Comprehension and recall from the informed consent process by phase I healthy volunteers before dose administration.

AIMS/BACKGROUND: A fundamental part of all clinical trials is informed consent, reflecting the respect for the volunteer's autonomy. Research participation is voluntary; therefore, certain aspects of the proposed study must be disclosed so that volunteers can make an informed decision. In this study, we aimed to examine the level of comprehension and recall of healthy volunteers from the informed consent process. METHODS: The study was carried out at a single phase I clinical trials unit. A questionnaire was administered to each volunteer to assess recall of important aspects of the study at the day-1 visit following the informed consent process. The questionnaire contained seven questions regarding study objectives, route, frequency and type of drug administration, adverse effects, number of subjects previously exposed and remuneration. One point was awarded for each correct answer. RESULTS: A total of 266 volunteers were administered the questionnaire. The mean total score (±standard deviation) for all volunteers was 4.5 ± 1.1 points out of 7, with a range of 0.8-6.7. For all 10 studies, 91% of volunteers responded correctly when answering about the route of administration, and 90% were able to accurately state the correct payment amount. Only 7% were able to repeat the aims of the study correctly. CONCLUSION: The poor performance of our study volunteers raises concerns about recall of information prior to study drug administration. This has implications for the volunteer's safety and ability to provide true informed consent. Interventions to improve recall prior to dosing should be undertaken.

Prevalence and factors associated with polypharmacy in older people with cancer.

PURPOSE: Polypharmacy has been associated with drug-drug interactions, adverse drug events, hospitalisation and increased mortality. The purpose of this study was to investigate the prevalence and factors associated with polypharmacy in older people with cancer. PATIENTS AND METHODS: Patients aged≥70 years (n=385) presenting to the medical oncology outpatient clinic at Royal Adelaide Hospital between January 2009 and July 2010 completed a structured data collection instrument. The instrument included domains related to medications, diagnoses, instrumental activities of daily living (IADLs), Karnofsky Performance Scale (KPS), physical function (SF-36), pain (ten-point visual analogue scale, VAS), weight loss (patient self-reported over previous 6 months), exhaustion (CES-D) and distress (ten-point VAS). Frailty was computed using Fried's frailty phenotype. Logistic regression was used to compute unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between polypharmacy (defined as five or more self-reported daily medications) and clinical parameters. RESULTS: Polypharmacy was present in 57% (n=221) of patients. When adjusting for age, gender and Charlson Comorbidity Index (CCI), polypharmacy was associated with being pre-frail (OR=2.35, 95%CI=1.43-3.86) and frail (OR=4.48, 95%CI=1.90-10.54) compared to being robust. When adjusting for age, gender, exhaustion, KPS, IADLs, pain and distress, polypharmacy was associated with higher CCI scores (OR=1.58, 95%CI=1.29-1.94) and poorer physical function (OR=1.13, 95%CI=1.06-1.20). CONCLUSIONS: Polypharmacy is highly prevalent in older people with cancer and associated with impaired physical function and being pre-frail and frail compared to being robust. Research is needed to identify strategies to minimize patients' medication regimens.

Salivary inflammatory biomarkers are predictive of mild cognitive impairment and Alzheimer's disease in a feasibility study.

Alzheimer's disease (AD) is an insidious disease. Its distinctive pathology forms over a considerable length of time without symptoms. There is a need to detect this disease, before even subtle changes occur in cognition. Hallmark AD biomarkers, tau and amyloid-ß, have shown promising results in CSF and blood. However, detecting early changes in these biomarkers and others will involve screening a wide group of healthy, asymptomatic individuals. Saliva is a feasible alternative. Sample collection is economical, non-invasive and saliva is an abundant source of proteins including tau and amyloid-ß. This work sought to extend an earlier promising untargeted mass spectrometry study in saliva from individuals with mild cognitive impairment (MCI) or AD with age- and gender-matched cognitively normal from the South Australian Neurodegenerative Disease cohort. Five proteins, with key roles in inflammation, were chosen from this study and measured by ELISA from individuals with AD (n = 16), MCI (n = 15) and cognitively normal (n = 29). The concentrations of Cystatin-C, Interleukin-1 receptor antagonist, Stratifin, Matrix metalloproteinase 9 and Haptoglobin proteins had altered abundance in saliva from AD and MCI, consistent with the earlier study. Receiver operating characteristic analysis showed that combinations of these proteins demonstrated excellent diagnostic accuracy for distinguishing both MCI (area under curve = 0.97) and AD (area under curve = 0.97) from cognitively normal. These results provide evidence for saliva being a valuable source of biomarkers for early detection of cognitive impairment in individuals on the AD continuum and potentially other neurodegenerative diseases.

