Proteomic Analysis of Spatial Heterogeneity Identifies HMGB2 as Putative Biomarker of Tumor Progression in Adult-Type Diffuse Astrocytomas.

Although grading is defined by the highest histological grade observed in a glioma, most high-grade gliomas retain areas with histology reminiscent of their low-grade counterparts. We sought to achieve the following: (i) identify proteins and molecular pathways involved in glioma evolution; and (ii) validate the high mobility group protein B2 (HMGB2) as a key player in tumor progression and as a prognostic/predictive biomarker for diffuse astrocytomas. We performed liquid chromatography tandem mass spectrometry (LC-MS/MS) in multiple areas of adult-type astrocytomas and validated our finding in multiplatform-omics studies and high-throughput IHC analysis. LC-MS/MSdetected proteomic signatures characterizing glioma evolution towards higher grades associated with, but not completely dependent, on IDH status. Spatial heterogeneity of diffuse astrocytomas was associated with dysregulation of specific molecular pathways, and HMGB2 was identified as a putative driver of tumor progression, and an early marker of worse overall survival in grades 2 and 3 diffuse gliomas, at least in part regulated by DNA methylation. In grade 4 astrocytomas, HMGB2 expression was strongly associated with proliferative activity and microvascular proliferation. Grounded in proteomic findings, our results showed that HMGB2 expression assessed by IHC detected early signs of tumor progression in grades 2 and 3 astrocytomas, as well as identified GBMs that had a better response to the standard chemoradiation with temozolomide.

Countering the declining use of lithium therapy: a call to arms.

For over half a century, it has been widely known that lithium is the most efficacious treatment for bipolar disorder. Yet, despite this, its prescription has consistently declined over this same period of time. A number of reasons for this apparent disparity between evidence and clinical practice have been proposed, including a lack of confidence amongst clinicians possibly because of an absence of training and lack of familiarity with the molecule. Simultaneously, competition has grown within the pharmacological armamentarium for bipolar disorder with newer treatments promoting an image of being safer and easier to prescribe primarily because of not necessitating plasma monitoring, which understandably is appealing to patients who then exercise their preferences accordingly. However, these somewhat incipient agents are yet to reach the standard lithium has attained in terms of its efficacy in providing prophylaxis against the seemingly inevitable recrudescence of acute episodes that punctuates the course of bipolar disorder. In addition, none of these mimics have the additional benefits of preventing suicide and perhaps providing neuroprotection. Thus, a change in strategy is urgently required, wherein myths regarding the supposed difficulties in prescribing lithium and the gravity of its side-effects are resolutely dispelled. It is this cause to which we have pledged our allegiance and it is to this end that we have penned this article.

TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways.

GBM (Glioblastoma) is the most lethal CNS (Central nervous system) tumor in adults, which inevitably develops resistance to standard treatments leading to recurrence and mortality. TRIB1 is a serine/threonine pseudokinase which functions as a scaffold platform that initiates degradation of its substrates like C/EBPα through the ubiquitin proteasome system and also activates MEK and Akt signaling. We found that increased TRIB1 gene expression associated with worse overall survival of GBM patients across multiple cohorts. Importantly, overexpression of TRIB1 decreased RT/TMZ (radiation therapy/temozolomide)-induced apoptosis in patient derived GBM cell lines in vitro. TRIB1 directly bound to MEK and Akt and increased ERK and Akt phosphorylation/activation. We also found that TRIB1 protein expression was maximal during G2/M transition of cell cycle in GBM cells. Furthermore, TRIB1 bound directly to HDAC1 and p53. Importantly, mice bearing TRIB1 overexpressing tumors had worse overall survival. Collectively, these data suggest that TRIB1 induces resistance of GBM cells to RT/TMZ treatments by activating the cell proliferation and survival pathways thus providing an opportunity for developing new targeted therapeutics.

ICD-11 and bipolar II disorder: so much ado and yet nothing new.

The long-awaited 11th revision of the International Classification of Diseases (ICD-11) makes important advances but simultaneously compromises on some aspects, which may have a negative impact on clinical practice. This editorial illustrates the double-edged nature of some of the changes in ICD-11, focusing on mood disorders and specifically the subtyping of bipolar disorder.

