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Objective: To assess the impact of publicly reporting a statewide fetal growth restriction (FGR) performance indicator.Design: Retrospective cohort study from 2000 to 2017.Setting: All maternity services in Victoria, Australia.Population: A total of 1 231 415 singleton births at ≥32 weeks of gestation.Methods: We performed an interrupted time-series analysis to assess the impact of publicly reporting an FGR performance indicator on the rate of detection for severe cases of small for gestational age (SGA). Rates of perinatal mortality and morbidity and obstetric intervention were assessed for severe SGA pregnancies and pregnancies delivered for suspected SGA.Main Outcome Measures: Gestation at delivery, obstetric management and perinatal outcome.Results: The public reporting of a statewide FGR performance indicator was associated with a steeper reduction per quarter in the percentage of severe SGA undelivered by 40 weeks of gestation, from 0.13 to 0.51% (P = 0.001), and a decrease in the stillbirth rate by 3.3 per 1000 births among those babies (P = 0.01). Of babies delivered for suspected SGA, the percentage with birthweights ≥ 10th centile increased from 41.4% (n = 307) in 2000 to 53.3% (n = 1597) in 2017 (P < 0.001). Admissions to a neonatal intensive care unit for babies delivered for suspected SGA but with a birthweight ≥ 10th centile increased from 0.8 to 2.0% (P < 0.001).Conclusions: The public reporting of an FGR performance indicator has been associated with the improved detection of severe SGA and a decrease in the rate of stillbirth among those babies, but with an increase in the rate of iatrogenic birth for babies with normal growth.Tweetable Abstract: The public reporting of hospital performance is associated with a reduction in stillbirth, but also with unintended interventions. [ABSTRACT FROM AUTHOR]

Importance: Sport-related concussion (SRC), a form of mild traumatic brain injury, is a prevalent occurrence in collision sports. There are no well-established approaches for tracking neurobiologic recovery after SRC., Objective: To examine the levels of serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in Australian football athletes who experience SRC., Design, Setting, and Participants: A cohort study recruiting from April 10, 2021, to September 17, 2022, was conducted through the Victorian Amateur Football Association, Melbourne, Australia. Participants included adult Australian football players with or without SRC. Data analysis was performed from May 26, 2023, to March 27, 2024., Exposure: Sport-related concussion, defined as at least 1 observable sign and/or 2 or more symptoms., Main Outcomes and Measures: Primary outcomes were serum GFAP and NfL levels at 24 hours, and 1, 2, 4, 6, 8, 12, and 26 weeks. Secondary outcomes were symptoms, cognitive performance, and return to training times., Results: Eighty-one individuals with SRC (median age, 22.8 [IQR, 21.3-26.0] years; 89% male) and 56 control individuals (median age, 24.6 [IQR, 22.4-27.3] years; 96% male) completed a total of 945 of 1057 eligible testing sessions. Compared with control participants, those with SRC exhibited higher GFAP levels at 24 hours (mean difference [MD] in natural log, pg/mL, 0.66 [95% CI, 0.50-0.82]) and 4 weeks (MD, 0.17 [95% CI, 0.02-0.32]), and NfL from 1 to 12 weeks (1-week MD, 0.31 [95% CI, 0.12-0.51]; 2-week MD, 0.38 [95% CI, 0.19-0.58]; 4-week MD, 0.31 [95% CI, 0.12-0.51]; 6-week MD, 0.27 [95% CI, 0.07-0.47]; 8-week MD, 0.36 [95% CI, 0.15-0.56]; and 12-week MD, 0.25 [95% CI, 0.04-0.46]). Growth mixture modeling identified 2 GFAP subgroups: extreme prolonged (16%) and moderate transient (84%). For NfL, 3 subgroups were identified: extreme prolonged (7%), moderate prolonged (15%), and minimal or no change (78%). Individuals with SRC who reported loss of consciousness (LOC) (33% of SRC cases) had higher GFAP at 24 hours (MD, 1.01 [95% CI, 0.77-1.24]), 1 week (MD, 0.27 [95% CI, 0.06-0.49]), 2 weeks (MD, 0.21 [95% CI, 0.004-0.42]) and 4 weeks (MD, 0.34 [95% CI, 0.13-0.55]), and higher NfL from 1 week to 12 weeks (1-week MD, 0.73 [95% CI, 0.42-1.03]; 2-week MD, 0.91 [95% CI, 0.61-1.21]; 4-week MD, 0.90 [95% CI, 0.59-1.20]; 6-week MD, 0.81 [95% CI, 0.50-1.13]; 8-week MD, 0.73 [95% CI, 0.42-1.04]; and 12-week MD, 0.54 [95% CI, 0.22-0.85]) compared with SRC participants without LOC. Return to training times were longer in the GFAP extreme compared with moderate subgroup (incident rate ratio [IRR], 1.99 [95% CI, 1.69-2.34]; NfL extreme (IRR, 3.24 [95% CI, 2.63-3.97]) and moderate (IRR, 1.43 [95% CI, 1.18-1.72]) subgroups compared with the minimal subgroup, and for individuals with LOC compared with those without LOC (IRR, 1.65 [95% CI, 1.41-1.93])., Conclusions and Relevance: In this cohort study, a subset of SRC cases, particularly those with LOC, showed heightened and prolonged increases in GFAP and NfL levels, that persisted for at least 4 weeks. These findings suggest that serial biomarker measurement could identify such cases, guiding return to play decisions based on neurobiologic recovery. While further investigation is warranted, the association between prolonged biomarker elevations and LOC may support the use of more conservative return to play timelines for athletes with this clinical feature.

Ulcerative colitis (UC) is an idiopathic inflammatory disease of the large intestine, which impacts millions worldwide. Current interventions aimed at treating UC symptoms can have off-target effects, invoking the need for alternatives that may provide similar benefits with less unintended consequences. This study builds on our initial data, which showed that panaxynol-a novel, potent, bioavailable compound found in American ginseng-can suppress disease severity in murine colitis. Here we explore the underlying mechanisms by which panaxynol improves both chronic and acute murine colitis. Fourteen-week-old C57BL/6 female mice were either given three rounds of dextran sulfate sodium (DSS) in drinking water to induce chronic colitis or one round to induce acute colitis. Vehicle or panaxynol (2.5 mg/kg) was administered via oral gavage three times per week for the study duration. Consistent with our previous findings, panaxynol significantly ( P < 0.05) improved the disease activity index and endoscopic scores in both models. Using the acute model to examine potential mechanisms, we show that panaxynol significantly ( P < 0.05) reduced DSS-induced crypt distortion, goblet cell loss, and mucus loss in the colon. 16S Sequencing revealed panaxynol altered microbial composition to suppress colitis-enriched genera (i.e., Enterococcus, Eubacterium, and Ruminococcus ). In addition, panaxynol significantly ( P < 0.05) suppressed macrophages and induced regulatory T-cells in the colonic lamina propria. The beneficial effects of panaxynol on mucosal and crypt architecture, combined with its microbial and immune-mediated effects, provide insight into the mechanisms by which panaxynol suppresses murine colitis. Overall, this data is promising for the use of panaxynol to improve colitis in the clinic. NEW & NOTEWORTHY In the current study, we report that panaxynol ameliorates chemically induced murine colitis by improving colonic crypt and mucosal architecture, suppressing colitis-enriched microbes, reducing macrophages, and promoting the differentiation of regulatory T-cells in the colonic lamina propria. This study suggests that this novel natural compound may serve as a safe and effective treatment option for colitis patients.

