Cooperation between geriatricians and general practitioners for improved pharmacotherapy in home-dwelling elderly people receiving polypharmacy - the COOP Study : study protocol for a cluster randomised controlled trial

Background: Polypharmacy and inappropriate drug use is associated with negative health outcomes among older people. Various interventions for improving drug treatment have been evaluated, but the majority of studies are limited by the use of surrogate outcomes or suboptimal design. Thus, the potential for clinically significant improvements from different interventions is still unclear. The main objective of this study is therefore to evaluate the effect upon patient-relevant endpoints of a cooperation between geriatricians and general practitioners on complex drug regimens in home-dwelling elderly people. Methods: This is a cluster randomised, single-blind, controlled trial where general practitioners are invited to participate with patients from their lists. The patients must be 70 years or older, use at least seven different medications and have their medications administered by the home nursing service. We plan to recruit 200 patients, with randomisation at physician level. The intervention consists of three main parts: ( 1) clinical geriatric assessment of the patient, combined with a thorough review of their medications; ( 2) a meeting between the geriatrician and general practitioner, where the two physicians combine their competence and knowledge and discuss the drug list systematically; ( 3) clinical follow-up, depending on the medication changes that have been done. The study period is 24 weeks, and the patients are assessed at baseline, 16 and 24 weeks. The primary outcome measure is health-related quality of life according to the 15D instrument. Secondary outcome measures include physical and cognitive functioning, medication appropriateness, falls, carer burden, use of health services ( hospital or nursing home admissions, use of home nursing services) and mortality. Discussion: Our choice of patient-relevant outcome measures will hopefully provide new knowledge on the potential for clinical improvements after performing comprehensive medication reviews in home-dwelling elderly people receiving polypharmacy.Peer reviewe

Effect of Clinical Geriatric Assessments and Collaborative Medication Reviews by Geriatrician and Family Physician for Improving Health-Related Quality of Life in Home-Dwelling Older Patients Receiving Polypharmacy: A Cluster Randomized Clinical Trial.

IMPORTANCE Polypharmacy and inappropriate drug regimens are major health concerns among older adults. Various interventions focused on medication optimization strategies have been carried out, but the effect on patient-relevant outcomes remains uncertain. Objective To investigate the effect of clinical geriatric assessments and collaborative medication reviews by geriatrician and family physician (FP) on health-related quality of life and other patient-relevant outcomes in home-dwelling older patients receiving polypharmacy. Design, Setting, and Participants Cluster randomized, single-blind, clinical trial. Norwegian FPs were recruited from March 17, 2015, to March 16, 2017, to participate in the trial with their eligible patients. Participants were home-dwelling patients 70 years or older, using at least 7 medications regularly, and having their medications administered by the home nursing service. Patients in the control group received usual care. Randomization occurred at the FP level. A modified intent-to-treat analysis was used. Intervention The intervention consisted of 3 main parts: (1) clinical geriatric assessment of the patients combined with a thorough review of their medications; (2) a meeting between the geriatrician and the FP; and (3) clinical follow-up. Main Outcomes and Measures The primary outcome was health-related quality of life as assessed by the 15D instrument (score range, 0-1; higher scores indicate better quality of life, with a minimum clinically important change of +/- 0.015) at week 16. Secondary outcomes included changes in medication appropriateness, physical and cognitive functioning, use of health services, and mortality. Results Among 174 patients (mean [SD] age, 83.3 [7.3] years; 67.8% women; 87 randomized to the intervention group and 87 randomized to the control [usual care] group) in 70 FP clusters (36 intervention and 34 control), 158 (90.8%) completed the trial. The mean (SD) 15D instrument score at baseline was 0.708 (0.121) in the intervention group and 0.714 (0.113) in the control group. At week 16, the mean (SD) 15D instrument score was 0.698 (0.164) in the intervention group and 0.655 (0.184) in the control group, with an estimated between-group difference of 0.045 (95% CI, 0.004-0.086; P = .03). Several secondary outcomes were also in favor of the intervention. There were more drug withdrawals, reduced dosages, and new drug regimens started in the intervention group. Conclusions and Relevance This study's findings indicate that, among older patients exposed to polypharmacy, clinical geriatric assessments and collaborative medication reviews carried out by a geriatrician in cooperation with the patient's FP can result in positive effects on health-related quality of life.Peer reviewe

Impact of White Matter Lesions on Cognition in Stroke Patients Free from Pre-Stroke Cognitive Impairment: A One-Year Follow-Up Study

Background/Aim: Post-stroke cognitive impairment and dementia may be caused by pure vascular, pure degenerative or mixed disease. The relation between post-stroke cognitive impairment and the combination of vascular pathology and degenerative changes is less evaluated. We aimed to evaluate the associations between white matter lesions (WMLs) and patient performance 1 year after stroke on tests of executive functioning, memory and visuospatial function, adjusted for the effects of lifestyle and disease-related factors, including medial temporal lobe atrophy (MTLA). Methods: Patients with a first-ever stroke or transient ischemic attack were invited to participate in the study. The associations between the cognitive test performances and WMLs were studied using linear regression [Trail Making Test B (TMT B) and 10-word test] and logistic regression (Clock Drawing Test). Results: In total, 199 patients completed the follow-up. The TMT B (p = 0.029) and the 10-word test (p = 0.014) were significantly associated with WMLs; however, the Clock Drawing Test (p = 0.19) was not. The TMT B (p = 0.018) and the 10-word test (p ≤ 0.001) were both significantly associated with MTLA. Conclusion: Impaired executive functioning and memory are significantly associated with WMLs and MTLA. The mechanisms explaining post-stroke cognitive impairment are multifactorial, including different types of vascular pathology and coexisting vascular and degenerative changes

