Differences in cancer clinical trial activity and trial characteristics at metropolitan and rural trial sites in Victoria, Australia.

OBJECTIVE: Cancer clinical trials (CCTs) provide access to emerging therapies and extra clinical care. We aimed to describe the volume and characteristics of CCTs available across Victoria, Australia, and identify factors associated with rural trial location. METHODS: Quantitative analysis of secondary data from Cancer Council Victoria's Clinical Trials Management Scheme dataset. DESIGN: A cross-sectional study design was used. SETTING: CCTs were available Victoria-wide in 2018. PARTICIPANTS: There were 1669 CCTs and 5909 CCT participants. MAIN OUTCOME MEASURES: Rural CCT location was assessed as a binary variable with categories of 'yes' (modified Monash [MM] categories 2-7) and 'no' (MM category 1). MM categories were determined from postcodes. The highest ('least rural') MM category was used for postcodes with multiple MM categories. RESULTS: Of 1669 CCTs, 168 (10.1%) were conducted in rural areas. Of 5909 CCT participants, 315 (5.3%) participated in rural CCTs. There were 526 CCTs (31.5%) with 1907 (32.3%) newly enrolled participants. Of 1892 newly enrolled participants with postcode data, 488 (25.8%) were rural residents. Of them, 368 (75.4%) participated in metropolitan CCTs. In a multivariable logistic regression analysis for all 1669 CCTs, odds of a rural rather than metropolitan CCT location were significantly (p-value <0.05) lower for early-phase than late-phase trials and non-solid than solid tumour trials but significantly (p-value <0.05) higher for non-industry than industry-sponsored trials. CONCLUSIONS: In Victoria, 10% of CCTs are at rural sites. Most rural-residing CCT participants travel to metropolitan sites, where there are more late-phase, non-solid-tumour and industry-sponsored trials. Approaches to increase the volume and variety of rural CCTs should be considered.

Controlling Excited State Localization in Bichromophoric Photosensitizers via the Bridging Group.

A series of photosensitizers comprised of both an inorganic and an organic chromophore are investigated in a joint synthetic, spectroscopic, and theoretical study. This bichromophoric design strategy provides a means by which to significantly increase the excited state lifetime by isolating the excited state away from the metal center following intersystem crossing. A variable bridging group is incorporated between the donor and acceptor units of the organic chromophore, and its influence on the excited state properties is explored. The Franck-Condon (FC) photophysics and subsequent excited state relaxation pathways are investigated with a suite of steady-state and time-resolved spectroscopic techniques in combination with scalar-relativistic quantum chemical calculations. It is demonstrated that the presence of an electronically conducting bridge that facilitates donor-acceptor communication is vital to generate long-lived (32 to 45 µs), charge-separated states with organic character. In contrast, when an insulating 1,2,3-triazole bridge is used, the excited state properties are dominated by the inorganic chromophore, with a notably shorter lifetime of 60 ns. This method of extending the lifetime of a molecular photosensitizer is, therefore, of interest for a range of molecular electronic devices and photophysical applications.

PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons.

Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72 dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. TGF-ß1 was one of the top predicted regulators of this ECM signature and polyGR expression in human induced pluripotent stem cell neurons was sufficient to induce TGF-ß1 followed by COL6A1. Knockdown of TGF-ß1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-ß1 or COL6A1 in induced pluripotent stem cell-derived motor neurons of patients with C9ALS/FTD protected against glutamate-induced cell death. Altogether, our findings reveal a neuroprotective and conserved ECM signature in C9ALS/FTD.

Immune checkpoint inhibitor therapy for advanced cutaneous squamous cell carcinoma in Australia: a retrospective real world cohort study.

