndrome (FXS), caused by the loss of function of the Fmr1 gene, is characterized by varying degrees of intellectual disability, autistic features, and sensory hypersensitivity. Despite phenotypic rescue in animal deletion models, clinical trials in humans have been unsuccessful, likely due to the heterogeneous nature of FXS. To uncover the basis of individual- and subgroup-level variation driving treatment failures, we propose to test and modulate thalamocortical drive as a novel “bottom-up” neural probe to understand the mechanics of FXS-relevant circuits. Our study employs trial-level EEG analyses (neurodynamics) to detect fine-grained differences in brain activity using sensory and statistical learning paradigms in children with FXS, autism spectrum disorder (ASD), and typically developing controls. Parallel analysis in the FXS knockout mouse model will clarify its relevance to human FXS subgroups. In a randomized crossover study, we will evaluate the efficacy of closed-loop auditory entrainment, indexed on individual neurodynamic measures, aiming to normalize neural responses and enhance statistical learning performance. We anticipate this approach will yield opportunities to identify more effective early interventions that alter the trajectory of intellectual development in FXS.

ABSTRACTVitamin K refers to a group of lipid‐soluble vitamins that exist in two natural isoforms; phylloquinone (PK, vitamin K1) and menaquinones (MKs, vitamin K2). Phylloquinone, the primary dietary source, is found abundantly in green vegetables and plant oils. Menaquinones (MK‐4 through MK‐13) are synthesized by anaerobic bacteria and may be obtained through the diet from fermented foods and animal products (e.g., meats, dairy and eggs). Originally recognized for its role in blood coagulation, vitamin K is an essential cofactor for the posttranslational carboxylation of vitamin K‐dependent proteins (VKDPs), which are implicated in various physiological processes including; blood coagulation, calcium homeostasis, as well as metabolic and inflammatory pathways. Therefore, vitamin K has attracted considerable research interest for its potential implications in several diseases. While promising, the specific roles of vitamin K in various health conditions, the quantity of vitamin K (both PK and MKs) required for the function of various VKDPs, and the influence of genetics on vitamin K metabolism, remain unclear. This review aims to (i) provide an overview of the structure, dietary sources, metabolism, and physiological roles of vitamin K, including those relating to; cardiovascular diseases, type 2 diabetes, respiratory conditions, musculoskeletal health and cancer; (ii) discuss the impact of genetic factors on vitamin K status and how such factors modulate the role of vitamin K in the aforementioned chronic diseases; and (iii) outline key directions for future research.

Higher intake of cruciferous and allium vegetables is associated with lower cardiometabolic risk. Little research has investigated the cardiometabolic effects of S-methyl cysteine sulfoxide (SMCSO), found abundant in these vegetables. This study hypothesizes that SMCSO will blunt development of metabolic syndrome features in mice fed high-fat feed. Fifty C57BL/6 male mice are randomly assigned to standard-chow, high-fat, or high-fat supplemented with low-SMCSO (43mgkg-1 body weight [BW]day-1), medium-SMCSO (153mgkg-1 BWday-1), or high-SMCSO (256mgkg-1 BWday-1) for 12-weeks. High-fat with SMCSO did not prevent diet-induced obesity, glucose intolerance, or hypercholesterolemia. Mice fed high-fat with SMCSO has higher hepatic lipids than mice fed standard-chow or high-fat alone. Urinary SMCSO increases at 6- and 12-weeks in the low-SMCSO group, before reducing 46% and 28% in the medium- and high-SMCSO groups, respectively, at 12-weeks, suggesting possible tissue saturation. Interestingly, two SMCSO-fed groups consume significantly more feed, without significant weight gain. Due to limitations in measuring consumed feed, caution should be taken interpreting these results. SMCSO (43-256mgkg-1 BWday-1) does not ameliorate metabolic syndrome features in high-fat fed mice. Substantial knowledge gaps remain. Further studies should administer SMCSO separately (i.e., gavage), with metabolic studies exploring tissue levels to better understand its physiological action.

LAY SUMMARY Families offer vital mental health and well-being support to Veterans and public safety personnel. This study offers a model of how families can experience moral distress from service cultures that exclude them, leaving families stuck, exacerbating a sense of moral distress resulting from perceived organizational betrayal felt in the context of families’ help-seeking experiences. The model was informed by in-depth interviews conducted in Australia with 25 family members with experience seeking help and providing support to a family member who is a Veteran or public safety personnel. The interviews provided a detailed description of how embedded and aligned families were to a member’s service role, and their profound sense of betrayal and distress when attempts to support family members’ mental health were thwarted. Families may experience moral distress from identifying the problem and potential support solutions, but having nowhere to go to realize those supports for their family member. The implications for Veteran and public safety organizations as well as health professionals to promote more meaningful involvement of families is discussed.

