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Background: Knowledge within the field of multiple sclerosis treatment during pregnancy is vital to ensure the most optimal clinical practice. Immunomodulatory treatment in pregnancy could in theory affect the normal development and maturation of the immune system of the fetus with a potential increased risk of infections, consequently. We therefore set out to investigate whether exposure to interferon-beta in utero affected the risk of acquiring infections in early childhood. Methods: This retrospective matched cohort study utilized data from the Danish Multiple Sclerosis Registry linked with national Danish registries to identify all children born of mothers with MS in Denmark from 1998 to 2018. The study included 510 children exposed to interferon-beta in utero. The children were matched 1:1 on various of demographic characteristics with children born to mothers with untreated MS and 1:3 with children born to mothers without MS. Each child was followed for up to five years. Using individual-level data, we investigated all-cause mortality, rate of hospital admissions due to infections, and redeemed prescriptions of antibiotics. The primary statistical model applied was a negative binomial regression analysis. Results: We found no differences in childhood mortality, for hospital admissions the rate ratio compared to healthy controls was 0.79 (0.62–1.00). Regarding antibiotic prescriptions, the results were similar (RR 1.00 (0.90–1.11). Furthermore, we found no certain dose-response relationship between interferon-beta exposure duration and hospital admission rate (P = 0.47) or redeemed antibiotic prescription (P = 0.71). Conclusion: Exposure to interferon-beta during gestation has little to no impact on the risk of acquiring significant infections during the first five years of childhood.

Background: Knowledge within the field of multiple sclerosis treatment during pregnancy is vital to ensure the most optimal clinical practice. Immunomodulatory treatment in pregnancy could in theory affect the normal development and maturation of the immune system of the fetus with a potential increased risk of infections, consequently. We therefore set out to investigate whether exposure to interferon-beta in utero affected the risk of acquiring infections in early childhood. Methods: This retrospective matched cohort study utilized data from the Danish Multiple Sclerosis Registry linked with national Danish registries to identify all children born of mothers with MS in Denmark from 1998 to 2018. The study included 510 children exposed to interferon-beta in utero. The children were matched 1:1 on various of demographic characteristics with children born to mothers with untreated MS and 1:3 with children born to mothers without MS. Each child was followed for up to five years. Using individual-level data, we investigated all-cause mortality, rate of hospital admissions due to infections, and redeemed prescriptions of antibiotics. The primary statistical model applied was a negative binomial regression analysis. Results: We found no differences in childhood mortality, for hospital admissions the rate ratio compared to healthy controls was 0.79 (0.62–1.00). Regarding antibiotic prescriptions, the results were similar (RR 1.00 (0.90–1.11). Furthermore, we found no certain dose-response relationship between interferon-beta exposure duration and hospital admission rate (P = 0.47) or redeemed antibiotic prescription (P = 0.71). Conclusion: Exposure to interferon-beta during gestation has little to no impact on the risk of acquiring significant infections during the first five years of childhood.

Health care databases are often used in pharmacoepidemiological studies to determine patient drug use. These data can include drug dispensings from the pharmacy or drug prescriptions by doctors. These data do not always reflect the actual use of a medicine by patients, as patients can decide to not use a drug or use the drug differently than what is registered in these databases. When these two do not align, it is called exposure misclassification. In this thesis, we evaluated how researchers report on assessing drug use in databases, the extent of exposure misclassification and the impact thereof on when studying the association between a drug and (un)intended effects. First, we found that reporting of how researchers assess drug use was insufficient in most studies. We also saw that exposure misclassification and other suboptimal methodological choices when designing observational studies may have an impact on the study conclusions. This was for example shown for studies on benefits of hydroxychloroquine for COVID19 patients. In addition, we looked at how using different databases might lead to misclassification of drug exposure assessment. We found, for example, that about 10% of the prescriptions prescribed by GPs are not collected from the pharmacy. Patients’ drug use is thus overestimated when prescription databases are being used. We also showed that misclassification can occur when a database contains prescriptions from a single type of doctor (e.g., general practitioners), while drugs can also be prescribed by different doctors (e.g., hospital specialists). And lastly, we show that it is important to take into account how long drugs remain in the body when measuring their effects. For amiodarone, the impact of not accounting for this on the effect estimates was however limited. To conclude, measuring use of drugs, or assessment of drug exposure, in pharmacoepidemiological studies and reporting thereof could be improved, thereby contributing to more reliable

Cannabis, a drug derived from the plant Cannabis Sativa, is one of the most commonly used drugs worldwide, with a rich history of medicinal application. The increased use of cannabis in recent history has led to a rapid diversification of cannabis strains, each with unique levels of major cannabinoid constituents including tetrahydrocannabinol (THC), the main psychoactive component of cannabis, and cannabidiol (CBD). As social and legislative attitudes towards cannabis begin to change, more people are seeking out this drug for its purported health benefits, many of which are thought to be attributable to CBD. Using four novel high-CBD, low-THC extracts, this research seeks to explore the long-term effects of chronic cannabis exposure on behaviour in a rodent model. Results from this study demonstrate that there are few long-term effects of chronic, high-CBD cannabis exposure on behaviour and that the changes that were observed were not of detriment.

Cannabis, a drug derived from the plant Cannabis Sativa, is one of the most commonly used drugs worldwide, with a rich history of medicinal application. The increased use of cannabis in recent history has led to a rapid diversification of cannabis strains, each with unique levels of major cannabinoid constituents including tetrahydrocannabinol (THC), the main psychoactive component of cannabis, and cannabidiol (CBD). As social and legislative attitudes towards cannabis begin to change, more people are seeking out this drug for its purported health benefits, many of which are thought to be attributable to CBD. Using four novel high-CBD, low-THC extracts, this research seeks to explore the long-term effects of chronic cannabis exposure on behaviour in a rodent model. Results from this study demonstrate that there are few long-term effects of chronic, high-CBD cannabis exposure on behaviour and that the changes that were observed were not of detriment.

