β-Estradiol-dependent activation of the JAK/STAT pathway requires p/CIP and CARM1

The steroid receptor coactivator p/CIP, also known as SRC-3, is an oncogene commonly amplified in breast and ovarian cancers. p/CIP is known to associate with coactivator arginine methyltransferase 1 (CARM1) on select estrogen responsive genes. We have shown, using a ChIP-on-chip approach, that in response to stimulation with 17β-estradiol (E2), the p/CIP/CARM1 complex is recruited to 204 proximal promoters in MCF-7 cells. Many of the complex target genes have been previously implicated in signaling pathways related to oncogenesis. Jak2, a member of the Jak/Stat signaling cascade, is one of the direct E2-dependent targets of the p/CIP/CARM1 complex. Following E2-treatment, histone modifications at the Jak2 promoter are reflective of a transcriptionally permissive gene, and modest changes in RNA and protein expression lead us to suggest that an additional factor(s) may be required for a more notable transcriptional and functional response. Bioinformatic examination of the 204 proximal promoter sequences of p/CIP/CARM1 targets supports the idea that transcription factor crosstalk is likely the favored mechanism of E2-dependent p/CIP/CARM1 complex recruitment. This data may have implications towards understanding the oncogenic role of p/CIP in breast cancer and ultimately allow for the identification of new prognostic indicators and/or viable therapeutic targets. © 2013

A Multidomain Intervention Program for Older People with Dementia: A Pilot Study

Background: Multidomain interventions have been shown to be effective in improving cognition, quality of life, reducing neuropsychiatric symptoms and delaying progression of functional impairment or disability in dementia patients. To investigate the multidomain intervention in other populations and diverse cultural and geographical settings, this pilot study will assess the feasibility of a multidomain intervention for older people with dementia in nursing homes in Vietnam. Methods: Participants will be randomized into two equal groups, to receive either a multidomain intervention (intervention group) or regular health advice (control group). The intervention will include physical, cognitive, and social interventions as well as management of metabolic and vascular risk factors. We will hypothesize that the multidomain intervention will be feasible in Vietnam, and participants who receive the intervention will show improvement in quality of life, behaviors, functional ability, cognitive function, sleep, and in reduction of falls, use of healthcare services, and death rate compared to those in the control group during the 6 months intervention period and after the 6 months extended follow-up. Discussion: This is the first study to evaluate the feasibility of a multidomain intervention program for older people with dementia in nursing homes in Vietnam. The results from the trial will inform clinicians and the public of the possibility of comprehensive treatment beyond simply drug treatments for dementia. This paves the way for further studies to evaluate the long-term effects of multidomain interventions in dementia patients. Furthermore, the research results will provide information on the effectiveness of multidomain interventions which will inform policy development on dementia. Trial Registration: The trial is registered with ClinicalTrials.gov identifier: NCT04948450 on 02/07/2021

Deprescribing interventions and their impact on medication adherence in community-dwelling older adults with polypharmacy: a systematic review

Background: Polypharmacy, and the associated adverse drug events such as non-adherence to prescriptions, is a common problem for elderly people living with multiple comorbidities. Deprescribing, i.e. the gradual withdrawal from medications with supervision by a healthcare professional, is regarded as a means of reducing adverse effects of multiple medications including non-adherence. This systematic review examines the evidence of deprescribing as an effective strategy for improving medication adherence amongst older, community dwelling adults. Methods: A mixed methods review was undertaken. Eight bibliographic database and two clinical trials registers were searched between May and December 2017. Results were double screened in accordance with pre-defined inclusion/exclusion criteria related to polypharmacy, deprescribing and adherence in older, community dwelling populations. The Mixed Methods Appraisal Tool (MMAT) was used for quality appraisal and an a priori data collection instrument was used. For the quantitative studies, a narrative synthesis approach was taken. The qualitative data was analysed using framework analysis. Findings were integrated using a mixed methods technique. The review was performed in accordance with the PRISMA reporting statement. Results: A total of 22 original studies were included, of which 12 were RCTs. Deprescribing with adherence as an outcome measure was identified in randomised controlled trials (RCTs), observational and cohort studies from 13 countries between 1996 and 2017. There were 17 pharmacy-led interventions; others were led by General Practitioners (GP) and nurses. Four studies demonstrated an overall reduction in medications of which all studies corresponded with improved adherence. A total of thirteen studies reported improved adherence of which 5 were RCTs. Adherence was reported as a secondary outcome in all but one study. Conclusions: There is insufficient evidence to show that deprescribing improves medication adherence. Only 13 studies (of 22) reported adherence of which only 5 were randomised controlled trials. Older people are particularly susceptible to non-adherence due to multi-morbidity associated with polypharmacy. Bio-psycho-social factors including health literacy and multi-disciplinary team interventions influence adherence. The authors recommend further study into the efficacy and outcomes of medicines management interventions. A consensus on priority outcome measurements for prescribed medications is indicated

