Sex chromosome-encoded protein homologs: current progress and open questions.

The complexity of biological sex differences is markedly evident in human physiology and pathology. Although many of these differences can be ascribed to the expression of sex hormones, another contributor to sex differences lies in the sex chromosomes beyond their role in sex determination. Although largely nonhomologous, the human sex chromosomes express seventeen pairs of homologous genes, referred to as the 'X-Y pairs.' The X chromosome-encoded homologs of these Y-encoded proteins are crucial players in several cellular processes, and their dysregulation frequently results in disease development. Many diseases related to these X-encoded homologs present with sex-biased incidence or severity. By contrast, comparatively little is known about the differential functions of the Y-linked homologs. Here, we summarize and discuss the current understanding of five of these X-Y paired proteins, with recent evidence of differential functions and of having a potential link to sex biases in disease, highlighting how amino acid-level sequence differences may differentiate their functions and contribute to sex biases in human disease.

Sex Difference in the Treatment of Dupuytren's Disease: A Systematic Review and Meta-Analysis of Clinical Trials.

Purpose: The aim of this study was to assess the sex differences in enrollment into clinical trials for Dupuytren's disease (DD), treatment efficacy, and complications. Methods: Three databases were searched; Ovid MEDLINE, Ovid EMBASE, and EBSCO CINAHL. Included studies were clinical trials on adult patients with DD. Exclusion criteria were non-English studies and other study designs. Two independent reviewers completed abstract screening, full-text review, and data extraction. The number and percentage of studies that reported ad hoc analyses for sex differences in treatment efficacy, tolerability, and complications were reported. A meta-analysis was performed on the proportion of female participants enrolled in clinical trials for DD. Results: A total of 3172 references were screened, and 59 studies were identified for full-text review. We identified 28 clinical trials for DD of which none reported secondary analyses for sex differences. Only 2 trials discussed sex differences in complications, and one trial reported sex differences in tolerability. The proportion of female participants in the meta-analysis was 19.5% [95% CI: 16.1-23.0%]. Conclusion: Sex differences in the clinical trials for DD are not widely considered in clinical trials despite their critical role. Males and females do not have equal representation in clinical trials for DD. Future studies should account for sex differences in the design and the analysis of clinical trials.

Objectif: La présente étude visait à évaluer les différences selon les sexes à l'égard de l'inscription à des études cliniques sur la maladie de Dupuytren (MD), l'efficacité du traitement et les complications. Méthodologie: Les chercheurs ont fouillé trois bases de données, soit Ovid MEDLINE, Ovid EMBASE et EBSCO CINAHL et ont retenu les études cliniques sur les patients adultes atteints de MD. Ils ont exclu les études qui n'étaient pas rédigées en anglais et qui reposaient sur d'autres méthodologies. Deux analystes indépendants ont examiné les résumés, analysé les textes intégraux et extrait les données. Ils ont rendu compte du nombre et du pourcentage d'études qui ont fait état d'analyses ponctuelles sur les différences selon les sexes à l'égard de l'efficacité du traitement, de la tolérabilité et des complications. Ils ont procédé à une méta-analyse sur la proportion de participantes inscrites aux études cliniques sur la MD. Résultats: Au total, les chercheurs ont examiné 3172 références et ont retenu 59 études en vue d'en évaluer le texte intégral. Ils ont répertorié 28 études cliniques sur la MD, et aucune ne contenait d'analyses secondaires sur les différences selon les sexes. Seulement deux études abordaient les différences selon les sexes pour ce qui est des complications, et une étude constatait des différences selon les sexes quant à la tolérabilité. Dans la méta-analyse, la proportion de participantes s'élevait à 19,5% [IC à 95% : 16,1% à 23,0%]. Conclusion: On ne tient pas tellement compte des différences selon les sexes dans les études cliniques sur la MD, malgré leur rôle capital. Les hommes et les femmes ne sont pas représentés équitablement dans les essais cliniques sur la MD. De prochaines études devraient tenir compte des différences selon les sexes au moment d'établir la méthodologie des études cliniques et de les analyser.

Time to surgical management of distal radius fractures: effects on health care utilization and functional outcomes.