Cannabis, a drug derived from the plant Cannabis Sativa, is one of the most commonly used drugs worldwide, with a rich history of medicinal application. The increased use of cannabis in recent history has led to a rapid diversification of cannabis strains, each with unique levels of major cannabinoid constituents including tetrahydrocannabinol (THC), the main psychoactive component of cannabis, and cannabidiol (CBD). As social and legislative attitudes towards cannabis begin to change, more people are seeking out this drug for its purported health benefits, many of which are thought to be attributable to CBD. Using four novel high-CBD, low-THC extracts, this research seeks to explore the long-term effects of chronic cannabis exposure on behaviour in a rodent model. Results from this study demonstrate that there are few long-term effects of chronic, high-CBD cannabis exposure on behaviour and that the changes that were observed were not of detriment.

Cannabis, a drug derived from the plant Cannabis Sativa, is one of the most commonly used drugs worldwide, with a rich history of medicinal application. The increased use of cannabis in recent history has led to a rapid diversification of cannabis strains, each with unique levels of major cannabinoid constituents including tetrahydrocannabinol (THC), the main psychoactive component of cannabis, and cannabidiol (CBD). As social and legislative attitudes towards cannabis begin to change, more people are seeking out this drug for its purported health benefits, many of which are thought to be attributable to CBD. Using four novel high-CBD, low-THC extracts, this research seeks to explore the long-term effects of chronic cannabis exposure on behaviour in a rodent model. Results from this study demonstrate that there are few long-term effects of chronic, high-CBD cannabis exposure on behaviour and that the changes that were observed were not of detriment.

Cannabis, a drug derived from the plant Cannabis Sativa, is one of the most commonly used drugs worldwide, with a rich history of medicinal application. The increased use of cannabis in recent history has led to a rapid diversification of cannabis strains, each with unique levels of major cannabinoid constituents including tetrahydrocannabinol (THC), the main psychoactive component of cannabis, and cannabidiol (CBD). As social and legislative attitudes towards cannabis begin to change, more people are seeking out this drug for its purported health benefits, many of which are thought to be attributable to CBD. Using four novel high-CBD, low-THC extracts, this research seeks to explore the long-term effects of chronic cannabis exposure on behaviour in a rodent model. Results from this study demonstrate that there are few long-term effects of chronic, high-CBD cannabis exposure on behaviour and that the changes that were observed were not of detriment.

Prenatal drug exposure is a common clinical phenomenon in pregnancy cases. Pregnancy is a fragile period of time for both the mother and the fetus. Therefore, strict drug regulation is important to ensure the safety and wellbeing of the developing fetus. Certain drugs, once thought to be safe, have been found to have detrimental effects on the normal development of functioning organ systems in the fetus. Current research has identified drugs that when taken during pregnancy can result in the onset of fetal physical abnormalities, impaired brain development, and disrupted organogenesis and organ function. Thalidomide, losartan, opioids, alcohol, and caffeine are reviewed to identify the trends in the literature on prenatal drug exposure and the implications of drug usage during pregnancy. Although the Food & Drug Administration (FDA) are active in regulation, educational programs for pregnant/lactating women and epidemiological research on both prescribed and over-the-counter drugs on the fetus is necessary to preserve maternal health and, consequently, the health of the baby.

Cannabis, a drug derived from the plant Cannabis Sativa, is one of the most commonly used drugs worldwide, with a rich history of medicinal application. The increased use of cannabis in recent history has led to a rapid diversification of cannabis strains, each with unique levels of major cannabinoid constituents including tetrahydrocannabinol (THC), the main psychoactive component of cannabis, and cannabidiol (CBD). As social and legislative attitudes towards cannabis begin to change, more people are seeking out this drug for its purported health benefits, many of which are thought to be attributable to CBD. Using four novel high-CBD, low-THC extracts, this research seeks to explore the long-term effects of chronic cannabis exposure on behaviour in a rodent model. Results from this study demonstrate that there are few long-term effects of chronic, high-CBD cannabis exposure on behaviour and that the changes that were observed were not of detriment.

Cannabis, a drug derived from the plant Cannabis Sativa, is one of the most commonly used drugs worldwide, with a rich history of medicinal application. The increased use of cannabis in recent history has led to a rapid diversification of cannabis strains, each with unique levels of major cannabinoid constituents including tetrahydrocannabinol (THC), the main psychoactive component of cannabis, and cannabidiol (CBD). As social and legislative attitudes towards cannabis begin to change, more people are seeking out this drug for its purported health benefits, many of which are thought to be attributable to CBD. Using four novel high-CBD, low-THC extracts, this research seeks to explore the long-term effects of chronic cannabis exposure on behaviour in a rodent model. Results from this study demonstrate that there are few long-term effects of chronic, high-CBD cannabis exposure on behaviour and that the changes that were observed were not of detriment.

Cannabis, a drug derived from the plant Cannabis Sativa, is one of the most commonly used drugs worldwide, with a rich history of medicinal application. The increased use of cannabis in recent history has led to a rapid diversification of cannabis strains, each with unique levels of major cannabinoid constituents including tetrahydrocannabinol (THC), the main psychoactive component of cannabis, and cannabidiol (CBD). As social and legislative attitudes towards cannabis begin to change, more people are seeking out this drug for its purported health benefits, many of which are thought to be attributable to CBD. Using four novel high-CBD, low-THC extracts, this research seeks to explore the long-term effects of chronic cannabis exposure on behaviour in a rodent model. Results from this study demonstrate that there are few long-term effects of chronic, high-CBD cannabis exposure on behaviour and that the changes that were observed were not of detriment.

Cannabis, a drug derived from the plant Cannabis Sativa, is one of the most commonly used drugs worldwide, with a rich history of medicinal application. The increased use of cannabis in recent history has led to a rapid diversification of cannabis strains, each with unique levels of major cannabinoid constituents including tetrahydrocannabinol (THC), the main psychoactive component of cannabis, and cannabidiol (CBD). As social and legislative attitudes towards cannabis begin to change, more people are seeking out this drug for its purported health benefits, many of which are thought to be attributable to CBD. Using four novel high-CBD, low-THC extracts, this research seeks to explore the long-term effects of chronic cannabis exposure on behaviour in a rodent model. Results from this study demonstrate that there are few long-term effects of chronic, high-CBD cannabis exposure on behaviour and that the changes that were observed were not of detriment.

