Antibiotic-Associated Acute Kidney Injury Among Older Adults: A Case-Crossover Study.

BACKGROUND AND OBJECTIVES: Drug-related acute kidney injury is quite common in older adults. The associated drugs, including antibiotics, are often co-prescribed. The objective of this study was to ascertain antibiotic-associated acute kidney injury (AKI) in older adults aged 65 years or above in New Zealand using a case-crossover study design. METHODS: The International Statistical Classification of Diseases and Related Health Problems, tenth revision, Australian modification code N17.x was used to identify all individuals aged 65 years and above with a diagnosis of incident AKI on admission between 1 January 2005 and 31 December 2020, from the New Zealand National Minimum Data Set. A case-crossover cohort for antibiotic exposures, with a 3 day case period and two 30 day washout periods, summed up to a 66 day study period, was created. Using conditional logistic regression, the changed odds of AKI due to exposure to an antibiotic was calculated as matched odds ratios and their 95% confidence intervals. RESULTS: A total of 2399 incident cases of AKI were identified between 2005 and 2020 among older adults. The adjusted odds of consuming sulfamethoxazole/trimethoprim antibiotic during the case period was 3.57 times (95% CI 2.86-4.46) higher than the reference period among the incident AKI cases. Fluoroquinolone utilization was also associated with incident AKI (adjusted OR = 2.56; 95% CI 1.90-3.46). CONCLUSION: The potential of sulfamethoxazole/trimethoprim and fluoroquinolones to be associated with AKI raises the significant need for vigilant prescribing of these antibiotics in older adults.

Acute renal failure and cardiac arrhythmias associated with remdesivir use in patients with COVID-19 infections: Analysis using the US FDA adverse event reporting system.

BACKGROUND: Recently, antivirals, including remdesivir, have been repurposed to treat COVID-19 infections. Initial concerns have been raised about the adverse renal and cardiac events associated with remdesivir. OBJECTIVE: This study aimed to analyse the adverse renal and cardiac events associated with remdesivir in patients with COVID-19 infections using the US FDA adverse event reporting system. METHOD: A case/non-case method was used to determine adverse drug events associated with remdesivir as the primary suspect drug between January 1, 2020, and November 11, 2021, for patients with COVID-19 infections. Cases were reports for remdesivir with ≥1 ADEs as preferred terms included in the Medical Dictionary of Regulatory Activities (MedDRA) system organ classes 'Renal and urinary disorders' or 'cardiac' disorders. To measure disproportionality in reporting of ADEs, frequentist approaches, including the proportional reporting ratio (PRR) and reporting odds ratio (ROR), were used. The empirical Bayesian Geometric Mean (EBGM) score and information component (IC) value were calculated using a Bayesian approach. A signal was defined as the lower limit of 95% confidence intervals of ROR ≥ 2, PRR ≥ 2, IC > 0, and EBGM > 1 for ADEs with ≥4 reports. Sensitivity analyses were undertaken by excluding reports for non-Covid indications and medications strongly associated with AKI and cardiac arrhythmias. RESULTS: In the main analysis for remdesivir use in patients with COVID-19 infections, we identified 315 adverse cardiac events comprising 31 different MeDRA PTs and 844 adverse renal events comprising 13 different MeDRA PTs. Regarding adverse renal events, disproportionality signals were noted for "renal failure" (ROR = 2.8 (2.03-3.86); EBGM = 1.92 (1.58-2.31), "acute kidney injury" (ROR = 16.11 (12.52-20.73); EBGM = 2.81 (2.57-3.07), "renal impairment" (ROR = 3.45 (2.68-4.45); EBGM = 2.02 (1.74-2.33). Regarding adverse cardiac events, strong disproportionality signals were noted for "electrocardiogram QT prolonged" (ROR = 6.45 (2.54-16.36); EBGM = 2.04 (1.65-2.51), "pulseless electrical activity" (ROR = 43.57 (13.64-139.20); EBGM = 2.44 (1.74-3.33), "sinus bradycardia" (ROR = 35.86 (11.16-115.26); EBGM = 2.82 (2.23-3.53), "ventricular tachycardia" (ROR = 8.73 (3.55-21.45); EBGM = 2.52 (1.89-3.31). The risk of AKI and cardiac arrythmias were confirmed by sensitivity analyses. CONCLUSION: This hypothesis-generating study identified AKI and cardiac arrhythmias associated with remdesivir use in patients with COVID-19 infections. The relationship between AKI and cardiac arrhythmias should be further investigated using registries or large clinical data to assess the impact of age, genetics, comorbidity, and the severity of Covid infections as potential confounders.

