Multiple Instance Learning Improves Ames Mutagenicity Prediction for Problematic Molecular Species.

The prediction of Ames mutagenicity continues to be a concern in both regulatory and pharmacological toxicology. Traditional quantitative structure-activity relationship (QSAR) models of mutagenicity make predictions based on molecular descriptors calculated on a chemical data set used in their training. However, it is known that molecules such as aromatic amines can be non-mutagenic themselves but metabolically activated by S9 rodent liver enzyme in Ames tests forming molecules such as iminoquinones or amine substituents that better stabilize mutagenic nitrenium ions in known pathways of mutagenicity. Modern in silico modeling methods can implicitly model these metabolites through consideration of the structural elements relevant to their formation but do not include explicit modeling of these metabolites' potential activity. These metabolites do not have a known individual mutagenicity label and, in their current state, cannot be fitted into a traditional QSAR model. Multiple instance learning (MIL) however can be applied to a group of metabolites and their parent under a single mutagenicity label. Here we trained MIL models on Ames data, first with an aromatic amines data set (n = 457), a class known to require metabolic activation, and subsequently on a larger data set (n = 6505) incorporating multiple molecular species. MIL was shown to be able to predict Ames mutagenicity with performance in line with previously established models (balanced accuracy = 0.778), suggesting its potential utility in Ames prediction applications. Furthermore, the MIL model predicted well on identified hard-to-predict molecule groups relative to the models in which these molecule groups were identified. These results are presumably due to the increased consideration of the metabolic contribution to the mutagenic outcome. Further exploration of MIL as a supplement to existing models could aid in the prediction of chemicals where implicit modeling of metabolites cannot fully grasp their characteristics. This paper demonstrates the potential of an MIL approach to modeling Ames tests with S9 and is particularly relevant to metabolically activated xenobiotic mutagens.

Mechanistic Task Groupings Enhance Multitask Deep Learning of Strain-Specific Ames Mutagenicity.

The Ames test is a gold standard mutagenicity assay that utilizes various Salmonella typhimurium strains with and without S9 fraction to provide insights into the mechanisms by which a chemical can mutate DNA. Multitask deep learning is an ideal framework for developing QSAR models with multiple end points, such as the Ames test, as the joint training of multiple predictive tasks may synergistically improve the prediction accuracy of each task. This work investigated how toxicology domain knowledge can be used to handcraft task groupings that better guide the training of multitask neural networks compared to a naïve ungrouped multitask neural network developed on a complete set of tasks. Sixteen S. typhimurium ± S9 strain tasks were used to generate groupings based on mutagenic and metabolic mechanisms that were reflected in correlation data analyses. Both grouped and ungrouped multitask neural networks predicted the 16 strain tasks with a higher balanced accuracy compared with single task controls, with grouped multitask neural networks consistently featuring incremental increases in predictivity over the ungrouped approach. We conclude that the main variable driving these performance improvements is the general multitask effect with mechanistic task groupings acting as an enhancement step to further concentrate synergistic training signals united by a common biological mechanism. This approach enables incorporation of toxicology domain knowledge into multitask QSAR model development allowing for more transparent and accurate Ames mutagenicity prediction.

An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials.

The Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite, Plasmodium falciparum, by targeting PfATP4, an essential ion pump on the parasite surface. The structure of PfATP4 has not been determined. Here, we describe a public competition created to develop a predictive model for the identification of PfATP4 inhibitors, thereby reducing project costs associated with the synthesis of inactive compounds. Competition participants could see all entries as they were submitted. In the final round, featuring private sector entrants specializing in machine learning methods, the best-performing models were used to predict novel inhibitors, of which several were synthesized and evaluated against the parasite. Half possessed biological activity, with one featuring a motif that the human chemists familiar with this series would have dismissed as "ill-advised". Since all data and participant interactions remain in the public domain, this research project "lives" and may be improved by others.