Cannabis, a drug derived from the plant Cannabis Sativa, is one of the most commonly used drugs worldwide, with a rich history of medicinal application. The increased use of cannabis in recent history has led to a rapid diversification of cannabis strains, each with unique levels of major cannabinoid constituents including tetrahydrocannabinol (THC), the main psychoactive component of cannabis, and cannabidiol (CBD). As social and legislative attitudes towards cannabis begin to change, more people are seeking out this drug for its purported health benefits, many of which are thought to be attributable to CBD. Using four novel high-CBD, low-THC extracts, this research seeks to explore the long-term effects of chronic cannabis exposure on behaviour in a rodent model. Results from this study demonstrate that there are few long-term effects of chronic, high-CBD cannabis exposure on behaviour and that the changes that were observed were not of detriment.

Prenatal drug exposure is a common clinical phenomenon in pregnancy cases. Pregnancy is a fragile period of time for both the mother and the fetus. Therefore, strict drug regulation is important to ensure the safety and wellbeing of the developing fetus. Certain drugs, once thought to be safe, have been found to have detrimental effects on the normal development of functioning organ systems in the fetus. Current research has identified drugs that when taken during pregnancy can result in the onset of fetal physical abnormalities, impaired brain development, and disrupted organogenesis and organ function. Thalidomide, losartan, opioids, alcohol, and caffeine are reviewed to identify the trends in the literature on prenatal drug exposure and the implications of drug usage during pregnancy. Although the Food & Drug Administration (FDA) are active in regulation, educational programs for pregnant/lactating women and epidemiological research on both prescribed and over-the-counter drugs on the fetus is necessary to preserve maternal health and, consequently, the health of the baby.

BACKGROUND: Drug exposure assessment based on dispensing data can be misclassified when patients do not adhere to their therapy or when information about over-the-counter drugs is not captured in the study database. Previous research has considered hypothetical sensitivity and specificity values, whereas this study aims to assess the impact of literature-based real values of exposure misclassification.METHODS: A synthetic cohort study was constructed based on the proportion of exposure theoretically captured in a database (range 0.5-1.0) and the level of adherence (0.5-1.0). Three scenarios were explored: non-differential misclassification, differential misclassification (misclassifications dependent on an unmeasured risk factor doubling the outcome risk), and non-differential misclassification in a comparative effectiveness study (RRA and RRB both 2.0 compared to non-use, RRA-B 1.0).RESULTS: For the scenarios with non-differential misclassification, 25% non-adherence or 25% uncaptured exposure changed the RR from 2.0 to 1.75 and 1.95, respectively. Applying different proportions of non-adherence or uncaptured use (20% vs 40%) for subgroups with and without the risk factor, an RR of 0.95 was observed in the absence of a true effect (i.e., true RR = 1). In the comparative effectiveness study, no effect on RR was seen for different proportions of uncaptured exposure; however, different levels of non-adherence for the drugs (20% vs 40%) led to an underestimation of RRA-B (0.89).DISCUSSION: All scenarios led to biased estimates, but the magnitude of the bias differed across scenarios. When testing the robustness of findings of pharmacoepidemiologic studies, we recommend using realistic values of non-adherence and uncaptured exposure based on real-world data.

Cerebrovascular disorders have occurred more frequently in some Central Nervous System (CNS) disorders, such as epilepsy. Some CNS drugs have been associated with increased stroke risk. Our aim was to estimate the risk of ischaemic stroke in patients exposed to antiepileptic drugs (AED). Population-based matched case-control study using SIDIAP database, based in electronic health records from primary healthcare from Catalonia, Spain. Cases were those patients with a registered diagnosis of first stroke during 2009-2014. Up to 10 controls were selected for each case and matched by sex, age, and geographic area and without a prior diagnosis of stroke. We considered global drug exposure to AED, past and current exposure and exposure in monotherapy to each AED. 2,865 cases and 19,406 controls were exposed to AED during the study period. Global exposure to levetiracetam [(OR3.3, CI95 % 2.8-4.0)], phenytoin [OR1.5, CI95 % 1.2-41.9)], and valproic acid [(OR 1.3, CI95 % 1.1-1.6)], showed significantly association to ischaemic stroke that was also maintained with current exposure of levetiracetam [OR4.1, CI95 % 3.3-5.2)] and valproic acid [OR1.4, CI95 % 1.1-1.9)]. Current levetiracetam monotherapy showed a very high risk of ischaemic stroke [(OR 5.1, CI95 % 3.7-6.9)]. Drugs used for other conditions than epilepsy (pregabalin, gabapentin) were the most used AED and both did not show a risk. Levetiracetam shows a risk for stroke even when assessed in current monotherapy. The lack of data regarding the link with diagnosis and severity in our study makes it necessary to conduct further studies to confirm or dismiss our results, focussing on levetiracetam. The online version contains supplementary material available at 10.1186/s12883-021-02237-1

PURPOSE: Exposure definitions vary across pharmacoepidemiological studies. Therefore, transparent reporting of exposure definitions is important for interpretation of published study results. We aimed to assess the quality of reporting of exposure to identify where improvement may be needed.METHOD: We systematically reviewed observational pharmacoepidemiological studies that used routinely collected health data, published in 2017 in six pharmacoepidemiological journals. Reporting of exposure was scored using 11 items of the ISPE-ISPOR guideline on reporting of pharmacoepidemiological studies.RESULTS: Of the 91 studies included, all studies reported the type of exposure (100%), while most reported the exposure risk window (85%) and the exposure assessment window (98%). Operationalization of the exposure window was described infrequently: 16% (14/90) of the studies explicitly reported the presence or absence of an induction period if applicable, 11% (5/47), and 35% (17/49) reported how stockpiling and gaps between exposure episodes were handled, respectively, and 35% (17/49) explicitly mentioned the exposure extension. Switching/add-on was reported in 62% (50/81). How switching between drugs was dealt with and specific drug codes were reported in 52 (57%) and 24 (26%) studies, respectively.CONCLUSION: Publications of pharmacoepidemiological studies frequently reported the type of exposure, the exposure risk window, and the exposure assessment window. However, more details on exposure assessment are needed, especially when it concerns the operationalization of the exposure risk window (eg, the presence or absence of an induction period or exposure extension, handling of stockpiling and gaps, and specific codes), to allow for correct interpretation, reproducibility, and assessment of validity.

