Social isolation reinforces aging-related behavioral inflexibility by promoting neuronal necroptosis in basolateral amygdala.

Aging is characterized with a progressive decline in many cognitive functions, including behavioral flexibility, an important ability to respond appropriately to changing environmental contingencies. However, the underlying mechanisms of impaired behavioral flexibility in aging are not clear. In this study, we reported that necroptosis-induced reduction of neuronal activity in the basolateral amygdala (BLA) plays an important role in behavioral inflexibility in 5-month-old mice of the senescence-accelerated mice prone-8 (SAMP8) line, a well-established model with age-related phenotypes. Application of Nec-1s, a specific inhibitor of necroptosis, reversed the impairment of behavioral flexibility in SAMP8 mice. We further observed that the loss of glycogen synthase kinase 3α (GSK-3α) was strongly correlated with necroptosis in the BLA of aged mice and the amygdala of aged cynomolgus monkeys (Macaca fascicularis). Moreover, genetic deletion or knockdown of GSK-3α led to the activation of necroptosis and impaired behavioral flexibility in wild-type mice, while the restoration of GSK-3α expression in the BLA arrested necroptosis and behavioral inflexibility in aged mice. We further observed that GSK-3α loss resulted in the activation of mTORC1 signaling to promote RIPK3-dependent necroptosis. Importantly, we discovered that social isolation, a prevalent phenomenon in aged people, facilitated necroptosis and behavioral inflexibility in 4-month-old SAMP8 mice. Overall, our study not only revealed the molecular mechanisms of the dysfunction of behavioral flexibility in aged people but also identified a critical lifestyle risk factor and a possible intervention strategy.

Molecular characterization of size-segregated organic aerosols in the urban boundary layer in wintertime Beijing by FT-ICR MS.

Organic aerosols, complicated mixtures of organic compounds, are important constituents of atmospheric particulate matter. However, little is known about the size distributions and vertical profiles of these constituents at a molecular level in the urban boundary layer. Here, we characterized the molecular compositions of size-segregated samples collected simultaneously at two heights (8 m and 260 m above ground level) in urban Beijing during the winter of 2018. The CHO, CHNO, CHOS, and CHNOS subgroups in water-soluble organic carbon were characterized using a 15-T ultrahigh-resolution Fourier transform-ion cyclotron resonance (FT-ICR) mass spectrometer. We found that both their numbers and magnitudes increased with a decrease in the particle size, especially for high molecular weight (HMW) compounds, except CHNOS. The number of CHNOS species also increased in the coarse mode, presumably because the alkalinity could inhibit their hydrolysis in the coarse mode. The compounds in small particles with higher O/C ratios and carbon oxidation state were possibly more aged, while the coarse particles with more lipid- and peptide-like compounds should originate from fresh emissions. Moreover, as the oxidation state increases in small particles, functionalization is enhanced for sulfur-containing compounds with fracturing of the benzene ring, while CHO and CHNO are potentially dominated by demethylation with ring-retaining products. It is worth noting that common compounds with the same molecular characteristics accounted for more than 86% of the total compounds between 260 m and ground level (8 m), demonstrating that the aerosols were well mixed in the urban boundary layer. Nonetheless, the relative content of the compounds was higher at ground level due to the impact of primary emissions, which increased with the particle size. In addition, the compounds in submicron particles were more oxidized at 260 m, while the opposite was observed in the coarse mode.

mHealth education interventions in heart failure.