Heart Rate Variability in Children With Autism Spectrum Disorder and Associations With Medication and Symptom Severity.

Decreased heart rate variability (HRV) is considered a common marker of autonomic dysfunction that contributes to poor health outcomes. While some studies have suggested that children with autism spectrum disorder (ASD) show reduced HRV, research is yet to consider whether this may be associated with medication use and symptom severity. This study examined the relationship between resting state HRV, medication use and symptom severity in children diagnosed with ASD. Children with ASD (N = 86), aged between 3 and 12 years (M = 8.09), were compared to 44 neurotypical children of similar age (M = 7.15). Laboratory assessment of HRV involved 5 min of non-invasive baseline electrocardiogram assessments while participants viewed an age-appropriate non-verbal animated video. Time-domain and frequency-domain HRV measures were analyzed. ASD symptom severity was assessed using the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) and Social Responsiveness Scale (SRS-2). Results indicated that children with ASD exhibited reduced resting HRV relative to neurotypical children. Subsequent analyses within the ASD group suggested that this group difference was greater in children who were taking psychotropic medication (N = 36). Our data also provides tentative evidence of a relationship between HRV and social impairment symptoms in children with ASD, with more severe repetitive behaviors (as measured by the ADOS-2) associated with decreased resting HRV. Overall, these findings suggest that HRV may be atypical in children with ASD and suggest the importance of exploring HRV as a risk factor for cardiovascular health in this group. LAY SUMMARY: Cardiac activity, such as heart rate variability (HRV), can provide insight into the autonomic nervous system. This study reports on the association between resting-state HRV and autonomic nervous system activity in young children with autism spectrum disorder (ASD) compared to neurotypical children. These results may help us understand what underlies autonomic nervous system dysfunction and the potential pathophysiological mechanisms leading to increased cardiovascular risk in ASD.

A comparison of molecular representations for lipophilicity quantitative structure-property relationships with results from the SAMPL6 logP Prediction Challenge.

Effective representation of a molecule is required to develop useful quantitative structure-property relationships (QSPR) for accurate prediction of chemical properties. The octanol-water partition coefficient logP, a measure of lipophilicity, is an important property for pharmacological and toxicological endpoints used in the pharmaceutical and regulatory spheres. We compare physicochemical descriptors, structural keys, and circular fingerprints in their ability to effectively represent a chemical space and characterise molecular features to correlate with lipophilicity. Exploratory landscape continuity analyses revealed that whole-molecule physicochemical descriptors could map together compounds that were similar in both molecular features and logP, indicating higher potential for use in logP QSPRs compared to the substructural approach of structural keys and circular fingerprints. Indeed, logP QSPR models parameterised by physicochemical descriptors consistently performed with the lowest error. Our best performing model was a stochastic gradient descent-optimised multilinear regression with 1438 descriptors, returning an internal benchmark RMSE of 1.03 log units. This corroborates the well-established notion that lipophilicity is an additive, whole-molecule property. We externally tested the model by participating in the 2019 SAMPL6 logP Prediction Challenge and blindly predicting for 11 protein kinase inhibitor fragment-like molecules. Our model returned an RMSE of 0.49 log units, placing eighth overall and third in the empirical methods category (submission ID 'hdpuj'). Permutation feature importance analyses revealed that physicochemical descriptors could characterise predictive molecular features highly relevant to the kinase inhibitor fragment-like molecules.

LogP prediction performance with the SMD solvation model and the M06 density functional family for SAMPL6 blind prediction challenge molecules.

This work presents a quantum mechanical model for predicting octanol-water partition coefficients of small protein-kinase inhibitor fragments as part of the SAMPL6 LogP Prediction Challenge. The model calculates solvation free energy differences using the M06-2X functional with SMD implicit solvation and the def2-SVP basis set. This model was identified as dqxk4 in the SAMPL6 Challenge and was the third highest performing model in the physical methods category with 0.49 log Root Mean Squared Error (RMSE) for predicting the 11 compounds in SAMPL6 blind prediction set. We also collaboratively investigated the use of empirical models to address model deficiencies for halogenated compounds at minimal additional computational cost. A mixed model consisting of the dqxk4 physical and hdpuj empirical models found improved performance at 0.34 log RMSE on the SAMPL6 dataset. This collaborative mixed model approach shows how empirical models can be leveraged to expediently improve performance in chemical spaces that are difficult for ab initio methods to simulate.

Effect of GABA-Fortified Oolong Tea on Reducing Stress in a University Student Cohort.

GABA-containing tea has gained popularity as an accessible intervention to reduce the impact of chronic stress-induced autonomic imbalance and increased risk for cardiovascular disease despite a lack of evidence concerning the γ-aminobutyric acid (GABA) content in a cup of the tea and its effects on physiological and psychological stress as measures of cognitive function. We aimed to measure the effects of GABA-fortified tea consumption on heart rate variability (HRV) and stress in 30 participants using a pre-post cohort study design. Ten minute lead II ECG recordings were analyzed with Kubios software. Frequency domain parameters including total power, high and low frequency power, along with heart rate, were determined. A control group that consumed a non-fortified tea was included in the research. Statistical analysis was by two-way ANOVA for two-group comparison with time as an interaction and a significance level of p < 0.05. Oolong tea consumption led to a significant decrease in the immediate stress score and a significant improvement in HRV. We conclude that autonomic imbalance and HRV in people with acute stress is significantly reduced following a cup of GABA fortified oolong tea and highlights the complex interaction between autonomic nervous system function and mood.

Differences in LC3B expression and prognostic implications in oropharyngeal and oral cavity squamous cell carcinoma patients.

BACKGROUND: This study examined the prognostic significance of microtubule-associated protein light chain 3B (LC3B) expression in oropharyngeal and oral cavity squamous cell carcinoma (SCC). The prognostic significance of LC3B expression in relation to human papillomavirus (HPV) status in oropharyngeal SCC was also examined. METHODS: Tissue microarrays (TMAs) were constructed from formalin-fixed, paraffin-embedded oropharyngeal (n = 47) and oral cavity (n = 95) SCC tissue blocks from patients with long-term recurrence and overall survival data (median = 47 months). LC3B expression on tumour was assessed by immunohistochemistry and evaluated for associations with clinicopathological variables. LC3B expression was stratified into high and low expression cohorts using ROC curves with Manhattan distance minimisation, followed by Kaplan-Meier and multivariable survival analyses. Interaction terms between HPV status and LC3B expression in oropharyngeal SCC patients were also examined by joint-effects and stratified analyses. RESULTS: Kaplan-Meier survival and univariate analyses revealed that high LC3B expression was correlated with poor overall survival in oropharyngeal SCC patients (p = 0.007 and HR = 3.18, 95% CI 1.31-7.71, p = 0.01 respectively). High LC3B expression was also an independent prognostic factor for poor overall survival in oropharyngeal SCC patients (HR = 4.02, 95% CI 1.38-11.47, p = 0.011). In contrast, in oral cavity SCC, only disease-free survival remained statistically significant after univariate analysis (HR = 2.36, 95% CI 1.19-4.67, p = 0.014), although Kaplan-Meier survival analysis showed that high LC3B expression correlated with poor overall and disease-free survival (p = 0.046 and 0.011 respectively). Furthermore, oropharyngeal SCC patients with HPV-negative/high LC3B expression were correlated with poor overall survival in both joint-effects and stratified presentations (p = 0.024 and 0.032 respectively). CONCLUSIONS: High LC3B expression correlates with poor prognosis in oropharyngeal and oral cavity SCC, which highlights the importance of autophagy in these malignancies. High LC3B expression appears to be an independent prognostic marker for oropharyngeal SCC but not for oral cavity SCC patients. The difference in the prognostic significance of LC3B between oropharyngeal and oral cavity SCCs further supports the biological differences between these malignancies. The possibility that oropharyngeal SCC patients with negative HPV status and high LC3B expression were at particular risk of a poor outcome warrants further investigation in prospective studies with larger numbers.