Early parenting services in Australia offer brief structured residential programs to address moderate to severe non-psychotic mental health problems among women and unsettled infant/toddler behaviours. The aims were to (1) estimate the immediate and medium-term impact of a five-night psychoeducational residential early parenting program on postpartum depressive symptoms and (2) identify the factors associated with improvement or worsening of postpartum depressive symptoms after completing the program and six weeks post-discharge. Audit of routinely collected medical record data from pre-admission, pre-discharge and post-discharge assessments of a consecutive cohort of women admitted, with their infants/toddlers in a 15-month period to Masada Private Hospital Early Parenting Centre. Data included structured questions assessing: demographic characteristics, access to family and social support, past and current mental health problems, reproductive and obstetric health, chronic health conditions, breastfeeding problems, coincidental major life events, health risk behaviours and infant/toddler feeding, sleeping and crying behaviours. Standardised instruments included the Partner Interaction after Birth Scale (PIBS), the MacLean Screening Instrument for Borderline Personality Disorder (MSI-BPD), Modified Fatigue Assessment Scale (FAS) and selected items from the Karitane Parenting Confidence Scale. The primary outcomes were Edinburgh Postnatal Depression Scale scores at pre-discharge and follow up assessments. Data were analysed using multinomial logistic regression models in which individual and psychosocial characteristics at pre-admission were included as predictors of the likelihood of the changes of the outcomes from pre-admission to pre-discharge and follow up. Complete data from 1220 of 1290 (95%) eligible women were available to assess pre-admission to pre-discharge and from 559 (45.8%) to assess pre-discharge to six-week follow-up changes. The mean pre-admission EPDS score was 11.7 (95% CI: 11.5; 12.0), pre-discharge it was 7.1 (95% CI: 6.9; 7.4) and at six-week follow up it was 5.7 (95% CI: 5.3; 6.1). We found that almost all women experienced a clinically meaningful and rapid improvement in depressive symptoms of at least this magnitude (reduction in mean EPDS scores of 4.6 points from pre-admission to pre-discharge (five nights) and a further reduction of 1.2 points pre-discharge to follow up) (six weeks) and we identified an interpretable set of risk factors for symptoms that did not improve or worsened. The adverse outcomes were associated with having symptoms of borderline personality disorder, a partner experienced as lacking kindness and care, coincidental adverse events and having a child younger than six months. Residential early parenting programs, which take a psycho-educational approach to strengthening caregiving skills, maximising agency, and reducing helplessness, have a rapid beneficial effect on women's postpartum depressive symptoms. These programs provide a valuable and effective component of comprehensive mental health services. Long-term dialectical behaviour therapy is indicated for women with borderline personality disorder traits for whom early parenting programs alone are insufficient to improve depressive symptoms.

AimsIn a high-income country, Australia, it is unclear how raised systolic blood pressure (SBP) ranks among other risk factors regarding the overall and cardiovascular disease (CVD) burden, and whether the situation has changed over time.MethodsWe analysed the 2019 Global Burden of Disease (GBD) data, with focus on Australia. We assessed ten leading risk factors for all-cause and CVD deaths and disability-adjusted life-years (DALYs) and compared findings with the Australian Burden of Diseases Study.ResultsFrom 1990 to 2019, raised SBP remained the leading risk factor for attributable all-cause deaths (followed by dietary risks and tobacco use), accounting for 29,056/75,235 (95% Uncertainty Interval (UI) [24,863 to 32,915]) deaths in 1990; 21,845/76,893 [17,678 to 26,044] in 2010; and 25,498/90,393 [20,152 to 30,851] in 2019. Contributions of raised SBP to cardiovascular deaths for both sexes were 54.0% [45.8 to 61.5] in 1990, 44.0% [36.7 to 51.3] in 2010 and 43.7% [36.2 to 51.6] in 2019, respectively. The contribution of raised SBP to cardiovascular deaths declined between 1990 and 2010 but exhibited an increase in males from 2010 onwards, with figures of 52.6% [44.7 to 60.0] in 1990, 43.1% [36.0 to 50.5] in 2010 and 43.5% [35.7 to 51.4] in 2019. The contribution of raised SBP to stroke deaths and DALYs in males aged 25–49 years were higher than other age groups, in excess of 60% and increasing steeply between 2010 and 2019.ConclusionRaised SBP continues to be the leading risk factor for all-cause and cardiovascular deaths in Australia. We urge cross-disciplinary stakeholder engagement to implement effective strategies to detect, treat and control raised blood pressure as a central priority to mitigate the CVD burden.

N-Nitrosamines, carcinogenic compounds present in dietary and environmental sources and formed endogenously, are believed to be linked with the presence of nitrate and nitrite, both within dietary sources and after intake. To fully evaluate this potential threat to human health, an accurate analytical method to measure N-nitrosamines in biological matrices is necessary. We report a simple, fast, selective mass spectrometry method to detect N-nitrosamines in human urine. Analysis of seven N-nitrosamines, N-nitrosodimethylamine (NDMA), N-nitrosomethylethylamine (NMEA), N-nitrosodiethylamine (NDEA), N-nitrosopiperdine (NPIP), N-nitrosopyrrolidine (NPYR), N-nitrosodi-N-propylamine (NDPA) and N-nitrosodi-N-butylamine (NDBA) in urine was quantitated using Ultra High-Pressure Liquid Chromatography-tandem Mass spectrometry (UHPLC-MS/MS). A Sorbent supported Liquid Extraction (SLE) method was employed to extract N-nitrosamines from 24 hour collected human urine samples. The percent recovery varied between 74.3 to 110 and the limit of detection and limit of quantification ranged from 0.1 to 0.85 ng mL-1 and 0.22 to 2.06 ng mL-1 respectively. Precision for inter-day and intra-day assay yielded a % coefficient of variation between 4-10% for all measured compounds in urine. Linear regression analysis of calibration curves for N-nitrosamines measured in urine in the concentration range 0.4-12.8 ng mL-1 gave correlation coefficients, R2 0.9874-0.9962. Urinary excretion of N-nitrosamines measured in ten healthy subjects resulted in detection of most of the N-nitrosamines including NDMA, NDEA, NPYR, NDPA and NDBA by this method.