BACKGROUND: Heart failure (HF) is a chronic disease with significant impact on quality of life and presents many challenges to those diagnosed with the condition, due to a seemingly complex daily regimen of self-care which includes medications, monitoring of weight and symptoms, identification of signs of deterioration and follow-up and interaction with multiple healthcare services. Education is vital for understanding the importance of this regimen, and adhering to it. Traditionally, education has been provided to people with heart failure in a face-to-face manner, either in a community or a hospital setting, using paper-based materials or video/DVD presentations. In an age of rapidly-evolving technology and uptake of smartphones and tablet devices, mHealth-based technology (defined by the World Health Organization as mobile and wireless technologies to achieve health objectives) is an innovative way to provide health education which has the benefit of being able to reach people who are unable or unwilling to access traditional heart failure education programmes and services. OBJECTIVES: To systematically review and quantify the potential benefits and harms of mHealth-delivered education for people with heart failure. SEARCH METHODS: We performed an extensive search of bibliographic databases and registries (CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, IEEE Xplore, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) Search Portal), using terms to identify HF, education and mHealth. We searched all databases from their inception to October 2019 and imposed no restriction on language of publication. SELECTION CRITERIA: We included studies if they were conducted as a randomised controlled trial (RCT), involving adults (≥ 18 years) with a diagnosis of HF. We included trials comparing mHealth-delivered education such as internet and web-based education programmes for use on smartphones and tablets (including apps) and other mobile devices, SMS messages and social media-delivered education programmes, versus usual HF care. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias, and extracted data from all included studies. We calculated the mean difference (MD) or standardised mean difference (SMD) for continuous data and the odds ratio (OR) for dichotomous data with a 95% confidence interval (CI). We assessed heterogeneity using the I2 statistic and assessed the quality of evidence using GRADE criteria. MAIN RESULTS: We include five RCTs (971 participants) of mHealth-delivered education interventions for people with HF in this review. The number of trial participants ranged from 28 to 512 participants. Mean age of participants ranged from 60 years to 75 years, and 63% of participants across the studies were men. Studies originated from Australia, China, Iran, Sweden, and The Netherlands. Most studies included participants with symptomatic HF, NYHA Class II - III. Three studies addressed HF knowledge, revealing that the use of mHealth-delivered education programmes showed no evidence of a difference in HF knowledge compared to usual care (MD 0.10, 95% CI -0.2 to 0.40, P = 0.51, I2 = 0%; 3 studies, 411 participants; low-quality evidence). One study assessing self-efficacy reported that both study groups had high levels of self-efficacy at baseline and uncertainty in the evidence for the intervention (MD 0.60, 95% CI -0.57 to 1.77; P = 0.31; 1 study, 29 participants; very low-quality evidence).Three studies evaluated HF self-care using different scales. We did not pool the studies due to the heterogenous nature of the outcome measures, and the evidence is uncertain. None of the studies reported adverse events. Four studies examined health-related quality of life (HRQoL). There was uncertainty in the evidence for the use of mHealth-delivered education on HRQoL (MD -0.10, 95% CI -2.35 to 2.15; P = 0.93, I2 = 61%; 4 studies, 942 participants; very low-quality evidence). Three studies reported on HF-related hospitalisation. The use of mHealth-delivered education may result in little to no difference in HF-related hospitalisation (OR 0.74, 95% CI 0.52 to 1.06; P = 0.10, I2 = 0%; 3 studies, 894 participants; low-quality evidence). We downgraded the quality of the studies due to limitations in study design and execution, heterogeneity, wide confidence intervals and fewer than 500 participants in the analysis. AUTHORS' CONCLUSIONS: We found that the use of mHealth-delivered educational interventions for people with HF shows no evidence of a difference in HF knowledge; uncertainty in the evidence for self-efficacy, self-care and health-related quality of life; and may result in little to no difference in HF-related hospitalisations. The identification of studies currently underway and those awaiting classification indicate that this is an area of research from which further evidence will emerge in the short and longer term.

A transitional care intervention for hypertension control for older people with diabetes: A cluster randomized controlled trial.