QSAR ligand dataset for modelling mutagenicity, genotoxicity, and rodent carcinogenicity.

Five datasets were constructed from ligand and bioassay result data from the literature. These datasets include bioassay results from the Ames mutagenicity assay, Greenscreen GADD-45a-GFP assay, Syrian Hamster Embryo (SHE) assay, and 2 year rat carcinogenicity assay results. These datasets provide information about chemical mutagenicity, genotoxicity and carcinogenicity.

Combining machine learning models of in vitro and in vivo bioassays improves rat carcinogenicity prediction.

In vitro genotoxicity bioassays are cost-efficient methods of assessing potential carcinogens. However, many genotoxicity bioassays are inappropriate for detecting chemicals eliciting non-genotoxic mechanisms, such as tumour promotion, this necessitates the use of in vivo rodent carcinogenicity (IVRC) assays. In silico IVRC modelling could potentially address the low throughput and high cost of this assay. We aimed to develop and combine computational QSAR models of novel bioassays for the prediction of IVRC results and compare with existing software. QSAR models were generated from existing Ames (n = 6512), Syrian Hamster Embryonic (SHE, n = 410), ISSCAN rodent carcinogenicity (ISC, n = 834) and GreenScreen GADD45a-GFP (n = 1415) chemical datasets. These models mapped the molecular descriptors of each compound to their respective assay result using machine learning algorithms (adaboost, k-Nearest Neighbours, C.45 Decision Tree, Multilayer Perceptron, Random Forest). The best performing models were combined with k-Nearest Neighbours to create a cascade model for IVRC prediction. High QSAR model performance was observed from ten time 10-fold cross-validation with above 80% accuracy and 0.85 AUC for each assay dataset. The cascade model predicted rat carcinogenicity with 69.3% accuracy and 0.700 AUC. This study demonstrates the novelty of a combined approach for IVRC prediction, with higher performance than existing software.

Differences in survival outcome between oropharyngeal and oral cavity squamous cell carcinoma in relation to HPV status.

BACKGROUND: This study examined the prognostic significance of human papillomavirus (HPV) in patients with oropharyngeal and oral cavity squamous cell carcinoma (SCC). METHODS: Tissue microarrays were constructed from oropharyngeal and oral cavity SCC (n = 143). The presence of functional HPV in tumour was determined by combined assessments of p16 immunohistochemistry and HPV in situ hybridisation. RESULTS: Oropharyngeal SCC patients presented with more advanced disease in comparison with oral cavity SCC patients (P = 0.001). HPV is present in 60% and 61% of oropharyngeal and oral cavity SCC patients, respectively. HPV-positive oropharyngeal SCC patients with advanced TNM stages displayed better overall and disease-free survival outcomes than HPV-negative patients (P = 0.022 and 0.046, respectively). Such survival differences were not observed in oral cavity SCC. CONCLUSIONS: HPV is common in both oropharyngeal and oral cavity SCC and is associated with better survival outcome in oropharyngeal SCC but not in oral cavity SCC patients.

Medicine information exchange networks among healthcare professionals and prescribing in geriatric medicine wards.

AIMS: Effective transfer of information is vital for rational drug therapy. This is particularly important for older patients, who have a high prevalence of polypharmacy and are managed by multidisciplinary teams. We aimed to assess medicine information exchange (MIE) networks in geriatric medicine wards and whether they are associated with prescribing patterns. METHODS: We conducted network analysis in acute geriatric medicine wards from four hospitals to characterize MIE networks among multidisciplinary team members. Corresponding patient data were collected to analyze high-risk prescribing in conjunction with network characteristics. RESULTS: We found that junior doctors, senior nurses and pharmacists were central to MIE across all four hospitals. Doctors were more likely than other professions to receive medicines information in three hospitals. Reciprocity and the tendency to communicate within one's own profession also influenced network formation. No difference was observed in prescribing practice between hospitals. CONCLUSIONS: Understanding MIE networks can identify gaps in multidisciplinary communication that can be addressed. Networks may identify targets for dissemination of interventions to improve prescribing.