Mild traumatic brain injury (mTBI) involves damage to the cerebrovascular system. Vascular endothelial growth factor-A (VEGF-A) is an important modulator of vascular health and VEGF-A promotes the brain's ability to recover after more severe forms of brain injury; however, the role of VEGF-A in mTBI remains poorly understood. Bevacizumab (BEV) is a monoclonal antibody that binds to VEGF-A and neutralises its actions. To better understand the role of VEGF-A in mTBI recovery, this study examined how BEV treatment affected outcomes in rats given a mTBI. Adult Sprague-Dawley rats were assigned to sham-injury + vehicle treatment (VEH), sham-injury + BEV treatment, mTBI + VEH treatment, mTBI + BEV treatment groups. Treatment was administered intracerebroventricularly via a cannula beginning at the time of injury and continuing until the end of the study. Rats underwent behavioral testing after injury and were euthanized on day 11. In both females and males, BEV had a negative impact on cognitive function. mTBI and BEV treatment increased the expression of inflammatory markers in females. In males, BEV treatment altered markers related to hypoxia and vascular health. These novel findings of sex-specific responses to BEV and mTBI provide important insights into the role of VEGF-A in mTBI., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Huntington's disease (HD) is an inherited neurodegenerative disease involving progressive motor abnormalities, cognitive decline, and psychiatric disturbances. Depression and cognitive difficulties are among the most impactful symptoms of HD, yet the pathogenesis of these symptoms is not fully understood. HD involves low-level chronic inflammation and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which are linked to depression and cognitive impairment in non-HD populations. However, previous research on the relationships of these pathologies with depression and cognition in HD is limited and inconsistent., Methods: Fifty-three adults with the HD gene expansion (30 premanifest and 23 manifest) completed measures of depression and cognitive functioning. Forty-eight out of 53 participants provided hair samples for quantification of cortisol, and 34 participants provided blood samples for quantification of peripheral inflammatory cytokines. We examined the associations of four cytokines (interleukin [IL]-6, IL-10, IL-1β, and tumor necrosis factor [TNF]-α) and cortisol levels with depression and cognitive scores., Results: In unadjusted models, higher levels of plasma IL-6, IL-10, and TNF-α correlated with higher depression scores, and higher levels of IL-10 and TNF-α correlated with poorer cognitive performance. After controlling for age, sex, and body mass index, only the correlations of IL-10 with depression and cognitive performance remained significant. No correlations were evident with hair cortisol., Interpretations: Peripheral inflammation is associated with depression symptoms and cognitive impairment in HD. Our findings suggest that interactions between the immune and nervous systems are important in HD, and highlight the potential of chronic inflammation as a therapeutic target in early stages of HD., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: More than 650 million people are obese (BMI > 30) worldwide, which increases their risk for several metabolic diseases and cancer. While cachexia and obesity are at opposite ends of the weight spectrum, leading many to suggest a protective effect of obesity against cachexia, mechanistic support for obesity's benefit is lacking. Given that obesity and cachexia are both accompanied by metabolic dysregulation, we sought to investigate the impact of obesity on skeletal muscle mass loss and mitochondrial dysfunction in murine cancer cachexia., Methods: Male C57BL/6 mice were given a purified high fat or standard diet for 16 weeks before being implanted with 10 6 Lewis lung carcinoma (LLC) cells. Mice were monitored for 25 days, and hindlimb muscles were collected for cachexia indices and mitochondrial assessment via western blotting, high-resolution respirometry and transmission electron microscopy (TEM)., Results: Obese LLC mice experienced significant tumour-free body weight loss similar to lean (-12.8% vs. -11.8%, P = 0.0001) but had reduced survival (33.3% vs. 6.67%, χ 2  = 10.04, P = 0.0182). Obese LLC mice had reduced muscle weights (-24%, P < 0.0354) and mCSA (-16%, P = 0.0004) with similar activation of muscle p65 (P = 0.0337), and p38 (P = 0.0008). ADP-dependent coupled respiration was reduced in both Obese and Obese LLC muscle (-30%, P = 0.0072) consistent with reductions in volitional cage activity (-39%, P < 0.0001) and grip strength (-41%, P < 0.0001). TEM revealed stepwise reductions in intermyofibrillar and subsarcolemmal mitochondrial size with Obese (IMF: -37%, P = 0.0009; SS: -21%, P = 0.0101) and LLC (IMF: -40%, P = 0.0019; SS: -27%, P = 0.0383) mice. Obese LLC mice had increased pAMPK (T172; P = 0.0103) and reduced FIS1 (P = 0.0029) and DRP1 (P < 0.0001) mitochondrial fission proteins, which were each unchanged in Lean LLC. Further, mitochondrial TEM analysis revealed that Obese LLC mice had an accumulation of damaged and dysfunctional mitochondria (IMF: 357%, P = 0.0395; SS: 138%, P = 0.0174) in concert with an accumulation of p62 (P = 0.0328) suggesting impaired autophagy and clearance of damaged mitochondria. Moreover, we observed increases in electron lucent vacuoles only in Obese LLC muscle (IMF: 421%, P = 0.0260; SS: 392%, P = 0.0192), further supporting an accumulation of damaged materials that cannot be properly cleared in the obese cachectic muscle., Conclusions: Taken together, these results demonstrate that obesity is not protective against cachexia and suggest exacerbated impairments to mitochondrial function and quality control with a particular disruption in the removal of damaged mitochondria. Our findings highlight the need for consideration of the severity of obesity and pre-existing metabolic conditions when determining the impact of weight status on cancer-induced cachexia and functional mitochondrial deficits., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Immune cell-driven pathways are linked to cancer cachexia. Tumor presence is associated with immune cell infiltration whereas cytotoxic chemotherapies reduce immune cell counts. Despite these paradoxical effects, both cancer and chemotherapy can cause cachexia; however, our understanding of immune responses in the cachexia condition with cancer and chemotherapy is largely unknown. We sought to advance our understanding of the immunology underlying cancer and cancer with chemotherapy-induced cachexia. CD2F1 mice were given 10 6 C26 cells, followed by five doses of 5-fluorouracil (5FU; 30 mg/kg LM, ip) or PBS. Indices of cachexia and tumor (TUM), skeletal muscle (SKM), and adipose tissue (AT) immune cell populations were examined using high-parameter flow cytometry. Although 5FU was able to stunt tumor growth, % body weight loss and muscle mass were not different between C26 and C26 + 5FU. C26 increased CD11b + Ly6g + and CD11b + Ly6c Int inflammatory myeloid cells in SKM and AT; however, both populations were reduced with C26 + 5FU. tSNE analysis revealed 24 SKM macrophage subsets wherein 8 were changed with C26 or C26 + 5FU. C26 + 5FU increased SKM CD11b - CD11c + dendritic cells, CD11b - NK1.1 + NK-cells, and CD11b - B220 + B-cells, and reduced Ly6c Hi CX3CR1 + CD206 + CD163 Int CD11c - MHCII - infiltrated macrophages and other CD11b + Ly6c Hi myeloid cells compared with C26. Both C26 and C26 + 5FU had elevated CD11b + F480 + CD206 + MHCII - or more specifically Ly6c Lo CX3CR1 + CD206 + CD163 Int CD11c - MHCII - profibrotic macrophages. 5FU suppressed tumor growth and decreased SKM and AT inflammatory immune cells without protecting against cachexia suggesting that these cells are not required for wasting. However, profibrotic cells and muscle inflammatory/atrophic signaling appear consistent with cancer- and cancer with chemotherapy-induced wasting and remain potential therapeutic targets. NEW & NOTEWORTHY Despite being an immune-driven condition, our understanding of skeletal muscle and adipose tissue immune cells with cachexia is limited. Here, we identified immune cell populations in tumors, skeletal muscle, and adipose tissue in C26 tumor-bearing mice with/without 5-fluorouracil (5FU). C26 and C26 + 5FU had increased skeletal muscle profibrotic macrophages, but 5FU reduced inflammatory myeloid cells without sparing mass. Tumor presence and chemotherapy have contrasting effects on certain immune cells, which appeared not necessary for wasting.

Traumatic brain injuries (TBIs) and concussions are prevalent in collision sports, and there is evidence that levels of exposure to such sports may increase the risk of neurological abnormalities. Elevated levels of fluid-based biomarkers have been observed after concussions or among athletes with a history of participating in collision sports, and certain biomarkers exhibit sensitivity toward neurodegeneration. This study investigated a cohort of 28 male amateur athletes competing in "Masters" competitions for persons >35 years of age. The primary objective of this study was to compare the levels of blood and saliva biomarkers associated with brain injury, inflammation, aging, and neurodegeneration between athletes with an extensive history of collision sport participation (i.e., median = 27 years; interquartile range = 18-44, minimum = 8) and those with no history. Plasma proteins associated with neural damage and neurodegeneration were measured using Simoa ® assays, and saliva was analyzed for markers associated with inflammation and telomere length using quantitative real-time polymerase chain reaction. There were no significant differences between collision and non-collision sport athletes for plasma levels of glial fibrillary acidic protein, neurofilament light, ubiquitin C-terminal hydrolase L1, tau, tau phosphorylated at threonine 181, and brain-derived neurotrophic factor. Moreover, salivary levels of genes associated with inflammation and telomere length were similar between groups. There were no significant differences between groups in symptom frequency or severity on the Sport Concussion Assessment Tool-5th Edition. Overall, these findings provide preliminary evidence that biomarkers associated with neural tissue damage, neurodegeneration, and inflammation may not exhibit significant alterations in asymptomatic amateur athletes with an extensive history of amateur collision sport participation., Competing Interests: No competing financial interests exist., (© Lauren P. Giesler et al., 2024; Published by Mary Ann Liebert, Inc.)