Background: Therapeutic drug monitoring (TDM) is a tool to personalize and optimize dosing by measuring the drug concentration and subsequently adjusting the dose to reach a target concentration or exposure. The evidence to support TDM is however often ranked as expert opinion. Limitations in study design and sample size have hampered definitive conclusions of the potential added value of TDM. Objectives: We aim to give expert opinion and discuss the main points and limitations of available data from antibiotic TDM trials and emphasize key elements for consideration in design of future clinical studies to quantify the benefits of TDM. Sources: The sources were peer-reviewed publications, guidelines and expert opinions from the field of TDM. Content: This review focuses on key aspects of antimicrobial TDM study design: describing the rationale for a TDM study, assessing the exposure of a drug, assessing susceptibility of pathogens and selecting appropriate clinical endpoints. Moreover we provide guidance on appropriate study design.

Aim: To determine if empirical anti-pseudomonal beta-lactam antibiotic (BLA) dosing achieves adequate drug exposure in septic patients. Method(s): A single-centre, prospective pharmacokinetic study was conducted in Intensive Care Unit (ICU) patients with sepsis, receiving empirical therapy with piperacillin/tazobactam or meropenem. The pharmacokinetic/pharmacodynamic (PK/PD) targets were free BLA concentrations above the MIC at the mid-point (Concentration A, 50%f T > MIC) and end of the dosing interval (Concentration B, 100% fT > MIC). Sub-therapeutic concentrations were defined as concentration A < MIC, and sub-optimal as concentration B < MIC. The MIC breakpoint for Pseudomonas aeruginosa, as defined by The European Committee on Antimicrobial Susceptibility Testing (EUCAST) (available from ) was used. Result(s): Of the 37 eligible patients, 20 were receiving piperacillin/tazobactam (TZP), and 17 meropenem (MEM). PK data were available for 36 patients (concentration A) and 34 patients (concentration B). The median measured plasma concentrations (mg/L) were: piperacillin for doses 4 g 8-hourly and 4 g 6-hourly - concentration A 53.9 [14.38-123.71] and 36.44 [13.38-107.45], concentration B 8.01 [2.57-71.08] and 27.31 [3.32-59.76], MEM for doses 1 g 8-hourly and 2 g 8-hourly - concentration A 12.49 [7.35-23.63] and 30.5, concentration B 7.47 [2.97-11.33] and 9.31. 27.8% (10 of 36) of patients had sub-therapeutic concentrations (concentration A) and 50% (17 of 34) had sub-optimal concentrations (concentration B). Conclusion(s): Our study confirms that sub-therapeutic unbound plasma anti-pseudomonal BLA concentrations are common in critically ill septic patients and underscores the urgent need for future trials exploring the efficacy of BLA therapeutic drug monitoring in these patients.Copyright © 2020 The Society of Hospital Pharmacists of Australia

Objectives This review provides insights into the potential for aspirin to preserve bone mineral density (BMD) and reduce fracture risk, building knowledge of the risk-benefit profile of aspirin. Methods We conducted a systematic review and exploratory meta-analysis of observational studies. Electronic searches of MEDLINE and Embase, and a manual search of bibliographies was undertaken for studies published to 28 March 2018. Studies were included if: participants were men or women aged >=18 years; the exposure of interest was aspirin; and relative risks, ORs and 95% CIs for the risk of fracture or difference (percentage or absolute) in BMD (measured by dual energy X-ray absorptiometry) between aspirin users and non-users were presented. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklists for observational studies. Pooled ORs for any fracture and standardised mean differences (SMDs) for BMD outcomes were calculated using random-effects models. Results Twelve studies met the inclusion criteria and were included in the meta-analysis. Aspirin use was associated with a 17% lower odds for any fracture (OR 0.83, 95% CI 0.70 to 0.99; I 2 =71%; six studies; n=511 390). Aspirin was associated with a higher total hip BMD for women (SMD 0.03, 95% CI -0.02 to 0.07; I 2 =0%; three studies; n=9686) and men (SMD 0.06, 95% CI -0.02 to 0.13, I 2 =0%; two studies; n=4137) although these associations were not significant. Similar results were observed for lumbar spine BMD in women (SMD 0.03, 95% CI -0.03 to 0.09; I 2 =34%; four studies; n=11 330) and men (SMD 0.08; 95% CI -0.01 to 0.18; one study; n=432). Conclusions While the benefits of reduced fracture risk and higher BMD from aspirin use may be modest for individuals, if confirmed in prospective controlled trials, they may confer a large population benefit given the common use of aspirin in older people.Copyright © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No comme

Aim: To determine if empirical anti-pseudomonal beta-lactam antibiotic (BLA) dosing achieves adequate drug exposure in septic patients. Method(s): A single-centre, prospective pharmacokinetic study was conducted in Intensive Care Unit (ICU) patients with sepsis, receiving empirical therapy with piperacillin/tazobactam or meropenem. The pharmacokinetic/pharmacodynamic (PK/PD) targets were free BLA concentrations above the MIC at the mid-point (Concentration A, 50%f T > MIC) and end of the dosing interval (Concentration B, 100% fT > MIC). Sub-therapeutic concentrations were defined as concentration A < MIC, and sub-optimal as concentration B < MIC. The MIC breakpoint for Pseudomonas aeruginosa, as defined by The European Committee on Antimicrobial Susceptibility Testing (EUCAST) (available from ) was used. Result(s): Of the 37 eligible patients, 20 were receiving piperacillin/tazobactam (TZP), and 17 meropenem (MEM). PK data were available for 36 patients (concentration A) and 34 patients (concentration B). The median measured plasma concentrations (mg/L) were: piperacillin for doses 4 g 8-hourly and 4 g 6-hourly - concentration A 53.9 [14.38-123.71] and 36.44 [13.38-107.45], concentration B 8.01 [2.57-71.08] and 27.31 [3.32-59.76], MEM for doses 1 g 8-hourly and 2 g 8-hourly - concentration A 12.49 [7.35-23.63] and 30.5, concentration B 7.47 [2.97-11.33] and 9.31. 27.8% (10 of 36) of patients had sub-therapeutic concentrations (concentration A) and 50% (17 of 34) had sub-optimal concentrations (concentration B). Conclusion(s): Our study confirms that sub-therapeutic unbound plasma anti-pseudomonal BLA concentrations are common in critically ill septic patients and underscores the urgent need for future trials exploring the efficacy of BLA therapeutic drug monitoring in these patients.Copyright © 2020 The Society of Hospital Pharmacists of Australia