Multi-Omics, an Integrated Approach to Identify Novel Blood Biomarkers of Alzheimer's Disease.

The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer's disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD/MCI pathogenesis is unclear. This study compared the metabolomic and proteomic signature of plasma from cognitively normal (CN) and dementia patients diagnosed with MCI or AD, to identify specific cellular pathways and new biomarkers altered with the progression of the disease. We analysed 80 plasma samples from individuals with MCI or AD, as well as age- and gender-matched CN individuals, by utilising mass spectrometry methods and data analyses that included combined pathway analysis and model predictions. Several proteins clearly identified AD from the MCI and CN groups and included plasma actins, mannan-binding lectin serine protease 1, serum amyloid A2, fibronectin and extracellular matrix protein 1 and Keratin 9. The integrated pathway analysis showed various metabolic pathways were affected in AD, such as the arginine, alanine, aspartate, glutamate and pyruvate metabolism pathways. Therefore, our multi-omics approach identified novel plasma biomarkers for the MCI and AD groups, identified changes in metabolic processes, and may form the basis of a biomarker panel for stratifying dementia participants in future clinical trials.

Salivaomics as a Potential Tool for Predicting Alzheimer's Disease During the Early Stages of Neurodegeneration.

BACKGROUND: The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer's disease (AD) is poorly understood and the relationships between systemic abnormalities in metabolism and AD/AMCI pathogenesis are unclear. OBJECTIVE: The aim of the study was to compare the metabolomic and proteomic signature of saliva from cognitively normal and patients diagnosed with MCI or AD, to identify specific cellular pathways altered with the progression of the disease. METHODS: We analyzed 80 saliva samples from individuals with MCI or AD as well as age- and gender-matched healthy controls. Saliva proteomic and metabolomic analyses were conducted utilizing mass spectrometry methods and data combined using pathway analysis. RESULTS: We found significant alterations in multiple cellular pathways, demonstrating that at the omics level, disease progression impacts numerous cellular processes. Multivariate statistics using SIMCA showed that partial least squares-data analysis could be used to provide separation of the three groups. CONCLUSION: This study found significant changes in metabolites and proteins from multiple cellular pathways in saliva. These changes were associated with AD, demonstrating that this approach might prove useful to identify new biomarkers based upon integration of multi-omics parameters.

Frailty and Co-Prescribing of Potentially Interacting Drugs in New Users of Warfarin.

BACKGROUND: Warfarin is underutilised in frail older people because of the fear of bleeding complications. Drug interactions are an independent bleeding risk factor. However, the extent to which potential drug interactions are taken into account at warfarin therapy initiation in frail patients is not known. OBJECTIVE: The objective of this study was to investigate the use of potentially interacting drugs increasing the bleeding risk before and after warfarin initiation in frail and non-frail patients. METHODS: We conducted an observational study including inpatients aged ≥ 60 years initiated on warfarin in a tertiary hospital in Adelaide, South Australia. Frailty status was assessed with the Reported Edmonton Frail Scale. Medication charts were reviewed before and after warfarin initiation. RESULTS: In total, 151 patients (102 non-frail and 49 frail) were included. Before warfarin initiation, the use of clopidogrel and acetaminophen was more common in frail patients compared with non-frail patients (25.5% vs 10.2%, p = 0.0135, 63.8% vs 35.7% p = 0.0014, respectively). The use of non-steroidal anti-inflammatory drugs, 9.2% in non-frail patients and 6.4% in frail patients before warfarin initiation, was completely stopped after warfarin initiation in both groups. The use of antiplatelet drugs decreased from 56.1% in non-frail patients and 66.0 % in frail patients to 12.2% and 14.9%, respectively. Instead, the use of drugs affecting the metabolism of warfarin or vitamin K increased in both groups. No statistically significant difference was seen in the exposure to interacting drugs between study groups after warfarin initiation. Acetaminophen, senna glycosides and cytochrome P450 2C9 inhibiting drugs were the most common interacting drugs at discharge used in 49.0%, 18.4% and 20.4% of non-frail patients and 53.2%, 29.8% and 19.1% of frail patients, respectively. CONCLUSIONS: The overall frequency of potential drug interactions was moderate and frail patients were not exposed to warfarin drug interactions more often than non-frail patients. Further studies in larger study populations are required to verify these results.

