Novel Insights into Changes in Gene Expression within the Hypothalamus in Two Asthma Mouse Models: A Transcriptomic Lung-Brain Axis Study.

Patients with asthma experience elevated rates of mental illness. However, the molecular links underlying such lung-brain crosstalk remain ambiguous. Hypothalamic dysfunction is observed in many psychiatric disorders, particularly those with an inflammatory component due to many hypothalamic regions being unprotected by the blood-brain barrier. To gain a better insight into such neuropsychiatric sequelae, this study investigated gene expression differences in the hypothalamus following lung inflammation (asthma) induction in mice, using RNA transcriptome profiling. BALB/c mice were challenged with either bacterial lipopolysaccharide (LPS, E. coli) or ovalbumin (OVA) allergens or saline control (n = 7 per group), and lung inflammation was confirmed via histological examination of postmortem lung tissue. The majority of the hypothalamus was micro-dissected, and total RNA was extracted for sequencing. Differential expression analysis identified 31 statistically significant single genes (false discovery rate FDR5%) altered in expression following LPS exposure compared to controls; however, none were significantly changed following OVA treatment, suggesting a milder hypothalamic response. When gene sets were examined, 48 were upregulated and 8 were downregulated in both asthma groups relative to controls. REACTOME enrichment analysis suggests these gene sets are involved in signal transduction metabolism, immune response and neuroplasticity. Interestingly, we identified five altered gene sets directly associated with neurotransmitter signaling. Intriguingly, many of these altered gene sets can influence mental health and or/neuroinflammation in humans. These findings help characterize the links between asthma-induced lung inflammation and the brain and may assist in identifying relevant pathways and therapeutic targets for future intervention.

Inhibition of neutrophil rolling and migration by caADAMTS13 in vitro and in mouse models of thrombosis and inflammation.

Recent investigation of a constitutively active ADAMTS13 variant (caADAMTS13) in murine models of acute ischaemic stroke (AIS) have revealed a potential anti-inflammatory mechanism of action contributing to its protective effect. However, it remains unclear whether these observations are a direct result of VWF proteolysis by caADAMTS13. We have implemented state of the art in vitro assays of neutrophil rolling and transmigration to quantify the impact of caADAMTS13 on these processes. Moreover, we have tested caADAMTS13 in two in vivo assays of neutrophil migration to confirm the impact of the treatment on the neutrophil response to sterile inflammation. Neutrophil rolling, over an interleukin-1ß stimulated hCMEC/D3 monolayer, is directly inhibited by caADAMTS13, reducing the proportion of neutrophils rolling to 9.5 ± 3.8 % compared to 18.0 ± 4.5 % in untreated controls. Similarly, neutrophil transmigration recorded in real-time, was significantly suppressed in the presence of caADAMTS13 which reduced the number of migration events to a level like that in unstimulated controls (18.0 ± 4.5 and 15.8 ± 7.5 cells/mm2/h, respectively). Brain tissue from mice undergoing experimental focal cerebral ischaemia has indicated the inhibition of this process by caADAMTS13. This is supported by caADAMTS13's ability to reduce neutrophil migration into the peritoneal cavity in an ischaemia-independent model of sterile inflammation, with the VWF-dependent mechanism by which this occurs being confirmed using a second experimental stroke model. These findings will be an important consideration in the further development of caADAMTS13 as a potential therapy for AIS and other thromboinflammatory pathologies, including cardiovascular disease.

The impact of libraries and informationists on patient and population care: a mixed-methods study.

Objective: While several studies have examined the effectiveness of librarian interactions with clinicians and impact of librarians on patient care, no studies have explored a library's effects on population care. The goal of this study was to investigate the library's impact on both patient and population care. Methods: Using a sequential exploratory mixed-methods design, we first interviewed a small set of clinicians and researchers active in patient and population care. Based on the themes that we discovered through coding the interviews, we created a survey that was sent to faculty in the health sciences and the health system. Results: We collected data from a representative sample of our population. We discovered that all respondents value the library and informationists, using our services most for teaching, publishing, presenting, and professional development. Conclusion: We now have data to support our value to our population and to show where we can do more work to improve the use of our services. Our study shows the value of doing a mixed-methods sequential exploration in which themes that are important to our user community were identified prior to launching a large-scale survey.