BACKGROUND: Distal radius fractures are common injuries. Open reduction and internal fixation with volar locking plates is the most common approach for surgical fixation. This study investigated the association between time to surgery and health care utilization, income, and functional outcomes among patients undergoing open reduction and internal fixation for distal radius fracture. METHODS: We conducted a retrospective review of patients who underwent open reduction and internal fixation for isolated acute distal radius fracture between 2009 and 2019. Time to surgery was grouped as early (≤ 14 d) and delayed (> 14 d). We performed χ2 (or Fisher exact) and Wilcoxon rank sum (or Kruskal-Wallis) tests to provide statistical comparison of time to surgery by health care utilization and functional outcomes. Univariable and multivariable logistic regression analyses were performed to identify factors significantly associated with time to surgery. We included all significant univariables in the multivariable logistic regression model, which identified factors based on significant adjusted odds ratios (95% confidence intervals excluding the null) after we adjusted for confounding variables. RESULTS: We included 106 patients, with 36 (34.0%) in the group receiving early treatment and 70 (66.0%) in the group receiving delayed treatment. Patients in the delayed-treatment group attended significantly more clinic visits and postoperative hand therapy sessions. The group with delayed treatment demonstrated significantly lower degrees of wrist flexion at the first follow-up, but this difference did not persist. Patients with higher estimated income (> $39 405 per annum) had lower odds of delayed surgery than those with lower estimated income (≤ $39 405). CONCLUSION: Delayed time to surgery was associated with greater health care utilization and lower degrees of early wrist flexion. Access to care for lower-income patients warrants further evaluation.

Comparing the roles of sex chromosome-encoded protein homologs in gene regulation.

The X and Y chromosomes play important roles outside of human reproduction; namely, their potential contribution to human sex biases in physiology and disease. While sex biases are often thought to be an effect of hormones and environmental exposures, genes encoded on the sex chromosomes also play a role. Seventeen homologous gene pairs exist on the X and Y chromosomes whose proteins have critical functions in biology, from direct regulation of transcription and translation to intercellular signaling and formation of extracellular structures. In this review, we cover the current understanding of several of these sex chromosome-encoded protein homologs that are involved in transcription and chromatin regulation: SRY/SOX3, ZFX/ZFY, KDM5C/KDM5D, UTX/UTY, and TBL1X/TBL1Y. Their mechanisms of gene regulation are discussed, including any redundancies or divergent roles of the X- and Y-chromosome homologs. Additionally, we discuss associated diseases related to these proteins and any sex biases that exist therein in an effort to drive further research into how these pairs contribute to sexually dimorphic gene regulation in health and disease.

Biomarkers of neurodegeneration in schizophrenia: systematic review and meta-analysis.

QUESTION: Does neurodegenerative disease underlie the increased rate of dementia observed in older people with schizophrenia? Several studies have reported a higher prevalence of dementia in people with schizophrenia compared with the general population. This may reflect a higher risk of developing neurodegenerative diseases such as vascular dementia or Alzheimer's disease (AD). Alternatively, this may reflect non-pathological, age-related cognitive decline in a population with low cognitive reserve. STUDY SELECTION AND ANALYSIS: We reviewed papers that compared postmortem findings, hippocampal MRI volume or cerebrospinal fluid (CSF) markers of AD, between patients with schizophrenia with evidence of cognitive impairment (age ≥45 years) with controls. We subsequently performed a meta-analysis of postmortem studies that compared amyloid-ß plaques (APs) or neurofibrillary tangles (NFTs) in cognitively impaired patients with schizophrenia to normal controls or an AD group. FINDINGS: No studies found a significant increase of APs or NFTs in cognitively impaired patients with schizophrenia compared with controls. All postmortem studies that compared APs or NFTs in patients with schizophrenia to an AD group found significantly more APs or NFTs in AD. No studies found a significant differences in CSF total tau or phosphorylated tau between patients with schizophrenia and controls. The two studies which compared CSF Aß42 between patients with schizophrenia and controls found significantly decreased CSF Aß42 in schizophrenia compared with controls. Hippocampal volume findings were mixed. CONCLUSIONS: Studies have not found higher rates of AD-related pathology in cognitively impaired individuals with schizophrenia compared with controls. Higher rates of dementia identified in population studies may reflect a lack of specificity in clinical diagnostic tools used to diagnose dementia.