Influence of stroke and bleeding risk on prescribing of oral anticoagulants in older inpatients; has the availability of direct oral anticoagulants changed prescribing?

BACKGROUND: Little is known about changes in prescribing practices in Australia since the introduction of the direct oral anticoagulants (DOACs). Our objective was to examine if the availability of DOACs has coincided with a change in prescribing of oral anticoagulants in older hospital inpatients with regard to risk factors for stroke and bleeding. METHODS: A prospective observational study was conducted between October 2012 and August 2015 of inpatients aged over 60 years initiated on an oral anticoagulant in a large metropolitan, tertiary referral, public teaching hospital in Australia. Treatment groups were patients who commenced an oral anticoagulant prior to inclusion of DOACs on the formulary and those who commenced after the introduction of DOACs. Subgroup analyses were conducted in patients with atrial fibrillation (AF). Differences in clinical characteristics and risk for stroke and bleeding were calculated using the CHADS2 and HAS-BLED scores, respectively, were examined. RESULTS: A total of 289 patients were included. Inpatients prescribed an oral anticoagulant after the introduction of DOACs were significantly older, a greater proportion were female and more likely to have had a prior stroke. This was associated with a statistically higher CHADS2 score in the post-DOAC group. Similar findings were observed when limiting the sample to patients with AF. Patients with AF who were at greatest likelihood of having a bleeding event were less likely to be treated with a DOAC. CONCLUSION: Since the introduction of the DOACs, patients who may have previously received no therapy or suboptimal treatment were now more likely to be receiving anticoagulation, suggesting an appropriate change in prescribing practice.

Clinician agreement and influence of medication-related characteristics on assessment of polypharmacy.

It is not known how clinicians assess polypharmacy or the medication-related characteristics that influence their assessment. The aim of this study was to examine the level of agreement between clinicians when assessing polypharmacy and to identify medication-related characteristics that influence their assessment. Twenty cases of patients with varying levels of comorbidity and polypharmacy were used to examine clinician assessment of polypharmacy. Medicine-related factors within the cases included Beers and STOPP Criteria medicines, falls-risk medicines, drug burden index (DBI) medicines, medicines causing postural hypotension, and pharmacokinetic drug-drug interactions. Clinicians were asked to rate cases on the degree of polypharmacy, likelihood of harm, and potential for the medication list to be simplified. Inter-rater reliability analysis, correlations, and multivariate logistic regression analyses were conducted to identify medicine factors associated with clinicians' assessment. Eighteen expert clinicians were recruited (69.2% response rate). Strong agreement was observed in clinicians' assessment of polypharmacy (intraclass correlation coefficients [ICC] = 0.94), likelihood to cause harm (ICC = 0.89), and ability to simplify medication list (ICC = 0.90). Multivariate analyses demonstrated number of medicines (P < 0.0001) and DBI scores (P = 0.047) were significantly associated with assessment of polypharmacy. Medicines associated with harm were significantly associated with the number of medicines (P = 0.01) and Beers criteria medicines (P = 0.003). Ability to simplify the medication regimen was significantly associated with number of medicines (P = 0.03) and medicines from the STOPP criteria (P = 0.018). Among clinicians, strong consensus exists with regard to assessment of polypharmacy, medication harm, and ability to simplify medications. Definitions of polypharmacy need to take into account not only the numbers of medicines but also potential for medicines to cause harm or be inappropriate, and validate them against clinical outcomes.

Analgesic Use and Pain in Robust, Pre-Frail and Frail Older Outpatients with Cancer.