AIMS: To evaluate the effect of a nurse-coordinated hospital-initiated transitional care programme on hypertension control for older people with diabetes in China. DESIGN: A cluster randomized controlled trial. METHODS: A total of 10 wards (clusters) of four acute care hospitals participated in the trial. They were randomly assigned to the intervention group or the control group. A total of 270 participants (135 in each group) were recruited from these wards. Data were collected between June 2016 - June 2017. Participants in the intervention group received a 6-month hospital to home transitional care programme coordinated by discharge nurses and community nurses. The programme comprised self-management education, lifestyle changes, individualized medication treatment, structured telephone support, and primary care visits. Outcomes were measured at baseline, and 3 months and 6 months from the baseline. RESULTS: The mean age was 70.9 (SD 5.8) years and 55% of participants were men. The intervention group demonstrated a statistically significant decrease in mean systolic blood pressure of 10.7 mmHg and mean diastolic blood pressure of 4.1 mmHg compared with the control group. The findings also demonstrated significant improvements in HbA1c, hypertension knowledge, diabetes knowledge, treatment adherence, quality of life, hospital readmission, and emergency department visits in the intervention group compared with the control group. However, no significant differences in adverse events were observed between the two groups. CONCLUSIONS: A hospital-initiated and nurse-coordinated transitional care intervention improves hypertension control and reduces hospital readmissions for older people with diabetes. IMPACT: Lack hospital to home transitional care for hospitalized older people with hypertension and diabetes can result in high readmission rates and emergency department visits. A hospital-initiated and nurse-coordinated transitional care intervention built on collaboration between acute care hospitals and community health centres results in improved hypertension control and reduced readmissions for older people with diabetes and other chronic conditions. An integrated and well-coordinated care services between acute care hospitals and community health centres can strengthen the primary care approach to supporting self-management of hypertension, diabetes, and other ageing-associated health conditions for community-dwelling older people. TRIAL REGISTRATION: The trial was registered with the Australia New Zealand Clinical Trials Registry (ID: ACTRN12617001352392).

Effectiveness of an Avatar application for teaching heart attack recognition and response: A pragmatic randomized control trial.

AIMS: To evaluate the effectiveness of an Avatar application for educating people with acute coronary syndrome (heart attack). BACKGROUND: A lack of understanding of Acute Coronary Syndrome symptoms and appropriate responses often contribute to delay in seeking medical treatment. DESIGN: A single-centre, non-blinded, pragmatic randomized controlled trial. METHODS: Seventy Acute Coronary Syndrome patients were randomly assigned to the intervention (Avatar application) or usual care groups. Participants were followed up at 0, 1, and 6 months. Tobit Growth Curve Model was used to analyse the primary outcome-symptom knowledge; and the secondary outcomes-attitudes and beliefs. Heart attack action plan implementation and health care utilisation were analysed using Chi-square and Mann-Whitney U test. RESULTS: Of the 70 participants, 63% were male and the mean age of the participants was 64.7 (SD 11.7) years. Sixty-six (94.2%) participants completed follow-up. Between group differences on acute coronary syndrome (ACS) Response Index scores were statistically significant at 1-month and 6-month follow-ups (p < .01). The intervention group had a significant improvement in symptom knowledge, attitudes, and beliefs over the 6-month period (p < .001, p = .009, p < .001 respectively); and no significant improvement in the usual care group participants (p = .152, p = .068, p = .228). For healthcare use, at follow-up, there was a significant difference in ambulance use, between the intervention group and the usual care group (33.33% vs. 18.18%, p = .008; cardiac: 88.89% vs. 42.86%; p = .049); 85.14% of participants reported that the application helped them to feel more confident in recognizing and responding to symptoms in the future. CONCLUSION: The education app was effective in improving individuals' ACS knowledge, attitudes, and beliefs. A large multi-centre trial with a longer follow-up to evaluate the intervention's effectiveness on clinical outcomes will be our next step in evaluation. IMPACT: The content of AVATARS (Nurse Cora) app can be translated into different languages and evaluated for patients from different health settings and linguistic backgrounds. TRIAL REGISTRATION: This study has been registered with Australian New Zealand Clinical Trials Registry (ANZCTR). The trial registration number is ACTRN12616000803493.

Effectiveness of an avatar educational application for improving heart failure patients' knowledge and self-care behaviors: A pragmatic randomized controlled trial.