Transient, Image-Guided Gel-Dissection for Percutaneous Thermal Ablation.

Image-guided tumor ablative therapies are mainstay cancer treatment options but often require intra-procedural protective tissue displacement to reduce the risk of collateral damage to neighboring organs. Standard of care strategies, such as hydrodissection (fluidic injection), are limited by rapid diffusion of fluid and poor retention time, risking injury to adjacent organs, increasing cancer recurrence rates from incomplete tumor ablations, and limiting patient qualification. Herein, a "gel-dissection" technique is developed, leveraging injectable hydrogels for longer-lasting, shapeable, and transient tissue separation to empower clinicans with improved ablation operation windows and greater control. A rheological model is designed to understand and tune gel-dissection parameters. In swine models, gel-dissection achieves 24 times longer-lasting tissue separation dynamics compared to saline, with 40% less injected volume. Gel-dissection achieves anti-dependent dissection between free-floating organs in the peritoneal cavity and clinically significant thermal protection, with the potential to expand minimally invasive therapeutic techniques, especially across locoregional therapies including radiation, cryoablation, endoscopy, and surgery.

Acute pulmonary injury in hematology patients supported with pathogen-reduced and conventional platelet components.

ABSTRACT: Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen-reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of -1.5% (95% confidence interval [CI], -2.7 to -0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, -2.4%; 95% CI, -4.2 to -0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.

Emergency Medical Services Protocols for Assessment and Treatment of Patients with Ventricular Assist Devices.

BACKGROUND: Patients with ventricular assist devices (VADs) represent a growing population presenting to Emergency Medical Services (EMS), but little is known about their prehospital care. This study aimed to characterize current EMS protocols in the United States for patients with VADs. METHODS: States with state-wide EMS protocols were included. Protocols were obtained from the state EMS website. If not available, the office of the state medical director was contacted. For each state, protocols were analyzed for patient and VAD assessment and treatment variables. RESULTS: Of 32 states with state-wide EMS protocols, 21 had VAD-specific protocols. With 17 (81%) states noting a pulse may not be palpable, protocols recommended assessing alternate measures of perfusion and mean arterial pressure (MAP; 15 [71%]). Assessment of VAD was advised through listening for pump hum (20 [95%]) and alarms (20 [95%]) and checking the power supply (15 [71%]). For treatment, EMS prehospital consultation was required to begin chest compression in three (14%) states, and mechanical (device) chest compressions were not permitted in two (10%) states. Contact information for VAD coordinator was listed in a minority of five (24%) states. Transport of VAD equipment/backup bag was advised in 18 (86%) states. DISCUSSION: This national analysis of EMS protocols found VAD-specific EMS protocols are not universally adopted in the United States and are variable when implemented, highlighting a need for VAD teams to partner with EMS agencies to inform standardized protocols that optimize these patients' care.

Development of Cilofexor, an intestinally-biased Farnesoid X Receptor agonist, for the treatment of fatty liver disease.

The farnesoid X receptor (FXR) is a nuclear receptor that controls bile acid, lipid, and cholesterol metabolism. FXR-targeted drugs have shown promise in late-stage clinical trials for non-alcoholic steatohepatitis. Herein, we used clinical results from our first non-steroidal FXR agonist, Px-102 (4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid), to develop cilofexor, a potent, non-steroidal FXR agonist with a more manageable safety profile. Px-102 demonstrated the anticipated pharmacodynamic (PD) effects in healthy volunteers but caused a 2-fold increase in alanine aminotransferase (ALT) activity and changes in cholesterol levels. These data guided development of a high fat diet mouse model to screen FXR agonists based on ALT and cholesterol changes. Cilofexor was identified to elicit only minor changes in these parameters. The differing effects of cilofexor and Px-102 on ALT/cholesterol in the model could not be explained by potency or specificity, and we hypothesized that the relative contribution of intestinal and liver FXR activation may be responsible. Gene expression analysis from rodent studies revealed that cilofexor, but not Px-102, had a bias for FXR transcriptional activity in the intestine compared to the liver. Fluorescent imaging in hepatoma cells demonstrated similar subcellular localization for cilofexor and Px-102, but cilofexor was more rapidly washed out, consistent with a lower membrane residence time contributing to reduced hepatic transcriptional effects. Cilofexor demonstrated antisteatotic and antifibrotic efficacy in rodent models and antisteatotic efficacy in a monkey model, with the anticipated PD and a manageable safety profile in human phase I studies. Significance Statement FXR (farnesoid X receptor) agonists have shown promise in treating non-alcoholic steatohepatitis and other liver diseases in the clinic, but balancing efficacy with undesired side effects has been difficult. Here, we examined the preclinical and clinical effects of the first-generation FXR agonist, Px-102 (4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid), to enable the selection of an analog, cilofexor, with unique properties that reduced side effects yet maintained efficacy. Cilofexor is one of few remaining FXR agonists in clinical development.