Identifying future study designs for mental health and social wellbeing associated with diets of a cohort living in eco-regions:findings from the INSUM Expert Workshop

Diets influence our mental health and social wellbeing (MHSW) in multiple ways. A rising community concept, Eco-Regions, has gained interest. The research project “Indicators for assessment of health effects of consumption of sustainable, organic school meals in Ecoregions” (INSUM) aims to develop future-oriented research approaches to measure the potential health effects of more sustainable and healthy diets. This first part of the project focuses on MHSW with the goal to identify suitable study designs and indicators. The methodology is based on a 2-day workshop with an interdisciplinary group of experts. This paper describes commonly applied research methods on the nexus between diet and MHSW as presented by the experts and summarises key points from the discussions. The results show that the dominating tool to investigate MSHW is questionnaires. Questionnaires vary largely depending on the research design, such as participants or distribution channels. Cohort studies addressing families and including in-depth interventional and/or experimental studies may be suitable for an Eco-Region investigation. Those MHSW studies can be conducted and combined with measurements of somatic health effects. We conclude that indicators should be seen as complementary rather than independent. Explorative research designs are required to investigate complex Eco-Regions

Prescribed Doses of CYP2D6-Metabolized Drugs and Hemodynamic Responses in Relation to CYP2D6 Genotype Among Older Patients Exposed to Polypharmacy

Background: Many drugs with dose-dependent effects on hemodynamic variables are metabolized by cytochrome P450 2D6 (CYP2D6). The aim of this study was to compare prescribed dosages and hemodynamic responses of such drugs in relation to pharmacogenetic variability in CYP2D6 metabolism among patients aged ≥ 70 years exposed to polypharmacy. Materials and methods: We included 173 patients with detailed information about drug use. The patients were retrospectively subjected to CYP2D6 genotyping, which comprised the most common variant alleles encoding reduced, absent, or increased CYP2D6 metabolism. In order to compare dosages across different CYP2D6-metabolized drugs, all prescribed daily doses were harmonized to the 'percent of a daily defined dose' (DDD). The mean harmonized DDD was compared between genotype-predicted normal metabolizers (NMs) and patients with reduced or absent CYP2D6 enzyme activity, defined as intermediate or poor metabolizers (IMs/PMs). Blood pressure, pulse, and patient proportions with orthostatism and bradycardia were also compared between genotype subgroups. Results: The genotype-predicted phenotype subgroups comprised 79 NMs (45.7%), 75 IMs (43.4%), and 16 PMs (9.2%). There were no differences in dosing of CYP2D6 substrates between NMs and IMs/PMs (p = 0.76). A higher proportion of CYP2D6 IMs/PMs experienced orthostatism (p = 0.03), while there were no significant subgroup differences for the other hemodynamic variables. Conclusion: In this real-life clinical setting of patients aged ≥ 70 years, dosing of CYP2D6 substrates were not adjusted according to genotype-predicted CYP2D6 metabolism. The increased occurrence of orthostatism in patients with reduced/absent CYP2D6 metabolism may indicate that individualized dosing based on genotype has the potential to prevent adverse effects in these vulnerable patients

Novel nucleotide-packaging vaccine delivers antigen and poly(I:C) to dendritic cells and generate a potent antibody response in vivo

An issue with many current vaccines is the dependency on broadly inflammatory adjuvants, such as aluminum hydroxide or aluminum salts that affect many immune- and non-immune cells. These adjuvants are not necessarily activating all antigen-presenting cells (APCs) that take up the antigen and most likely they also activate APCs with no antigen uptake, as well as many non-immune cells. Conjugation of antigen and adjuvant would enable the use of smaller amounts of adjuvant and avoid unnecessary tissue damage and activation of bystander cells. It would ensure that all APCs that take up the antigen would also become activated and avoid that immature and non-activated APCs present the antigen to T cells without a co-stimulatory signal, leading to tolerogenesis. We have developed a novel vaccine that co-deliver antigen and a nucleotide adjuvant to the same APC and lead to a strong activation response in dendritic cells and macrophages. The vaccine is constructed as a fusion-protein with an antigen fused to the DNA/RNA-binding domain from the Hc2 protein from Chlamydia trachomatis. We have found that the fusion protein is able to package polyinosinic:polycytidylic acid (poly(I:C)) or dsDNA into small particles. These particles were taken up by macrophages and dendritic cells and led to strong activation and maturation of these cells. Immunization of mice with the fusion protein packaged poly(I:C) led to a stronger antibody response compared to immunization with a combination of poly(I:C) and antigen without the Hc2 DNA/RNA-binding domain.</p

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I-IV primary CRCs by gene expression (n = 403) or immunohistochemistry (n = 642) and in relation to 5-year relapse-free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX2 was prognostic only in stage IV, independent of chemotherapy. Among stage I-III patients not treated in an adjuvant setting, CDX2 loss was associated with a particularly poor survival in the BRAF-mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes. In stage III, the 5-year RFS rate was higher among patients with loss of CDX2 who received adjuvant chemotherapy than among patients who did not. The CDX2-negative cell lines were significantly more sensitive to chemotherapeutics than CDX2-positive cells, and the multidrug resistance genes MDR1 and CFTR were significantly downregulated both in CDX2-negative cells and in patient tumors. Loss of CDX2 in CRC is an adverse prognostic biomarker only in stage IV disease and appears to be associated with benefit from adjuvant chemotherapy in stage III. Early-stage patients not qualifying for chemotherapy might be reconsidered for such treatment if their tumor has loss of CDX2 and mutated BRAF.Peer reviewe