Physical activity and circulating inflammatory markers and cytokines during pregnancy: A population-based cohort study.

INTRODUCTION: Physical activity (PA) during pregnancy has numerous benefits, which may be mediated via effects on the immune system. However, supportive evidence is inconsistent and is mainly from studies in high-risk groups. We estimated the effect of PA during pregnancy on systemic inflammatory markers and cytokines in mothers recruited in the Barwon infant study. MATERIAL AND METHODS: The Barwon infant study is a prebirth cohort of 1064 mothers recruited in the Barwon Region of Victoria, Australia. Participants reported their previous week's PA at their 28-week antenatal appointment using the International PA Questionnaire. Women were grouped into low, moderate, and high PA categories based on daily duration and weekly frequency of walking, moderate- or vigorous-intensity PA. Women reporting moderate levels of PA, consistent with current recommendations, served as the comparison group. Markers of systemic inflammation, high-sensitivity C-reactive protein (hsCRP), glycoprotein acetyls (GlycA), and 17 cytokines were measured at 28 weeks gestation and log transformed as appropriate. Regression analyses adjusted for maternal smoking, gestational diabetes mellitus, prepregnancy BMI, and household size were performed. RESULTS: Compared to women in the moderate group (n = 371, 42%), women reporting low PA (n = 436, 50%) had 10.1% higher hsCRP (95% CI (3.7% to 16.6%), p < 0.01) while women in high PA (n = 76, 9%) had a 14% higher hsCRP (95% CI (3.1% to 24.8%), p = 0.01). Women in the high PA category had higher interleukin (IL)-4 (q = 0.03) and IL-9 (q = 0.03) levels compared to those in moderate category. Each vigorous MET minute/week was associated with lower GlycA (ß = -0.004, 95% CI (-0.044 to 0.035); p = 0.03). CONCLUSIONS: Low and high PA are each associated with higher hsCRP than moderate PA, suggesting that undertaking the recommended moderate PA during pregnancy decreases systemic inflammation. High PA affects T cell-associated cytokines during pregnancy. Evidence from our study suggests that PA can modulate the immune responses during pregnancy. Studies are now required to assess whether PA during pregnancy impacts maternal and infant clinical outcomes by modifying inflammatory responses.

Development and external validation of a head and neck cancer risk prediction model.

BACKGROUND: Head and neck cancer (HNC) incidence is on the rise, often diagnosed at late stage and associated with poor prognoses. Risk prediction tools have a potential role in prevention and early detection. METHODS: The IARC-ARCAGE European case-control study was used as the model development dataset. A clinical HNC risk prediction model using behavioral and demographic predictors was developed via multivariable logistic regression analyses. The model was then externally validated in the UK Biobank cohort. Model performance was tested using discrimination and calibration metrics. RESULTS: 1926 HNC cases and 2043 controls were used for the development of the model. The development dataset model including sociodemographic, smoking, and alcohol variables had moderate discrimination, with an area under curve (AUC) value of 0.75 (95% CI, 0.74-0.77); the calibration slope (0.75) and tests were suggestive of good calibration. 384 616 UK Biobank participants (with 1177 HNC cases) were available for external validation of the model. Upon external validation, the model had an AUC of 0.62 (95% CI, 0.61-0.64). CONCLUSION: We developed and externally validated a HNC risk prediction model using the ARCAGE and UK Biobank studies, respectively. This model had moderate performance in the development population and acceptable performance in the validation dataset. Demographics and risk behaviors are strong predictors of HNC, and this model may be a helpful tool in primary dental care settings to promote prevention and determine recall intervals for dental examination. Future addition of HPV serology or genetic factors could further enhance individual risk prediction.

The Effect of Palmitoylethanolamide (PEA) on Skeletal Muscle Hypertrophy, Strength, and Power in Response to Resistance Training in Healthy Active Adults: A Double-Blind Randomized Control Trial.