OBJECTIVES: To review the outcomes of immune checkpoint inhibitor (ICI) treatment of advanced cutaneous squamous cell carcinoma (CSCC) outside clinical trials. STUDY DESIGN: Retrospective observational study; review of patient records in fifteen Australian institutions. SETTING, PARTICIPANTS: All Australian adults with locally advanced or metastatic CSCC not amenable to curative surgery or radiotherapy treated with ICIs, 5 May 2017 - 23 May 2022, through a cemiplimab compassionate access scheme (Therapeutic Goods Administration Special Access Scheme) or who personally covered the cost of pembrolizumab prior to the start of the access scheme. MAIN OUTCOME MEASURES: Best overall response rate (ORR) according to standardised assessment criteria using the hierarchy: Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the modified World Health Organization clinical response criteria, and the Positron Emission Tomography Response Criteria (PERCIST 1.0); overall and progression-free survival. RESULTS: A total of 286 people with advanced CSCC received ICI therapy during May 2017 - May 2022 (cemiplimab, 270; pembrolizumab, 16). Their median age was 75.2 years (range, 39.3-97.5 years) and 232 were men (81%); median follow-up time was 12.2 months (interquartile range, 5.5-20.5 months). Eighty-eight people (31%) were immunocompromised, 27 had autoimmune disease, and 59 of 277 (21%) had ECOG performance scores of 2 or 3. The ORR was 60% (166 of 278 evaluable patients): complete responses were recorded for 74 (27%) and partial responses for 92 patients (33%). Twelve-month overall survival was 78% (95% confidence interval [CI], 72-83%); progression-free survival was 65% (95% CI, 58-70%). Poorer ECOG performance status was associated with poorer overall survival (per unit: adjusted hazard ratio [aHR], 3.0; 95% CI, 2.0-4.3) and progression-free survival (aHR, 2.4; 95% CI, 1.8-3.3), as was being immunocompromised (overall: aHR, 1.8; 95% CI, 1.1-3.0; progression-free: aHR, 1.8; 95% CI, 1.2-2.7). Fifty-five people (19%) reported immune-related adverse events of grade 2 or higher; there were no treatment-related deaths. CONCLUSION: In our retrospective study, the effectiveness and toxicity of ICI therapy were similar to those determined in clinical trials. Our findings suggest that ICIs could be effective and well tolerated by people with advanced CSCC who are ineligible for clinical trials.

Twelve tips for designing and implementing peer-led assessment writing schemes in health professions education.

Peer-led assessment (PLA) has gained increasing prominence within health professions education as an effective means of engaging learners in the process of assessment writing and practice. Involving students in various stages of the assessment lifecycle, including item writing, quality assurance, and feedback, not only facilitates the creation of high-quality item banks with minimal faculty input but also promotes the development of students' assessment literacy and fosters their growth as teachers. The advantages of involving students in the generation of assessments are evident from a pedagogical standpoint, benefiting both students and faculty. However, faculty members may face uncertainty when it comes to implementing such approaches effectively. To address this concern, this paper presents twelve tips that offer guidance on important considerations for the successful implementation of peer-led assessment schemes in the context of health professions education.

Esophageal Stent Migration Diagnosed With Point-of-Care Ultrasound.

This unique case depicts the first published report of a physician using point-of-care ultrasound to diagnose an esophageal stent migration. Discussed in this article are the sonographic findings that clinicians should be familiar with when evaluating patients with abdominal pain or chest pain who have a history of an esophageal stent. When coupled with a high index of suspicion, ultrasound can be one of the most portable, readily available, low-cost, and minimally invasive techniques for making a rapid diagnosis of esophageal stent migration.

Spontaneous intercostal herniation of lung and pleural fluid.

Thoracic hernias are characterized by the protrusion of the thoracic contents outside their normal anatomical confines. This case involves a left pleural effusion secondary to a spontaneous lung intercostal hernia (SLIH) in a 52-year-old male. Imaging revealed herniated pleural fluid in the intercostal space. Intra-operatively, there was herniation of the lung parenchyma into an intercostal defect. Pleural effusion secondary to a SLIH is an indication for surgical repair.

How Pulse Width Affects Laser Ablation of Organic Liquids.

Laser synthesis in liquids is often carried out in organic solvents to prevent oxidation of metals during nanoparticle generation and to produce tailored carbon-based nanomaterials. This work investigates laser ablation of neat organic liquids acetone, ethanol, n-hexane, and toluene with pulse widths ranging from 30 fs to 4 ps through measurements of reaction kinetics and characterization of the ablation products with optical spectroscopy and mass spectrometry. Increasing the pulse width from 30 fs to 4 ps impacts both the reaction kinetics and product distributions, suppressing the formation of solvent molecule dimers and oxidized molecules while enhancing the yields of gaseous molecules, sp-hybridized carbons, and fluorescent carbon dots. The observed trends are explained in the context of established ionization mechanisms and cavitation bubble dynamical processes that occur during ultrashort pulsed laser ablation of liquid media. The results of this work have important implications both for controlling the formation of carbon shells around metal nanoparticles during the ablation of solid targets in liquid and producing carbon nanomaterials directly from the ablation of organic liquids without a solid target.

Dyskeratosis Congenita: A Case Report of a Patient With Coronary Artery Disease.

Clinical evidence demonstrates that patients with telomere biology disorders, such as dyskeratosis congenita, are more prone to coronary artery disease. We present the case of a 43-year-old female diagnosed with dyskeratosis congenita with critical cardiovascular disease. She underwent coronary artery bypass graft (CABG) with improvement of her cardiac function. Although this is a rare genetic disease, further studies are warranted to investigate the underlying pathophysiology of cardiovascular disease in patients with dyskeratosis congenita.

Systematic Tuning of Electronic Ground and Excited States in Donor-Acceptor Dyes; Steps toward Designer Compounds for Modern Technologies.

The vibrational and electronic properties of six systematically altered donor-acceptor dyes were investigated with density functional theory (DFT), spectroscopy, and electrochemical techniques. The dyes incorporated a carbazole donor connected to a dithieno[3,2-b:2',3'-d]thiophene linker at either the C2 (m) or C3 (p) position. Indane-based acceptors contained either dimalononitrile (IndCN), ketone and malononitrile (InOCN) or diketone (IndO) electron accepting groups. Molecular geometries modeled by DFT using the BLYP functional and def2-TZVP basis set showed planar geometries containing large, extended π-systems and produced Raman spectra consistent with the experimental data. Electronic absorption spectra had transitions with π-π* character at wavelengths below 325 nm and a charge transfer (CT) transition region from 500 to 700 nm. The peak wavelength was dependent on the donor and acceptor architecture, with each modulating the HOMO and LUMO levels, respectively, supported by TD-DFT estimates using the LC-ωPBE* functional and 6-31g(d) basis set. The compounds showed emission in solution with quantum yields ranging from 0.004 to 0.6 and lifetimes of less than 2 ns. These were assigned to either π-π* or CT emissive states. Signals attributed to CT states exhibited positive solvatochromism and thermochromism. The spectral emission behavior of each compound trended with the acceptor unit moieties, where malononitrile units lead to greater π-π* character and ketones exhibited greater CT character.

Bidirectional alterations in brain temperature profoundly modulate spatiotemporal neurovascular responses in-vivo.

Neurovascular coupling (NVC) is a mechanism that, amongst other known and latent critical functions, ensures activated brain regions are adequately supplied with oxygen and glucose. This biological phenomenon underpins non-invasive perfusion-related neuroimaging techniques and recent reports have implicated NVC impairment in several neurodegenerative disorders. Yet, much remains unknown regarding NVC in health and disease, and only recently has there been burgeoning recognition of a close interplay with brain thermodynamics. Accordingly, we developed a novel multi-modal approach to systematically modulate cortical temperature and interrogate the spatiotemporal dynamics of sensory-evoked NVC. We show that changes in cortical temperature profoundly and intricately modulate NVC, with low temperatures associated with diminished oxygen delivery, and high temperatures inducing a distinct vascular oscillation. These observations provide novel insights into the relationship between NVC and brain thermodynamics, with important implications for brain-temperature related therapies, functional biomarkers of elevated brain temperature, and in-vivo methods to study neurovascular coupling.

High-throughput automated methods for classical and operant conditioning of Drosophila larvae.