Traumatic brain injury (TBI) is a key contributor to global morbidity that lacks effective treatments. Microbial infections are common in TBI patients, and their presence could modify the physiological response to TBI. It is estimated that one-third of the human population is incurably infected with the feline-borne parasite, Toxoplasma gondii, which can invade the central nervous system and result in chronic low-grade neuroinflammation, oxidative stress, and excitotoxicity-all of which are also important pathophysiological processes in TBI. Considering the large number of TBI patients that have a pre-existing T. gondii infection prior to injury, and the potential mechanistic synergies between the conditions, this study investigated how a pre-existing T. gondii infection modified TBI outcomes across acute, sub-acute and chronic recovery in male and female mice. Gene expression analysis of brain tissue found that neuroinflammation and immune cell markers were amplified in the combined T. gondii + TBI setting in both males and females as early as 2-h post-injury. Glutamatergic, neurotoxic, and oxidative stress markers were altered in a sex-specific manner in T. gondii + TBI mice. Structural MRI found that male, but not female, T. gondii + TBI mice had a significantly larger lesion size compared to their uninfected counterparts at 18-weeks post-injury. Similarly, diffusion MRI revealed that T. gondii + TBI mice had exacerbated white matter tract abnormalities, particularly in male mice. These novel findings indicate that a pre-existing T. gondii infection affects the pathophysiological aftermath of TBI in a sex-dependent manner, and may be an important modifier to consider in the care and prognostication of TBI patients., (© 2024. The Author(s).)

Background and Objectives: Blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have recently been Food and Drug Administration approved as predictors of intracranial lesions on CT after mild traumatic brain injury (mTBI). However, most cases with mTBI are CT negative, and no biomarkers are approved to assist diagnosis in these individuals. In this study, we aimed to determine the optimal combination of blood biomarkers to assist mTBI diagnosis in otherwise healthy adults younger than 50 years presenting to an emergency department within 6 hours of injury. To further understand the utility of biomarkers, we assessed how biological sex, presence or absence of loss of consciousness and/or post-traumatic amnesia (LOC/PTA), and delayed presentation affected classification performance., Methods: Blood samples, symptom questionnaires, and cognitive tests were prospectively conducted for participants with mTBI recruited from The Alfred Hospital Level 1 Emergency & Trauma Center and uninjured controls. Follow-up testing was conducted at 7 days. Simoa quantified plasma GFAP, UCH-L1, tau, neurofilament light chain (NfL), interleukin (IL)-6, and IL-1β. Area under the receiver operating characteristic (AUC) analysis assessed classification accuracy for diagnosed mTBI, and logistic regression models identified optimal biomarker combinations., Results: Plasma IL-6 (AUC 0.91, 95% CI 0.86-0.96), GFAP (AUC 0.85, 95% CI 0.78-0.93), and UCH-L1 (AUC 0.79, 95% CI 0.70-0.88) best differentiated mTBI (n = 74) from controls (n = 44) acutely (<6 hours), with NfL (AUC 0.81, 95% CI 0.72-0.90) the only marker to have such utility subacutely (7 days). Biomarker performance was similar between sexes and for participants with and without LOC/PTA, with the exception at 7 days, where GFAP and IL-6 retained some utility in female participants (GFAP: AUC 0.71, 95% CI 0.55-0.88; IL-6: AUC 0.71, 95% CI 0.55-0.87) and in those with LOC/PTA (GFAP: AUC 0.73, 95% CI 0.59-0.86; IL-6: AUC 0.71, 95% CI 0.57-0.84). Acute IL-6 ( R 2 = 0.50, 95% CI 0.34-0.64) outperformed GFAP and UCH-L1 combined ( R 2 = 0.35, 95% CI 0.17-0.50), with the best acute model featuring GFAP and IL-6 ( R 2 = 0.54, 95% CI 0.34-0.68)., Discussion: These findings indicate that adding IL-6 to a panel of brain-specific proteins such as GFAP and UCH-L1 might assist in the acute diagnosis of mTBI in adults younger than 50 years. Multiple markers had high classification accuracy in participants without LOC/PTA. When compared with the best-performing acute markers, subacute measures of plasma NfL resulted in minimal reduction in classification accuracy. Future studies will investigate the optimal time frame over which plasma IL-6 might assist diagnostic decisions and how extracranial trauma affects utility., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Problem: Breastfeeding has many important benefits for both mother and baby but sustained breastfeeding is sub-optimal., Background: Identifying women who need increased support to establish breastfeeding has the potential to improve this. Analysis of the relationship between primary postpartum haemorrhage (PPH) and primary severe PPH and breastfeeding may prove informative as PPH has potentially negative impacts on breastfeeding., Aim: To determine the relationship between PPH and severe PPH and breastfeeding at postnatal discharge and formula use for breastfed babies in hospital., Methods: Population-based retrospective cohort study using the Victorian Perinatal Data Collection for all liveborn singleton births at ≥ 37 weeks' gestation (n = 339,854) for 2009-13 in Victoria. Estimated blood loss was categorised as PPH ≥ 500 mL and severe PPH ≥ 1500 mL. Descriptive analysis was conducted and multivariable logistic regression was used to determine the adjusted odds ratio for the relationship between PPH/severe PPH and breastfeeding outcomes after adjustment for relevant confounders., Findings: Overall, 94.9% of women initiated breastfeeding. Babies whose mother had a PPH or severe PPH were less likely than others to be exclusively breastfeeding at discharge (aOR 0.88; (95% CI 0.86, 0.90) and aOR 0.57; (95% CI 0.53, 0.61) respectively). Formula - given to 25.9% of all breastfed babies - was more likely for those whose mothers had a PPH or severe PPH (aOR 1.15; (95% CI 1.12, 1.17) and aOR 2.15; (95% CI 2.01, 2.29) respectively., Conclusions: Women have greater challenges establishing exclusive breastfeeding following PPH and severe PPH. Improving support in hospital for women following PPH may increase breastfeeding success., Competing Interests: Conflict of interest None declared., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Currently available colorectal cancer (CRC) therapies have limited efficacy and severe adverse effects that may be overcome with the alternative use of natural compounds. We previously reported that panaxynol (PA), a bioactive component in American ginseng, possesses anticancer properties in vitro and suppresses murine colitis through its proapoptotic and anti-inflammatory properties. Because colitis is a predisposing factor of CRC and inflammation is a major driver of CRC, we sought to evaluate the therapeutic potential of PA in CRC. Azoxymethane-dextran sodium sulfate (AOM/DSS) mice (C57BL/6) were administered 2.5 mg/kg PA or vehicle 3 times/wk via oral gavage over 12 wk. PA improved clinical symptoms ( P ≤ 0.05) and reduced tumorigenesis ( P ≤ 0.05). This improvement may be reflective of PA's restorative effect on intestinal barrier function; PA upregulated the expression of essential tight junction and mucin genes ( P ≤ 0.05) and increased the abundance of mucin-producing goblet cells ( P ≤ 0.05). Given that macrophages play a substantial role in the pathogenesis of CRC and that we previously demonstrated that PA targets macrophages in colitis, we next assessed macrophages. We show that PA reduces the relative abundance of colonic macrophages within the lamina propria ( P ≤ 0.05), and this was consistent with a reduction in the expression of important markers of macrophages and inflammation ( P ≤ 0.05). We further confirmed PA's inhibitory effects on macrophages in vitro under CRC conditions ( P ≤ 0.05). These results suggest that PA is a promising therapeutic compound to treat CRC and improve clinical symptoms given its ability to inhibit macrophages and modulate the inflammatory environment in the colon. NEW & NOTEWORTHY We report that panaxynol (PA) reduces colorectal cancer (CRC) by improving the colonic and tumor environment. Specifically, we demonstrate that PA improves crypt morphology, upregulates crucial tight junction and mucin genes, and promotes the abundance of mucin-producing goblet cells. Furthermore, PA reduces macrophages and associated inflammation, important drivers of CRC, in the colonic environment. This present study provides novel insights into the potential of PA as a therapeutic agent to ameliorate CRC tumorigenesis.

It has been suspected that tumor resection surgery itself may accelerate breast cancer (BC) lung metastasis in some patients. Emodin, a natural anthraquinone found in the roots and rhizomes of various plants, exhibits anticancer activity. We examined the perioperative use of emodin in our established surgery wounding murine BC model. Emodin reduced primary BC tumor growth and metastasis in the lungs in both sham and surgical wounded mice, consistent with a reduction in proliferation and enhanced apoptosis (primary tumor and lungs). Further, emodin reduced systemic inflammation, most notably the number of monocytes in the peripheral blood and reduced pro-tumoral M2 macrophages in the primary tumor and the lungs. Consistently, we show that emodin reduces gene expression of select macrophage markers and associated cytokines in the primary tumor and lungs of wounded mice. Overall, we demonstrate that emodin is beneficial in mitigating surgical wounding accelerated lung metastasis in a model of triple-negative BC, which appears to be mediated, at least in part, by its actions on macrophages. These data support the development of emodin as a safe, low-cost, and effective agent to be used perioperatively to alleviate the surgery triggered inflammatory response and consequential metastasis of BC to the lungs., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The diagnosis of mild traumatic brain injury (mTBI) and early identification of patients who have persistent symptoms remains challenging. Symptoms are variably reported, and tests for cognitive impairment require specific expertise. The aim of this study was to assess the ability of plasma micro-ribonucleic acid (miRNA) biomarkers to distinguish between patients with mTBI and healthy controls. A secondary aim was to assess whether miRNA biomarker levels on the day of injury could predict persistent symptoms on day 7. Injured patients presented to an adult, tertiary referral hospital emergency department and were diagnosed with isolated mTBI (n = 75). Venous blood samples were collected within 6 h of injury. Symptom severity was assessed using the Rivermead Post-Concussion Symptom Questionnaire (RPQ) on the day of injury and at 7 days post-injury. The comparator group (n = 44) were healthy controls without any injury, who had bloods sampled and symptom severity assessed at the same time-point. Patients after mTBI reported higher symptom severity and had worse cognitive performance than the control group. Plasma miR423-3p levels were significantly higher among mTBI patients acutely post-injury compared to healthy controls and provided moderate discriminative ability (AUROC 0.67; 95 %CI: 0.57-0.77). None of the assessed miRNA biomarkers predicted persistent symptoms at 7 days. Plasma miR423-3p levels measured within 6 h of injury can discriminate for mTBI compared to healthy controls, with potential utility for screening after head injury or as an adjunct to the diagnosis of mTBI. Acute plasma miRNA levels did not predict patients who reported persistent symptoms at 7 days., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Traumatic brain injury (TBI) survivors often experience debilitating consequences. Due to the high impact nature of TBI, patients often experience concomitant peripheral injuries (ie, polytrauma). A common, yet often overlooked, comorbidity of TBI is chronic pain. Therefore, this study investigated how common concomitant peripheral injuries (ie, femoral fracture and muscle crush) can affect long-term behavioral and structural TBI outcomes with a particular focus on nociception. Rats were randomly assigned to 1 of 4 groups: polytrauma (POLY; ie, fracture + muscle crush + TBI), peripheral injury (PERI; ie, fracture + muscle crush + sham TBI), TBI (ie, sham fracture + sham muscle crush + TBI), and sham-injured (SHAM; ie, sham fracture + sham muscle crush + sham TBI). Rats underwent behavioral testing at 3-, 6-, and 11-weeks postinjury, and were then euthanized for postmortem magnetic resonance imaging (MRI). POLY rats had a persisting increase in pain sensitivity compared to all groups on the von Frey test. MRI revealed that POLY rats also had abnormalities in the cortical and subcortical brain structures involved in nociceptive processing. These findings have important implications and provide a foundation for future studies to determine the underlying mechanisms and potential treatment strategies for chronic pain in TBI survivors. PERSPECTIVE: Rats with TBI and concomitant peripheral trauma displayed chronic nociceptive pain and MRI images also revealed damaged brain structures/pathways that are involved in chronic pain development. This study highlights the importance of polytrauma and the affected brain regions for developing chronic pain., (Copyright © 2023 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) and stress are prevalent worldwide and can both result in life-altering health problems. While stress often occurs in the absence of TBI, TBI inherently involves some element of stress. Furthermore, because there is pathophysiological overlap between stress and TBI, it is likely that stress influences TBI outcomes. However, there are temporal complexities in this relationship (e.g., when the stress occurs) that have been understudied despite their potential importance. This paper begins by introducing TBI and stress and highlighting some of their possible synergistic mechanisms including inflammation, excitotoxicity, oxidative stress, hypothalamic-pituitary-adrenal axis dysregulation, and autonomic nervous system dysfunction. We next describe different temporal scenarios involving TBI and stress and review the available literature on this topic. In doing so we find initial evidence that in some contexts stress is a highly influential factor in TBI pathophysiology and recovery, and vice versa. We also identify important knowledge gaps and suggest future research avenues that will increase our understanding of this inherent bidirectional relationship and could one day result in improved patient care., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Mild traumatic brain injuries (mTBIs) are the most common form of acquired brain injury. Symptoms of mTBI are thought to be associated with a neuropathological cascade, potentially involving the dysregulation of neurometabolites, lipids, and mitochondrial bioenergetics. Such alterations may play a role in the period of enhanced vulnerability that occurs after mTBI, such that a second mTBI will exacerbate neuropathology. However, it is unclear whether mTBI-induced alterations in neurometabolites and lipids that are involved in energy metabolism and other important cellular functions are exacerbated by repeat mTBI, and if such alterations are associated with mitochondrial dysfunction., Methods: In this experiment, using a well-established awake-closed head injury (ACHI) paradigm to model mTBI, male rats were subjected to a single injury, or five injuries delivered 1 day apart, and injuries were confirmed with a beam-walk task and a video observation protocol. Abundance of several neurometabolites was evaluated 24 h post-final injury in the ipsilateral and contralateral hippocampus using in vivo proton magnetic resonance spectroscopy (1H-MRS), and mitochondrial bioenergetics were evaluated 30 h post-final injury, or at 24 h in place of 1H-MRS, in the rostral half of the ipsilateral hippocampus. Lipidomic evaluations were conducted in the ipsilateral hippocampus and cortex., Results: We found that behavioral deficits in the beam task persisted 1- and 4 h after the final injury in rats that received repetitive mTBIs, and this was paralleled by an increase and decrease in hippocampal glutamine and glucose, respectively, whereas a single mTBI had no effect on sensorimotor and metabolic measurements. No group differences were observed in lipid levels and mitochondrial bioenergetics in the hippocampus, although some lipids were altered in the cortex after repeated mTBI., Discussion: The decrease in performance in sensorimotor tests and the presence of more neurometabolic and lipidomic abnormalities, after repeated but not singular mTBI, indicates that multiple concussions in short succession can have cumulative effects. Further preclinical research efforts are required to understand the underlying mechanisms that drive these alterations to establish biomarkers and inform treatment strategies to improve patient outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Allen, Pham, Bond, O’Brien, Spitz, Shultz, Drew, Wright and McDonald.)

Objective: Professional jockeys experience high rates of concussion, workplace stress, and poor mental health. The present cross-sectional study, for the first time, concurrently assessed the potential interplay between concussion history and workplace stress with current depression symptoms., Method: Seventy-two professional flat-track jockeys (male = 49, female = 23) were grouped based on self-reported concussion history (CG; n = 56) and those who did not report a concussion history (NCG; total n = 16). Analyses featured both between (CG vs NCG) and within group (CG only) assessment on self-reported measures of workplace stress and depression symptoms (affect, daily functioning)., Results: Jockeys in the CG had more symptoms of negative affect than the NCG. This association, however, was nonsignificant after covarying for age, gender, and workplace stress. Higher workplace stress (p = .005) and gender (p = .001) were associated with poorer daily functioning after controlling for concussion history (CG vs. NCG) and age. Gender moderated the association between concussion group and poorer daily functioning (β = -18.739, t (71) = -2.924, p = .005), with the difference between CG and NCG significant for females, but not males (β = 33.648, t (71) = 3.420, p = .001)., Conclusions: The findings provide preliminary evidence that previously concussed females may be more likely to report poorer daily functioning than males with a history of concussion, and that workplace stress may reduce the association between a history of concussion and depression symptoms. Prospective studies are required to validate and extend these findings., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

A second mild traumatic brain injury (mTBI) sustained prior to neuropathological recovery can lead to exacerbated effects. Without objective indicators of this neuropathology, individuals may return to activities at risk of mTBI when their brain is still vulnerable. With axonal injury recognized as a neuropathological hallmark of mTBI, we hypothesized that serum levels of neurofilament light (NfL), a highly sensitive biomarker of axonal injury, may be predictive of vulnerability to worse outcomes in the event of a second mTBI. Given this hypothesis is difficult to test clinically, we used a two-hit model of mTBI in rats and staggered inter-injury intervals by 1-, 3-, 7-, or 14-days. Repeat-mTBI rats were dichotomized into NfL high (NfL>median at the time of re-injury) and NfL low (NfLhigh rats displaying more neurological signs and a greater potentiation of NfL levels after the second mTBI. Importantly, this potentiation phenomenon remained even when limiting analyses to rats with longer inter-injury intervals, providing evidence that vulnerability to re-injury may not be exclusively dependent on inter-injury interval. Finally, NfL levels correlated with, and were predictive of, the severity of neurological signs following the second mTBI. These findings provide evidence that measurement of NfL during mTBI recovery may be reflective of the vulnerability to a second mTBI, and as such may have utility to assist return to sport, duty and work decisions., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury is a common health problem affecting millions of people each year. BDNF has been investigated in the context of traumatic brain injury due to its crucial role in maintaining brain homeostasis. Val66Met is a functional single-nucleotide polymorphism that results in a valine-to-methionine amino acid substitution at codon 66 in the BDNF prodomain, which ultimately reduces secretion of BDNF. Here, we review experimental animal models as well as clinical studies investigating the role of the Val66Met single-nucleotide polymorphism in traumatic brain injury outcomes, including cognitive function, motor function, neuropsychiatric symptoms, and nociception. We also review studies investigating the role of BDNF on traumatic brain injury pathophysiology as well as circulating BDNF as a biomarker of traumatic brain injury.