BACKGROUND: Palmitoylethanolamide (PEA) has analgesic/anti-inflammatory properties that may be a suitable alternative to over-the-counter (OTC) non-steroidal analgesics/anti-inflammatories. While OTC pain medications can impair strength training adaptations, the mechanism of action of PEA is distinct from these and it may not negatively affect skeletal muscle adaptations to strength training. METHODS: The primary aim of this study was to investigate the effects of daily PEA supplementation (350 mg Levagen + equivalent to 300 mg PEA) combined with 8-weeks of resistance training on lean body mass with secondary aims addressing strength, power, sleep, and wellbeing compared to placebo (PLA) in young, healthy, active adults. In a randomized, controlled, double-blinded trial, 52 untrained, recreationally active participants aged 18-35 y were allocated to either the PEA or PLA groups. Participants consumed either 2 × 175 mg Levagen + PEA or identically matched maltodextrin capsules during an 8-week period of whole-body resistance training. This trial assessed the pre- to post- changes in total and regional lean body mass, muscular strength (1-RM bench, isometric mid-thigh pull), muscular power [countermovement jump (CMJ), bench throw], pain associated with exercise training, sleep, and wellbeing compared with the PEA or PLA condition. RESULTS: 48 Participants were included in the final intention to treat (ITT) analysis and we also conducted per protocol (PP) analysis (n = 42). There were no significant between-group differences for total or regional lean muscle mass post-intervention. There was a significantly higher jump height (CMJ) at week 10 in the PEA group compared to the PLA (Adjusted mean difference [95% CI] p-value; ITT: - 2.94 cm [- 5.15, - 0.74] p = 0.010; PP: - 2.93 cm [- 5.31, - 0.55] p = 0.017). The PLA group had higher 1-RM bench press post-intervention compared with the PEA group (ITT: 2.24 kg [0.12, 4.37] p = 0.039; PP: 2.73 kg [0.40, 5.06] p = 0.023). No significant treatment effects were noted for any of the other outcomes. CONCLUSION: PEA supplementation, when combined with 8 weeks of strength training, did not impair lean mass gains and it resulted in significantly higher dynamic lower-body power when compared with the PLA condition. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR: ACTRN12621001726842p).

Adverse Technical Events During Aortic Root Replacement.

BACKGROUND: Although adverse technical events during aortic root replacement (ARR) are not uncommon and are extremely challenging, there is scant literature to help surgeons prepare for such situations. We describe our experience of outstanding technical events during ARR. METHODS: This is a retrospective study of 830 consecutive ARRs at a single center from 2012 to 2022. Technical events were defined as intraoperative events that led to an unplanned cardiac procedure, need for mechanical circulatory support, or additional aortic cross-clamping. Logistic regression identified factors associated with operative mortality and technical events. RESULTS: Technical events occurred in 90 patients (10.8%) and were attributed to bleeding (n = 26), nonischemic ventricular dysfunction (n = 23), residual valve disease (n = 20), myocardial ischemia (n = 19), and iatrogenic dissection (n = 2). Prior sternotomy (odds ratio [OR], 2.38; 95% CI, 1.36-4.19; P = .002) and complex aortic valve disease (OR, 3.09; 95% CI, 1.09-8.75; P = .03) were associated with technical events. Patients with technical events had higher rates of operative mortality (6.7% vs 2.3%, P = .03) and all major postoperative complications. Surgical indications of dissection (OR, 13.57; 95% CI, 4.95-37.23; P < .001) and complex aortic valve disease (OR, 14.09; 95% CI, 3.67-54.02; P < .001) but not adverse technical events (OR, 2.42; 95% CI, 0.81-7.26; P = .11) were associated with operative mortality. CONCLUSIONS: Adverse technical events occurred in 10.8% of ARRs and were associated with reoperative sternotomies. Technical events are associated with increased postoperative complications.

Bed rest impairs the vestibular control of balance.

