Decreasing the load? Is a Multidisciplinary Multistep Medication Review in older people an effective intervention to reduce a patient's Drug Burden Index? Protocol of a randomised controlled trial

INTRODUCTION: Older people often use medications with anticholinergic or sedative side effects which increase the risk of falling and worsen cognitive impairment. The Drug Burden Index (DBI) is a measure of the burden of anticholinergic and sedative medications. Medication reviews are typically done by a pharmacist in collaboration with a general practitioner to optimise the medication use and reduce these adverse drug events. We will evaluate whether a Multidisciplinary Multistep Medication Review (3MR) is an effective intervention to reduce a patient's DBI. METHODS: A randomised controlled trial including 160 patients from 15 community pharmacies will be conducted. Per pharmacy, 1 pharmacist will perform a structured 3MR in close collaboration with the general practitioner, including the objective to reduce the DBI. ANALYSIS: Primary outcome-the difference in proportion of patients having a decrease in DBI≥0.5 in the intervention and control groups at follow-up. Secondary outcomes-anticholinergic and sedative side effects, falls, cognitive function, activities of daily living, quality of life, hospital admission, and mortality. ETHICS AND DISSEMINATION: The burden of patients will be kept at a minimum. The 3MR can be considered as usual care by the pharmacist and general practitioner. Medical specialists will be consulted, if necessary. The intervention is specifically aimed at older community-dwelling patients in an attempt to optimise prescribing, in particular, to reduce medication with anticholinergic and sedative properties. Study results will be published in peer-reviewed journals and will be distributed through information channels targeting professionals. TRIAL REGISTRATION NUMBER: NCT02317666; Pre-results

Drug Burden Index and Cognitive and Physical Function in Aged Care Residents:A Longitudinal Study

Objectives: Anticholinergic/antimuscarinic and sedative medications (eg, benzodiazepines) have been found to be associated with poorer cognitive and physical function and mobility impairment in older age. However, previous studies were mostly conducted among community-dwelling older individuals and had often a cross-sectional design. Accordingly, our aim was to examine longitudinal associations between cumulative exposure to anticholinergic and sedative medications and cognitive and physical function among residents from aged care homes. Design: Longitudinal study. Setting and Participants: A total of 4624 residents of Dutch aged care homes of whom data were collected between June 2005 and April 2014. Methods: Outcome measures were collected with the Long-Term Care Facilities assessment from the international Residential Assessment Instrument (interRAI-LTCF) and included the Cognitive Performance Scale, the Activities of Daily Living (ADL) Hierarchy scale, a timed 4-meter walk test, distance walked, hours of physical activity, and days being outside. Cumulative exposure to anticholinergic and sedative medications was calculated with the Drug Burden Index (DBI), a linear additive pharmacological dose-response model. Associations were examined with linear mixed models to take the potential dependence of observations into account (ie, data were collected at repeated assessment occasions of residents who were clustered in aged care homes). Analyses were adjusted for sex, age, dementia, comorbidity (neurological, psychiatric, cardiovascular, oncological, and pulmonary), fractures, depressive symptoms, and medications excluded from the DBI. Results: We observed significant longitudinal associations between a higher DBI and poorer ADLs, fewer hours of physical activity, and fewer days being outside. We found no significant longitudinal association between a higher DBI and poorer cognitive function. Conclusions and Implications: Over time, cumulative exposure to anticholinergic and sedative medications is associated with poorer physical but not cognitive function in aged care residents. Careful monitoring of aged care residents with high cumulative anticholinergic and sedative medication exposure is needed

Anticholinergic and Sedative Medications and Dynamic Gait Parameters in Older Patients