Molecular Engineering of Interleukin-2 for Enhanced Therapeutic Activity in Autoimmune Diseases.

The interleukin-2 (IL-2) cytokine plays a crucial role in regulating immune responses and maintaining immune homeostasis. Its immunosuppressive effects have been harnessed therapeutically via administration of low cytokine doses. Low-dose IL-2 has shown promise in the treatment of various autoimmune and inflammatory diseases; however, the clinical use of IL-2 is complicated by its toxicity, its pleiotropic effects on both immunostimulatory and immunosuppressive cell subsets, and its short serum half-life, which collectively limit the therapeutic window. As a result, there remains a considerable need for IL-2-based autoimmune disease therapies that can selectively target regulatory T cells with minimal off-target binding to immune effector cells in order to prevent cytokine-mediated toxicities and optimize therapeutic efficacy. In this review, we discuss exciting advances in IL-2 engineering that are empowering the development of novel therapies to treat autoimmune conditions. We describe the structural mechanisms of IL-2 signaling, explore current applications of IL-2-based compounds as immunoregulatory interventions, and detail the progress and challenges associated with clinical adoption of IL-2 therapies. In particular, we focus on protein engineering approaches that have been employed to optimize the regulatory T-cell bias of IL-2, including structure-guided or computational design of cytokine mutants, conjugation to polyethylene glycol, and the development of IL-2 fusion proteins. We also consider future research directions for enhancing the translational potential of engineered IL-2-based therapies. Overall, this review highlights the immense potential to leverage the immunoregulatory properties of IL-2 for targeted treatment of autoimmune and inflammatory diseases.

The clinical utility of immediate post-operative PACU plain film radiographs following uncomplicated open Latarjet procedure - An institutional series of consecutive patients.

Background: Immediate post-operative plain film radiograph x-rays in PACU following open Latarjet procedure are often ordered as routine. However, such radiographs utilize institutional cost and time, whilst potentially exposing patients to often-unnecessary additional radiation. This study sought to evaluate whether routine immediate post-operative radiographs following uncomplicated open Latarjet procedures impacted clinical decision-making in our institution. Methods: From 2017 to 2020, patients who underwent open Latarjet procedure by one of four fellowship-trained upper limb surgeons at a single institution were included in this study. Post-operative radiographs taken immediately in PACU were reviewed to determine if any reported radiographic findings impacted on clinical decision-making in the immediate post-operative setting. SPSS was used for descriptive statistics. Results: A total of 337 patients underwent an X-ray in PACU immediate after uncomplicated open Latarjet procedure. Overall, 98.5% were male (n = 332), the mean patient age of included patients was 22.9 ± 4.2 years. No patient had an abnormal finding on their post-operative x-ray. Two patients returned to the operating room in the immediate post-operative period, both requiring washout and debridement due to haemtoma or superficial wound infection. Conclusion: The findings of this study suggest that the use of post-operative plain films in PACU following open Latarjet procedure remains a costly use of resources, with little ultimate impact on clinical decision making in the short-term post-operatively. Level of Evidence: IV - Institutional Case Series of Consecutive Patients.

Evaluation of the efficacy and safety of amustaline/glutathione pathogen-reduced RBCs in complex cardiac surgery: the Red Cell Pathogen Inactivation (ReCePI) study-protocol for a phase 3, randomized, controlled trial.