Learning which stimuli (classical conditioning) or which actions (operant conditioning) predict rewards or punishments can improve chances of survival. However, the circuit mechanisms that underlie distinct types of associative learning are still not fully understood. Automated, high-throughput paradigms for studying different types of associative learning, combined with manipulation of specific neurons in freely behaving animals, can help advance this field. The Drosophila melanogaster larva is a tractable model system for studying the circuit basis of behaviour, but many forms of associative learning have not yet been demonstrated in this animal. Here, we developed a high-throughput (i.e. multi-larva) training system that combines real-time behaviour detection of freely moving larvae with targeted opto- and thermogenetic stimulation of tracked animals. Both stimuli are controlled in either open- or closed-loop, and delivered with high temporal and spatial precision. Using this tracker, we show for the first time that Drosophila larvae can perform classical conditioning with no overlap between sensory stimuli (i.e. trace conditioning). We also demonstrate that larvae are capable of operant conditioning by inducing a bend direction preference through optogenetic activation of reward-encoding serotonergic neurons. Our results extend the known associative learning capacities of Drosophila larvae. Our automated training rig will facilitate the study of many different forms of associative learning and the identification of the neural circuits that underpin them.

Investigation of the Geometric and Spectroscopic Properties of Four Twisted Triphenylpyridinium Donor-Acceptor Dyes.

The geometric and spectroscopic properties of four cationic N-aryl-2,4,6-triphenylpyridinium-based donor-acceptor dyes─1-[4-(9H-carbazol-9-yl)phenyl]-2,4,6-triphenylpyridinium, 1-[4-(N,N-diphenylamino)phenyl]-2,4,6-triphenylpyridinium, 1-(9-phenyl-9H-carbazol-3-yl)-2,4,6-triphenylpyridinium, and 1-(9-ethyl-9H-carbazol-3-yl)-2,4,6-triphenylpyridinium─are reported. The four dyes exhibited a twisted, quasi-perpendicular geometry about the central donor-acceptor bond, shown by X-ray crystallography and supported by Raman spectroscopy and DFT calculations. The electronic absorption spectra show weak charge transfer (CT) transitions at about 400 nm (ε ∼ 3000 L mol-1 cm-1). Time dependent (TD) DFT supported the nature of the CT transition, displaying an 89-97% shift in electron density from the donor to the acceptor upon electronic excitation. Excited state geometry calculations revealed significant geometry changes upon electronic excitation. Enhancement of vibrational modes attributable to this transition was also recognized in the resonance Raman spectra. Emission spectroscopies showed two distinct emission bands. The lower energy band, resulting from radiative decay of the CT excited state, exhibited large anomalous Stokes shifts of ∼9000 cm-1. Much of the Stokes shift was a consequence of geometry changes between the ground and excited states. This was confirmed by variable temperature emission studies, with Stokes shifts reducing by up to 3000 cm-1 upon cooling from 293 to 80 K. Additionally, a high energy aggregation induced emission band was present for two of the dyes, resulting from the inhibition of excited state geometry reorganization and supported by solid-state emission spectra. These phenomena exemplify the importance of geometry in short range donor-acceptor dyes such as these.

Exploring Australian regional cancer patients' experiences of clinical trial participation via telehealth.

INTRODUCTION: Regional cancer patients face various barriers in accessing specialist cancer services. Teletrials are a new model of care that utilise communications technologies to enable access to and participation in clinical trials close to home. The present study aimed to explore the experiences of regional cancer patients and their carers while participating in a teletrial, and those of regional patients who travelled to a metropolitan centre for trial participation. METHODS: A concurrent, mixed methods study design was used to address the study aim. Patient quality of life data were gathered for both groups and an audio-recorded semi-structured interview undertaken to explore patients' and carers' experiences of the two modes of trial participation. Greater weighting was given to the qualitative data. RESULTS: Participants described teletrials as an acceptable and valuable initiative that reduced overall burden of trial participation. Irrespective of mode of delivery, patients and carers identified access to trials and specialist cancer services as an important equity issue for regional cancer patients. DISCUSSION: From the perspective of regional cancer patients and carers, a teletrial offers convenient, acceptable access to a clinical trial. Although not all patients may want to engage in a teletrial, patients and carers agree that it offers equity of opportunity for trial participation, irrespective of where people live.

The Reciprocal Interaction Between Sleep and Alzheimer's Disease.