BACKGROUND: Anticholinergic and sedative medications are associated with poorer physical function in older age. Gait and physical function have traditionally been assessed with the time needed to execute objective function tests. Accelerometer-based gait parameters provide a precise capturing of gait dynamics and patterns and as such have added value. OBJECTIVES: This study examined the associations between cumulative exposure to anticholinergic and sedative medications and gait dimensions as assessed with accelerometer-based dynamic gait parameters. METHODS: Data were collected from outpatients of a diagnostic geriatric day clinic who underwent a comprehensive geriatric assessment (CGA). Cumulative exposure to anticholinergic and sedative medications was quantified with the Drug Burden Index (DBI), a linear additive pharmacological dose-response model. From a total of 22 dynamic gait parameters, the gait dimensions 'Regularity', 'Complexity', 'Stability', 'Pace', and 'Postural Control' were derived using factor analysis (and standardized total scores for these dimensions were calculated accordingly). Data were analyzed with multivariable linear regression analysis, in which adjustment was made for the covariates age, gender, body mass index (BMI), Mini Mental State Examination (MMSE) score, Charlson Comorbidity Index (CCI) including dementia, and number of medications not included in the DBI. RESULTS: A total of 184 patients participated, whose mean age was 79.8 years (± SD 5.8), of whom 110 (60%) were women and of whom 88 (48%) had polypharmacy (i.e., received treatment with ≥5 medications). Of the 893 medications that were prescribed in total, 157 medications (17.6%) had anticholinergic and/or sedative properties. Of the patients, 100 (54%) had no exposure (DBI = 0), 42 (23%) had moderate exposure (0 > DBI ≤ 1), while another 42 (23%) had high exposure (DBI >1) to anticholinergic and sedative medications. Findings showed that high cumulative exposure to anticholinergic and sedative medications was related with poorer function on the Regularity and Pace dimensions. Furthermore, moderate and high exposure were associated with poorer function on the Complexity dimension. CONCLUSIONS: These findings show that in older patients with comorbidities, cumulative anticholinergic and sedative exposure is associated with poorer function on multiple gait dimensions

Long-term exposure to anticholinergic and sedative medications and cognitive and physical function in later life

Background: Anticholinergic and sedative medications are frequently prescribed to older individuals. These medications are associated with short-term cognitive and physical impairment, but less is known about long-term associations. We therefore examined over twenty years whether cumulative exposure to these medications was related to poorer cognitive and physical functioning. Methods: Older adult participants of the Longitudinal Aging Study Amsterdam (LASA) were followed from 1992-2012. On 7 measurement occasions, cumulative exposure to anticholinergic and sedative medications was quantified with the Drug Burden Index (DBI), a linear additive pharmacological dose-response model. Cognitive functioning was assessed with the Mini Mental State Examination (MMSE), Alphabet Coding Task (ACT, 3 trials), Auditory Verbal Learning Test (AVLT, learning and retention condition), and Raven Colored Progressive Matrices (RCPM, 2 trials). Physical functioning was assessed with the Walking Test (WT), Cardigan Test (CT), Chair Stands Test (CST), Balance Test (BT), and self-reported Functional Independence (FI). Data were analyzed with linear mixed models adjusted for age, education, sex, living with a partner, BMI, depressive symptoms, co-morbidities (cardiovascular disease, diabetes, cancer, COPD, osteoarthritis, CNS diseases), and prescribed medications. Results: Longitudinal associations were found of the DBI with poorer cognitive functioning (less items correct on the 3 ACT trials, AVLT learning condition, and the 2 RCPM trials) and with poorer physical functioning (longer completion time on the CT, CST, and lower self-reported FI). Conclusions: This longitudinal analysis of data collected over 20 years, showed that higher long-term cumulative exposure to anticholinergic and sedative medications was associated with poorer cognitive and physical functioning

Impact of Diabetes on Postinfarction Heart Failure and Left Ventricular Remodeling

Diabetes mellitus, the metabolic syndrome, and the underlying insulin resistance are increasingly associated with diastolic dysfunction and reduced stress tolerance. The poor prognosis associated with heart failure in patients with diabetes after myocardial infarction is likely attributable to many factors, important among which is the metabolic impact from insulin resistance and hyperglycemia on the regulation of microvascular perfusion and energy generation in the cardiac myocyte. This review summarizes epidemiologic, pathophysiologic, diagnostic, and therapeutic data related to diabetes and heart failure in acute myocardial infarction and discusses novel perceptions and strategies that hold promise for the future and deserve further investigation

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

A highly virulent variant of HIV-1 circulating in the Netherlands

We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV-CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences-is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence