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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.

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.

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.

Purpose: The purpose 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: We used the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification code N17.9 to identify all individuals aged 65 years and above with a diagnosis of incident AKI between January 01, 2005, and December 31, 2020, from the New Zealand National Minimum Data Set. We created a case-crossover cohort for antibiotic exposures, with a 3-day observation period and two 30 days washout periods, summed up to a 66-day study period. We calculated the changed odds of AKI due to exposures to an antibiotic as matched odds ratios and their 95% confidence intervals, using conditional logistic regression. Results: We identified a total of 2399 incident cases of AKI between 2005 and 2020 among older adults. The adjusted odds of consuming a sulphonamide antibiotic during the case period was 3.57 times (95% CI: 2.86 to 4.46) higher than the reference period among the incident AKI cases. Fluoroquinolone utilisation was also associated with incident AKI (adjusted OR = 2.56; 95% CI: 1.90 to 3.46). The number needed to harm for sulphonamides and fluroquinolones were 6.55 (95% CI: 5.15 to 8.65) and 21.38 (95% CI: 13.97 to 36.41), respectively. Conclusion: The potential of sulphonamides and fluoroquinolones to be associated with AKI raises the significant need for vigilant prescribing of these antibiotics in frail older adults.

PurposeThe objectives of this study were to examine the overall utilisation of systematic antibiotics and the impact of the launch of the antimicrobial resistance action plan in older adults (65 years or more) living in New Zealand between 2005 and 2019, using data from a national database (Pharmaceutical collections), stratified by antibiotic class, patient age, and sex.MethodsPopulation-level systemic antibiotic dispensing data for older adults in New Zealand was analysed using repeated cross-sectional analysis between 01/01/2005 and 31/12/2019. Data were extracted on the prescribed systemic antibiotics using a unique identifier for each case. Antibiotic utilisation was measured in DDD/TOPD values. In addition, an interrupted time series (ITS) analysis using the autoregressive integrated moving average (ARIMA) models was performed to determine the impact of the antimicrobial resistance action plan.ResultsMost of the antibiotic classes included in this study showed a significant overall decrease in utilisation ranging from 38.64% for sulphonamides to 80.64% for fluoroquinolones compared to 2005. Systemic antibiotic utilisation decreased by 49.6% from the predicted usage between January 2018 and December 2019 following the launch of the antimicrobial resistance action plan. ARIMA model supported the reduction in utilisation with a step change of -0.2206 and slope change of -0.0029.ConclusionsThe ITS analysis has demonstrated that the intervention may have hugely impacted the antibiotic utilisation rate among older adults. Further studies are required to determine whether the reduced consumption rates of antibiotics are associated with reduced rates of antibiotic-associated adverse drug events such as acute kidney injury and haematological abnormalities.

Psychotropic medicine utilisation in older adults continues to be of interest because of overuse and concerns surrounding its safety and efficacy.This study aimed to characterise the utilisation of psychotropic medicines in older people in New Zealand.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).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.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.

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.This study aimed to identify the nervous system and gastrointestinal adverse drug events (ADEs) associated with solifenacin use in older adults (≥65 years).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.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).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.

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.

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.

Background Chronic pain is an important and debilitating symptom experienced by patients with axial Spondyloarthritis (axSpA). The patterns of pain and their associations in this patient group is poorly understood. The overall aim of the study is to investigate patterns of pain distribution in patients with axSpA using Margolis Pain Diagrams, and any associations with clinical and demographic measures. Methods We analysed data collected from individuals attending the axSpA outpatient clinic at the Royal National Hospital for Rheumatic Diseases in Bath. All participants were asked to record their pain on a pre-printed Margolis Pain diagram at each clinical visit. The number and distribution of painful areas were assessed and then categorised into regional or widespread pain, using pre-defined anatomical criteria. Descriptive analyses and any associations between pain distribution and demographic and clinical variables were assessed. Changes in pain distribution over time, using data from up to four clinic visits, were further investigated using a Sankey diagram. Results Of the 187 participants who had a baseline pain assessment, their mean age at diagnosis was 31.6 (11.9) years and 31.6% were female. 89.3% of patients reported pain at baseline, and of these 21.4%, 29.4 % and 38.5% reported pain in 1-2, 3-4, and 5-6 regions respectively. The most common sites of pain are in the Trunk (68.4%), followed by Head and Cervical (65.8%) and Left lower limb regions (58.8%). Univariate analyses did not reveal any significant associations between the presence of widespread pain and age at diagnosis, sex, smoking or HLA-B27 status. Disease activity, measured using Bath Ankylosing Spondylitis Disease Activity Index, was significantly higher in participants with widespread pain compared to those with regional pain OR 1.60 (1.30-1.96), and a trend towards higher sleep disturbance, was demonstrated OR 1.05 (1.00-1.10). Longitudinal analyses demonstrated considerable flux over time in the number and distribution of pain reported. Conclusion The Margolis Pain diagram is a practical instrument for assessing pain in axSpA patients. Several pain patterns were noted in patients with axSpA, and future research should focus on the potential impact on quality of life measures, response to treatment, and radiological findings. Disclosures R. Nishtala None. R. Barnett None. T. Chyou None. A. Soni None. R. Sengupta None.

Older people are susceptible to the adverse effects of anticholinergic medications, including cognitive impairment. A systematic review of observational studies reported mixed associations between high anticholinergic burden, a cumulative measure of anticholinergic medications, and cognitive performance in older people. Observational studies may have biased estimates of the impact of exposures, as the exposed and unexposed may systematically differ in covariates associated with the outcomes.

International audience; 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 phages(2,3). 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.CRISPR-Cas systems cannot eliminate temperate bacteriophages from bacterial populations and-in this context-the systems impose immunopathological costs on the host, creating selective pressures that may explain their patchy distribution in bacteria.

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.

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.

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.

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 the theme issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

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. A newly discovered feature within these evolutionary dynamics is 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 the theme issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

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 the theme issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

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 the theme issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

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. A newly discovered feature within these evolutionary dynamics is 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 the theme issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

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. A newly discovered feature within these evolutionary dynamics is 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 the theme issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

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 the theme issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

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. A newly discovered feature within these evolutionary dynamics is 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 the theme issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

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 the theme issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

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. A newly discovered feature within these evolutionary dynamics is 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 the theme issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

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 the theme issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

The primary aim was to examine and compare the increased risk of incident diabetes associated with second-generation antipsychotics (SGAs) and first-generation antipsychotics (FGAs), with and without adjusting for potential confounding factors. The secondary aim was to recalculate the relative risks of diabetes onset using a semi-symmetric bidirectional case-crossover (SSBC) design to adjust for time-trend bias. Prescription records (2005–2015) of antipsychotics were sourced from New Zealand Pharmaceutical Collections. The first-time diabetes diagnosis was extracted from the National Minimal Dataset. Relative risks (RRs) of diabetes onset were calculated using conditional logistic regression. Time-trend bias was corrected by recalculating the RR using a SSBC design. Among 645 individuals, the risk of diabetes onset is higher in SGA users (ARR = 8.72, 95% CI = [5.57, 13.67]) compared to FGA users (ARR = 5.68, 95% CI = [3.43, 9.39]). The increased risk of diabetes onset associated with quetiapine is higher (ARR = 7.47, 95% CI = [4.10, 13.62]), compared to haloperidol (ARR = 5.05, 95% CI = [2.91, 8.75]). However, the increased risk of diabetes onset associated with olanzapine (ARR = 2.27, 95% CI = [0.86, 5.98]) is insignificant after adjusting for concomitant use of effect modifiers and other antipsychotic drugs. The results support that the magnitude of the risk of diabetes is higher with SGA use compared with FGA use, and the risk is higher when co-prescribed. Confounding by indication and time-varying confounders such as body mass index could bias the risk of onset of diabetes. Marginal structural models could provide more precise estimates of the risk of onset of diabetes following exposure to antipsychotics.

Discontinuation of statins may be considered for older individuals with a cancer, multi-morbidity, approaching end-of-life and in primary prevention. The aim of this study is to investigate the relationship between the rates of statin discontinuation in the last 12 months of life and a diagnosis of cancer, and in individuals using statins for primary or secondary prevention. A case-control study of matched cases and controls. Matching was based on age, Charlson comorbidity index scores and socioeconomic status. Prescription and diagnostic data for 20,482 individuals who were aged over 75 years, were in their last 12 months of life and were receiving statins during the study period (1 January 2007 to 31 December 2012). After propensity score matching, we identified 4832 cases with a diagnosis of cancer and 4809 matched controls. We used Cox regression to test the relationship between the relative risk of statin discontinuation and a diagnosis of cancer, and in individuals using statins for primary or secondary prevention. Statins were discontinued in 70.4% of older adults with a diagnosis of cancer and 55.8% of those without cancer (P < 0.05). The Cox regression analysis supports that a diagnosis of cancer can increase the rate of statin discontinuation compared with individuals without a diagnosis of cancer regardless of whether statins were used for primary or secondary prevention (P < 0.05). The findings from this study support that statins are likely to be discontinued in the last year of life in older people with limited life expectancy from cancer, even if statins were indicated for secondary prevention of cardiovascular disease.

Pharmacoepidemiology is an eclectic blend of epidemiology, clinical pharmacology and biostatistics. In New Zealand there have been recent advances in pharmacoepidemiology to examine drug utilisation, monitor adverse drug events and complement pharmacovigilance. This paper attempts to describe the past, present and future of pharmacoepidemiology, particularly in the area of translational research with a particular focus on medicine use and safety. New Zealand is well-positioned globally to make significant contributions to the knowledge base of drug safety in real-world settings.

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’.

SummaryWhat is known and objective Prescription sequence symmetry analyses (PSSA) is a ubiquitous tool employed in pharmacoepidemiological research to predict adverse drug reactions (ADRs). Several studies have reported the advantage of PSSA as a method that can be applied to a large prescription database with computational ease. The objective of this study was to validate New Zealand (NZ) prescription database as a potential source for identifying ADRs using the PSSA method. Methods We analysed de-identified individual-level prescription data for people aged 65 years and above for the period 2005 to 2014 from the pharmaceutical collections supplied by the NZ Ministry of Health. We selected six positive controls that have been previously investigated and reported for causing ADRs. The six positive controls identified were amiodarone (repeated twice), frusemide, simvastatin, lithium and fluticasone. Amiodarone and lithium have been reported to induce thyroid dysfunction. Simvastatin reported to cause muscle cramps while fluticasone is well documented to cause oral candidiasis. Thyroxine was identified as a marker drug to treat hypothyroidism associated with amiodarone and lithium. Carbimazole was identified as a marker drug to treat hyperthyroidism associated with amiodarone use. Quinine sulphate was identified as a marker drug to treat muscle cramps associated with statins. In addition, we also analysed six negative controls that are unlikely to be associated with ADRs. The main outcome measure is to determine associations with ADRs using adjusted sequence ratios (ASR), and 95% confidence intervals Results and discussion Our analyses confirmed a significant signal for all six positive controls. Significant positive associations were noted for amiodarone [ASR = 3·57, 95% CI (3·17–4·02)], and lithium chloride induced hypothyroidism [ASR = 3·43, 95% CI (2·55–4·70)]. Amiodarone was also strongly associated with hyperthyroidism [ASR = 8·81 95% CI (5·86–13·77)]. Simvastatin was associated with muscle cramps [ASR = 1·69, 95% CI (1·61–1·77)]. Fluticasone was positively associated with oral candidiasis [ASR = 2·34, 95% CI (2·19–2·50)]. Frusemide was associated with hypokalaemia [ASR = 2·94, 95% CI (2·83–3·05]). No strong associations were noted for the negative pairs. It is important to highlight that PSSA automatically controls for all confounding factors including unknown and unmeasured confounding variables, plus the effect of temporal trend in prescriptions, and hence allows a more robust ADR detection especially when confounding factors are difficult to determine or measure. What is new and conclusion New Zealand prescription database can be a potential source to identify ADRs engaging the PSSA method, and this could complement pharmacovigilance surveillance in NZ. The PSSA can be an important method for post-marketing surveillance and monitoring of ADRs which have relatively short latency. However, the predictive validity of PSSA will be compromised in certain scenarios, particularly when sample size is small, when new drugs are in the market and data are sparse.

Objectives The primary objective was to evaluate the risk of fractures associated with use of zopiclone, a new Z-hypnotic, in a population-based cohort of older people in New Zealand (NZ) in a real-world setting. The secondary objective was to examine a nonlinear relationship with age and risk for fractures in zopiclone users. Design Population-based cohort study with a case-crossover design. Setting A nationwide representative sample of New Zealanders aged 65 years and older sourced from the pharmaceutical collections and hospital discharges. Participants 74,787 older individuals with a first-time fracture between January 1, 2005, and December 31, 2015, were analyzed using a case-crossover design for fracture risk with zopiclone use. Measurements Prescription records (2005–2014) of zopiclone were sourced from NZ Pharmaceutical Collections (Pharms). The first-time coded diagnosis of fracture was extracted from the National Minimal Datasets. Datasets were linked by a unique patient identifier to set up case-crossover designs. Relative risks (RRs) of fracture associated with zopiclone was calculated using conditional logistic regression. A varying-coefficient conditional logistic model was employed to examine the influence of age as a risk factor for fractures. Results The risk of fracture associated with zopiclone is higher [RR = 1.45, 95% confidence interval (CI) = 1.37–1.55], compared to non-use. The increased risk of fracture associated with zopiclone [adjusted relative risk (ARR) = 1.36, 95% CI = 1.28–1.45] remained significant after adjusting for concomitant use of alpha blockers, antipsychotics, beta blockers, benzodiazepines, and tricyclic antidepressants. The varying coefficient model showed that the risk of fracture increases significantly and monotonically with age. Conclusion The results support that the magnitude of the risk of fracture is higher with use of zopiclone compared to non-use. Prescribers must be aware that the relationship between age and fracture risk is nonlinear, and the oldest old are highly vulnerable to fractures with zopiclone use.