It is becoming increasingly recognized that patients with a variety of neurodegenerative diseases exhibit disordered sleep/wake patterns. While sleep impairments have typically been thought of as sequelae of underlying neurodegenerative processes in sleep-wake cycle regulating brain regions, including the brainstem, hypothalamus, and basal forebrain, emerging evidence now indicates that sleep deficits may also act as pathophysiological drivers of brain-wide disease progression. Specifically, recent work has indicated that impaired sleep can impact on neuronal activity, brain clearance mechanisms, pathological build-up of proteins, and inflammation. Altered sleep patterns may therefore be novel (potentially reversible) dynamic functional markers of proteinopathies and modifiable targets for early therapeutic intervention using non-invasive stimulation and behavioral techniques. Here we highlight research describing a potentially reciprocal interaction between impaired sleep and circadian patterns and the accumulation of pathological signs and features in Alzheimer's disease, the most prevalent neurodegenerative disease in the elderly.

Aη-α and Aη-ß peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo.

BACKGROUND: Amyloid precursor protein (APP) processing is central to Alzheimer's disease (AD) etiology. As early cognitive alterations in AD are strongly correlated to abnormal information processing due to increasing synaptic impairment, it is crucial to characterize how peptides generated through APP cleavage modulate synapse function. We previously described a novel APP processing pathway producing η-secretase-derived peptides (Aη) and revealed that Aη-α, the longest form of Aη produced by η-secretase and α-secretase cleavage, impaired hippocampal long-term potentiation (LTP) ex vivo and neuronal activity in vivo. METHODS: With the intention of going beyond this initial observation, we performed a comprehensive analysis to further characterize the effects of both Aη-α and the shorter Aη-ß peptide on hippocampus function using ex vivo field electrophysiology, in vivo multiphoton calcium imaging, and in vivo electrophysiology. RESULTS: We demonstrate that both synthetic peptides acutely impair LTP at low nanomolar concentrations ex vivo and reveal the N-terminus to be a primary site of activity. We further show that Aη-ß, like Aη-α, inhibits neuronal activity in vivo and provide confirmation of LTP impairment by Aη-α in vivo. CONCLUSIONS: These results provide novel insights into the functional role of the recently discovered η-secretase-derived products and suggest that Aη peptides represent important, pathophysiologically relevant, modulators of hippocampal network activity, with profound implications for APP-targeting therapeutic strategies in AD.

Clinical significance and mechanisms associated with segmental UPD.

Whole chromosome uniparental disomy (UPD) has been well documented with mechanisms largely understood. However, the etiology of segmental limited UPD (segUPD) is not as clear. In a 10-year period of confirming (> 300) cases of whole chromosome UPD, we identified 86 segmental cases in both prenatal and postnatal samples. Thirty-two of these cases showed mosaic segmental UPD at 11p due to somatic selection associated with Beckwith-Wiedemann syndrome. This study focuses on apparent mechanisms associated with the remaining cases, many of which appear to represent corrections of genomic imbalance such as deletions and derivative chromosomes. In some cases, segmental UPD was associated with the generation of additional genomic imbalance while in others it apparently resulted in restoration of euploidy. Multiple tests utilizing noninvasive prenatal testing (NIPT), chorionic villus sampling (CVS) and amniotic fluid samples from the same pregnancy revealed temporal evidence of correction and a "hotspot" at 1p. Although in many cases the genomic imbalance was dosage "repaired" in the analyzed tissue, clinical effects could be sustained due to early developmental effects of the original imbalance or due to its continued existence in other tissues. In addition, if correction did not occur in the gametes there would be recurrence risks for the offspring of those individuals. Familial microarray allele patterns are presented that differentiate lack of gamete correction from somatic derived gonadal mosaicism. These results suggest that the incidence of segUPD mediated correction is underestimated and may explain the etiology of some clinical phenotypes which are undetected by routine microarray analysis and many exome sequencing studies.

Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study.