Objectives This review provides insights into the potential for aspirin to preserve bone mineral density (BMD) and reduce fracture risk, building knowledge of the risk-benefit profile of aspirin. Methods We conducted a systematic review and exploratory meta-analysis of observational studies. Electronic searches of MEDLINE and Embase, and a manual search of bibliographies was undertaken for studies published to 28 March 2018. Studies were included if: participants were men or women aged >=18 years; the exposure of interest was aspirin; and relative risks, ORs and 95% CIs for the risk of fracture or difference (percentage or absolute) in BMD (measured by dual energy X-ray absorptiometry) between aspirin users and non-users were presented. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklists for observational studies. Pooled ORs for any fracture and standardised mean differences (SMDs) for BMD outcomes were calculated using random-effects models. Results Twelve studies met the inclusion criteria and were included in the meta-analysis. Aspirin use was associated with a 17% lower odds for any fracture (OR 0.83, 95% CI 0.70 to 0.99; I 2 =71%; six studies; n=511 390). Aspirin was associated with a higher total hip BMD for women (SMD 0.03, 95% CI -0.02 to 0.07; I 2 =0%; three studies; n=9686) and men (SMD 0.06, 95% CI -0.02 to 0.13, I 2 =0%; two studies; n=4137) although these associations were not significant. Similar results were observed for lumbar spine BMD in women (SMD 0.03, 95% CI -0.03 to 0.09; I 2 =34%; four studies; n=11 330) and men (SMD 0.08; 95% CI -0.01 to 0.18; one study; n=432). Conclusions While the benefits of reduced fracture risk and higher BMD from aspirin use may be modest for individuals, if confirmed in prospective controlled trials, they may confer a large population benefit given the common use of aspirin in older people.Copyright © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No comme

The optimisation of antibiotic dosing therapy with therapeutic drug monitoring is widely recommended. The aim of therapeutic drug monitoring is to help the clinician to achieve target pharmacokinetic/pharmacodynamic parameters, maximising efficacy and minimising toxicity. Computerised programs, utilising the Bayesian estimation procedures, are able to achieve target concentrations in a greater percentage of patients earlier in the course of therapy compared to linear regression analysis and population methods. This article summarises various methods for dose optimisation of antibiotics with a focus on Bayesian programs.Copyright © 2019, Springer Nature Switzerland AG.

Rats were exposed to nickel oxide nanoparticles (NiO-NP) inhalation at 0.23 ± 0.01 mg/m3 for 4 h a day 5 times a week for up to 10 months. The rat organism responded to this impact with changes in cytological and some biochemical characteristics of the bronchoalveolar lavage fluid along with a paradoxically little pronounced pulmonary pathology associated with a rather low chronic retention of nanoparticles in the lungs. There were various manifestations of systemic toxicity, including damage to the liver and kidneys; a likely allergic syndrome as indicated by some cytological signs; transient stimulation of erythropoiesis; and penetration of nickel into the brain from the nasal mucous membrane along the olfactory pathway. Against a picture of mild to moderate chronic toxicity of nickel, its in vivo genotoxic effect assessed by the degree of DNA fragmentation in nucleated blood cells (the RAPD test) was pronounced, tending to increasing with the length of the exposure period. When rats were given orally, in parallel with the toxic exposure, a set of innocuous substances with differing mechanisms of expected bioprotective action, the genotoxic effect of NiO-NPs was found to be substantially attenuated. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

The optimisation of antibiotic dosing therapy with therapeutic drug monitoring is widely recommended. The aim of therapeutic drug monitoring is to help the clinician to achieve target pharmacokinetic/pharmacodynamic parameters, maximising efficacy and minimising toxicity. Computerised programs, utilising the Bayesian estimation procedures, are able to achieve target concentrations in a greater percentage of patients earlier in the course of therapy compared to linear regression analysis and population methods. This article summarises various methods for dose optimisation of antibiotics with a focus on Bayesian programs.Copyright © 2019, Springer Nature Switzerland AG.

Background: Psychedelic microdosing is the trending practice of using tiny repeated doses of psychedelic substances to facilitate a range of supposed benefits. With only a few published studies to date, the subject is still under-researched, and more knowledge is warranted. Social media and internet discussion forums have played a vital role in the growing visibility of the microdosing phenomenon, and the present study utilized YouTube contents to improve comprehension of the microdosing practice as well as the social interactions and discussions around microdosing. Methods: Microdosing self-disclosure in YouTube videos and their following comments were qualitatively analyzed by inductive thematic analysis. Various software was utilized to enable gathering and sorting relevant data. Results: Microdosing of psychedelic substances, primarily LSD and psilocybin, was used for therapeutic and enhancement purposes, and predominantly beneficial effects were reported. Many different applications and outcomes were discussed, and therapeutic effects for depression appeared especially noteworthy. Intentions for use were recognized as an influencing factor for the progression and outcomes of microdosing. The function of social interactions was mainly to discuss views on the microdosing phenomenon, strategies for optimal results, minimize risks, and share emotional support. Conclusions: Potentially, microdosing could provide some of the same benefits (for certain conditions) as full-dose interventions with less risk of adverse reactions related to the sometimes intense experiences of higher doses. Microdosing may well also mean additional benefits, as well as risks, through the repeated exposure over extended periods.