Analysis of the nervous system and gastrointestinal adverse events associated with solifenacin in older adults using the US FDA adverse event reporting system.

BACKGROUND: Antimuscarinics are the backbone of the pharmacological management of overactive bladder. Still, concerns have been raised over the nervous system (NS) adverse drug events (AEs) due to their dissimilarities to muscarinic receptor-subtype affinities. OBJECTIVE: This study aimed to identify the nervous system and gastrointestinal adverse drug events (ADEs) associated with solifenacin use in older adults (≥65 years). METHODS: A case/non-case analysis was performed on the reports submitted to the FDA Adverse Event Reporting System (FAERS) between 01/01/2004 and 30/06/2020. Cases were reports for solifenacin with ≥1 ADEs as preferred terms included in the Medical Dictionary of Regulatory Activities (MedDRA) system organ classes 'nervous system' or 'gastrointestinal' disorders. Non-cases were all other remaining reports for solifenacin. The case/non-cases was compared between solifenacin and other bladder antimuscarinics. Frequentist approaches, including the proportional reporting ratio (PRR) and reporting odds ratio (ROR), were used to measure disproportionality. The empirical Bayesian Geometric Mean (EBGM) score and information component (IC) value were calculated using a Bayesian approach. A signal was defined as the lower limit of 95% confidence intervals of ROR ≥ 2, PRR ≥ 2, IC > 0, EBGM > 1, for ADEs with ≥4 reports. RESULTS: 107 MedDRA preferred terms (PTs) comprising 970 ADE reports were retrieved for nervous system disorders associated with solifenacin. For gastrointestinal disorders, 129 MedDRA PTs comprising 1817 ADE reports were retrieved. Statistically significant results were found for 'altered state of consciousness': ROR = 9.71 (2.13-44.35), PRR = 9.69 (2.12-44.2) and IC = 1.29 (0.93-1.66). CONCLUSIONS: The disproportionality reporting of 'altered state of consciousness', a previously unidentified ADE, was unexpected. Further monitoring of this ADE is needed to ensure patient safety, as this could be linked to poor balance and falls in older adults.

The natural history of chronic widespread pain in patients with axial spondyloarthritis: a cohort study with clinical and self-tracking data.

OBJECTIVES: This study investigates longitudinal patterns, predictors and long-term impact of pain in axial spondyloarthritis (axSpA), using clinical and self-tracking data. METHODS: The presence of multisite pain (MSP), affecting at least six of nine body regions using a Margolis pain drawing, and subsequent chronic widespread pain (CWP), MSP at more than one timepoint, was assessed in a cohort of axSpA patients. Incident MSP (MSP at two consecutive visits or more), intermittent MSP (MSP at two or more non-consecutive visits) and persistent MSP (MSP at each visit) were described. Demographic, clinical and self-tracking measures were compared for the CWP vs non-CWP groups using Students t test, Wilcoxon-Mann-Whitney and χ2 test for normal, non-normal and categorical data, respectively. Predictors of CWP were evaluated using logistic regression modelling. RESULTS: A total of 136 patients, mean clinical study duration of 120 weeks (range 27-277 weeks) were included, with sufficient self-tracking data in 97 patients. Sixty-eight (50%) patients reported MSP during at least one clinical visit: eight (6%) incident MSP; 16 (12%) persistent MSP; and 44 (32%) intermittent MSP. Forty-six (34%) of the cohort had CWP. All baseline measures of disease activity, function, quality of life, sleep disturbance, fatigue and overall activity impairment were significant predictors of the development of CWP. BASDAI and BASFI scores were significantly higher in those with CWP and self-tracking data revealed significantly worse pain, fatigue, sleep quality and stress. CONCLUSIONS: The development of CWP is predicted by higher levels of disease activity and burden at baseline. It also impacts future disease activity and wellbeing.

An Updated Analysis of Psychotropic Medicine Utilisation in Older People in New Zealand from 2005 to 2019.