AIM: To evaluate the effectiveness of education using avatars for improving patients' heart failure knowledge and self-care. BACKGROUND: A lack of knowledge and self-care contributes to poor outcomes and rehospitalization for people with heart failure. DESIGN: A multi-centred, non-blinded pragmatic randomized controlled trial. METHODS: Heart failure patients were randomly assigned to intervention (avatar education application) or usual care groups. Participants were followed up at baseline, 30 and 90 days. ANCOVA was used to compare the scores of heart failure knowledge and self-care, between the two groups. Fisher's exact test was used to compare the two groups' heart failure-cause readmission. Bivariate exact binary logistic regression was used to identify the predictors associated with baseline levels of knowledge. RESULTS: A total of 36 participants were recruited (between October 2018 - March 2019). The mean age of participants was 67.5 (SD 11.3) years. At enrolment, approximately half (47.2%) have been living with Heart Failure for over 5 years. Two groups were comparable at baseline in their demographic and clinical characteristics. At 90 days, the intervention group participants had a higher increase in knowledge score on the Dutch Heart Failure Knowledge Scales compared with the control group (22.2% versus 3.7% P = .002, partial η2  = 0.262, 95% CI -2.755 to -0.686). There was no between-group difference observed at 30- or 90-day follow-up, on self-care behaviour (Self-care of heart failure index) or healthcare use. Overall satisfaction with the avatar app was 91.3%. CONCLUSION: The addition of a co-designed avatar app to usual care improved knowledge in our group of Heart Failure participants at 30 days and continued to increase up to 90 days. The results suggest that our avatar app was perceived as an enjoyable and engaging means of delivering critical knowledge and self-care information. IMPACT: Heart failure is associated with poor clinical outcomes (i.e., readmission rates and mortality rate) and substantial economic burden. The effectiveness of Heart Failure patient education using avatar have not been investigated previously. In this study, the avatar app improved knowledge and self-care behaviours. This innovation could be used at the bedside, at home by nurses, patients and families. TRIAL REGISTRATION: Australian New Zealand Trial Registry ACTRN12617001403325.

Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding.

Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2-expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioral experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Overall, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience.

Evaluation of the effectiveness of an interactive avatar-based education application for improving heart failure patients' knowledge and self-care behaviours: A pragmatic randomized controlled trial protocol.

AIM: The aim of this study was to evaluate the effectiveness of an avatar-based education application for improving knowledge and self-care behaviour in patients with heart failure (HF). BACKGROUND: Avatar-based technologies for supporting education are an innovative approach for patients with low literacy, low health literacy and English as a second language. The use of avatar technologies for patient education has shown benefits in improving knowledge, self-care behaviours and quality of life in chronic diseases such as cancer, diabetes and depression. Research has demonstrated positive outcomes in clinical practice. However, the effectiveness of this technology has not been evaluated among patients with HF. DESIGN: A multi-centred, non-blinded randomized, two-armed parallel pragmatic, controlled trial. METHOD: Eighty-eight participants will be recruited from the HF clinics at three public hospitals and randomized into either control or intervention groups. The intervention group will receive the avatar-based education plus usual care. The control group will receive usual care. The primary outcome is HF knowledge, secondary outcomes include; improved self-care behaviours, readmission and satisfaction. Data will be collected at the baseline and at 1- and 3-month follow-ups. DISCUSSION: This study will measure the effectiveness of avatar-based education on patients' knowledge and self-care behaviours following HF. The evidence will be evaluated in terms of the reduction in patients' readmission.

An avatar-based education application to improve patients' knowledge of and response to heart attack symptoms: A pragmatic randomized controlled trial protocol.

AIM: To evaluate the effectiveness of an interactive, avatar-based education application to improve knowledge of and response to heart attack symptoms in people who are at risk of a heart attack. BACKGROUND: Poor knowledge of heart attack symptoms is recognized as a significant barrier to timely medical treatment. Numerous studies have demonstrated that technology can assist in patient education to improve knowledge and self-care. DESIGN: A single-center, non-blinded, two parallel groups, pragmatic randomized controlled trial. METHODS: Seventy patients will be recruited from the coronary care unit of a public hospital. Eligible participants will be randomized to either the usual care or the intervention group (usual care plus avatar-based heart attack education app). The primary outcome of this study is knowledge. Secondary outcomes include response to heart attack symptoms, health service use and satisfaction. Study participants will be followed up for 6 months. DISCUSSION: This study will evaluate the avatar-based education app as a method to deliver vital information to patients. Participants' knowledge of and response to heart attack symptoms, and their health service use, will be assessed to evaluate the intervention effectiveness.