Prolonged bed rest impairs standing balance but the underlying mechanisms are uncertain. Previous research suggests strength loss is not the cause, leaving impaired sensorimotor control as an alternative. Here we examine vestibular control of posture in 18 male volunteers before and after 60 days of bed rest. Stochastic vestibular stimulation (SVS) was used to evoke sway responses before, 1 and 6 days after bed rest under different head yaw orientations. The directional accuracy and precision of these responses were calculated from ground reaction force vectors. Bed rest caused up to 63% increases in spontaneous standing sway and 31% reductions in leg strength, changes which were uncorrelated. The increase in sway was exacerbated when the eyes were closed. Mean directions of SVS-evoked sway responses were unaffected, being directed towards the anodal ear and rotating in line with head orientation in the same way before and after bed rest. However, individual trial analysis revealed 25%-30% increases in directional variability, which were significantly correlated with the increase in spontaneous sway (r = 0.48-0.71; P ≤ 0.044) and were still elevated on day 6 post-bed rest. This reveals that individual sway responses may be inappropriately oriented, a finding masked by the averaging process. Our results confirm that impaired balance following prolonged bedrest is not related to loss of strength. Rather, they demonstrate that the sensorimotor transformation process which converts vestibular feedback into appropriately directed balance responses is impaired. KEY POINTS: Prolonged inactivity impairs balance but previous research suggests this is not caused by loss of strength. Here we investigated vestibular control of balance before and after 60 days of bed rest using electrical vestibular stimulation (EVS) to evoke sway responses. Spontaneous sway significantly increased and muscle strength reduced following bed rest, but, in keeping with previous research, these two effects were not correlated. While the overall accuracy of EVS-evoked sway responses was unaffected, their directional variability significantly increased following bed rest, and this was correlated with the increases in spontaneous sway. We have shown that the ability to transform head-centred vestibular feedback into an appropriately directed body sway response is negatively affected by prolonged inactivity; this may contribute to the impaired balance commonly observed following bed rest.

Neuroanatomical distribution of fluorophores within adult RXFP3 Cre-tdTomato/YFP mouse brain.

Relaxin-family peptide 3 receptor (RXFP3) is activated by relaxin-3 in the brain to influence arousal and related functions, such as feeding and stress responses. Two transgenic mouse lines have recently been developed that co-express different fluorophores within RXFP3-expressing neurons: either yellow fluorescent protein (YFP; RXFP3-Cre/YFP mice) or tdTomato (RXFP3-Cre/tdTomato mice). To date, the characteristics of neurons that express RXFP3-associated fluorophores in these mice have only been investigated in the bed nucleus of the stria terminalis and the hypothalamic arcuate nucleus. To better determine the utility of these fluorophore-expressing mice for further research, we characterised the neuroanatomical distribution of fluorophores throughout the brain of these mice and compared this to the published distribution of Rxfp3 mRNA (detected by in situ hybridisation) in wildtype mice. Coronal sections of RXFP3-Cre/YFP (n = 8) and RXFP3-Cre/tdTomato (n = 8) mouse brains were imaged, and the density of fluorophore-expressing cells within various brain regions/nuclei was qualitatively assessed. Comparisons with our previously reported RXFP3 mRNA distribution revealed that of 212 brain regions that contained either fluorophore or RXFP3 mRNA, approximately half recorded densities that were within two qualitative measurements of each other (on a 9-point scale), including hippocampal dentate gyrus and amygdala subregions. However, many brain areas with likely non-authentic, false-positive, or false-negative fluorophore expression were also detected, including the cerebellum. Therefore, this study provides a guide to which brain regions should be prioritized for future study of RXFP3 in these mice, to better understand the neuroanatomy and function of this intriguing, neuronal peptide receptor.

First Isolation of Japanese Encephalitis Virus Genotype IV from Mosquitoes in Australia.

Introduction: Widespread transmission of Japanese encephalitis virus (JEV) genotype four (GIV) occurred across mainland Australia in 2022. This resulted in forty-five human cases, including seven deaths, and the identification of JEV infection in over 80 commercial piggeries. Materials and Methods: We collected mosquitoes which were trapped using CO2-baited light traps deployed near piggeries reporting disease or in regions linked to human cases in the Wide Bay region in the state of Queensland. Mosquitoes from four traps yielded JEV RNA by real-time RT-PCR. Pools containing RNA positive mosquitoes were inoculated onto mosquito cell monolayers. Discussion: A single isolate of JEV was obtained from a pool of mixed mosquito species. Near whole genome sequencing and phylogenetic analysis of the JEV isolate demonstrated its high genomic relatedness with JEV GIV pig sequences sampled from Queensland and the state of New South Wales in 2022. Conclusion: We report the first isolation of JEV GIV from mosquitoes collected in Australia. With only a few JEV GIV isolates available globally, the isolate we report will be essential for future research of JEV host interactions, evolution and disease markers, and development of effective therapies, vaccines, diagnostic assays, and mosquito control strategies.

Addressing ethnic disparities in neurological research in the United Kingdom: An example from the prospective multicentre COVID-19 Clinical Neuroscience Study.

BACKGROUND: Minority ethnic groups have often been underrepresented in research, posing a problem in relation to external validity and extrapolation of findings. Here, we aimed to assess recruitment and retainment strategies in a large observational study assessing neurological complications following SARS-CoV-2 infection. METHODS: Participants were recruited following confirmed infection with SARS-CoV-2 and hospitalisation. Self-reported ethnicity was recorded alongside other demographic data to identify potential barriers to recruitment. RESULTS: 807 participants were recruited to COVID-CNS, and ethnicity data were available for 93.2%. We identified a proportionate representation of self-reported ethnicity categories, and distribution of broad ethnicity categories mirrored individual centres' catchment areas. White ethnicity within individual centres ranged between 44.5% and 89.1%, with highest percentage of participants with non-White ethnicity in London-based centres. Examples are provided how to reach potentially underrepresented minority ethnic groups. CONCLUSIONS: Recruitment barriers in relation to potentially underrepresented ethnic groups may be overcome with strategies identified here.

Setting the context for a complex dental intervention of role substitution in care homes: Initial process evaluation findings.

OBJECTIVES: SENIOR (uSing rolE-substitutioN In care homes to improve oRal health) is a randomised controlled trial designed to determine whether role substitution could improve oral health for this population. A parallel process evaluation was undertaken to understand context. This paper reports on the first phase of the process evaluation. BACKGROUND: The oral health and quality-of-life of older adults residing in care homes is poorer than those in the community. Oral health care provision is often unavailable and a concern and challenge for managers. The use of Dental Therapists and Dental Nurses rather than dentists could potentially meet these needs. MATERIALS AND METHODS: Semi-structured interviews were conducted with 21 key stakeholders who either worked or had experience of dependent care settings. Questions were theoretically informed by the: Promoting Action on Research Implementation in Health Services (PAHRIS) framework. The focus was on contextual factors that could influence adoption in practice and the pathway-to-impact. Interviews were fully transcribed and analysed thematically. RESULTS: Three themes (receptive context, culture, and leadership) and 11 codes were generated. Data show the complexity of the setting and contextual factors that may work as barriers and facilitators to intervention delivery. Managers are aware of the issues regarding oral health and seek to provide best care, but face many challenges including staff turnover, time pressures, competing needs, access to services, and financial constraints. Dental professionals recognise the need for improvement and view role substitution as a viable alternative to current practice. CONCLUSION: Although role substitution could potentially meet the needs of this population, an in-depth understanding of contextual factors appeared important in understanding intervention delivery and implementation.

Acetabular "Fleck" Sign: Outcomes of Surgical Repair.