Nogo receptor 1 is the high affinity receptor for the potent myelin-associated inhibitory factors that make up part of the inflammatory extracellular milieu during experimental autoimmune encephalomyelitis. Signalling through the Nogo receptor 1 complex has been shown to be associated with axonal degeneration in an animal model of multiple sclerosis, and neuronal deletion of this receptor homologue, in a disease specific manner, is associated with preserving axons even in the context of neuroinflammation. The local delivery of Nogo receptor(1-310)-Fc, a therapeutic fusion protein, has been successfully applied as a treatment in animal models of spinal cord injury and glaucoma. As multiple sclerosis and experimental autoimmune encephalomyelitis exhibit large numbers of inflammatory cell infiltrates within the CNS lesions, we utilized transplantable haematopoietic stem cells as a cellular delivery method of the Nogo receptor(1-310)-Fc fusion protein. We identified CNS-infiltrating macrophages as the predominant immune-positive cell type that overexpressed myc-tagged Nogo receptor(1-310)-Fc fusion protein at the peak stage of experimental autoimmune encephalomyelitis. These differentiated phagocytes were predominant during the extensive demyelination and axonal damage, which are associated with the engulfment of the protein complex of Nogo receptor(1-310)-Fc binding to myelin ligands. Importantly, mice transplanted with haematopoietic stem cells transduced with the lentiviral vector carrying Nogo receptor(1-310)-Fc and recovered from the peak of neurological decline during experimental autoimmune encephalomyelitis, exhibiting axonal regeneration and eventual remyelination in the white matter tracts. There were no immunomodulatory effects of the transplanted, genetically modified haematopoietic stem cells on immune cell lineages of recipient female mice induced with experimental autoimmune encephalomyelitis. We propose that cellular delivery of Nogo receptor(1-310)-Fc fusion protein through genetically modified haematopoietic stem cells can modulate multifocal experimental autoimmune encephalomyelitis lesions and potentiate neurological recovery., Competing Interests: All other authors listed declare no competing financial and/or non-financial interests in relation to the work described., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Post-traumatic epilepsy (PTE) is a debilitating chronic outcome of traumatic brain injury (TBI), and neuroinflammation is implicated in increased seizure susceptibility and epileptogenesis. However, how common clinical factors, such as infection, may modify neuroinflammation and PTE development has been understudied. The neurotropic parasite, Toxoplasma gondii (T. gondii) incurably infects one-third of the world's population. Thus, many TBI patients have a pre-existing T. gondii infection at the time of injury. T. gondii infection results in chronic low-grade inflammation and altered signaling pathways within the brain, and preliminary clinical evidence suggest that it may be a risk factor for epilepsy. Despite this, no studies have considered how a pre-existing T. gondii infection may alter the development of PTE., Methods: This study aimed to provide insight into this knowledge gap by assessing how a pre-existing T. gondii infection alters susceptibility to, and severity of, pentylenetetrazol (PTZ)-induced seizures (i.e., a surrogate marker of epileptogenesis/PTE) at a chronic stage of TBI recovery. We hypothesized that T. gondii will increase the likelihood and severity of seizures following PTZ administration, and that this would occur in the presence of intensified neuroinflammation. To test this, 6-week old male and female C57BL/6 Jax mice were intraperitoneally injected with 50,000 T. gondii tachyzoites or with the PBS vehicle only. At 12-weeks old, mice either received a severe TBI via controlled cortical impact or sham injury. At 18-weeks post-injury, mice were administered 40 mg/kg PTZ and video-recorded for evaluation of seizure susceptibility. Fresh cortical tissue was then collected for gene expression analyses., Results: Although no synergistic effects were evident between infection and TBI, chronic T. gondii infection alone had robust effects on the PTZ-seizure response and gene expression of markers related to inflammatory, oxidative stress, and glutamatergic pathways. In addition to this, females were more susceptible to PTZ-induced seizures than males. While TBI did not impact PTZ responses, injury effects were evident at the molecular level., Discussion: Our data suggests that a pre-existing T. gondii infection is an important modifier of seizure susceptibility independent of brain injury, and considerable attention should be directed toward delineating the mechanisms underlying this pro-epileptogenic factor., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Baker, Uboldi, Tonkin, Wright, Vo, Wilson, Mychasiuk, McDonald, Semple, Sun and Shultz.)

There is a recognized need for objective tools for detecting and tracking clinical and neuropathological recovery after sports-related concussion (SRC). Although computerized neurocognitive testing has been shown to be sensitive to cognitive deficits after SRC, and some blood biomarkers have shown promise as indicators of axonal and glial damage, the potential utility of these measures in isolation and combination for assisting SRC diagnosis and tracking recovery is not well understood. To provide new insights, we conducted a prospective study of 64 male and female professional flat-track jockeys (49 non-SRC, 15 SRC), with each jockey undergoing symptom evaluation, cognitive testing using the CogSport battery, and serum biomarker quantification of glial fibrillary acidic protein (GFAP), tau, and neurofilament light (NfL) using a Simoa HD-X Analyzer. Measures were performed at baseline (i.e., pre-injury), and 2 and 7 days and 1 and 12 months after SRC. Symptoms were most pronounced at 2 days and had largely resolved by either 7 days or 1 month. CogSport testing at 2 days revealed cognitive impairments relative to both non-concussed peers and their own pre-injury baselines, with SRC classification utility found at 2 days, and to a slightly lesser extent, at 7 days. Relatively prolonged changes in serum NfL were observed, with elevated levels and classification utility persisting beyond the resolution of SRC symptoms and cognitive deficits. Finally, SRC classification performance throughout the 1st month after SRC was optimized through the combination of cognitive testing and serum biomarkers. Considered together, these findings provide further evidence for a role of computerized cognitive testing and fluid biomarkers of neuropathology as objective measures to assist in the identification of SRC and the monitoring of clinical and neuropathological recovery.

Fluorouracil/5-flourouracil (5FU) is a first-line chemotherapy drug for many cancer types; however, its associated toxicities contribute to poor quality of life and reduced dose intensities negatively impacting patient prognosis. While obesity remains a critical risk factor for most cancers, our understanding regarding how obesity may impact chemotherapy's toxicities is extremely limited. C56BL/6 mice were given high fat (Obese) or standard diets (Lean) for 4 months and then subjected to three cycles of 5FU (5d-40 mg/kg Lean Mass, 9d rest) or PBS vehicle control. Shockingly, only 60% of Obese survived 3 cycles compared to 100% of Lean, and Obese lost significantly more body weight. Dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5FU catabolism, was reduced in obese livers. Total white blood cells, neutrophils, and lymphocytes were reduced in Obese 5FU compared to Lean 5FU and PBS controls. While adipocyte size was not affected by 5FU in Obese, skeletal muscle mass and myofibrillar cross section area were decreased following 5FU in Lean and Obese. Although adipose tissue inflammatory gene expression was not impacted by 5FU, distinct perturbations to skeletal muscle inflammatory gene expression and immune cell populations (CD45 + Immune cells, CD45 + CD11b + CD68 + macrophages and CD45 + CD11b + Ly6c lo/int macrophage/monocytes) were observed in Obese only. Our evidence suggests that obesity induced liver pathologies and reduced DPD exacerbated 5FU toxicities. While obesity has been suggested to protect against cancer/chemotherapy-induced cachexia and other toxicities, our results demonstrate that obese mice are not protected, but rather show evidence of increased susceptibility to 5FU-induced cytotoxicity even when dosed for relative lean mass.

A cachexia diagnosis is associated with a doubling in hospital stay and increased healthcare cost for cancer patients and most cachectic patients do not survive treatment. Unfortunately, complexity in treating cachexia is amplified by both the underlying malignancy and the anti-cancer therapy which can independently promote cachexia. Quercetin, an organic polyphenolic flavonoid, has demonstrated anti-inflammatory and antioxidant properties with promise in protecting against cancer and chemotherapy-induced dysfunction; however, whether quercetin is efficacious in maintaining muscle mass in tumor-bearing animals receiving chemotherapy has not been investigated. C26 tumor-bearing mice were given 5-fluorouracil (5FU; 30 mg/kg of lean mass i.p.) concomitant with quercetin (Quer; 50 mg/kg of body weight via oral gavage) or vehicle. Both C26 + 5FU and C26 + 5FU + Quer had similar body weight loss; however, muscle mass and cross-sectional area was greater in C26 + 5FU + Quer compared to C26 + 5FU. Additionally, C26 + 5FU + Quer had a greater number and larger intermyofibrillar mitochondria with increased relative protein expression of mitochondrial complexes V, III, and II as well as cytochrome c expression. C26 + 5FU + Quer also had increased MFN1 and reduced FIS1 relative protein expression without apparent benefits to muscle inflammatory signaling. Our data suggest that quercetin protected against cancer and chemotherapy-induced muscle mass loss through improving mitochondrial homeostatic balance.

The diagnosis, prognosis, and treatment of mild traumatic brain injuries (mTBIs), such as concussions, are significant unmet medical issues. The kinetic forces that occur in mTBI adversely affect the cerebral vasculature, making cerebrovascular injury (CVI) a pathophysiological hallmark of mTBI. Given the importance of a healthy cerebrovascular system in overall brain function, CVI is likely to contribute to neurological dysfunction after mTBI. As such, CVI and related pathomechanisms may provide objective biomarkers and therapeutic targets to improve the clinical management and outcomes of mTBI. Despite this potential, until recently, few studies have focused on the cerebral vasculature in this context. This article will begin by providing a brief overview of the cerebrovascular system followed by a review of the literature regarding how mTBI can affect the integrity and function of the cerebrovascular system, and how this may ultimately contribute to neurological dysfunction and neurodegenerative conditions. We then discuss promising avenues of research related to mTBI biomarkers and interventions that target CVI, and conclude that a clinical approach that takes CVI into account could result in substantial improvements in the care and outcomes of patients with mTBI.

Ulcerative colitis (UC) is a chronic disease that is characterized by diffuse inflammation of the colonic and rectal mucosa. The burden of UC is rising globally with significant disparities in levels and trends of disease in different countries. The pathogenesis of UC involves the presence of pathogenic factors including genetic, environmental, autoimmune, and immune-mediated components. Evidence suggests that disturbed interactions between the host immune system and gut microbiome contribute to the origin and development of UC. Current medications for UC include antibiotics, corticosteroids, and biological drugs, which can have deleterious off-target effects on the gut microbiome, contributing to increased susceptibility to severe infections and chronic immunosuppression. Alternative, nonpharmacological, and behavioral interventions have been proposed as safe and effective treatments to alleviate UC, while also holding the potential to improve overall life quality. This mini-review will discuss the interactions between the immune system and the gut microbiome in the case of UC. In addition, we suggest nonpharmacological and behavioral strategies aimed at restoring a proper microbial-immune relationship.

Introduction: Pregnant women are at higher risk of severe illness from coronavirus disease 2019 (COVID-19) than non-pregnant women of a similar age. Early in the COVID-19 pandemic, it was clear that evidenced-based guidance was needed, and that it would need to be updated rapidly. The National COVID-19 Clinical Evidence Taskforce provided a resource to guide care for people with COVID-19, including during pregnancy. Care for pregnant and breastfeeding women and their babies was included as a priority when the Taskforce was set up, with a Pregnancy and Perinatal Care Panel convened to guide clinical practice., Main Recommendations: As of May 2022, the Taskforce has made seven specific recommendations on care for pregnant women and those who have recently given birth. This includes supporting usual practices for the mode of birth, umbilical cord clamping, skin-to-skin contact, breastfeeding, rooming-in, and using antenatal corticosteroids and magnesium sulfate as clinically indicated. There are 11 recommendations for COVID-19-specific treatments, including conditional recommendations for using remdesivir, tocilizumab and sotrovimab. Finally, there are recommendations not to use several disease-modifying treatments for the treatment of COVID-19, including hydroxychloroquine and ivermectin. The recommendations are continually updated to reflect new evidence, and the most up-to-date guidance is available online (https://covid19evidence.net.au)., Changes in Management Resulting From the Guidelines: The National COVID-19 Clinical Evidence Taskforce has been a critical component of the infrastructure to support Australian maternity care providers during the COVID-19 pandemic. The Taskforce has shown that a rapid living guidelines approach is feasible and acceptable., (© 2022 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Approximately one-third of all breast cancer mortality results from metastatic recurrence after initial success of surgery and/or therapy. Although primary tumor removal is widely accepted as beneficial, it has long been suspected that surgery itself contributes to accelerated metastatic recurrence. We investigated surgical wounding's impact on tumor progression and lung metastasis in a murine model of triple negative breast cancer (TNBC). Ten-week-old female mice were inoculated with 4 T1 cells (week 0) and were either subjected to a 2 cm long cutaneous contralateral incision (wounded) or control (non-wounded) on week 2 and monitored for 3 weeks (week 5). Mice with surgical wounding displayed significantly accelerated tumor growth observable as early as 1-week post wounding. This was confirmed by increased tumor volume and tumor weight, post-mortem. Further, surgical wounding increased metastasis to the lungs, as detected by IVIS imaging, in vivo and ex vivo (week 5). As expected then, wounded mice displayed decreased apoptosis and increased proliferation in both the primary tumor and in the lungs. Flow cytometry revealed that primary tumors from wounded mice exhibited increased tumor associated macrophages and specifically M2-like macrophages, which are important in promoting tumor development, maintenance, and metastasis. Immunofluorescence staining and gene expression data further confirms an increase in macrophages in both the primary tumor and the lungs of wounded mice. Our data suggests that surgical wounding accelerates tumor progression and lung metastasis in a mouse model of TNBC, which is likely mediated, at least in part by an increase in macrophages., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

miRNA155 (miR155) has emerged as an important regulator of breast cancer (BrCa) development. Studies have consistently noted an increase in miR155 levels in serum and/or tissues in patients with BrCa. However, what is less clear is whether this increase in miR155 is a reflection of oncogenic or tumor suppressive properties. To study the effects of miR155 in a transgenic model of BrCA, we developed an MMTV-PyMT mouse deficient in miR155 (miR155 -/- PyMT). miR155 -/- mice ( n = 11) exhibited reduced tumor number and volume palpations at ∼14-18 wk of age compared with miR155 sufficient littermates ( n = 12). At 19 wk, mammary glands were excised from tumors for RT-PCR, and tumors were counted, measured, and weighed. miR155 -/- PyMT mice exhibited reduced tumor volume, number, and weight, which was confirmed by histopathological analysis. There was an increase in apoptosis with miR155 deficiency and a decrease in proliferation. As expected, miR155 deficiency resulted in upregulated gene expression of suppressor of cytokine signaling 1 (Socs1)-its direct target. There was a reduction in gene expression of macrophage markers (CD68, Adgre1, Itgax, Mrc1) with miR-155 -/- and this was confirmed with immunofluorescence staining for F4/80. miR155 -/- increased expression of M1 macrophage marker Nos2 and reduced expression of M2 macrophage markers IL-10, IL-4, Arg1, and MMP9. Overall, miR155 deficiency reduced BrCA and improved the tumor microenvironment through the reduction of genes associated with protumorigenic processes. However, given the inconsistencies in the literature, additional studies are needed before any attempts are made to harness miR155 as a potential oncogenic or tumor suppressive miRNA. NEW & NOTEWORTHY To examine the effects of miR155 in a transgenic model of breast cancer, we developed an MMTV-PyMT mouse-deficient in miR155. We demonstrate that global loss of miR155 resulted in blunted tumor growth through modulating the tumor microenvironment. Specifically, miR155-deficient mice had smaller and less invasive tumors, an increase in apoptosis and a decrease in proliferation, a reduction in tumor-associated macrophages, and the expression of genes associated with protumoral processes.

Mild traumatic brain injury (mTBI) is a common and unmet clinical issue, with limited treatments available to improve recovery. The cerebrovascular system is vital to provide oxygen and nutrition to the brain, and a growing body of research indicates that cerebrovascular injury contributes to mTBI symptomatology. Vascular endothelial growth factor-A (VEGF-A) is a potent promoter of angiogenesis and an important modulator of vascular health. While indirect evidence suggests that increased bioavailability of VEGF-A may be beneficial after mTBI, the direct therapeutic effects of VEGF-A in this context remains unknown. This study therefore aimed to determine whether intracerebroventricular administration of recombinant VEGF-A could improve recovery from mTBI in a rat model. Male and female Sprague-Dawley rats were assigned to four groups: sham + vehicle (VEH), sham + VEGF-A, mTBI + VEH, mTBI + VEGF-A. The mTBI was induced using the lateral impact model, and treatment began at the time of the injury and continued until the end of the study. Rats underwent behavioral testing between days 1 and 10 post-injury, and were euthanized on day 11 for post-mortem analysis. In males, the mTBI + VEGF-A group had significantly worse cognitive recovery in the water maze than all other groups. In females, the VEGF treatment worsened cognitive performance in the water maze regardless of mTBI or sham injury. Analysis of hippocampal tissue found that these cognitive deficits occurred in the presence of gene expression changes related to neuroinflammation and hypoxia in both male and female rats. These findings indicate that the VEGF-A treatment paradigm tested in this study failed to improve mTBI outcomes in either male or female rats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Baker, Wilson, Brady, Mychasiuk, Yamakawa, Vo, Wilson, McDonald and Shultz.)

Introduction: The Australian National COVID-19 Clinical Evidence Taskforce was established in March 2020 to maintain up-to-date recommendations for the treatment of people with coronavirus disease 2019 (COVID-19). The original guideline (April 2020) has been continuously updated and expanded from nine to 176 recommendations, facilitated by the rapid identification, appraisal, and analysis of clinical trial findings and subsequent review by expert panels., Main Recommendations: In this article, we describe the recommendations for treating non-pregnant adults with COVID-19, as current on 1 August 2022 (version 61.0). The Taskforce has made specific recommendations for adults with severe/critical or mild disease, including definitions of disease severity, recommendations for therapy, COVID-19 prophylaxis, respiratory support, and supportive care., Changes in Management as a Result of the Guideline: The Taskforce currently recommends eight drug treatments for people with COVID-19 who do not require supplemental oxygen (inhaled corticosteroids, casirivimab/imdevimab, molnupiravir, nirmatrelvir/ritonavir, regdanvimab, remdesivir, sotrovimab, tixagevimab/cilgavimab) and six for those who require supplemental oxygen (systemic corticosteroids, remdesivir, tocilizumab, sarilumab, baricitinib, casirivimab/imdevimab). Based on evidence of their achieving no or only limited benefit, ten drug treatments or treatment combinations are not recommended; an additional 42 drug treatments should only be used in the context of randomised trials. Additional recommendations include support for the use of continuous positive airway pressure, prone positioning, and endotracheal intubation in patients whose condition is deteriorating, and prophylactic anticoagulation for preventing venous thromboembolism. The latest updates and full recommendations are available at www.covid19evidence.net.au., (© 2022 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

5-Fluorouracil (5FU) remains a first-line chemotherapeutic for several cancers despite its established adverse side effects. Reduced blood counts with cytotoxic chemotherapies not only expose patients to infection and fatigue, but can disrupt tissue repair and remodeling, leading to lasting functional deficits. We sought to characterize the impact of 5FU-induced leukopenia on skeletal muscle in the context of remodeling. First, C57BL/6 mice were subjected to multiple dosing cycles of 5FU and skeletal muscle immune cells were assessed. Second, mice given 1 cycle of 5FU were subjected to 1.2% BaCl 2 intramuscularly to induce muscle damage. One cycle of 5FU induced significant body weight loss, but only three dosing cycles of 5FU induced skeletal muscle mass loss. One cycle of 5FU reduced skeletal muscle CD45 + immune cells with a particular loss of infiltrating CD11b + Ly6c Hi monocytes. Although CD45 + cells returned following three cycles, CD11b + CD68 + macrophages were reduced with three cycles and remained suppressed at 1 mo following 5FU administration. One cycle of 5FU blocked the increase in CD45 + immune cells 4 days following BaCl 2 ; however, there was a dramatic increase in CD11b + Ly6g + neutrophils and a loss of CD11b + Ly6c Hi monocytes in damaged muscle with 5FU compared with PBS. These perturbations resulted in increased collagen production 14 and 28 days following BaCl 2 and a reduction in centralized nuclei and myofibrillar cross-sectional area compared with PBS. Together, these results demonstrate that cytotoxic 5FU impairs muscle damage repair and remodeling concomitant with a loss of immune cells that persists beyond the cessation of treatment. NEW & NOTEWORTHY We examined the common chemotherapeutic 5-fluorouracil's (5FU) impact on skeletal muscle immune cells and skeletal muscle repair. 5FU monotherapy decreased body weight and muscle mass, and perturbed skeletal muscle immune cells. In addition, 5FU decreased skeletal muscle immune cells and impaired infiltration following damage contributing to disrupted muscle repair. Our results demonstrate 5FU's impact on skeletal muscle and provide a potential explanation for why some patients may be unable to properly repair damaged tissue.

Competing Interests: TJO declares investigator-initiated research payments and consultancy fees paid to his institution from Eisai, UCB, Supernus, Biogen, ES Therapeutics, Epidarex, LivaNova, and Kinoxis Therapeutics; and payments to his institution for participation on an advisory board from ES Therapeutics and Kinoxis Therapeutics. SRS and SJM declare no competing interests.

Purpose of Review: Mucositis of the gastrointestinal tract is a debilitating side effect of chemotherapy that negatively influences treatment tolerance and patient life quality. This review will evaluate the recent literature on nonpharmacological strategies that have the potential to improve chemotherapy-induced mucositis (CIM)., Recent Findings: Alternatives to pharmacological approaches have shown great promise in preventing CIM. Natural products, including curcumin, ginseng, quercetin, and patchouli all show potential in mitigating CIM. In addition, dietary patterns, such as the elemental diet, high fiber diet, and diets high in amino acids have documented benefits in preventing CIM. Perhaps the greatest advancement coming to this arena in recent years is in the field of probiotics. Indeed, research on single species as well as probiotic mixtures show potential in reducing CIM insofar as probiotics are now being suggested for treatment of CIM by governing bodies. Although behavioral interventions including psychological interventions and exercise interventions have shown promise in reducing cancer therapy-related side effects, more work in this domain is warranted and particularly in the context of CIM., Summary: Alternatives to pharmacological approaches show great potential for use in prevention and treatment of CIM and should be further developed for use in the clinic., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Clinical decisions related to sports-related concussion (SRC) are challenging, because of the heterogenous nature of SRC symptoms coupled with the current reliance on subjective self-reported symptom measures. Sensitive and objective methods that can diagnose SRC and determine recovery would aid clinical management, and there is evidence that SRC induces changes in circulating protein biomarkers, indicative of neuroaxonal injury. However, potential blood biomarkers related to other pathobiological responses linked to SRC are still poorly understood. Therefore, here we analyzed blood samples from concussed (male = 30; female = 9) and non-concussed (male = 74; female = 27) amateur Australian rules football players collected during the pre-season (i.e., baseline), and at 2, 6, and 13 days post-SRC to determine time-dependent changes in serum levels of biomarkers related to glial (i.e., brain lipid-binding protein [BLBP]; phosphoprotein enriched in astrocytes 15) and cerebrovascular injury (i.e., von Willebrand factor, claudin-5), inflammation (i.e., fibrinogen, high mobility group box protein 1), and oxidative stress (i.e., 4-hydroxynoneal). In females, BLBP levels were significantly decreased at 2 days post-SRC compared with their pre-season baseline; however, area under the receiver operating characteristic curve (AUROC) analysis found that BLBP was unable to distinguish between SRC and controls. In males, AUROC analysis revealed a statistically significant change at 2 days post-SRC in the serum levels of 4-hydroxynoneal, however the associated AUROC value (0.6373) indicated little clinical utility for this biomarker in distinguishing SRC from controls. There were no other statistically significant findings. These results indicate that the serum biomarkers tested in this study hold little clinical value in the management of SRC at 2, 6, and 13 days post-injury.

Background: The obstetric triage decision aid (OTDA) consists of 10 common pregnancy complaints with key signs and symptoms generating a triage score based on targeted questioning responses. It was developed to provide a standardised approach for obstetric triage conducted by midwives and emergency nurses as neither professional group are expert in the triage of pregnant and postpartum women., Aim: To evaluate implementation of the OTDA into an emergency department (ED) and maternity assessment unit (MAU)., Methods: The OTDA was introduced to the ED and MAU of a hospital in Australia. A range of implementation strategies were utilised and assessed by pre and post staff survey, and a three-month post-audit of unscheduled maternity presentations. The primary outcome was adoption rate of the OTDA. Secondary outcomes were staff confidence and waiting times. Analyses were undertaken using SPSS (v24). Paired analysis was conducted on staff surveys., Results: There were a total of 2829 unscheduled presentations: ED (n=708) and MAU (n=2121), 88.1% were triaged using the OTDA, used more in the MAU than the ED (93.2% vs 72.7%; p<.001). In the MAU, women seen within 15min of arrival improved significantly from 42.0% to 78.0%. There was improvement in the self-rated confidence (p=.002) and competence (p=.004) by nurses and midwives to conduct obstetric triage., Conclusion: The introduction of the OTDA required different approaches to change practice. There were improvements in staff self-rated confidence and competence, a reduction in clinical risk associated with under-triage in the ED and improved prioritisation of care in the MAU., (Copyright © 2021 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.)