BACKGROUND: Pain management can be challenging in frail older people with cancer due to drug-drug interactions and heightened susceptibility to adverse drug events. OBJECTIVE: To investigate the relationship between analgesic use and pain by frailty status in older outpatients with cancer. METHODS: A total of 385 consecutive patients aged 70 years and over who presented to an outpatient oncology clinic between January 2009 and July 2010 completed structured assessments of analgesic use (opioids, paracetamol or non-steroidal anti-inflammatory drugs), pain (10-point visual analogue scale) and clinical factors. Frailty was derived using modified Fried's frailty phenotype. Logistic regression was used to compute adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) for the relationship between analgesic use and pain for each frailty group (robust, pre-frail or frail). RESULTS: For robust outpatients (n = 101), there was weak evidence for a 30 % relative increase in the adjusted odds of analgesic use between outpatients who differed by one unit of pain score (95 % CI 0.995-1.71, p = 0.0532). For pre-frail outpatients (n = 190), there was evidence for a negative quadratic relationship (adjusted OR for the quadratic coefficient: 0.952, 95 % CI 0.910-0.993, p = 0.0244). For frail outpatients (n = 94), there was an 8 % relative increase in the adjusted odds of analgesic use between outpatients who differed by one unit of pain score, but no statistical evidence for association (95 % CI 0.934-1.26; p = 0.298). CONCLUSIONS: These findings can be considered for the ongoing development of safe, effective strategies for analgesic use in older outpatients with cancer.

Statin use and pain in older people with cancer: a cross-sectional study.

OBJECTIVES: To investigate statin use and pain in people with cancer aged 70 to 79 and 80 and older. DESIGN: Cross-sectional. SETTING: Medical oncology outpatient clinic at the Royal Adelaide Hospital. PARTICIPANTS: Individuals aged 70 and older who presented consecutively between January 2009 and June 2010 (n = 385), of whom 106 were aged 80 and older. MEASUREMENTS: Participants completed a structured data collection instrument, documenting medication use, comorbidities and a general pain assessment (10-point visual analogue scale (VAS)). Unadjusted and adjusted logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with statin use. RESULTS: The prevalence of statin use was 35% (n = 97) in people aged 70 to 79 and 39% (n = 41) in those aged 80 and older. After adjusting for age, sex, Charlson Comorbidity Index, and analgesic use, statin use was associated with self-reported pain (VAS ≥ 5) (OR = 4.09, 95% CI = 1.32-12.68) in people aged 80 and older but not in those aged 70 to 79. Half of participants using statins (51% n = 70) had a palliative treatment approach. Of the 41 statin users aged 80 and older, 20 (49%) were using statins for primary prevention. CONCLUSION: The prevalence of statin use was similar in people aged 70 to 79 years and those aged 80 and older, with statin use associated with self-reported pain in people aged 80 and older. This highlights a potential benefit of "deprescribing" statins in older people with cancer, especially those aged 80 and older.

Potentially inappropriate medication use in older people with cancer: prevalence and correlates.

OBJECTIVES: Potentially inappropriate medication (PIM) use has been associated with an increase in adverse drug events, hospitalization and mortality. This study investigated the prevalence and factors associated with PIM use in patients presenting to a medical oncology outpatient clinic. MATERIALS AND METHODS: Consecutive patients (n=385) aged ≥ 70 years referred to a medical oncology outpatient clinic between January 2009 and July 2010 completed a structured data collection instrument. The instrument assessed medication use, diagnoses, self-reported falls in the previous six months, pain (10-point visual analog scale [VAS]) and distress (10-point VAS). Frailty was defined using exhaustion, weight loss, Karnofsky Performance Scale, instrumental activities of daily living and physical function. PIM use was defined by the Beers Criteria. Logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with PIM use. RESULTS: In total, 26.5% (n=102) of the sample used ≥1 PIM. The five most prevalent classes of PIMs were benzodiazepines (n=34, 8.8%), tricyclic antidepressants (n=16, 4.2%), alpha-adrenoreceptor antagonists (prazosin) (n=15, 3.9%), propulsives (metoclopramide) (n=15, 3.9%) and non-steroidal anti-inflammatory drugs (n=14, 3.6%). In multivariate analyses, PIM use was associated with age 75-79 years (OR 1.83; 95%CI 1.02-3.26) compared to age 70-74 years, using ≥ 5 medications (OR 4.10; 95%CI 2.26-7.44) compared to <5 medications and being frail (OR 3.05; 95%CI 1.18-7.87) compared to being robust. CONCLUSION: More than one quarter of older people with cancer used one or more PIMs, and this was associated with being frail compared to being robust.