BACKGROUND: Traumatic, posterior hip dislocations in the pediatric population are typically managed by closed reduction to achieve a concentric hip joint. The presence of an acetabular "fleck" sign, despite concentric reduction, has been shown to signify significant hip pathology. The purpose of this study was to evaluate the outcomes of open labral repair through a surgical hip dislocation (SHD) in a consecutive series of patients with an acetabular "fleck" sign associated with a traumatic hip dislocation/subluxation. METHODS: A retrospective review of patients between 2008 and 2022 who presented to a single, level 1 pediatric trauma center with a traumatic posterior hip dislocation/subluxation was performed. Patients were included if they had an acetabular "fleck" sign on advanced imaging and underwent open labral repair through SHD. Medical records were reviewed for sex, age, laterality, mechanism of injury (MOI), and associated orthopaedic injuries. The modified Harris hip score (mHHS) was utilized as the primary clinical outcomes measure. Patients were assessed for the presence of heterotopic ossification (HO) and complications, including implant issues, infection, avascular necrosis (AVN), and post-traumatic dysplasia. RESULTS: Twenty-nine patients (23 male, average age: 13.0±2.7 y; range: 5.2 to 17.3) were identified. Eighteen injuries were sports related, 9 caused by motor vehicle accidents, and 1 pedestrian struck. All patients were found to have an acetabular "fleck" sign on CT (26 patients) or MRI (5 patients). Associated injuries included: femoral head fracture (n=6), pelvic ring injury (n=3), ipsilateral femur fracture (n=2), and ipsilateral PCL avulsion (n=1). At the latest follow-up (2.2±1.4 y), all patients had returned to preinjury activity/sport. Three patients developed asymptomatic, grade 1 HO in the greater trochanter region. There was no incidence of AVN. One patient developed post-traumatic acetabular dysplasia due to early triradiate closure. mHHS scores showed excellent outcomes (n=21, 94.9±7.4, range: 81 to 100.1). CONCLUSIONS: The acetabular "fleck" sign indicates a consistent pattern of osteochondral avulsion of the posterior/superior labrum. Restoring native hip anatomy and stability is likely to improve outcomes. SHD with open labral repair in these patients produces excellent clinical outcomes, with no reported cases of AVN. LEVEL OF EVIDENCE: Level IV-therapeutic.

Mini review: Asymmetric Müllerian duct development in the chicken embryo.

Müllerian ducts are paired embryonic tubes that give rise to the female reproductive tract. In humans, the Müllerian ducts differentiate into the Fallopian tubes, uterus and upper portion of the vagina. In birds and reptiles, the Müllerian ducts develop into homologous structures, the oviducts. The genetic and hormonal regulation of duct development is a model for understanding sexual differentiation. In males, the ducts typically undergo regression during embryonic life, under the influence of testis-derived Anti-Müllerian Hormone, AMH. In females, a lack of AMH during embryogenesis allows the ducts to differentiate into the female reproductive tract. In the chicken embryo, a long-standing model for development and sexual differentiation, Müllerian duct development in females in asymmetric. Only the left duct forms an oviduct, coincident with ovary formation only on the left side of the body. The right duct, together with the right gonad, becomes vestigial. The mechanism of this avian asymmetry has never been fully resolved, but is thought to involve local interplay between AMH and sex steroid hormones. This mini-review re-visits the topic, highlighting questions in the field and proposing a testable model for asymmetric duct development. We argue that current molecular and imaging techniques will shed new light on this curious asymmetry. Information on asymmetric duct development in the chicken model will inform our understanding of sexual differentiation in vertebrates more broadly.

Mechanical Circulatory Support During Surgical Revascularization for Ischemic Cardiomyopathy.

BACKGROUND: This study aimed to describe the use of perioperative mechanical circulatory support (MCS) and its impact on outcomes in patients with ischemic cardiomyopathy who were undergoing surgical revascularization. METHODS: Patients with an ejection fraction <35% who underwent isolated coronary artery bypass grafting (CABG) from 2015 to 2021 were identified (N = 378). Patients were divided into no MCS, preoperative MCS, and postoperative MCS groups on the basis of timing of MCS initiation, which included intraaortic balloon pump, extracorporeal membrane oxygenation, or Impella device (Abiomed) use. The primary outcome of interest was operative mortality. RESULTS: The median Society of Thoracic Surgeons Predicted Risk of Mortality was 2.4%. Sixty-six percent (n = 246) of patients had a previous myocardial infarction, and 61.8% of these patients were within 21 days of CABG. Twenty-one patients (5.6%) presented in cardiogenic shock. The preoperative MCS cohort consisted of 31 patients (8.2%) who underwent CABG a median of 2 days after MCS initiation. Thirty (7.9%) patients required postoperative MCS. Independent risk factors for requiring postoperative MCS included the preoperative ejection fraction (odds ratio, 0.93; P = .01 and the presence of preoperative MCS (odds ratio, 3.06; P = .02). Overall, operative mortality was 3.4%, and 3-year survival was 87.0%. Operative mortality in patients who did and did not receive preoperative MCS was 7.7% and 2.9% (P = .12) with no difference in long-term survival (P = .80), whereas patients requiring postoperative MCS had significantly increased operative (16.7%) and late mortality (63%; P <.01). CONCLUSIONS: CABG can be performed safely in patients with ischemic cardiomyopathy with selective use of perioperative MCS. Despite advanced disease severity, patients requiring preoperative MCS demonstrate acceptable short- and long-term survival. Patients requiring postoperative MCS have increased postoperative morbidity and mortality.