BACKGROUND: Red blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leukocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen-reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies. METHODS: ReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, parallel-design, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥ 0.3 mg/dL (or 26.5 µmol/L) from pre-surgery baseline within 48 ± 4 h of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen-reduced RBCs through 75 days after the last study transfusion. With ≥ 292 evaluable, transfused patients (> 146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%. DISCUSSION: RBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen-reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBCs.

Mutant forms of DDX3X with diminished catalysis form hollow condensates that exhibit sex-specific regulation.

Mutations in the RNA helicase DDX3X, implicated in various cancers and neurodevelopmental disorders, often impair RNA unwinding and translation. However, the mechanisms underlying this impairment and the differential interactions of DDX3X mutants with wild-type (WT) X-linked DDX3X and Y-linked homolog DDX3Y remain elusive. This study reveals that specific DDX3X mutants more frequently found in disease form distinct hollow condensates in cells. Using a combined structural, biochemical, and single-molecule microscopy study, we show that reduced ATPase and RNA release activities contribute to condensate formation and the catalytic deficits result from inhibiting the catalytic cycle at multiple steps. Proteomic investigations further demonstrate that these hollow condensates sequester WT DDX3X/DDX3Y and other proteins crucial for diverse signaling pathways. WT DDX3X enhances the dynamics of heterogeneous mutant/WT hollow condensates more effectively than DDX3Y. These findings offer valuable insights into the catalytic defects of specific DDX3X mutants and their differential interactions with wild-type DDX3X and DDX3Y, potentially explaining sex biases in disease.

DDX3X and DDX3Y constitutively form nano-sized RNA-protein clusters that foster enzymatic activity.

DEAD-box helicases, which are crucial for many aspects of RNA metabolism, often contain intrinsically disordered regions (IDRs), whose functions remain unclear. Using multiparameter confocal microscopy, we reveal that sex chromosome-encoded homologous RNA helicases, DDX3X and DDX3Y, form nano-sized RNA-protein clusters (RPCs) that foster their catalytic activities in vitro and in cells. The IDRs are critical for the formation of these RPCs. A thorough analysis of the catalytic cycle of DDX3X and DDX3Y by ensemble biochemistry and single molecule photon bursts in the confocal microscope showed that RNA release is a major step that differentiates the unwinding activities of DDX3X and DDX3Y. Our findings provide new insights that the nano-sized helicase RPCs may be the normal state of these helicases under non-stressed conditions that promote their RNA unwinding and act as nucleation points for liquid-liquid phase separation under stress. This mechanism may apply broadly among other members of the DEAD-box helicase family.

Online clinical tools to support the use of new plasma biomarker diagnostic technology in the assessment of Alzheimer's disease: a narrative review.

Recent advances in new diagnostic technologies for Alzheimer's disease have improved the speed and precision of diagnosis. However, accessing the potential benefits of this technology poses challenges for clinicians, such as deciding whether it is clinically appropriate to order a diagnostic test, which specific test or tests to order and how to interpret test results and communicate these to the patient and their caregiver. Tools to support decision-making could provide additional structure and information to the clinical assessment process. These tools could be accessed online, and such 'e-tools' can provide an interactive interface to support patients and clinicians in the use of new diagnostic technologies for Alzheimer's disease. We performed a narrative review of the literature to synthesize information available on this research topic. Relevant studies that provide an understanding of how these online tools could be used to optimize the clinical utility of diagnostic technology were identified. Based on these, we discuss the ways in which e-tools have been used to assist in the diagnosis of Alzheimer's disease and propose recommendations for future research to aid further development.

dTrmt10A impacts Hsp70 chaperone m6A levels and the stress response in the Drosophila brain.

Chronic cellular stress has a profound impact on the brain, leading to degeneration and accelerated aging. Recent work has revealed the vital role of RNA modifications, and the proteins responsible for regulating them, in the stress response. In our study, we defined the role of CG14618/dTrmt10A, the Drosophila counterpart of human TRMT10A a N1-methylguanosine methyltransferase, on m6A regulation and heat stress resilience in the Drosophila brain. By m6A-IP RNA sequencing on Drosophila head tissue, we demonstrated that manipulating dTrmt10A levels indirectly regulates m6A levels on polyA + RNA. dTrmt10A exerted its influence on m6A levels on transcripts enriched for neuronal signaling and heat stress pathways, similar to the m6A methyltransferase Mettl3. Intriguingly, its impact primarily targeted 3' UTR m6A, setting it apart from the majority of Drosophila m6A-modified transcripts which display 5' UTR enrichment. Upregulation of dTrmt10A led to increased resilience to acute heat stress, decreased m6A modification on heat shock chaperones, and coincided with decreased decay of chaperone transcripts and increased translation of chaperone proteins. Overall, these findings establish a potential mechanism by which dTrmt10A regulates the acute brain stress response through m6A modification.

Exploring the brain epitranscriptome: perspectives from the NSAS summit.

Increasing evidence reinforces the essential function of RNA modifications in development and diseases, especially in the nervous system. RNA modifications impact various processes in the brain, including neurodevelopment, neurogenesis, neuroplasticity, learning and memory, neural regeneration, neurodegeneration, and brain tumorigenesis, leading to the emergence of a new field termed neuroepitranscriptomics. Deficiency in machineries modulating RNA modifications has been implicated in a range of brain disorders from microcephaly, intellectual disability, seizures, and psychiatric disorders to brain cancers such as glioblastoma. The inaugural NSAS Challenge Workshop on Brain Epitranscriptomics hosted in Crans-Montana, Switzerland in 2023 assembled a group of experts from the field, to discuss the current state of the field and provide novel translational perspectives. A summary of the discussions at the workshop is presented here to simulate broader engagement from the general neuroscience field.

Evaluation of clinical benefits of treatments for Alzheimer's disease.

The need for regulatory approval of new therapies for the treatment of Alzheimer's disease-a progressive neurodegenerative condition-has made the assessment of treatment efficacy an urgent priority for discussion and investigation in the field. In the first part of this Personal View, we summarise current views on what constitutes a clinically meaningful benefit from treatment for Alzheimer's disease, including the concept of a minimum treatment effect against which to compare trial outcomes and its limitations. Considering existing and divergent definitions of clinically meaningful change, we define this concept in the second part of the Personal View by proposing a new approach that consecutively considers whether a treatment benefit for Alzheimer's disease is noticeable, valuable, and worthwhile in the context of costs and risks. This approach could be a useful foundation from which the field can move forwards on this issue and address existing gaps in understanding.

Heart rate variability and risk of agitation in Alzheimer's disease: the Atherosclerosis Risk in Communities Study.

Agitation in Alzheimer's disease is common and may be related to impaired emotion regulation capacity. Heart rate variability, a proposed index of autonomic and emotion regulation neural network integrity, could be associated with agitation propensity in Alzheimer's disease. We used the Atherosclerosis Risk in Communities Study cohort data, collected over seven visits spanning over two decades, to investigate whether heart rate variability (change) was associated with agitation risk in individuals clinically diagnosed with dementia due to Alzheimer's disease. Agitation (absence/presence) at Visit 5, the primary outcome, was based on the Neuropsychiatric Inventory agitation/aggression subscale, or a composite score comprising the total number of agitation/aggression, irritability, disinhibition and aberrant motor behaviour subscales present. Visit 1-5 heart rate variability measures were the log-transformed root mean square of successive differences in R-R intervals and standard deviation of normal-to-normal R-R intervals obtained from resting, supine, standard 12-lead ECGs. To aid interpretability, heart rate variability data were scaled such that model outputs were expressed for each 0.05 log-unit change in heart rate variability (which approximated to the observed difference in heart rate variability with every 5 years of age). Among 456 participants who had dementia, 120 were clinically classified to have dementia solely attributable to Alzheimer's disease. This group showed a positive relationship between heart rate variability and agitation risk in regression models, which was strongest for measures of (potentially vagally mediated) heart rate variability change over the preceding two decades. Here, a 0.05 log-unit of heart rate variability change was associated with an up to 10-fold increase in the odds of agitation and around a half-unit increase in the composite agitation score. Associations persisted after controlling for participants' cognitive status, heart rate (change), sociodemographic factors, co-morbidities and medications with autonomic effects. Further confirmatory studies, incorporating measures of emotion regulation, are needed to support heart rate variability indices as potential agitation propensity markers in Alzheimer's disease and to explore underlying mechanisms as targets for treatment development.