BACKGROUND: Psychotropic medicine utilisation in older adults continues to be of interest because of overuse and concerns surrounding its safety and efficacy. OBJECTIVE: This study aimed to characterise the utilisation of psychotropic medicines in older people in New Zealand. METHODS: We conducted a repeated cross-sectional analysis of national dispensing data from 1 January, 2005 to 31 December, 2019. We defined utilisation using the Anatomical Therapeutic Chemical classification defined daily dose system. Utilisation was measured in terms of the defined daily dose (DDD) per 1000 older people per day (TOPD). RESULTS: Overall, the utilisation of psychotropic medicines increased marginally by 0.42% between 2005 and 2019. The utilisation increased for antidepressants (72.42 to 75.21 DDD/TOPD) and antipsychotics (6.06-19.04 DDD/TOPD). In contrast, the utilisation of hypnotics and sedatives (53.74-38.90 DDD/TOPD) and anxiolytics decreased (10.20-9.87 DDD/TOPD). The utilisation of atypical antipsychotics increased (4.06-18.72 DDD/TOPD), with the highest percentage change in DDD/TOPD contributed by olanzapine (520.6 %). In comparison, utilisation of typical antipsychotics was relatively stable (2.00-2.06 DDD/TOPD). The utilisation of venlafaxine increased remarkably by 5.7 times between 2005 and 2019. The utilisation of zopiclone was far greater than that of other hypnotics in 2019. CONCLUSIONS: There was only a marginal increase in psychotropic medicines utilisation from 2005 to 2019 in older adults in New Zealand. There was a five-fold increase in the utilisation of antipsychotic medicines. Continued monitoring of psychotropic medicine utilisation will be of interest to understand the utilisation of antidepressants and antipsychotic medicines during the coronavirus disease 2019 pandemic year.

Antibacterial-associated acute kidney injury among older adults: A post-marketing surveillance study using the FDA adverse events reporting system.

PURPOSE: Antibacterials induce a differential risk of acute kidney injury (AKI) in older adults. This study investigated the reporting risk of AKI associated with antibacterials using the individual case safety reports (ICSRs) submitted to the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: A case/non-case method was used to assess AKI risk associated with antibacterials between 1 January 2000 and 30 September 2021. Cases were ICSRs for antibacterials with AKI as preferred terms included in the Medical Dictionary of Regulatory Activities (MedDRA) system organ classes 'Renal and urinary disorders' disorders. The analyses were completed on a de-duplicated data set containing only the recent version of the ICSR. Signals were defined by a lower 95% confidence interval (CI) of reporting odds ratio (ROR) ≥ 2, proportional reporting ratio (PRR) ≥ 2, information component (IC) > 0, Empirical Bayes Geometric Mean (EBGM) > 1 and reports ≥4. Sensitivity analyses were conducted a priori to assess the robustness of signals. RESULTS: A total of 3 680 621 reports on ADEs were retrieved from FAERS over the study period, of which 92 194 were antibacterial reports. Gentamicin, sulfamethoxazole, trimethoprim and vancomycin consistently gave strong signals of disproportionality on all four disproportionality measures and across the different sensitivity analyses: gentamicin (ROR = 2.95[2.51-3.46]), sulfamethoxazole (ROR = 2.97[2.68-3.29]), trimethoprim (ROR = 2.81[2.29-3.46]) and vancomycin (ROR = 3.35[3.08-3.64]). CONCLUSION: Signals for gentamicin, sulfamethoxazole, trimethoprim and vancomycin were confirmed by using antibacterials as a comparator, adjusting for drug-related competition bias and event-related competition bias.

Risk of delirium associated with antimuscarinics in older adults: A case-time-control study.

BACKGROUND: Older adults are at an increased risk of delirium because of age, polypharmacy, multiple comorbidities and acute illness. Antimuscarinics are the backbone of the pharmacological management of overactive bladder. However, the safety profiles of antimuscarinics vary because of their dissimilarities to muscarinic receptor-subtype affinities and are associated with differential central anticholinergic adverse effects. OBJECTIVE: This study aimed to examine delirium risk in new users of oxybutynin and solifenacin in older adults (≥ 65 years). In the secondary analyses, we examined the risk of delirium by type and dose of antimuscarinic. METHOD: We applied a case-time-control design to investigate delirium risk in older adults who started taking oxybutynin and solifenacin. We used a nationwide inpatient hospital data (2005-2016), National Minimum Data Set, maintained by the Ministry of Health, New Zealand (NZ), to identify older adults with a new-onset diagnosis of delirium. Eligible patients were older adults aged 65 at entry into the cohort on 1/1/2006. We used dispensing claims data to determine antimuscarinic treatment exposure. The antimuscarinic included in the study were new users of oxybutynin and solifenacin. These two antimuscarinics are subsidised by the Pharmaceutical Management Agency and are the most frequently used antimuscarinic in NZ. A conditional logistic regression model was used to compute matched odds ratios (MORs) and 95% confidence intervals (CIs). In the case-time-control design, we made separate analyses to evaluate the dose-response risk of delirium. RESULTS: We identified 4818 individuals (mean age 82.14) from 2005 to 2015 with incident delirium and were exposed to at least one of the antimuscarinic of interest. The case-time-control matched odds ratio (MOR) for delirium with oxybutynin was (2.06, 95% confidence interval [CI] 1.07-3.96). Solifenacin was not associated with delirium (0.89 95%CI 0.64-1.23). In the sensitivity analyses, the case-time-control MOR for delirium using a shorter risk period (0-3 days) did not change the results. The dose-response risk of delirium was significant for oxybutynin (0.05, 95%CI 0.02-0.08) but not for solifenacin (-0.01, 95%CI -0.03 to 0.00). In addition, in the subgroup analyses, a statistically significant association of delirium was found for oxybutynin but not for solifenacin in the non-dementia cohort (2.11,95% CI 1.08-4.13) and the dementia cohort (1.25, 95%CI 0.05-26.9). CONCLUSION: The study found that oxybutynin but not solifenacin is associated with a risk of new-onset delirium in older adults. The higher blockade of M1 and M2 receptors by oxybutynin is likely to contribute to delirium than solifenacin, which is highly selective for the M3 receptor subtype. Therefore, the treatment choice with an M3 selective agent must be given due consideration, particularly in those with pre-existing cognitive impairment.

Identifying frequent drug combinations associated with delirium in older adults: Application of association rules method to a case-time-control design.

BACKGROUND: Older adults are at an increased risk of delirium because of age, polypharmacy, multiple comorbidities, frailty, and acute illness. Although medication-induced delirium in older adults is well understood, limited population-level evidence is available, particularly on combinations of medications associated with delirium in older adults. OBJECTIVES: We aimed to apply association rule analysis to identify drug combinations contributing to delirium risk in adults aged 65 and older using a case-time-control design. METHOD: We sourced a nationwide representative sample of New Zealander's aged ≥65 years from the pharmaceutical collections and hospital discharge information. Prescription records (2005-2015) were obtained from New Zealand pharmaceutical collections (Pharms). Medication exposures were coded as binary variables (exposed vs. not exposed) at the individual drug level. All medications, including antimicrobials, antihistamines, diuretics, opioids, and nonsteroidal anti-inflammatory medications, were considered drugs of interest. The first-time coded diagnosis of delirium was extracted from the National Minimal Dataset (NMDS). A unique patient identifier linked the prescription dataset to the event dataset to set up a case-time-control cohort, indexed at the first delirium event. Association rules were then applied to identify frequent drug combinations in the case and the control periods (l-day with a 35-day washout period) that are statistically associated with delirium, and the association was tested by computing a time-trend adjusted matched odds-ratio (MOR) and its 95% confidence interval (CI). RESULTS: We identified 28 503 individuals (mean age 84.1 years) from 2005 to 2015 with delirium. Our combined association rule and case-time-control analysis identified several drug classes, including antipsychotics, benzodiazepines, opioids, and diuretics associated with delirium. Our analysis also identified frequently used drug combinations that are associated with delirium. Examples include combined exposures to quetiapine and furosemide (MOR = 6.17; 95%CI = [2.05-18.54]), haloperidol (MOR = 4.81; 95%CI = [3.16-6.69]), combined exposures to furosemide, omeprazole, and lorazepam (MOR = 3.94; 95%CI = [3.03-5.10]), and fentanyl exposure (MOR = 3.46; 95%CI [2.05-9.21]). CONCLUSION: The association rule method applied to a case-time-control design is a novel approach to identifying drug combinations contributing to delirium with adjustment for any temporal trends in exposures. The study provides new insight into the combination of medicines linked to delirium.

Analysis of the US FDA adverse event reporting system to identify adverse cardiac events associated with hydroxychloroquine in older adults.