Six-Minute Walk Test for Assessing Physical Functional Capacity in Chronic Heart Failure.

PURPOSE OF THE REVIEW: The six-minute walk test (6MWT) is a submaximal exercise test for evaluating physical functional capacity. This review aims to report the research on the use of the 6MWT in chronic heart failure (CHF) that has been published in the past 5 years. RECENT FINDINGS: The 6MWT distance does not accurately reflect peak VO2. Minimal clinically important difference in the 6MWT distance, and additional measurements, such as heart rate recovery, can assist in the interpretation of the 6MWT distance, so management decisions can be made. Incorporating mobile apps and information technology in measuring the 6MWT distance extends the usefulness of this simple walk test and improve remote monitoring of patients with CHF. The 6MWT is a useful tool in CHF programs. However, interpretation of the 6MWT distance must be with caution. With the advancement in technology, the 6MWT has the potential to facilitate the monitoring of people living in rural and remote areas.

Cardiac Rehabilitation: Unraveling the Complexity of Referral and Current Models of Delivery.

BACKGROUND: Evidence-based guidelines recommend strategies for reducing risk factors for secondary prevention of acute coronary syndromes, yet referral to and completion of programs to deliver this advice are poor. PURPOSE: In this article we describe the complexity of factors that influence referral and delivery of evidence-based cardiac rehabilitation (CR) programs through an Australian context and provide direction for solutions for clinicians and policy makers to consider. The Ecological Approach is used as a framework to synthesize evidence. The approach has 5 categories, the characteristics of which may act as barriers and enablers to the promotion and adoption of health behaviors and includes (a) interpersonal factors, (b) interpersonal factors, (c) institutional factors, (d) community networks, and (e) public policy. CONCLUSIONS: Despite the context of strong evidence for efficacy, this review highlights systematic flaws in the implementation of CR, an important intervention that has been shown to improve patient outcomes and prevent cardiac events. Recommendations from this review include standardization of program delivery, improvement of data capture, use of technological innovations and social networks to facilitate delivery of information and support, and establishment of a cohesive, consistent message through interorganizational collaboration involved in CR. CLINICAL IMPLICATIONS: These avenues provide direction for potential solutions to improve the uptake of CR and secondary prevention.

Development of a synchronous recording and photo-stimulating electrode in multiple brain neurons.

The investigation of brain networks and neural circuits involves the crucial aspects of observing and modulating neurophysiological activity. Recently, opto-electrodes have emerged as an efficient tool for electrophysiological recording and optogenetic stimulation, which has greatly facilitated the analysis of neural coding. However, implantation and electrode weight control have posed significant challenges in achieving long-term and multi-regional brain recording and stimulation. To address this issue, we have developed a mold and custom-printed circuit board-based opto-electrode. We report successful opto-electrode placement and high-quality electrophysiological recordings from the default mode network (DMN) of the mouse brain. This novel opto-electrode facilitates synchronous recording and stimulation in multiple brain regions and holds promise for advancing future research on neural circuits and networks.

The effectiveness of interactive cardiac rehabilitation web applications versus usual care on programme completion in patients with cardiovascular disease: A systematic review and meta-analysis of randomised controlled trials.

INTRODUCTION: Although available evidence demonstrates positive clinical outcomes for patients attending and completing cardiac rehabilitation, the effectiveness of interactive cardiac rehabilitation web applications on programme completion has not been systematically examined. METHODS: This JBI systematic review of effects included studies measuring effectiveness of interactive cardiac rehabilitation web applications compared to telephone, and centre-based programmes. Outcome data were pooled under programme completion and clinical outcomes (body mass index, low-density lipoproteins, and blood pressure). Databases including MEDLINE (via Ovid), Cochrane Library, Scopus (via Elsevier) and CINAHL (via EBSCO) published in English were searched. Articles were screened and reviewed by two independent reviewers for inclusion, and the JBI critical appraisal tool and Grading of Recommendations Assessment, Development and Evaluation tool were applied to appraise and assess the certainty of the findings of the included studies. A meta-analysis of the primary and secondary outcomes used random effects models. RESULTS: In total, nine studies involving 1175 participants who participated in web-based cardiac rehabilitation to usual care were identified. The mean critical appraisal tool score was 76 (standard deviation: 9.7) with all (100%) studies scoring >69%, and the certainty of evidence low. Web-based programmes were 43% more likely to be completed than usual care (risk ratio: 1.43; 95% confidence interval: 0.96, 2.13) There was no difference between groups for clinical outcomes. DISCUSSION: Despite the relatively small number of studies, high heterogeneity and the limited outcome measures, the results appeared to favour web-based cardiac rehabilitation with regard to programme completion.

