Safety and feasibility of transcutaneous vagus nerve stimulation in mild cognitive impairment: VINCI-AD study protocol.

BACKGROUND: Over 55 million adults are living with dementia globally, which is projected to reach 157 million by 2050. Mild cognitive impairment (MCI), a syndrome of memory impairment with intact activities of daily living, may precede dementia by several years. Around 5-15% of individuals with MCI convert to dementia annually. Novel treatments which delay progression of MCI to dementia are urgently needed. Transcutaneous vagal nerve stimulation (tVNS) is a non-invasive neuromodulation technique that targets the vagus nerve. Importantly, tVNS has been shown to improve cognition in healthy volunteers, but has not been extensively examined as a potential therapeutic approach in MCI. VINCI-AD will examine the safety and feasibility of tVNS in older adults with MCI. DESIGN: VINCI-AD is an investigator-led, single-site, single-blind, sham-controlled crossover pilot study which aims to assess the safety and feasibility of tVNS in 40 participants with amnestic MCI. All participants will attend for three consecutive study visits during which they will be randomised to receive no stimulation (baseline), active tVNS stimulation (stimulation at cymba conchae of left ear) or sham tVNS stimulation (at earlobe). Safety will be primarily assessed by ascertainment of adverse events. Further safety assessment will examine the impact of acute tVNS on subjective (orthostatic symptoms), peripheral (finometry-based blood pressure) and central (assessed via Near Infrared Spectroscopy [NIRS]) haemodynamic responses to active stand. Feasibility will be determined using a custom-designed occupational assessment of device usability. Exploratory secondary analysis in VINCI-AD will examine the potential impact of acute tVNS on associative memory, spatial memory and inhibitory control to inform sample size estimates for future trials of tVNS in older adults with MCI. DISCUSSION: VINCI-AD will report on the safety (adverse events/haemodynamic responses to active stand) and feasibility of tVNS as a potential therapeutic option in MCI. Detailed reporting of study eligibility and completion rates will be reported. Exploratory analysis will examine the potential cognitive benefits of acute tVNS on cognitive function in MCI to report potential effect sizes that may inform future clinical trials in this cohort. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT05514756 . Trial Registration Number NCT05514756 (24th August 2022 for this protocol, version 1.0.).

Deprescribing in multi-morbid older people with polypharmacy: agreement between STOPPFrail explicit criteria and gold standard deprescribing using 100 standardized clinical cases.

PURPOSE: Older people with advanced frailty are among the highest consumers of medications. When life expectancy is limited, some of these medications are likely to be inappropriate. The aim of this study was to compare STOPPFrail, a concise, easy-to-use, deprescribing tool based on explicit criteria, with gold standard, systematic geriatrician-led deprescribing. METHODS: One hundred standardized clinical cases involving 1024 medications were prepared. Clinical cases were based on anonymized hospitalized patients aged ≥ 65 years, with advanced frailty (Clinical Frailty Scale ≥ 6), receiving ≥ 5 regular medications, who were selected from a recent observational study. Level of agreement between deprescribing methods was measured by Cohen's kappa coefficient. Sensitivity and positive predictive value of STOPPFrail-guided deprescribing relative to gold standard deprescribing was also measured. RESULTS: Overall, 524 medications (51.2%) of medications prescribed to this frail, elderly cohort were potentially inappropriate by gold standard criteria. STOPPFrail-guided deprescribing led to the identification of 70.2% of the potentially inappropriate medications. Cohen's kappa was 0.60 (95% confidence interval 0.55-0.65; p < 0.001) indicating moderate agreement between STOPPFrail-guided and gold standard deprescribing. The positive predictive value of STOPPFrail was 89.3% indicating that the great majority of deprescribing decisions aligned with gold standard care. CONCLUSIONS: STOPPFrail removes an important barrier to deprescribing by explicitly highlighting circumstances where commonly used medications can be safely deprescribed in older people with advanced frailty. Our results suggest that in multi-morbid older patients with advanced frailty, the use of STOPPFrail criteria to address inappropriate polypharmacy may be reasonable alternative to specialist medication review.

CDK4/6 inhibitors in breast cancer.