PURPOSE: The purpose of this study is to analyze the US FDA Adverse Event Reporting System (FAERS) to identify adverse cardiac events of hydroxychloroquine in older adults. METHOD: A case/non-case method was used to determine adverse events associated with hydroxychloroquine as the primary suspect drug between January 1, 2004, and December 31, 2019, for older adults (≥65 years). Adverse events are preferred terms (PTs) defined in MedDRA. We used frequentist approaches, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR) to measure disproportionality. We used Bayesian approaches to derive information component (IC) value and Empirical Bayesian Geometric Mean (EBGM) score. Signals were defined as the number of reports > 3 and the lower limit of 95% confidence intervals (CI) of ROR ≥ 2, PRR ≥ 2, IC > 0, EBGM > 1. RESULTS: We identified 334 adverse cardiac events comprising 71 different MedDRA PTs from 2004 to 2019 for hydroxychloroquine in older adults. Strong disproportionality signals were noted for "Restrictive cardiomyopathy" (ROR = 272.43 (138.09-537.47); EBGM = 149.78 (77.34-264.67), "Right ventricular hypertrophy" (219.49 (85.32-564.70); 102.74 (39.67-222.81), "Cardiac septal hypertrophy" (226.77 (78.65-653.80); 93.82 (32.19-219.81), "Myocardial fibrosis" (57.29 (21.06-155.85); 42.99 (14.74-100.75), and "Cardiotoxicity" (43.90 (26.66-72.27); 40.28 (24.02-63.72). CONCLUSIONS: The risk of cardiomyopathy and myocardial disorders is high following exposure to hydroxychloroquine in older adults. Due to the current lack of safety data from randomized controlled trials as well as large observational studies to confirm the risk of adverse cardiac events associated with hydroxychloroquine, findings from analyses of post-marketing data may serve as interim guidance.

Comparative risk of Parkinsonism associated with olanzapine, risperidone and quetiapine in older adults-a propensity score matched cohort study.

PURPOSE: The purpose of this study was to examine the incidence of Parkinsonism in new users of second-generation antipsychotics (SGAs) in older adults (≥65 years). In the secondary analyses, we examined the risk of Parkinsonism by type and dose of SGA and conducted age-sex interactions. METHOD: This population-based study included older adults who had a new-onset diagnosis of Parkinsonism and who started taking olanzapine, risperidone or quetiapine between 1 January 2005, and 30 December 2016. The Cox proportional hazard (COXPH) model with inverse probability treatment weighted (IPTW) covariates was used to evaluate the risk of new-onset Parkinsonism associated with SGAs, using quetiapine as the reference. We used the Generalized Propensity Score method to evaluate the dose-response risk of Parkinsonism associated with SGAs. RESULTS: After IPTW adjustment for covariates, the COXPH model showed that compared to quetiapine, the use of olanzapine and risperidone were associated with an increased risk of Parkinsonism. The IPTW-hazard ratios are 1.76 (95% confidence interval 1.57-1.97) and 1.31 (95%CI 1.16-1.49), respectively. The dose-response risk of Parkinsonism was highest for olanzapine with a hazard ratio of 1.69 (95%CI 1.40-2.05) and the least for quetiapine with a hazard ratio of 1.22 (95%CI 1.14-1.31). The risk of Parkinsonism in the 65 to 74-year age group was higher for both sexes with risperidone compared to olanzapine, but the risk increased with olanzapine for both sexes in the 85+ age group. CONCLUSION: The study found that the risk of new-onset Parkinsonism in older adults is 31% and 76% higher with risperidone and olanzapine respectively compared to quetiapine.

Publisher Correction: Targeting of temperate phages drives loss of type I CRISPR-Cas systems.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Identifying drug combinations associated with acute kidney injury using association rules method.