Differential Deployment of REST and CoREST Promotes Glial Subtype Specification and Oligodendrocyte Lineage Maturation

The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a master transcriptional regulator that binds to numerous genomic RE1 sites where it acts as a molecular scaffold for dynamic recruitment of modulatory and epigenetic cofactors, including corepressor for element-1-silencing transcription factor (CoREST). CoREST also acts as a hub for various cofactors that play important roles in epigenetic remodeling and transcriptional regulation. While REST can recruit CoREST to its macromolecular complex, CoREST complexes also function at genomic sites independently of REST. REST and CoREST perform a broad array of context-specific functions, which include repression of neuronal differentiation genes in neural stem cells (NSCs) and other non-neuronal cells as well as promotion of neurogenesis. Despite their involvement in multiple aspects of neuronal development, REST and CoREST are not believed to have any direct modulatory roles in glial cell maturation.We challenged this view by performing the first study of REST and CoREST in NSC-mediated glial lineage specification and differentiation. Utilizing ChIP on chip (ChIP-chip) assays, we identified distinct but overlapping developmental stage-specific profiles for REST and CoREST target genes during astrocyte (AS) and oligodendrocyte (OL) lineage specification and OL lineage maturation and myelination, including many genes not previously implicated in glial cell biology or linked to REST and CoREST regulation. Amongst these factors are those implicated in macroglial (AS and OL) cell identity, maturation, and maintenance, such as members of key developmental signaling pathways and combinatorial transcription factor codes.Our results imply that REST and CoREST modulate not only neuronal but also glial lineage elaboration. These factors may therefore mediate critical developmental processes including the coupling of neurogenesis and gliogenesis and neuronal-glial interactions that underlie synaptic and neural network plasticity and homeostasis in health and in specific neurological disease states

Geriatrician perspectives on perioperative care: a qualitative study

Background: Perioperative medicine services for older surgical patients are being developed across several countries. This qualitative study aims to explore geriatricians’ perspectives on challenges and opportunities for developing and delivering integrated geriatrics perioperative medicine services. Methods: A qualitative phenomenological semi-structured interview design. All geriatric medicine departments in acute public hospitals across Australia and New Zealand (n = 81) were approached. Interviews were conducted with 38 geriatricians. Data were analysed thematically using a framework approach. Results: Geriatricians identified several system level barriers to developing geriatrics perioperative medicine services. These included lack of funding for staffing, encroaching on existing consultative services, and competing clinical priorities. The key barrier at the healthcare professional level was the current lack of clarity of roles within the perioperative care team. Key facilitators were perceived unmet patient needs, existing support for geriatrician involvement from surgical and anaesthetic colleagues, and the unique skills geriatricians can bring to perioperative care. Despite reporting barriers, geriatricians are contemplating and implementing integrated proactive perioperative medicine services. Geriatricians identified a need to support other specialties gain clinical experience in geriatric medicine and called for pragmatic research to inform service development. Conclusions: Geriatricians perceive several challenges at the system and healthcare professional levels that are impacting current development of geriatrics perioperative medicine services. Yet their strong belief that patient needs can be met with their specialty skills and their high regard for team-based care, has created opportunities to implement innovative multidisciplinary models of care for older surgical patients. The barriers and evidence gaps highlighted in this study may be addressed by qualitative and implementation science research. Future work in this area may include application of patient-reported measures and qualitative research with patients to inform patient-centred perioperative care

Geriatric Comanagement of Older Vascular Surgery Inpatients Reduces Hospital-Acquired Geriatric Syndromes