BACKGROUND: CH5126766 (also known as VS-6766, and previously named RO5126766), a novel MEK-pan-RAF inhibitor, has shown antitumour activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumour activity of this drug in patients with solid tumours and multiple myeloma harbouring RAS-RAF-MEK pathway mutations. METHODS: We did a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study at the Royal Marsden National Health Service Foundation Trust (London, UK). Patients were eligible for the study if they were aged 18 years or older, had cancers that were refractory to conventional treatment or for which no conventional therapy existed, and if they had a WHO performance status score of 0 or 1. For the dose-escalation phase, eligible patients had histologically or cytologically confirmed advanced or metastatic solid tumours. For the basket dose-expansion phase, eligible patients had advanced or metastatic solid tumours or multiple myeloma harbouring RAS-RAF-MEK pathway mutations. During the dose-escalation phase, we evaluated three intermittent oral schedules (28-day cycles) in patients with solid tumours: (1) 4·0 mg or 3·2 mg CH5126766 three times per week; (2) 4·0 mg CH5126766 twice per week; and (3) toxicity-guided dose interruption schedule, in which treatment at the recommended phase 2 dose (4·0 mg CH5126766 twice per week) was de-escalated to 3 weeks on followed by 1 week off if patients had prespecified toxic effects (grade 2 or worse diarrhoea, rash, or creatinine phosphokinase elevation). In the basket dose-expansion phase, we evaluated antitumour activity at the recommended phase 2 dose, determined from the dose-escalation phase, in biomarker-selected patients. The primary endpoints were the recommended phase 2 dose at which no more than one out of six patients had a treatment-related dose-limiting toxicity, and the safety and toxicity profile of each dosing schedule. The key secondary endpoint was investigator-assessed response rate in the dose-expansion phase. Patients who received at least one dose of the study drug were evaluable for safety and patients who received one cycle of the study drug and underwent baseline disease assessment were evaluable for response. This trial is registered with ClinicalTrials.gov, NCT02407509. FINDINGS: Between June 5, 2013, and Jan 10, 2019, 58 eligible patients were enrolled to the study: 29 patients with solid tumours were included in the dose-escalation cohort and 29 patients with solid tumours or multiple myeloma were included in the basket dose-expansion cohort (12 non-small-cell lung cancer, five gynaecological malignancy, four colorectal cancer, one melanoma, and seven multiple myeloma). Median follow-up at the time of data cutoff was 2·3 months (IQR 1·6-3·5). Dose-limiting toxicities included grade 3 bilateral retinal pigment epithelial detachment in one patient who received 4·0 mg CH5126766 three times per week, and grade 3 rash (in two patients) and grade 3 creatinine phosphokinase elevation (in one patient) in those who received 3·2 mg CH5126766 three times per week. 4·0 mg CH5126766 twice per week (on Monday and Thursday or Tuesday and Friday) was established as the recommended phase 2 dose. The most common grade 3-4 treatment-related adverse events were rash (11 [19%] patients), creatinine phosphokinase elevation (six [11%]), hypoalbuminaemia (six [11%]), and fatigue (four [7%]). Five (9%) patients had serious treatment-related adverse events. There were no treatment-related deaths. Eight (14%) of 57 patients died during the trial due to disease progression. Seven (27% [95% CI 11·6-47·8]) of 26 response-evaluable patients in the basket expansion achieved objective responses. INTERPRETATION: To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumour activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation. FUNDING: Chugai Pharmaceutical.

Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer's Disease.

Identifying effective treatments for Alzheimer's disease (AD) has proven challenging and has instigated a shift in AD research focus toward the earliest disease-initiating cellular mechanisms. A key insight has been an increase in soluble Aß oligomers in early AD that is causally linked to neuronal and circuit hyperexcitability. However, other accumulating AD-related peptides and proteins, including those derived from the same amyloid precursor protein, such as Aη or sAPPα, and autonomously, such as tau, exhibit surprising opposing effects on circuit dynamics. We propose that the effects of these on neuronal circuits have profound implications for our understanding of disease complexity and heterogeneity and for the development of personalized diagnostic and therapeutic strategies in AD. Here, we highlight important peptide-specific mechanisms of dynamic pathological disequilibrium of cellular and circuit activity in AD and discuss approaches in which these may be further understood, and theoretically and experimentally leveraged, to elucidate AD pathophysiology.