BACKGROUND: Older adults are at an increased risk of acute kidney injury (AKI) because of aging, multiple comorbidities, and polypharmacy. OBJECTIVES: The aim of this case-crossover study was to apply association rule (AR) analysis to ascertain drug combinations contributing to the risk of AKI in adults aged 65 years and older. METHODS: We sourced a nationwide representative sample of New Zealanders aged ≥65 years from the pharmaceutical collections and hospital discharge information. Prescription records (2005-2015) of drugs of interest were sourced from New Zealand pharmaceutical collections (Pharms). We classified medication exposure, as a binary variable, at individual drug level belonging to medication classes including antimicrobials, antihistamines, diuretics, opioids, nonsteroidal anti-inflammatory medications. Several studies have associated the drugs of interest from these medication classes with AKI in older adults. We extracted the first-time coded diagnosis of AKI from the National Minimal Data Set. A unique patient identifier linked the prescription data set to the event data set, to set up a case-crossover cohort, indexed at the first AKI event. ARs were then applied to identify frequent drug combinations in the case and the control periods (l-day observation with a 35-day washout period), and the association of AKI with each frequent drug combination was tested by computing a matched odds ratio (MOR) and its 95% confidence interval (CI). RESULTS: We identified 55 747 individuals (mean age 82.14) from 2005 to 2014 with incident AKI and exposed to at least one of the drugs of interest. ARs identified several medication classes including antimicrobials, nonsteroidal anti-inflammatory drugs, and opioids are associated with AKI. The frequently used medicines associated with AKI are trimethoprim (MOR = 1.68; 95% CI = [1.54-1.80]), ondansetron (MOR = 1.43; 95% CI = [1.25-1.64]), codeine phosphate plus metoclopramide (MOR = 1.37; 95% CI = [1.11-1.63]), and norfloxacin (MOR = 1.24; 95% CI [1.05-1.42]). CONCLUSIONS: We applied ARs, a novel methodology, to big data to ascertain drug combinations associated with AKI. ARs uncovered previously implicated medication classes that increase the risk of AKI in older adults. The finding that ondansetron increases the risk of AKI requires further investigation.

Targeting of temperate phages drives loss of type I CRISPR-Cas systems.

On infection of their host, temperate viruses that infect bacteria (bacteriophages; hereafter referred to as phages) enter either a lytic or a lysogenic cycle. The former results in lysis of bacterial cells and phage release (resulting in horizontal transmission), whereas lysogeny is characterized by the integration of the phage into the host genome, and dormancy (resulting in vertical transmission)1. Previous co-culture experiments using bacteria and mutants of temperate phages that are locked in the lytic cycle have shown that CRISPR-Cas systems can efficiently eliminate the invading phages2,3. Here we show that, when challenged with wild-type temperate phages (which can become lysogenic), type I CRISPR-Cas immune systems cannot eliminate the phages from the bacterial population. Furthermore, our data suggest that, in this context, CRISPR-Cas immune systems are maladaptive to the host, owing to the severe immunopathological effects that are brought about by imperfect matching of spacers to the integrated phage sequences (prophages). These fitness costs drive the loss of CRISPR-Cas from bacterial populations, unless the phage carries anti-CRISPR (acr) genes that suppress the immune system of the host. Using bioinformatics, we show that this imperfect targeting is likely to occur frequently in nature. These findings help to explain the patchy distribution of CRISPR-Cas immune systems within and between bacterial species, and highlight the strong selective benefits of phage-encoded acr genes for both the phage and the host under these circumstances.

Examining the Risks of Major Bleeding Events in Older People Using Antithrombotics.

BACKGROUND: Real-world evidence for the safety of using antithrombotics in older people with multimorbidity is limited. We investigated the risks of gastrointestinal bleeding (GI-bleeding) and intracranial (IC-bleeding) associated with antithrombotics either as monotherapy, dual antiplatelet therapy (DAPT) or as triple therapy (TT) [DAPT plus anticoagulant] in older individuals aged 65 years and above. METHODS: We identified all individuals, 65 years and above, who had a first-time event of either IC- or GI-bleeding event from the hospital discharge data. We employed a case-crossover design and conditional logistic regression analyses to estimate the adjusted relative risks (ARR) of bleeding. RESULTS: We found 66,500 individuals with at least one event of IC- or GI-bleeding between 01/01/2005 and 31/12/2014. DAPT use was associated with an increased risk relative to non-use of any antithrombotics in IC-bleeding (ARR = 3.13, 95% CI = [2.64, 3.72]) and GI-bleeding (ARR = 1.34, 95% CI = [1.14, 1.57]). The increased bleeding risk relative to non-use of any antithrombotics was highest with TT use (IC-bleeding, ARR = 17.28, 95% CI = [6.69, 44.61]; GI-bleeding, ARR = 4.85, 95% CI = [1.51, 15.57]). CONCLUSIONS: Using population-level data, we were able to obtain estimates on the bleeding risks associated with antithrombotic agents in older people often excluded from clinical trials because of either age or comorbidities.

Genome-wide correlation analysis suggests different roles of CRISPR-Cas systems in the acquisition of antibiotic resistance genes in diverse species.