Pharmacokinetics of oseltamivir in infants under the age of 1 year.

BACKGROUND: Oseltamivir is the only antiviral treatment recommended for influenza in young children over the age of 1 year. There is scant data on oseltamivir pharmacokinetics (PK) in infants <1 year. We set out to perform PK measurements in infants who received oseltamivir. METHODS: This study was a prospective, uncontrolled, open label evaluation of the pharmacokinetics of oseltamivir metabolism, safety of oseltamivir, viral clearance in infants <12 months diagnosed with influenza by nasopharyngeal influenza nucleic acid antigen test (NAAT). Blood levels of the prodrug oseltamivir and its active carboxylate were measured prior to a dose of oseltamivir and at 4 time points afterwards, to calculate Cmax (ng/mL), Tmax (h), AUC0-t (ng h/mL) and time for AUC (h). RESULTS: Four children with influenza A received oral oseltamivir, 2.35-3 mg/kg/dose. This dose range produced a target oseltamivir carboxylate plasma concentration in excess of the proposed 12-h target AUC of 3800 ng h/mL, selected from earlier studies to avert resistance. One patient developed GIT adverse event: dry retching. CONCLUSION: Oseltamivir was well tolerated at a dose of 2.35-3 mg/kg/dose twice a day in infants under the age of 1 year. In general agreement with earlier data, these doses produced a target oseltamivir carboxylate plasma exposure in excess of the proposed 12-h target exposure of AUC equal to 3800 ng h/mL in two patients. The limited plasma concentration data in the remaining two patients were not inconsistent with the target exposure being reached.

Methodological Comparisons of Heart Rate Variability Analysis in Patients With Type 2 Diabetes and Angiotensin Converting Enzyme Polymorphism.

Angiotensin converting enzyme (ACE) polymorphism has been shown to be important in hypertension progression and also in diabetes complications, especially associated with heart disease. Heart rate variability (HRV) is an established measure for classification of autonomic function regulating heart rate, based on the interbeat interval time series derived from a raw ECG recording. Results of this paper show that the length (number of interbeat intervals) and preprocessing of the tachogram affect the HRV analysis outcome. The comparison was based on tachogram lengths of 250, 300, 350, and 400 RR-intervals and five preprocessing approaches. An automated adaptive preprocessing method for the heart rate biosignal and tachogram length of 400 interbeat intervals provided the best classification. HRV results differed for the Type 2 Diabetes Mellitus (T2DM) group between the I/I genotype and the I/D and D/D genotypes, whereas for controls there was no significant difference in HRV between genotypes. Selecting an appropriate length of recording and automated preprocessing has confirmed that there is an effect of ACE polymorphism including the I/I genotype and that I/I should not be combined with I/D genotype in determining the extent of autonomic modulation of the heart rate.

Older peoples' attitudes regarding polypharmacy, statin use and willingness to have statins deprescribed in Australia.

