Improving the strategy to identify historical military remains: a literature review and Y-STR meta-analysis.

The identification of historical military remains by Unrecovered War Casualties-Army (UWC-A) currently relies on Y-chromosome Short Tandem Repeat (Y-STR) testing when maternal relatives are not available, or when a mitochondrial DNA match does not provide sufficient certainty of identification. However, common Y-STR profiles (using Yfiler™) between sets of remains or families often prevent identification. To resolve these cases, an investigation of additional Y-DNA markers is needed for their potential inclusion into the DNA identification strategy. The number of genetic transmissions between missing soldiers and their living relatives needs to be considered to avoid false exclusions between paternal relatives. Analysis of 236 World War I/II (WWI/II) era pairs of relatives identified up to seven genetic transmissions between WWII soldiers and their living relatives, and nine for WWI. Previous Y-STR meta-analyses were published approximately 10 years ago when rapidly mutating markers were relatively new. This paper reports a contemporary literature review and meta-analysis of 35 studies (which includes 23 studies not previously used in meta-analysis) and 23 commonly used Y-STR's mutation rates to inform the inclusion of additional loci to UWC-A's DNA identification strategy. Meta-analysis found mutation data for a given Y-STR locus could be pooled between studies and that the mutation rates were significantly different between some loci (at P < 0.05). Based on this meta-analysis, we have identified two additional markers from PowerPlex® Y23 for potential inclusion in UWC-A's identification strategy. Further avenues for potential experimental exploration are discussed. Key points: From 236 UWC-A pairs of relatives, we observed up to nine genetic transmissions between WWI soldiers and their living relatives, and seven for WWII.MedCalc® software for meta-analysis utilizing the Freeman-Tukey transformation was run, which analysed 35 published studies and 23 commonly used loci. Previous Y-STR mutation rate meta-analyses are now 10 years old; this paper includes 23 studies that were not included in previous meta-analyses.Through meta-analysis, we identify two markers from PowerPlex® Y23 for potential inclusion in UWC-A's historical remains identification strategy (alongside Yfiler™). We discuss potential next steps for experimental exploration of additional Y-DNA markers.

DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies. We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC.

Dizziness Directly Influences Postconcussion Symptoms and Is Predictive of Poorer Mental Health in UK Military Personnel: A Retrospective Analysis.

OBJECTIVE: To investigate the contribution of dizziness to postconcussion symptoms, depression, and anxiety symptoms. SETTING: Mild traumatic brain injury (mTBI) service, Defence Medical Rehabilitation Centre, Stanford Hall. PARTICIPANTS: Two hundred eighty-three UK military personnel from the Royal Navy, Royal Airforce, Royal Marines, and British Army. DESIGN: A retrospective analysis of data from the Ministry of Defence medical records database. MAIN MEASURES: Sixteen-item Rivermead Post Concussion Symptoms Questionnaire, Generalized Anxiety Disorder 7-item scale, Patient Health Questionnaire-9, The Dizziness Handicap Inventory. RESULTS: Injuries from sports or falls were the most common mechanism of mTBI, accounting for 23%, respectively. Chi-square analysis indicated that individuals with dizziness and postconcussion symptoms (PCS) had greater severity of PCS, depression, and anxiety than those with PCS alone. Mediation analysis showed dizziness directly and independently influenced the severity of PCS, despite the indirect effects of mediating depression and anxiety symptoms. CONCLUSION: Comorbid dizziness and PCS were predictive of poorer mental health compared with PCS alone. In addition, dizziness directly influenced the severity of PCS irrespective of the indirect effects of mental health symptoms. These observations suggest that treating dizziness with vestibular rehabilitation may improve PCS and mental health.

Psychedelics as Novel Therapeutics in Alzheimer's Disease: Rationale and Potential Mechanisms.

Serotonin 2A receptor (5-HT2AR) agonist "classic psychedelics" are drawing increasing interest as potential mental health treatments. Recent work suggests psychedelics can exert persisting anxiolytic and antidepressant effects lasting up to several months after a single administration. Data indicate acute subjective drug effects as important psychological factors involved in observed therapeutic benefits. Additionally, animal models have shown an important role for 5-HT2AR agonists in modulating learning and memory function with relevance for Alzheimer's Disease (AD) and related dementias. A number of biological mechanisms of action are under investigation to elucidate 5-HT2AR agonists' therapeutic potential, including enhanced neuroplasticity, anti-inflammatory effects, and alterations in brain functional connectivity. These diverse lines of research are reviewed here along with a discussion of AD pathophysiology and neuropsychiatric symptoms to highlight classic psychedelics as potential novel pharmacotherapies for patients with AD. Human clinical research suggests a possible role for high-dose psychedelic administration in symptomatic treatment of depressed mood and anxiety in early-stage AD. Preclinical data indicate a potential for low- or high-dose psychedelic treatment regimens to slow or reverse brain atrophy, enhance cognitive function, and slow progression of AD. In conclusion, rationale and potential approaches for preliminary research with psychedelics in patients with AD are presented, and ramifications of this line of investigation for development of novel AD treatments are discussed.

"Lest we forget": An overview of Australia's response to the recovery and identification of unrecovered historic military remains.

The Australian Defence Force (ADF) is responsible for the recovery and identification of its historic casualties. With over 30,000 still unrecovered from past conflicts including World War One (WW1) and World War Two (WWII), the Australian Army and Royal Australian Air Force have teams that research, recover, identify and oversee the burial (or reburial) of the remains of soldiers and airmen who continue to be found each year. The Royal Australian Navy is also responsible for its unrecovered casualties. Collectively the priorities of the various services within the ADF are the respectful recovery and treatment of the dead, thorough forensic identification efforts, resolution for families and honouring the ADF's proud history of service and sacrifice. What is unique about the approach of the ADF is that the respective services retain responsibility for their historic losses, while a joint approach is taken on policies and in the utilisation of the pool of forensic specialists. Section One describes the process undertaken by the Australian Army in the recovery, identification and burial or repatriation of soldiers through its specialised unit Unrecovered War Casualties - Army (UWC-A). Section Two describes the role of the Royal Australian Air Force in the recovery of aircraft and service personnel through their specialised unit Historic Unrecovered War Casualties - Air Force (HUWC-AF). An overview of the operations of each service and case studies is presented for each section.

Navigating Institutional Challenges: Design to Enable Community Participation in Social Learning for Freshwater Planning.

Social learning is a process suited to developing understanding and concerted action to tackle complex resource dilemmas, such as freshwater management. Research has begun to recognise that in practice social learning encounters a variety of institutional challenges from the shared habits and routines of stakeholders (organised by rules, norms and strategies) that are embedded in organisational structures and norms of professional behaviour. These institutional habits and routines influence the degree of willingness to engage with stakeholders, and expectations of behaviours in social learning processes. Considering this, there has been a call to understand how institutions influence social learning and emergent outcomes. We addresses this by presenting a heuristic for implementing social learning cognisant of institutional context to answer three questions: (i) How institutional influences impact implementation of social learning design; (ii) how implementation of social learning design modifies institutions influencing social learning; and (iii) how these changes in design and institutions together shape social learning outcomes? To answer these questions a freshwater planning exercise was designed, implemented and evaluated as a social learning process with community groups in two New Zealand catchments. Incorporating participatory reflection enabled the project team to modify social learning design to manage institutional influences hindering progress toward outcomes. Findings emphasise that social learning is underpinned by participants' changing assumptions about what constitutes the institution of learning itself-from instruction to a dynamic, collective and emergent process. Reflecting on these assumptions also challenged participants' expectations about their own and others' behaviours and roles in freshwater planning.