CRISPR-Cas systems are widespread in bacterial and archaeal genomes, and in their canonical role in phage defence they confer a fitness advantage. However, CRISPR-Cas may also hinder the uptake of potentially beneficial genes. This is particularly true under antibiotic selection, where preventing the uptake of antibiotic resistance genes could be detrimental. Newly discovered features within these evolutionary dynamics are anti-CRISPR genes, which inhibit specific CRISPR-Cas systems. We hypothesized that selection for antibiotic resistance might have resulted in an accumulation of anti-CRISPR genes in genomes that harbour CRISPR-Cas systems and horizontally acquired antibiotic resistance genes. To assess that question, we analysed correlations between the CRISPR-Cas, anti-CRISPR and antibiotic resistance gene content of 104 947 reference genomes, including 5677 different species. In most species, the presence of CRISPR-Cas systems did not correlate with the presence of antibiotic resistance genes. However, in some clinically important species, we observed either a positive or negative correlation of CRISPR-Cas with antibiotic resistance genes. Anti-CRISPR genes were common enough in four species to be analysed. In Pseudomonas aeruginosa, the presence of anti-CRISPRs was associated with antibiotic resistance genes. This analysis indicates that the role of CRISPR-Cas and anti-CRISPRs in the spread of antibiotic resistance is likely to be very different in particular pathogenic species and clinical environments. This article is part of a discussion meeting issue 'The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems'.

Prediction and diversity of tracrRNAs from type II CRISPR-Cas systems.

Type II CRISPR-Cas9 systems require a small RNA called the trans-activating CRISPR RNA (tracrRNA) in order to function. The prediction of these non-coding RNAs in prokaryotic genomes is challenging because they have dissimilar structures, having short stems (3-6 bp) and non-canonical base-pairs e.g. G-A. Much of the tracrRNA is involved in base-pairing interactions with the CRISPR RNA, or itself, or in RNA-protein interactions with Cas9. Here we develop a new bioinformatic tool to predict tracrRNAs. On an experimentally verified test set the algorithm achieved a high sensitivity and specificity, and a low false discovery rate (FDR) on genome analysis. Analysis of representative RefSeq genomes (5462) detected 275 tracrRNAs from 165 genera. These tracrRNAs could be grouped into 15 clusters which were used to build covariance models. These clusters included Streptococci and Staphylococci tracrRNAs from the CRISPR-Cas9 systems which are currently used for gene editing. Compensating base changes observed in the models were consistent with the experimental structures of single guide RNAs (sgRNAs). Other clusters, for which there are not yet structures available, were predicted to form novel tracrRNA folds. These clusters included a large and divergent tracrRNA set from Bacteroidetes. These computational models contribute to the understanding of CRISPR-Cas biology, and will assist in the design of further engineered CRISPR-Cas9 systems. The tracrRNA prediction software is available through a galaxy web server.

Association rules method and big data: Evaluating frequent medication combinations associated with fractures in older adults.

BACKGROUND: The association rules method is a novel methodology to ascertain patterns of medication use and combinations associated with adverse drug events. OBJECTIVES: The aim of this case-crossover study was to apply the association rules method to ascertain medication combinations contributing to the risk of fractures in older adults. METHODS: A nationwide representative sample of New Zealanders aged ≥65 years was sourced from the pharmaceutical collection. The first-time coded diagnosis of fracture was extracted from the National Minimum Dataset. Association rule method is a data mining technique that can be used to quickly traverse big datasets to identify a combination of items that co-occur. The association rules method were applied to identify frequent 11 medication combinations in the case and the control periods (1-14 days as hazard period, with 35-day washout period), and the association of fractures with each frequent medication combination were tested by computing a matched odd ratio (OR) and its 95% CI. RESULTS: We identified a total of 72 184 individuals (mean age 81.5 years) from 2005 to 2014 with incident fracture and exposed to at least 1 medication of interest. The association rules method revealed codeine phosphate (aOR = 11.50, 95% CI, 7.09-15.20, concomitantly with ibuprofen), zopiclone (aOR = 2.34, 95% CI, 1.49-3.67, concomitantly with morphine) and quetiapine (OR = 1.95, 95% CI, 1.28-2.98, concomitantly with zopiclone) were associated with fractures. CONCLUSION: The association rules method identified medication exposure combinations containing psychotropic medications and codeine are frequently associated with fractures. This novel methodology applied to big data can be an important tool to ascertain medication combinations associated with adverse drug events.