BACKGROUND: Deprescribing is the process of medication withdrawal with the aims of reducing the harms of potentially inappropriate medication use and improving patient outcomes. Deprescribing of statins may be indicated for some older people, because the evidence for benefit in primary prevention of cardiovascular disease is limited and there is an increased risk of side effects in old age. OBJECTIVE: To determine older peoples' attitudes and beliefs regarding medication use and their willingness to have regular medications, particularly statins, deprescribed. Setting An Australian acute-care hospital. METHOD: A cross-sectional study of patients admitted to a teaching hospital in Sydney, Australia, aged ≥65 years and taking a statin was conducted. Attitudes and beliefs regarding medication use and willingness to have medications or statins deprescribed were captured using the validated Patients' Attitudes Towards Deprescribing questionnaire, supplemented with additional statin-specific questions. MAIN OUTCOME MEASURES: Older inpatients' attitudes and perspectives towards stopping medications, in particular statins. RESULTS: Overall, 180 participants were recruited, with a median age of 78 years, (interquartile range 71-85). Eighty-nine percent (95% CI 84.4-93.6) of participants reported that they would be willing to stop one or more of their regular medications if their doctor said it was possible. Ninety-five percent (95% CI 91.8-98.2) agreed that they would be willing to have a statin deprescribed. Moreover, 94% (95% CI 90.5-97.5) of participants expressed concern regarding the potential side effects of taking a statin. CONCLUSION: The majority of older inpatients using statins are willing to have one or more of their current medications, including statins, deprescribed. These findings can be used to inform clinical practice and interventional statin deprescribing studies to optimise medication use in older adults.

Ischemic heart disease, prescription of optimal medical therapy and geriatric syndromes in community-dwelling older men: A population-based study.

BACKGROUND: Guideline recommended management of ischemic heart disease (IHD) suggests the concomitant use of antiplatelet, beta-blocker, renin angiotensin system blocker and statin therapy. In older people exposure to multiple medications has been associated with adverse events and geriatric syndromes. The study aimed to investigate the use of medications for IHD in older men with and without geriatric syndromes, and whether adherence to medication guidelines impacts on adverse outcomes. METHODS: Community-dwelling men, aged ≥ 70 years and enrolled in the Concord Health and Ageing in Men Project were studied. Data on self-reported IHD, number of guideline recommended medications (use of four guideline medications considered optimal medical therapy) and geriatric syndromes (frailty, falls, cognitive impairment and urinary incontinence) were obtained. Cox regression was used to assess the relationship between optimal medical therapy and adverse outcomes (mortality and institutionalization), stratifying by geriatric syndromes. RESULTS: At baseline, 462 (27%) men self-reported a history of IHD and of these, 226 (49%) had at least one geriatric syndrome. Among men with IHD, no significant difference was observed in patterns of prescribing between those with and without geriatric syndromes. Compared to zero medications, optimal medical therapy among men with IHD was associated with lower mortality [hazard ratio, HR = 0.40 (95% CI: 0.21-0.95)] and institutionalization risk (HR=0.31; 95% CI: 0.09-0.81). The presence of geriatric syndromes did not modify the association of increasing use of guideline recommended medications and clinical outcomes. CONCLUSION: In older men with IHD, greater adherence to medication guidelines appears to be positively associated with better clinical outcomes, independent of geriatric syndromes.

Electrocardiogram derived QRS duration associations with elevated central aortic systolic pressure (CASP) in a rural Australian population.

BACKGROUND: Prolonged electrocardiogram QRS durations are often present in hypertensive patients. Small increases in QRS duration serve as independent risk factors for both increased cardiovascular and all-cause mortality. Aortic stiffness is associated with increases in central aortic systolic blood pressure (CASP). However CASP and ECG QRS duration interactions have not been established in rural community populations. Our aims are to determine if QRS duration > 100 msec is associated with an elevated CASP measure in an Australian rural population. METHODS: A retrospective cross sectional population was obtained from the CSU Diabetes Screening Research Initiative data base where 68 participants had both central aortic pressure recorded and ECG derived QRS duration. Central aortic pressure was determined by directly recording radial arterial tonometry and brachial cuff pressure (HealthStats, Singapore). Resting 12-lead electrocardiograms were obtained from each subject using a Welch Allyn PC-Based ECG system. RESULTS: The population had a mean CASP of 137.8 mmHg, higher than previously reported in other population studies. In 8/68 subjects with a prolonged cardiac QRS duration >120 msec, CASP ranged from 129 mmHg - 182 mmHg. When subgroup analysis was stratified on the basis QRS duration <100 msec and ≥100 msec significant differences (p = 0.036) were observed for mean CASP, 130.6 mmHg ± 15.6 (SD) versus 140.6 mmHg ± 16.8 (SD), respectively. CONCLUSIONS: Our results suggest that an arbitrary CASP reading greater than a value 140 mmHg raises suspicion of a prolonged QRS duration. QRS durations ≥100 msec in an aging rural population are associated with higher CASP measures. Our results also suggest in aging Australian rural populations CASP is likely to be elevated, possibly due to age related aortic stiffening.