Novel insights on genetics and epigenetics as clinical targets for paediatric astrocytoma.

Paediatric and adult astrocytomas are notably different, where clinical treatments used for adults are not as effective on children with the same form of cancer and these treatments lead to adverse long-term health concerns. Integrative omics-based studies have shown the pathology and fundamental molecular characteristics differ significantly and cannot be extrapolated from the more widely studied adult disease. Recent clinical advances in our understanding of paediatric astrocytomas, with the aid of next-generation sequencing and epigenome-wide profiling, have led to the identification of key canonical mutations that vary based on the tumour location and age of onset. These driver mutations, in particular the identification of the recurrent histone H3 mutations in high-grade tumours, have confirmed the important role epigenetic dysregulations play in cancer progression. This review summarises the current updates of the classification, epidemiology, pathogenesis and clinical management of paediatric astrocytoma based on their grades and the ongoing clinical trials. It also provides novel insights on genetic and epigenetic alterations as diagnostic biomarkers, highlighting the potential of targeting these pathways as therapeutics for this devastating childhood cancer.

Significance of isolated postoperative atrial fibrillation in thoracic aortic aneurysm repair.

OBJECTIVE: Although postoperative atrial fibrillation has been shown to be associated with worse survival after thoracic aortic surgery, its effect on outcomes independently from other postoperative complications is not well understood. METHODS: This is a single-center retrospective study of patients who underwent open thoracic aortic aneurysm repair between March 2005 and March 2021. Postoperative atrial fibrillation was defined as new-onset atrial fibrillation that developed during the index hospital stay. Patients with preoperative atrial fibrillation were excluded. Postoperative major complications included reoperation for bleeding, respiratory failure, acute renal failure, and stroke. Variables associated with postoperative atrial fibrillation were analyzed with multivariable regression. Survival of patients without major complications was compared between patients without atrial fibrillation and patients with postoperative atrial fibrillation after propensity score matching for baseline and intraoperative characteristics. RESULTS: Of 1454 patients, 520 (35.8%) were observed to have postoperative atrial fibrillation. Patients with postoperative atrial fibrillation had a higher rate of postoperative major complications than those without atrial fibrillation (20.2% vs 12.2%, P < .001). Ten-year survival was 82.0% in patients with postoperative atrial fibrillation and 87.0% in patients without atrial fibrillation (P = .008). In the cohort of patients without complications, 10-year survival was similar between patients with and without postoperative atrial fibrillation after propensity score matching (83.6% vs 83.8%, P = .75). CONCLUSIONS: Postoperative atrial fibrillation is common after open proximal thoracic aortic aneurysm repair. Although development of major postoperative complications is associated with postoperative atrial fibrillation and decreased long-term survival, isolated postoperative atrial fibrillation does not appear to influence long-term survival.

Resolving the mechanisms underlying epithelial-to-mesenchymal transition of the lateral plate mesoderm.

Formation of the vertebrate limb buds begins with a localized epithelial-to-mesenchymal transition (EMT) of the somatic lateral plate mesoderm (LPM). While the processes that drive proliferation and outgrowth of the limb mesenchyme are well established, the fundamental mechanisms that precede this process and initiate EMT are less understood. In this review, we outline putative drivers of EMT of the LPM, drawing from analyses across a range of vertebrates and developmental models. We detail the expression patterns of key EMT transcriptional regulators in the somatic LPM of the presumptive limb fields, and their potential role in producing a mesenchymal cell fate. These include a putative cooperative role between the EMT inducers PRRX1 and TWIST1, supported by evidence in zebrafish and chicken models but unconfirmed data from mice. As such, additional functional data are required to definitively determine the mechanisms that initiate and drive EMT of the somatic LPM, a critical transition preceding formation of the limb bud mesenchyme.