Deregulation of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) axis can occur through a number of mechanisms and contributes towards the unrestrained growth witnessed in a variety of cancers including breast cancers. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising preclinical and clinical results in breast cancer and other tumours. A number of trials assessing antitumour efficacy in various disease settings and combinations are ongoing. The cyclin D1-CDK-Rb axis and its role in the cell cycle of normal and cancer cells are delineated. The early pan-CDK inhibitor flavopiridol and subsequent preclinical and clinical development of selective CDK4/6 inhibitors are described. Ongoing studies in breast cancer with novel CDK4/6 inhibitors (palbociclib, abemaciclib and ribociclib) are explored. A literature search of these topics was performed through PubMed. Abstracts from major oncology meetings were also reviewed. Selective CDK4/6 inhibitors, as represented by the competing compounds currently in clinical development, comprise a novel, safe and, thus far, promisingly efficacious group of drugs. Considerable resources are being devoted towards exploring the efficacy of these drugs in combination with endocrine therapies, an approach that has yielded encouraging results and accelerated approval by the US Food and Drugs Administration for one of these agents (palbociclib). The results of confirmatory phase 3 trials are, however, awaited. We discuss further therapy combinations in development and highlight potential areas for caution including the potential for antagonistic interactions with cytotoxic chemotherapies.

How comprehensive is our comprehensive geriatric assessment in clinical practice? An Irish perspective.

PURPOSE: Comprehensive geriatric assessment (CGA) is the cornerstone of high-quality care for older adults. There is no current gold standard to guide what should be included as the baseline measure for CGAs. We examined what metrics are being captured in CGA baseline assessments completed by community based integrated care teams in Ireland. METHODS: CGA's care pathways in Ireland are usually initiated with a written document that establish patients baseline in various assessment areas. These documents were the focus of this study. We completed a cross-sectional study of the components captured in CGA baseline assessments completed in a community setting. We contacted operational leads in each of the community health organisations in Ireland and requested a copy of their current initial baseline screening document for CGA. RESULTS: We reviewed 16 individual CGA baseline documents for analysis in this study. Common assessment areas in all documents included frailty (with the Rockwood Clinical frailty scale used in 94%, n = 15), cognition (4AT-56% of CGAs, MMSE-25%, MOCA-25%, AMTS-19%, AD8-19%, Addenbrookes-13%, 6CIT-13%, mini cog-6%), mobility (100%, n = 16), falls (100%, n = 16), continence (100% n = 16), nutrition (100% n = 16). Mood (94%, n = 15), pain (44%, n = 7), bone health (63%, n = 10), sleep (62%, n = 10) and skin integrity (56%, n = 9). Formal functional assessment was completed in 94% (n = 15) of CGAs with the Barthel index being the tool most used 81% (n = 13). Half of the CGAs included a section describing carer strain (50%, n = 8). The majority of CGAs included a patient centred question which was some variation of 'what matters most to me' (75% n = 11). 87.5% of assessments included a care plan summary (n = 14). CONCLUSIONS: This report highlights that the core tenets of CGA are being assessed across different community based initial CGA screening instruments. There was significant variability in the discussion of challenging topics such as carer strain and social well-being. Our results should prompt a discussion about whether a minimum dataset should be developed for inclusion in nationwide initial baseline CGA document, aiming to improve standardisation of assessments, which will impact areas highlighted for intervention and ultimately guide population health policy.

Delirium care in hospitals in Ireland on World Delirium Awareness Day 2023.

BACKGROUND: Acute, transient, but sometimes persistent, delirium is characterized by a sharp disruption in attention, consciousness, and cognitive function, and can be caused by many medications and disorders. Delirium occurrence and negative consequences, such as falls and functional decline, can be decreased with multifactorial prevention and timely detection. AIMS: To describe current clinical practice in relation to the prevention, assessment, and management of delirium in Irish hospitals; awareness-raising and educational activities; and barriers to good practice. METHODS: On World Delirium Awareness Day (15th March 2023), a global survey was conducted of delirium prevalence and care. A senior clinical staff member on each participating ward reported on delirium prevalence at 8AM and 8PM, and on usual ward practice; this data was entered into an online survey by a data collector (typically a clinician from the site, visiting several wards to record data). This study reports data from Irish hospitals. RESULTS: In total, 132 wards from 15 hospitals across Ireland participated. Almost 60% of wards used 'personal judgment' for delirium assessment. Having at least one delirium training session in the preceding year was associated with greater use of a formal assessment tool (60.3% versus 18.8%; p < 0.001). Wards reported staff training/education as the main priority to improve care, but 72.7% of wards identified insufficient time to train staff as a key barrier. CONCLUSIONS: Clinical practice related to delirium care requires improvement. Awareness raising and staff training require more focus and time in busy clinical settings.

Falls and fractures in the acute care setting: A retrospective cohort study.

OBJECTIVES: Falls with fracture in hospitalised patients remain a common occurrence with significant morbidity and mortality. Our objectives were to determine the characteristics of patients who suffer falls with fractures in hospital, and to examine whether outcomes in this cohort differ from those of patients who fall without sustaining a fracture. METHODS: Coding data pertaining to a 6-year period (2012-2017) were interrogated. Patients coded as having suffered a fall in hospital during this period were identified and divided into those who did and those who did not suffer fractures due to their fall. Patient demographics and comorbidities were compared between groups and outcome measures examined with descriptive statistics and binary logistic regression. RESULTS: From 236,720 inpatient admissions, 721 falls were recorded, 128 of which were associated with a fracture. Delirium (30% in those who suffered a fracture vs. 21% in those who did not, p < 0.040), dementia (23% vs. 13%, p < 0.004), female sex (53% vs. 44%, p < 0.020) and older age (76.8 vs. 72.8 years, p < 0.010) were associated with falls with fractures in hospital. Falls with fractures were associated with a longer length of inpatient stay by 9.2 days (95% CI 5.5-12.9, p < 0.001) and were an independent predictor of inpatient mortality. CONCLUSIONS: Greater understanding of characteristics of patients at risk of falls with fractures, as well as knowledge of the considerable associated morbidity and mortality, will help to prognosticate when these events occur and, potentially, to put preventative measures in place.

Barriers to brain health behaviours: results from the Five Lives Brain Health Ireland Survey.

Modifiable risk factors for dementia remain prevalent in Ireland. A detailed examination of barriers to risk reduction behaviours in an Irish context has heretofore been lacking. Many existing studies examining barriers to brain health behaviours fail to examine how they might vary across different modifiable risk factors. This study undertook a detailed assessment of barriers to individual risk reduction behaviours. As existing research suggests that barriers may vary across sociodemographic factors, we sought to investigate the distribution of barriers across age, gender, educational status, and household income. The Five Lives Brain Health Ireland Survey is a cross-sectional survey that was distributed online amongst a non-patient population. The survey captured the following: (1) Sociodemographic factors; (2) Barriers to brain health behaviours; (3) Exposure to, and knowledge of, modifiable risk factors for dementia, namely diet, social interaction, exercise, hypertension, sleep, current low mood/depression, current smoking, alcohol consumption, cognitive stimulation, hearing impairment, diabetes, air pollution, and head injury; (4) Participants' perceptions regarding potential for dementia prevention, and risk reduction. Lack of motivation was the most prevalent barrier to consuming a healthy diet (64%, n = 213), physical activity (77.7%, n = 167), smoking cessation (68%, n = 85), and moderation of alcohol intake (56.3%, n = 67). Practical factors were the most prevalent barriers to addressing low mood (56.5%, n = 87), air pollution (30.1%, n = 58), hearing impairment (63.8%, n = 44), diabetes (11.1%, n = 5), and head injury (80%, n = 8). Emotional factors were the most prevalent barriers to engaging in mentally stimulating activity (56.9%, n = 66), social activity (54.9%, n = 302), and good sleep (70.1%, n = 129). Lack of knowledge was the most prevalent barrier to hypertension control (14.4%, n = 29). Distribution of barriers varied across age, gender, educational status, and household income. This study investigated barriers to lifestyle change to improve brain health in an Irish sample of adults aged 50 and above. Detailed subtyping of barriers, as well as examination of differences according to age, gender, education, and income were undertaken. The heterogeneity of barriers to brain health behaviours revealed in this study highlights the necessity to tailor public health interventions to their target population, taking into account the gender, age, educational status, and income of recipients.