Background: Psychedelic microdosing is the trending practice of using tiny repeated doses of psychedelic substances to facilitate a range of supposed benefits. With only a few published studies to date, the subject is still under-researched, and more knowledge is warranted. Social media and internet discussion forums have played a vital role in the growing visibility of the microdosing phenomenon, and the present study utilized YouTube contents to improve comprehension of the microdosing practice as well as the social interactions and discussions around microdosing. Methods: Microdosing self-disclosure in YouTube videos and their following comments were qualitatively analyzed by inductive thematic analysis. Various software was utilized to enable gathering and sorting relevant data. Results: Microdosing of psychedelic substances, primarily LSD and psilocybin, was used for therapeutic and enhancement purposes, and predominantly beneficial effects were reported. Many different applications and outcomes were discussed, and therapeutic effects for depression appeared especially noteworthy. Intentions for use were recognized as an influencing factor for the progression and outcomes of microdosing. The function of social interactions was mainly to discuss views on the microdosing phenomenon, strategies for optimal results, minimize risks, and share emotional support. Conclusions: Potentially, microdosing could provide some of the same benefits (for certain conditions) as full-dose interventions with less risk of adverse reactions related to the sometimes intense experiences of higher doses. Microdosing may well also mean additional benefits, as well as risks, through the repeated exposure over extended periods.

Tyramine, formed by the decarboxylation of tyrosine, is a natural constituent of numerous food products. As an indirect sympathomimetic, it can have potentially dangerous hypertensive effects. In vitro data indicated that the pharmacokinetics of tyramine possibly depend on the organic cation transporter OCT1 genotype and on the CYP2D6 genotype. Since tyramine is a prototypic substrate of monoamine oxidase A (MAO-A), genetic polymorphisms in MAO-A may also be relevant. The aims of this study were to identify to what extent the interindividual variation in pharmacokinetics and pharmacodynamics of tyramine is determined by genetic polymorphisms in OCT1, CYP2D6, and MAO-A. Beyond that, we wanted to evaluate tyramine as probe drug for the in vivo activity of MAO-A and OCT1. Therefore, the pharmacokinetics, pharmacodynamics, and pharmacogenetics of tyramine were studied in 88 healthy volunteers after oral administration of a 400 mg dose. We observed a strong interindividual variation in systemic tyramine exposure, with a mean AUC of 3.74 min*µg/ml and a high mean CL/F ratio of 107 l/min. On average, as much as 76.8% of the dose was recovered in urine in form of the MAO-catalysed metabolite 4-hydroxyphenylacetic acid (4-HPAA), confirming that oxidative deamination by MAO-A is the quantitatively most relevant metabolic pathway. Systemic exposure of 4-HPAA varied only up to 3-fold, indicating no strong heritable variation in peripheral MAO-A activity. Systolic blood pressure increased by more than 10 mmHg in 71% of the volunteers and correlated strongly with systemic tyramine concentration. In less than 10% of participants, individually variable blood pressure peaks by >40 mmHg above baseline were observed at tyramine concentrations of >60 µg/l. Unexpectedly, the functionally relevant polymorphisms in OCT1 and CYP2D6, including the CYP2D6 poor and ultra-rapid metaboliser genotypes, did not significantly affect tyramine pharmacokinetics or pharmacodynamics. Also, the MOA-A ge

Background: Psychedelic microdosing is the trending practice of using tiny repeated doses of psychedelic substances to facilitate a range of supposed benefits. With only a few published studies to date, the subject is still under-researched, and more knowledge is warranted. Social media and internet discussion forums have played a vital role in the growing visibility of the microdosing phenomenon, and the present study utilized YouTube contents to improve comprehension of the microdosing practice as well as the social interactions and discussions around microdosing. Methods: Microdosing self-disclosure in YouTube videos and their following comments were qualitatively analyzed by inductive thematic analysis. Various software was utilized to enable gathering and sorting relevant data. Results: Microdosing of psychedelic substances, primarily LSD and psilocybin, was used for therapeutic and enhancement purposes, and predominantly beneficial effects were reported. Many different applications and outcomes were discussed, and therapeutic effects for depression appeared especially noteworthy. Intentions for use were recognized as an influencing factor for the progression and outcomes of microdosing. The function of social interactions was mainly to discuss views on the microdosing phenomenon, strategies for optimal results, minimize risks, and share emotional support. Conclusions: Potentially, microdosing could provide some of the same benefits (for certain conditions) as full-dose interventions with less risk of adverse reactions related to the sometimes intense experiences of higher doses. Microdosing may well also mean additional benefits, as well as risks, through the repeated exposure over extended periods.

Background: Psychedelic microdosing is the trending practice of using tiny repeated doses of psychedelic substances to facilitate a range of supposed benefits. With only a few published studies to date, the subject is still under-researched, and more knowledge is warranted. Social media and internet discussion forums have played a vital role in the growing visibility of the microdosing phenomenon, and the present study utilized YouTube contents to improve comprehension of the microdosing practice as well as the social interactions and discussions around microdosing. Methods: Microdosing self-disclosure in YouTube videos and their following comments were qualitatively analyzed by inductive thematic analysis. Various software was utilized to enable gathering and sorting relevant data. Results: Microdosing of psychedelic substances, primarily LSD and psilocybin, was used for therapeutic and enhancement purposes, and predominantly beneficial effects were reported. Many different applications and outcomes were discussed, and therapeutic effects for depression appeared especially noteworthy. Intentions for use were recognized as an influencing factor for the progression and outcomes of microdosing. The function of social interactions was mainly to discuss views on the microdosing phenomenon, strategies for optimal results, minimize risks, and share emotional support. Conclusions: Potentially, microdosing could provide some of the same benefits (for certain conditions) as full-dose interventions with less risk of adverse reactions related to the sometimes intense experiences of higher doses. Microdosing may well also mean additional benefits, as well as risks, through the repeated exposure over extended periods.

Background: Psychedelic microdosing is the trending practice of using tiny repeated doses of psychedelic substances to facilitate a range of supposed benefits. With only a few published studies to date, the subject is still under-researched, and more knowledge is warranted. Social media and internet discussion forums have played a vital role in the growing visibility of the microdosing phenomenon, and the present study utilized YouTube contents to improve comprehension of the microdosing practice as well as the social interactions and discussions around microdosing. Methods: Microdosing self-disclosure in YouTube videos and their following comments were qualitatively analyzed by inductive thematic analysis. Various software was utilized to enable gathering and sorting relevant data. Results: Microdosing of psychedelic substances, primarily LSD and psilocybin, was used for therapeutic and enhancement purposes, and predominantly beneficial effects were reported. Many different applications and outcomes were discussed, and therapeutic effects for depression appeared especially noteworthy. Intentions for use were recognized as an influencing factor for the progression and outcomes of microdosing. The function of social interactions was mainly to discuss views on the microdosing phenomenon, strategies for optimal results, minimize risks, and share emotional support. Conclusions: Potentially, microdosing could provide some of the same benefits (for certain conditions) as full-dose interventions with less risk of adverse reactions related to the sometimes intense experiences of higher doses. Microdosing may well also mean additional benefits, as well as risks, through the repeated exposure over extended periods.