Self-efficacy: a useful construct to promote physical activity in people with stable chronic heart failure.

AIM: To explore the conceptual underpinnings of self-efficacy to address the barriers to participating in physical activity and propose a model of intervention. BACKGROUND: The benefits of physical activity in reducing cardiovascular risk have led to evidence-based recommendations for patients with heart disease, including those with chronic heart failure. However, adherence to best practice recommendations is often suboptimal, particularly in those individuals who experience high symptom burden and feel less confident to undertake physical activity. Self-efficacy is the degree of confidence an individual has in his/her ability to perform behaviour under several specific circumstances. Four factors influence an individual's level of self-efficacy: (1) past performance, (2) vicarious experience, (3) verbal persuasion and (4) physiological arousal. DESIGN: Discursive. METHODS: Using the method of a discursive paper, this article seeks to explore the conceptual underpinnings of self-efficacy to address the barriers to participating in physical activity and proposes a model of intervention, the Home-Heart-Walk, to promote physical activity and monitor functional status. CONCLUSIONS: Implementing effective interventions to promote physical activities require appreciation of factors impacting on behaviour change. Addressing concepts relating to self-efficacy in physical activity interventions may promote participation and adherence in the longer term. RELEVANCE TO CLINICAL PRACTICE: The increasing burden of chronic disease and the emphasis on self-management strategies underscore the importance of promoting adherence to recommendations, such as physical activity.

User Experience (UX) Design as a co-design methodology: lessons learned during the development of a web-based portal for cardiac rehabilitation.

Person-centred care advocates for co-design of all healthcare services and research interventions by the end-user. Co-design is widely used, but the methodological approaches, evaluation, and reporting of outcomes are often poorly defined. One methodology for co-design is the User Experience Design which provides guidance and theoretical frameworks to inform development and reporting measures. This article outlines the application of this approach in the development of a web-based cardiac rehabilitation program and reports on the very positive experiences of the patients involved in the process and how their input strategically influenced outcomes.

Alzheimer-like tau accumulation in dentate gyrus mossy cells induces spatial cognitive deficits by disrupting multiple memory-related signaling and inhibiting local neural circuit.

Abnormal tau accumulation and spatial memory loss constitute characteristic pathology and symptoms of Alzheimer disease (AD). Yet, the intrinsic connections and the mechanism between them are not fully understood. In the current study, we observed a prominent accumulation of the AD-like hyperphosphorylated and truncated tau (hTau N368) proteins in hippocampal dentate gyrus (DG) mossy cells of 3xTg-AD mice. Further investigation demonstrated that the ventral DG (vDG) mossy cell-specific overexpressing hTau for 3 months induced spatial cognitive deficits, while expressing hTau N368 for only 1 month caused remarkable spatial cognitive impairment with more prominent tau pathologies. By in vivo electrophysiological and optic fiber recording, we observed that the vDG mossy cell-specific overexpression of hTau N368 disrupted theta oscillations with local neural network inactivation in the dorsal DG subset, suggesting impairment of the ventral to dorsal neural circuit. The mossy cell-specific transcriptomic data revealed that multiple AD-associated signaling pathways were disrupted by hTau N368, including reduction of synapse-associated proteins, inhibition of AKT and activation of glycogen synthase kinase-3ß. Importantly, chemogenetic activating mossy cells efficiently attenuated the hTau N368-induced spatial cognitive deficits. Together, our findings indicate that the mossy cell pathological tau accumulation could induce the AD-like spatial memory deficit by inhibiting the local neural network activity, which not only reveals new pathogenesis underlying the mossy cell-related spatial memory loss but also provides a mouse model of Mossy cell-specific hTau accumulation for drug development in AD and the related tauopathies.