The diagnosis of bipolar disorder in children and adolescents: Past, present and future.

AIMS: This article examines the ongoing debate concerning the diagnosis of bipolar disorder in children and adolescents. This contentious issue has generated robust discussion over the past two decades without consensus, and as such the true prevalence of so-called paediatric bipolar disorder (PBD) remains unknown. In this article we offer a solution to break this deadlock. METHODS: Recent meta-analyses and additional literature concerning the definition and prevalence of PBD was critically reviewed with a view to understanding the perspectives of those developing the taxonomy of PBD, and those engaged in research and clinical practice. RESULTS: A key finding is the lack of iteration and meaningful communication between the various groups interested in PBD that stems from deep-seated problems within our classificatory systems. This undermines our research efforts and complicates clinical practice. These problems make the already difficult diagnosis of bipolar disorder in adults even more challenging to transpose to younger populations, and additional complexities arise when parsing clinical phenomenology from normative developmental changes in youth. Therefore, in those manifesting bipolar symptoms post-puberty, we argue for the use of adolescent bipolar disorder to describe bipolar symptoms whereas in pre-pubertal children, we propose a reconceptualisation that allows symptomatic treatment to be advanced whilst requiring critical review of these symptoms over time. CONCLUSION: Significant changes in our current taxonomy are necessary and to be clinically meaningful, these revisions to our diagnoses need to be developmentally-informed.

Difficult decision-making in major depressive disorder: Practical guidance based on clinical research and experience.

OBJECTIVES: To extend current published guidance regarding the management of major depression in clinical practice, by examining complex cases that reflect real-world patients, and to integrate evidence and experience into recommendations. METHODS: The authors who contributed to recently published clinical practice guidelines were invited to identify important gaps in extant guidance. Drawing on clinical experience and shared knowledge, they then generated four fictional case studies to illustrate the real-world complexities of managing mood disorders. The cases focussed specifically on issues that are not usually addressed in clinical practice guidelines. RESULTS: The four cases are discussed in detail and each case is summarised using a life chart and accompanying information. The four cases reflect important real-world challenges that clinicians face when managing mood disorders in day-to-day clinical practice. To partly standardise the presentation of each case and for ease of reference we provide a Time Line, History Box and Management Chart, along with a synopsis where relevant. Discussion and formulation of the cases illustrate how to manage the complexities of each case and provide one possible pathway to achieving functional recovery. CONCLUSION: These cases draw on the combined clinical experience of the authors and illustrate how to approach diagnostic decision-making when treating major depressive disorder and having to contend with complex presentations. The cases are designed to stimulate discussion and provide a real-world context for the formulation of mood disorders.

Increasing accessibility to biomechanics for Black students with early exposure through NBD.

From the perspective of a Black woman in the biomechanics field, it is my observation that many Black biomechanists are exposed to the field of biomechanics late into their academic careers. STEM (science, technology, and mathematics) is such a broad/encompassing field, yet students are only typically given a narrow introduction to biology and chemistry prior to college. These basic science courses are not enough to continue recruiting and building a pathway for future scientists to pursue STEM careers in the interdisciplinary field of biomechanics. Outreach programs, like National Biomechanics Day (NBD), can expose students to biomechanics earlier than the usual undergraduate exposure for those majoring in health/exercise science, kinesiology, or biomedical/mechanical engineering. NBD has increased accessibility to biomechanics, which has led to increases in diversity, equity, and inclusion in the biomechanics community, particularly for young Black students. Outreach programs like NBD are crucial to reaching, engaging, and recruiting future young Black biomechanists, and others from underrepresented communities, within the US and beyond.

Positioning of psychodynamic psychotherapy in the treatment of depression: A comparison of the RANZCP 2020 and NICE 2022 guidelines.