Objective: This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon beta, fingolimod or natalizumab. Method(s): We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and 1-year on-treatment follow-up from MSBase. Three pairwise propensity score-matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed. Result(s): The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon (p = 0.05), similar to fingolimod (p = 0.31) and higher than on natalizumab (p = 0.042). The probability of disability accumulation on cladribine was similar to interferon (p = 0.37) and fingolimod (p = 0.089) but greater than natalizumab (p = 0.021). The probability of disability improvement was higher on cladribine than interferon (p = 0.00017), fingolimod (p = 0.0025) or natalizumab (p = 0.00099). Sensitivity analyses largely confirmed the above results. Conclusion(s): Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon beta and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab.Copyright © The Author(s), 2017.

Background Vedolizumab (VDZ), an alpha4beta7 anti-integrin antibody, is efficacious in the induction and maintenance of remission in ulcerative colitis (UC) and Crohn's disease (CD). In the GEMINI long-term safety study, enrolled patients received 4-weekly VDZ. Upon completion, patients were switched to 8-weekly VDZ in Australia. The clinical success rate of treatment de-escalation for patients in remission on VDZ has not been described previously. Aim To determine the proportion of patients who relapsed after switching from 4 to 8-weekly VDZ, the mean time to relapse, and the recapture rate when switching back to 8-weekly dosing. Materials and methods This was a retrospective, observational, multicenter study of patients previously recruited into GEMINI long-term safety in Australia. Data on the demographics and biochemical findings were collected. Results There were 34 patients [23 men, mean age 49.1 (+/-13.1) years] and their mean disease duration was 17.6 (+/-8.5) years. The mean 4-weekly VDZ infusion duration was 286.5 (+/-48.8) weeks. A total of five (15%) patients relapsed on dose-interval increase (4/17 UC, 1/17 CD) at a median duration from dose interval lengthening to flare of 14 weeks (interquartile range=6-25). Eighty percent (4/5) of patients re-entered remission following dose-interval decrease back to 4-weekly. No clinical predictors of relapse could be determined because of the small cohort size. Conclusion The risk of patients relapsing when switching from 4 to 8-weekly VDZ ~15% and is similar between CD and UC. Dose-interval decrease recaptures 80% of patients who relapsed. Therapeutic drug monitoring of VDZ may be of clinical relevance.Copyright © 2018 Wolters Kluwer Health, Inc.

Background: Infants born preterm following exposure to in utero inflammation/chorioamnionitis are at high risk of brain injury and life-long neurological deficits. In this study, we assessed the efficacy of early intervention umbilical cord blood (UCB) cell therapy in a large animal model of preterm brain inflammation and injury. We hypothesised that UCB treatment would be neuroprotective for the preterm brain following subclinical fetal inflammation. Method(s): Chronically instrumented fetal sheep at 0.65 gestation were administered lipopolysaccharide (LPS, 150 ng, 055:B5) intravenously over 3 consecutive days, followed by 100 million human UCB mononuclear cells 6 h after the final LPS dose. Controls were administered saline instead of LPS and cells. Ten days after the first LPS dose, the fetal brain and cerebrospinal fluid were collected for analysis of subcortical and periventricular white matter injury and inflammation. Result(s): LPS administration increased microglial aggregate size, neutrophil recruitment, astrogliosis and cell death compared with controls. LPS also reduced total oligodendrocyte count and decreased mature myelinating oligodendrocytes. UCB cell therapy attenuated cell death and inflammation, and recovered total and mature oligodendrocytes, compared with LPS. Conclusion(s): UCB cell treatment following inflammation reduces preterm white matter brain injury, likely mediated via anti-inflammatory actions.Copyright © 2018 S. Karger AG, Basel.

Objective: This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon beta, fingolimod or natalizumab. Method(s): We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and 1-year on-treatment follow-up from MSBase. Three pairwise propensity score-matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed. Result(s): The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon (p = 0.05), similar to fingolimod (p = 0.31) and higher than on natalizumab (p = 0.042). The probability of disability accumulation on cladribine was similar to interferon (p = 0.37) and fingolimod (p = 0.089) but greater than natalizumab (p = 0.021). The probability of disability improvement was higher on cladribine than interferon (p = 0.00017), fingolimod (p = 0.0025) or natalizumab (p = 0.00099). Sensitivity analyses largely confirmed the above results. Conclusion(s): Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon beta and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab.Copyright © The Author(s), 2017.

Background Vedolizumab (VDZ), an alpha4beta7 anti-integrin antibody, is efficacious in the induction and maintenance of remission in ulcerative colitis (UC) and Crohn's disease (CD). In the GEMINI long-term safety study, enrolled patients received 4-weekly VDZ. Upon completion, patients were switched to 8-weekly VDZ in Australia. The clinical success rate of treatment de-escalation for patients in remission on VDZ has not been described previously. Aim To determine the proportion of patients who relapsed after switching from 4 to 8-weekly VDZ, the mean time to relapse, and the recapture rate when switching back to 8-weekly dosing. Materials and methods This was a retrospective, observational, multicenter study of patients previously recruited into GEMINI long-term safety in Australia. Data on the demographics and biochemical findings were collected. Results There were 34 patients [23 men, mean age 49.1 (+/-13.1) years] and their mean disease duration was 17.6 (+/-8.5) years. The mean 4-weekly VDZ infusion duration was 286.5 (+/-48.8) weeks. A total of five (15%) patients relapsed on dose-interval increase (4/17 UC, 1/17 CD) at a median duration from dose interval lengthening to flare of 14 weeks (interquartile range=6-25). Eighty percent (4/5) of patients re-entered remission following dose-interval decrease back to 4-weekly. No clinical predictors of relapse could be determined because of the small cohort size. Conclusion The risk of patients relapsing when switching from 4 to 8-weekly VDZ ~15% and is similar between CD and UC. Dose-interval decrease recaptures 80% of patients who relapsed. Therapeutic drug monitoring of VDZ may be of clinical relevance.Copyright © 2018 Wolters Kluwer Health, Inc.