VGLUT3 neurons in median raphe control the efficacy of spatial memory retrieval via ETV4 regulation of VGLUT3 transcription.

The raphe nucleus is critical for feeding, rewarding and memory. However, how the heterogenous raphe neurons are molecularly and structurally organized to engage their divergent functions remains unknown. Here, we genetically target a subset of neurons expressing VGLUT3. VGLUT3 neurons control the efficacy of spatial memory retrieval by synapsing directly with parvalbumin-expressing GABA interneurons (PGIs) in the dentate gyrus. In a mouse model of Alzheimer's disease (AD mice), VGLUT3→PGIs synaptic transmission is impaired by ETV4 inhibition of VGLUT3 transcription. ETV4 binds to a promoter region of VGLUT3 and activates VGLUT3 transcription in VGLUT3 neurons. Strengthening VGLUT3→PGIs synaptic transmission by ETV4 activation of VGLUT3 transcription upscales the efficacy of spatial memory retrieval in AD mice. This study reports a novel circuit and molecular mechanism underlying the efficacy of spatial memory retrieval via ETV4 inhibition of VGLUT3 transcription and hence provides a promising target for therapeutic intervention of the disease progression.

Molecularly defined and functionally distinct cholinergic subnetworks.

Cholinergic neurons in the medial septum (MS) constitute a major source of cholinergic input to the forebrain and modulate diverse functions, including sensory processing, memory, and attention. Most studies to date have treated cholinergic neurons as a single population; as such, the organizational principles underling their functional diversity remain unknown. Here, we identified two subsets (D28K+ versus D28K-) of cholinergic neurons that are topographically segregated in mice, Macaca fascicularis, and humans. These cholinergic subpopulations possess unique electrophysiological signatures, express mutually exclusive marker genes (kcnh1 and aifm3 versus cacna1h and gga3), and make differential connections with physiologically distinct neuronal classes in the hippocampus to form two structurally defined and functionally distinct circuits. Gain- and loss-of-function studies on these circuits revealed their differential roles in modulation of anxiety-like behavior and spatial memory. These results provide a molecular and circuitry-based theory for how cholinergic neurons contribute to their diverse behavioral functions.

Implementation and prospective evaluation of the Country Heart Attack Prevention model of care to improve attendance and completion of cardiac rehabilitation for patients with cardiovascular diseases living in rural Australia: a study protocol.

INTRODUCTION: Despite extensive evidence of its benefits and recommendation by guidelines, cardiac rehabilitation (CR) remains highly underused with only 20%-50% of eligible patients participating. We aim to implement and evaluate the Country Heart Attack Prevention (CHAP) model of care to improve CR attendance and completion for rural and remote participants. METHODS AND ANALYSIS: CHAP will apply the model for large-scale knowledge translation to develop and implement a model of care to CR in rural Australia. Partnering with patients, clinicians and health service managers, we will codevelop new approaches and refine/expand existing ones to address known barriers to CR attendance. CHAP will codesign a web-based CR programme with patients expanding their choices to CR attendance. To increase referral rates, CHAP will promote endorsement of CR among clinicians and develop an electronic system that automatises referrals of in-hospital eligible patients to CR. A business model that includes reimbursement of CR delivered in primary care by Medicare will enable sustainable access to CR. To promote CR quality improvement, professional development interventions and an accreditation programme of CR services and programmes will be developed. To evaluate 12-month CR attendance/completion (primary outcome), clinical and cost-effectiveness (secondary outcomes) between patients exposed (n=1223) and not exposed (n=3669) to CHAP, we will apply a multidesign approach that encompasses a prospective cohort study, a pre-post study and a comprehensive economic evaluation. ETHICS AND DISSEMINATION: This study was approved by the Southern Adelaide Clinical Human Research Ethics Committee (HREC/20/SAC/78) and by the Department for Health and Wellbeing Human Research Ethics Committee (2021/HRE00270), which approved a waiver of informed consent. Findings and dissemination to patients and clinicians will be through a public website, online educational sessions and scientific publications. Deidentified data will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBER: ACTRN12621000222842.