"OBJECTIVE: This study evaluates the impact of a novel model of care called Geriatric Comanagement of Older Vascular surgery inpatients on clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: A pre-post study of geriatric comanagement, comparing prospectively recruited preintervention (February-October 2019) and prospectively recruited postintervention (January-December 2020) cohorts. Consecutively admitted vascular surgery patients age ≥65 years at a tertiary academic hospital in Concord and with an expected length of stay (LOS) greater than 2 days were recruited. INTERVENTION: A comanagement model where a geriatrician was embedded within the vascular surgery team and delivered proactive comprehensive geriatric assessment based interventions. METHODS: Primary outcomes of incidence of hospital-acquired geriatric syndromes, delirium, and LOS were compared between groups using univariable and multivariable logistic regression analyses. Prespecified subgroup analysis was performed by frailty status. RESULTS: There were 150 patients in the preintervention group and 152 patients in the postintervention group. The postintervention group were more frail [66 (43.4%) vs 45 (30.0%)], urgently admitted [72 (47.4%) vs 56 (37.3%)], and nonoperatively managed [52 (34.2%) vs 33 (22.0%)]. These differences were attributed to the coronavirus disease 2019 pandemic during the postintervention phase. The postintervention group had fewer hospital-acquired geriatric syndromes [74 (48.7%) vs 97 (64.7%); P = .005] and reduced incident delirium [5 (3.3%) vs 15 (10.0%); P = .02], in unadjusted and adjusted analyses. Cardiac [8 (5.3%) vs 30 (20.0%); P < .001] and infective complications [4 (2.6%) vs 12 (8.0%); P = .04] were also fewer. LOS was unchanged. Frail patients in the postintervention group experienced significantly fewer geriatric syndromes including delirium. CONCLUSIONS AND IMPLICATIONS: This is the first prospective study of inpatient geriatric comanagement for older vascular surgery patients. Reductions in hospital-acquired geriatric syndromes including delirium, and cardiac and infective complications were observed after implementing geriatric comanagement. These benefits were also demonstrated in the frail subgroup.

Stakeholders' preferences for the design and delivery of virtual care services: A systematic review of discrete choice experiments

This systematic review aimed to synthesise evidence from discrete choice experiments (DCEs) eliciting preferences for virtual models of care, as well as to assess the quality of those DCEs and compare the relative preferences for different stakeholder groups. Articles were included if published between January 2010 and December 2022. Data were synthesised narratively, and attributes were assessed for frequency, significance, and relative importance using a semi-quantitative approach. Overall, 21 studies were included encompassing a wide range of virtual care modalities, with the most common setting being virtual consultations for outpatient management of chronic conditions. A total of 135 attributes were identified and thematically classified into six categories: service delivery, service quality, technical aspects, monetary aspects, health provider characteristics and health consumer characteristics. Attributes related to service delivery were most frequently reported but less highly ranked. Service costs were consistently significant across all studies where they appeared, indicating their importance to the respondents. All studies examining health providers' preferences reported either system performance or professional endorsement attributes to be the most important. Substantial heterogeneity in attribute selection and preference outcomes were observed across studies reporting on health consumers’ preferences, suggesting that the consideration of local context is important in the design and delivery of person-centred virtual care services. In general, the experimental design and analysis methods of included studies were clearly reported and justified. An improvement was observed in the quality of DCE design and analysis in recent years, particularly in the attribute development process. Given the continued growth in the use of DCEs within healthcare settings, further research is needed to develop a standardised approach for quantitatively synthesising DCE findings. There is also a need for further research on preferences for virtual care in post-pandemic contexts, where emerging evidence suggests that preferences may differ to those observed in pre-pandemic times.</p

Leveraging genetic diversity to identify small molecules that reverse mouse skeletal muscle insulin resistance

Systems genetics has begun to tackle the complexity of insulin resistance by capitalising on computational advances to study high-diversity populations. ‘Diversity Outbred in Australia (DOz)’ is a population of genetically unique mice with profound metabolic heterogeneity. We leveraged this variance to explore skeletal muscle’s contribution to whole-body insulin action through metabolic phenotyping and skeletal muscle proteomics of 215 DOz mice. Linear modelling identified 553 proteins that associated with whole-body insulin sensitivity (Matsuda Index) including regulators of endocytosis and muscle proteostasis. To enrich for causality, we refined this network by focusing on negatively associated, genetically regulated proteins, resulting in a 76-protein fingerprint of insulin resistance. We sought to perturb this network and restore insulin action with small molecules by integrating the Broad Institute Connectivity Map platform and in vitro assays of insulin action using the Prestwick chemical library. These complementary approaches identified the antibiotic thiostrepton as an insulin resistance reversal agent. Subsequent validation in ex vivo insulin-resistant mouse muscle and palmitate-induced insulin-resistant myotubes demonstrated potent insulin action restoration, potentially via upregulation of glycolysis. This work demonstrates the value of a drug-centric framework to validate systems-level analysis by identifying potential therapeutics for insulin resistance