The impact of frailty on pharmacokinetics in older people: using gentamicin population pharmacokinetic modeling to investigate changes in renal drug clearance by glomerular filtration.

PURPOSE: Frailty, a multifactorial biological syndrome characterized by a cumulative dysregulation of physiological processes, is associated with changes in pharmacokinetics and pharmacodynamics. The aim of this study was to quantify the effect of frailty on glomerular filtration of drugs, using the probe drug gentamicin. METHODS: Gentamicin concentrations and clinical data including the Reported Edmonton Frail Scale score were pooled from two prospective observational inpatient studies, one on prophylactic gentamicin for urologic surgery and one on therapeutic gentamicin for the empiric treatment of sepsis. Population pharmacokinetic modeling was performed using non-linear mixed effects modeling (NONMEM program) to determine the impact of frailty on gentamicin clearance. RESULTS: A one-compartment linear pharmacokinetic model best described the data and the addition of frailty to the model reduced the random variability in gentamicin clearance by 12 % after adjustment for renal function (estimated creatinine clearance using lean body weight) and lean body weight. Frail patients had an approximately 12 % lower (bootstrapping results: 14 % median) gentamicin clearance than non-frail patients (calculated as a fractional effect of frailty). CONCLUSIONS: Frailty may independently predict reduced clearance of gentamicin in older patients. Frailty could be considered in the development of dosing guidelines for drugs that undergo significant excretion through glomerular filtration.

Prevalence and impact of fall-risk-increasing drugs, polypharmacy, and drug-drug interactions in robust versus frail hospitalised falls patients: a prospective cohort study.

BACKGROUND: Several measures of medication exposure are associated with adverse outcomes in older people. Exposure to and the clinical outcomes of these measures in robust versus frail older inpatients are not known. OBJECTIVE: In older robust and frail patients admitted to hospital after a fall, we investigated the prevalence and clinical impact of fall-risk-increasing drugs (FRIDs), total number of medications, and drug-drug interactions (DDIs). METHODS: Patients ≥60 years of age admitted with a fall to a tertiary referral teaching hospital in Sydney were recruited and frailty was assessed. Data were collected at admission, discharge, and 2 months after admission. RESULTS: A total of 204 patients were recruited (mean age 80.5 ± 8.3 years), with 101 robust and 103 frail. On admission, compared with the robust, frail participants had significantly higher mean ± SD number of FRIDs (frail 3.4 ± 2.2 vs. robust 1.6 ± 1.5, P < 0.0001), total number of medications (9.8 ± 4.3 vs. 4.4 ± 3.3, P < 0.0001), and DDI exposure (35 vs. 5 %, P = 0.001). Number of FRIDs on discharge was significantly associated with recurrent falls [odds ratio (OR) 1.7 (95 % confidence interval [CI] 1.3-2.1)], which were most likely to occur with 1.5 FRIDs in the frail and 2.5 FRIDs in the robust. Number of medications on discharge was also associated with recurrent falls [OR 1.2 (1.0-1.3)], but DDIs were not. CONCLUSION: Exposure to FRIDs and other measures of high-risk medication exposures is common in older people admitted with falls, especially the frail. Number of FRIDs and to a lesser extent total number of medicines at discharge were associated with recurrent falls.