OBJECTIVE: To compare the 2022 NICE guidelines (NG222) and 2020 RANZCP clinical practice guidelines (MDcpg2020) recommendations for the treatment of depression using psychodynamic psychotherapy. CONCLUSIONS: Both guidelines recommend psychological interventions first-line. However, only short-term psychodynamic psychotherapy (STPP) is recommended, and in the NG222 it is ranked last for less severe depression and 7th for more severe depression. In contrast, cognitive behavioural therapy and behavioural activation are deemed the more clinically effective and cost-effective psychological therapies. And antidepressants play a significant role - largely in more severe depression.

Significant age by childhood trauma interactions on grey matter volumes: A whole brain VBM analysis.

BACKGROUND: Childhood trauma is deleterious to long term brain development. The changes are variable, and depend on gender, age and the nature of the trauma. In this exploratory analysis, we investigated the effects of exposure to emotional trauma on grey matter (GM) volumes in adolescent females. METHODS: We explored GM volumes in non-clinical females aged 12-17 years who had been exposed to either higher (HET; N = 75) or minimal (MET; N = 127) emotional trauma. High-resolution T1-weighted structural images were analysed with an optimised FSL-VBM protocol. The General Linear Model was run on HET versus MET with continuous age as an interaction. Mean GM volumes were extracted from significant corrected age interaction statistical maps and scrutinised with SPSS®. RESULTS: We observed greater HET*age than MET*age interactions (corrected p-value = 0.0002), in 4 separate bilateral cortical regions associated with mood disorders. Scrutiny of these regions showed significant GM volume enlargements in the early adolescent HET group (p = 0.017) and reductions in the late adolescent HET group (p < 0.0001). Notably, there were no differences in middle adolescence (p > 0.05). LIMITATIONS: Causality cannot be inferred from this cross-sectional study and the onset of trauma cannot be determined using retrospective measures. CONCLUSIONS: Whilst GM volumes diminish from early adolescence onwards, our results show that HET impacts this brain development, perhaps first via unstable adaptative mechanisms, followed by maladaptive processes in late adolescence. This suggests that compromises of emotional and cognitive self-regulation in mood disorders may underpin the structural abnormalities observed across multiple brain regions in these teenage girls.

Biomechanics in Africa: current state and potential for growth.

The potential of biomechanics for improving human health and performance is well established in many parts of the world. However, across most of Africa, biomechanics remains relatively underdeveloped. The discussion around biomechanics in the continent has increased in recent times and young African scientists are pursuing career opportunities in biomechanics-related fields within Africa and in other parts of the world. New institutions and programmes that focus on biomechanics teaching and research are also starting up around the continent. The advent of the National Biomechanics Day event, formation of the first formal biomechanics society in South Africa, along with many collaborations with relevant stakeholder organizations around the world underpin the expansion of biomechanics in Africa. This article aims to summarize the current state and describe aspirations for the future of biomechanics in Africa.

Improving Communication Between ICU Nurses and Anesthesia Providers Using a Standardized Handoff Protocol.

PURPOSE: This quality improvement (QI) project aimed to improve handoff communication between intensive care unit (ICU) nurses and anesthesia providers using a standardized preoperative handoff protocol for nonemergent and noncardiac procedures. DESIGN: A quality improvement project. METHODS: Following project approval, the project team provided staff education regarding a pre-populated handoff tool from the electronic medical record (EMR) adapted for perioperative use. In addition, the project team assessed the providers' perception and satisfaction with handoff communication before and after the intervention. FINDINGS: Of the 128 transfers, 76% completed the handoff tool during the 1-month implementation phase. CRNAs (n = 60), Registered Nurses (RNs; n = 88), and anesthesia residents (n = 30) completed the pre-and post-implementation surveys. Pre-implementation, 40% of providers were dissatisfied with communication, and only 14% reported dissatisfaction post-implementation. Also, 40% of providers believed this handoff protocol increased the amount of accurate information shared during reports without delaying the transition of care. CONCLUSIONS: The standardized handoff tool appears to improve information sharing during the transfer of care and improve provider satisfaction with the handoff process. Long term, it may reduce adverse patient events and improve outcomes. Use of a pre-populated handoff tool from the EMR provides a cost-effective solution to decrease erroneous reporting by removing human error associated with the recall.