Don't call me elderly: a review of medical journals' use of ageist literature.

PURPOSE: Older people do not want to be called 'elderly' (Falconer et al. in BMJ 334: 75-88, 2007). The UN Committee on Economic, Social and Cultural Rights of Older Persons agreed in 1995 that the term 'older persons' is preferred over 'elderly' 'seniors' and 'the aged'. Medical literature may lag behind this trend and continued to refer to older adults by nomenclature that they find stigmatising. We examined the use of stigmatising language in two medical journals.  METHODS: All articles published by Age and Ageing and European Geriatric Medicine from January 2018 to December 2020 were reviewed. The articles were searched for the use of the words 'elderly', 'senior', and 'the aged' as well as 'older'. RESULTS: 383 articles were published in the EGM and 511 in Age and Ageing. In the EGM, 80 articles (20.8%) used stigmatising language. In Age and Ageing, 90 (17.6%) used stigmatising language. CONCLUSION: While progress has been made in reframing the language used in journal articles compared to previous studies (Lundebjerg et al. in J Am Geriatr Soc 65: 1386-1388, 2017), more can be done to ensure our compliance with addressing older adults by their preferred terminology.

"The Wandering Nerve Linking Heart and Mind" - The Complementary Role of Transcutaneous Vagus Nerve Stimulation in Modulating Neuro-Cardiovascular and Cognitive Performance.

The vagus nerve is the longest nerve in the human body, providing afferent information about visceral sensation, integrity and somatic sensations to the CNS via brainstem nuclei to subcortical and cortical structures. Its efferent arm influences GI motility and secretion, cardiac ionotropy, chonotropy and heart rate variability, blood pressure responses, bronchoconstriction and modulates gag and cough responses via palatine and pharyngeal innervation. Vagus nerve stimulation has been utilized as a successful treatment for intractable epilepsy and treatment-resistant depression, and new non-invasive transcutaneous (t-VNS) devices offer equivalent therapeutic potential as invasive devices without the surgical risks. t-VNS offers exciting potential as a therapeutic intervention in cognitive decline and aging populations, classically affected by reduced cerebral perfusion by modulating both limbic and frontal cortical structures, regulating cerebral perfusion and improving parasympathetic modulation of the cardiovascular system. In this narrative review we summarize the research to date investigating the cognitive effects of VNS therapy, and its effects on neurocardiovascular stability.

Modifiable risk factors for dementia, and awareness of brain health behaviors: Results from the Five Lives Brain Health Ireland Survey (FLBHIS).

Up to 40% of dementias globally are attributable to modifiable risk factors. Many existing studies examining attitudes to brain health are limited by a failure to consider a range of pertinent risk factors and associated barriers to protective behaviors. In Ireland, self-reported knowledge of dementia is poor compared to other conditions. In this context, the current study aimed to explore exposure to and awareness of specific modifiable risk factors for dementia. We also aimed to investigate whether exposure to these risk factors is associated with demographic and socioeconomic factors. A cross-sectional survey was administered to 555 voluntary participants in February 2022. The survey captured the following information: (1) Sociodemographic factors; (2) Exposure to, as well as knowledge of modifiable risk factors for dementia, namely diet, social interaction, exercise, hypertension, sleep, depression, smoking, alcohol consumption, cognitive stimulation, hearing impairment, diabetes, air pollution, and head injury. The study population comprised 551 participants (50.3% male; 49.6% female). Mean age was 59.7 years. Modifiable risk factors for dementia were prevalent. Relative to females, male gender was significantly associated with multiple risk factors. Whilst 65.6% of participants believed that lifestyle improvements can decrease a person's risk of developing dementia, only 31.4% believed that dementia could be prevented. Head injury (90.9%, n = 500), low mental stimulation (85.3%, n = 469), and alcohol consumption (77.8%, n = 428) were the three most commonly recognized risk factors. Awareness was significantly greater in both university groups (undergraduate and postgraduate) for multiple risk factors. Our findings demonstrate that the distribution of exposure to modifiable risk factors for dementia is unequal across gender and age groups, and that awareness levels vary across risk factors. These findings highlight that focus surrounding dementia prevention should shift toward individual risk profiling and should be tailored toward an individual's specific needs.