Jockeys work in high-risk environments that rely heavily on attention- and decision-making to perform well and safely. Workplace stress literature has often overlooked the impact of stress on cognition, and designs that include physiological measures are rare. This study assessed the prospective concurrent relationships between workplace stress, depression symptoms and low-grade inflammation with cognitive performance among professional jockeys. Professional jockeys ( N  = 35, M age  = 32.29) provided information on workplace stress and depression symptoms, with serum levels of inflammatory cytokines (IL-6, IL-10, TNFα) and cytokine balance (IL-6: IL-10, TNFα: IL-10) quantified with SIMOA, and cognitive performance with CogSport computer-based testing battery. These measures were repeated after a twelve-month interval. Increased workplace stress between testing intervals was associated to an increased cytokine imbalance (β = 0.447, p = .015) after controlling for age and gender. Increases in cytokine imbalance occurred in unison with decreases in attention (β = 0.516, p = .002), decision-making (β = 0.452, p = .009) and working memory (β = 0.492, p = .004). These preliminary findings suggest the underlying mechanisms linking workplace stress and reduced cognitive performance may be influenced by measures of low-grade inflammation and specifically a cytokine imbalance. Our findings suggest a measure of cytokine balance may explain the heterogenous findings in previous studies that have focussed solely on the association of workplace stress with pro-inflammatory cytokines. Future work is needed however, to provide a broader evidence-base for our claims to better inform designs to intervene in the higher workplace stress-poorer cognition relationship., Competing Interests: The authors declare that they have no conflict of interest. This work was supported by 10.13039/501100009207AgriFutures Australia (formerly 10.13039/501100000982RIRDC), Racing Victoria Pty. Ltd, and a La Trobe University Postgraduate Research Scholarship., (© 2022 The Authors.)

Introduction: Sports-related concussion (SRC) is a common form of brain injury that lacks reliable methods to guide clinical decisions. MicroRNAs (miRNAs) can influence biological processes involved in SRC, and measurement of miRNAs in biological fluids may provide objective diagnostic and return to play/recovery biomarkers. Therefore, this prospective study investigated the temporal profile of circulating miRNA levels in concussed male and female athletes., Methods: Pre-season baseline blood samples were collected from amateur Australian rules football players (82 males, 45 females). Of these, 20 males and 8 females sustained an SRC during the subsequent season and underwent blood sampling at 2-, 6- and 13-days post-injury. A miRNA discovery Open Array was conducted on plasma to assess the expression of 754 known/validated miRNAs. miRNA target identified were further investigated with quantitative real-time PCR (qRT-PCR) in a validation study. Data pertaining to SRC symptoms, demographics, sporting history, education history and concussion history were also collected., Results: Discovery analysis identified 18 candidate miRNA. The consequent validation study found that plasma miR-221-3p levels were decreased at 6d and 13d, and that miR-27a-3p levels were decreased at 6d, when compared to baseline. Moreover, miR-27a and miR-221-3p levels were inversely correlated with SRC symptom severity., Conclusion: Circulating levels of miR-27a-3p and miR-221-3p were decreased in the sub-acute stages after SRC, and were inversely correlated with SRC symptom severity. Although further studies are required, these analyses have identified miRNA biomarker candidates of SRC severity and recovery that may one day assist in its clinical management., Competing Interests: Declaration Of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Micro riboneucleic acids (miRNAs) may be transcribed after brain injury and be detectable in plasma. This study aimed to assess the discriminative ability of seven miRNAs in plasma to differentiate between patients with mild traumatic brain injury (mTBI) and healthy controls. Changes in miRNA levels over 28 days were compared to changes in self-reported symptom profile. This was a prospective cohort study with longitudinal measurements of miRNA levels and symptom self-report. The Rivermead Post-Concussion Symptom Questionnaire (RPQ) was used to determine symptom severity. Mean normalised expression ratios (NER) of miRNAs at day 0 between mTBI and healthy controls were compared. An analysis of response profiles compared the response over time of miRNA species with RPQ symptom severity. miRNA levels of subjects who were defined to have "recovered" on Day 7 and 28 were compared to "non-recovered" subjects. There were 28 mTBI patients and 30 healthy controls included for analysis. Symptom severity was significantly higher on the day of injury among mTBI subjects (p < 0.001), and miRNA 32-5p levels were also higher (p = 0.009). Change of miRNA levels were similar to RPQ change at Day 7, but significantly different at Day 28. Differences were observed among miRNA levels of recovered subjects. This study demonstrated differences in miRNA levels among mTBI subjects compared to healthy controls and different miRNA levels among those who had recovered compared to those reporting symptoms. The change in profiles of miRNAs was different to symptom severity, suggesting that the two measures reflect different aspects of brain injury and recovery., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mr. Edmond Sorich is the director of Glia Diagnostics. Glia Diagnostics holds an exclusive IP licence agreement associated with miRNA listed in this manuscript. It did not contribute to any funding related to the study., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Gastrointestinal (GI) cancers cause one-third of all cancer-related deaths worldwide. Natural compounds are emerging as alternative or adjuvant cancer therapies given their distinct advantage of manipulating multiple pathways to both suppress tumor growth and alleviate cancer comorbidities; however, concerns regarding efficacy, bioavailability, and safety are barriers to their development for clinical use. Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a Chinese herb-derived anthraquinone, has been shown to exert anti-tumor effects in colon, liver, and pancreatic cancers. While the mechanisms underlying emodin's tumoricidal effects continue to be unearthed, recent evidence highlights a role for mitochondrial mediated apoptosis, modulated stress and inflammatory signaling pathways, and blunted angiogenesis. The goals of this review are to (1) highlight emodin's anti-cancer properties within GI cancers, (2) discuss the known anti-cancer mechanisms of action of emodin, (3) address emodin's potential as a treatment complementary to standard chemotherapeutics, (4) assess the efficacy and bioavailability of emodin derivatives as they relate to cancer, and (5) evaluate the safety of emodin.

Objective: Stress, inflammation, and depression are associated to coronary heart disease (CHD). However, how these constructs collectively contribute to CHD incidence is not well understood. For the first time, this study explored the concurrent relationship between workplace stress, depression symptomology and levels of low-grade inflammation with future CHD incidence., Methods: Data from the 5-year intervals at phase 5, 7, and 9 of the Whitehall II study (N = 8348, M age  = 56) provided measures of workplace stress, depression symptomology, inflammation (interleukin-6, C-reactive protein, fibrinogen), and CHD incidence. The proposed stress-inflammation-depression-CHD pathway was assessed with a longitudinal design incorporating a structural equation model (SEM) that measured if changes in stress, depression, and inflammation between phase 5 to phase 7 predicted first-time CHD events between phases 7 and 9., Results: The SEM empirically supported this proposed pathway and demonstrated excellent model fit, χ (72) = 3582.959, p < .001, CFI = 0.896, RMSEA = 0.076 (CI 90  = 0.074, 0.079), while depression symptoms mediated the association between workplace stress and CHD incidence, B = 0.003 (CI 90  = 0.001, 0.004). Further, survival analysis indicated that individuals with higher mean scores (across phases) of depression symptoms or fibrinogen levels were more likely to experience a first time CHD event., Conclusions: Increases in depression symptoms and fibrinogen levels may be good indicators of future CHD morbidity among older employees. Future research is encouraged to monitor negative affective states and the potential use of biobehavioural options to reduce depression and inflammation that may mitigate CHD risk., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Serum neurofilament light (NfL) is an emerging biomarker of traumatic brain injury (TBI). However, the effect of peripheral injuries such as long bone fracture and skeletal muscle injury on serum NfL levels is unknown. Therefore, the aim of this study was to determine whether serum NfL levels can be used as a biomarker of TBI in the presence of concomitant peripheral injuries., Methods: Rats were randomly assigned to one of four injury groups: polytrauma (muscle crush + fracture + TBI; n = 11); peripheral injuries (muscle crush + fracture + sham-TBI; n = 12); TBI-only (sham-muscle crush + sham-fracture + TBI; n = 13); and triple-sham (n = 7). At 2-days post-injury, serum levels of NfL were quantified using a Simoa HD-X Analyzer., Results: Compared to triple-sham rats, serum NfL concentrations were higher in rats with peripheral injuries-only, TBI-only, and polytrauma. When compared to peripheral injury-only rats, serum NfL levels were higher in TBI-only and polytrauma rats. No differences were found between TBI-only and polytrauma rats., Conclusion: Serum NfL levels did not differ between TBI-only and polytrauma rats, indicating that significant peripheral injuries did not affect the sensitivity and specificity of serum NfL as a biomarker of moderate TBI. However, the finding of elevated serum NfL levels in rats with peripheral injuries in the absence of a TBI suggests that the presence of such injuries may limit the utility of NfL as a biomarker of less severe TBI (eg, concussion)., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)