Background: Infants born preterm following exposure to in utero inflammation/chorioamnionitis are at high risk of brain injury and life-long neurological deficits. In this study, we assessed the efficacy of early intervention umbilical cord blood (UCB) cell therapy in a large animal model of preterm brain inflammation and injury. We hypothesised that UCB treatment would be neuroprotective for the preterm brain following subclinical fetal inflammation. Method(s): Chronically instrumented fetal sheep at 0.65 gestation were administered lipopolysaccharide (LPS, 150 ng, 055:B5) intravenously over 3 consecutive days, followed by 100 million human UCB mononuclear cells 6 h after the final LPS dose. Controls were administered saline instead of LPS and cells. Ten days after the first LPS dose, the fetal brain and cerebrospinal fluid were collected for analysis of subcortical and periventricular white matter injury and inflammation. Result(s): LPS administration increased microglial aggregate size, neutrophil recruitment, astrogliosis and cell death compared with controls. LPS also reduced total oligodendrocyte count and decreased mature myelinating oligodendrocytes. UCB cell therapy attenuated cell death and inflammation, and recovered total and mature oligodendrocytes, compared with LPS. Conclusion(s): UCB cell treatment following inflammation reduces preterm white matter brain injury, likely mediated via anti-inflammatory actions.Copyright © 2018 S. Karger AG, Basel.

Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (F-ic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined F-ic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. F-ic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery.

Objectives: To determine factors associated with damage accrual in a prospective cohort of patients with SLE. Method(s): Patients with SLE who attended the Lupus Clinic at Monash Health, Australia, between 2007 and 2013 were studied. Clinical variables included disease activity (Systemic Lupus Erythematosus Disease Activity Index-2K, SLEDAI-2K), time-adjusted mean SLEDAI, cumulative glucocorticoid dose and organ damage (Systemic Lupus International Collaborating Clinics Damage Index (SDI)). Multivariate logistic regression analyses were performed to identify factors associated with damage accrual. Result(s): A total of 162 patients were observed over a median (IQR) 3.6 (2.0-4.7) years. Seventy-five per cent (n=121) of patients received glucocorticoids. Damage accrual was significantly more frequent in glucocorticoid-exposed patients (42% vs 15%, p<0.01). Higher glucocorticoid exposure was independently associated with overall damage accrual after controlling for factors including ethnicity and disease activity and was significant at time-adjusted mean doses above 4.42 mg prednisolone/day; the OR of damage accrual in patients in the highest quartile of cumulative glucocorticoid exposure was over 10. Glucocorticoid exposure was independently associated with damage accrual in glucocorticoid-related and nonglucocorticoid related domains of the SDI. Conclusion(s): Glucocorticoid use is independently associated with the accrual of damage in SLE, including in non-glucocorticoid related domains.

Background: Bromodomain and Extra-Terminal (BET) proteins are a highly conserved family of epigenetic 'readers' that recognise and bind acetylated lysine residues on histones and other proteins to modulate gene expression. BET proteins are enriched at enhancer regions regulating oncogenic transcription and inhibitors (BETi) displace BET proteins from chromatin leading to suppression of oncogenes (e.g. cMYC). BETi elicit a heterogeneous range of tumour cell responses including apoptosis, growth arrest, differentiation, and senescence. However, responses to single agent BETi are self-limited in vivo and drug resistance uniformly emerges in preclinical modelling. As BETinhibitors (BETi) are now being clinically evaluated in both haematological and solid malignancies, the focus is now shifting to the design of effective combination strategies for phase II studies. Aim(s): BETi have potent anti-inflammatory properties, including chromatinindependent downregulation of NFkB signalling. However, broader mechanisms of immunomodulation by BETi in the context of anti-tumour responses remain poorly defined. Having previously discovered NK- and T-cell immunostimulatory activity of an acetyllysine mimetic fragment (n-methylpyrrolidone), we sought to evaluate the immunomodulatory activity of the prototypical theinodiazapine BETi, JQ1. Method(s): Utilising the syngeneic model of transplanted Emu-Myc aggressive 'Burkitt-like' lymphoma we first compared the efficacy of JQ1 in wild-type (immunocompetent) and immunodeficient RAG1-/- or RAG2-/-cgamma-/-mice. To interrogate the functional interaction between JQ1 and the immune system, we profiled changes in tumour cell immunogenicity following drug exposure by flow cytometry. Result(s): We observed a 50% reduction in the survival advantage conveyed by JQ1 in mice deficient in T- and/or B-lymphocytes compared to immunocompetent controls. Notably, tumour-infiltrating lymphocytes (TILs) and peripheral blood T-cells from wild-type mice faili

Context: The paracetamol-aminotransferase multiplication product (APAP x ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses. Objective(s): The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose. Method(s): We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase >=1000 IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L. Result(s): Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product <10,000 mg/L x IU/L developed hepatotoxicity (sensitivity 100% [95%CI 48%, 100%], specificity 97% [90%, 100%]). Specificity fell to 54% (95%CI: 34, 59%) at a product cut-off point <1500 mg/L x IU/L. When calculated within eight hours of ingestion, mild elevations of the multiplication product fell quickly on repeat testing in patients without ALI or hepatotoxicity. Conclusion(s): In modified-release paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000 mg/L x IU/L, it was very strongly assoc

Kidney transplant recipients are at a high risk of developing cancers after transplantation. Switching from calcineurin inhibitors to sirolimus has been shown to prevent secondary nonmelanoma skin cancer but whether everolimus with reduced exposure to calcineurin inhibitors has similar anti-cancer effects remains unknown. Therefore, we compared the risk of incident cancer over seven years of follow-up among kidney transplant recipients randomized to everolimus plus reduced exposure cyclosporine versus mycophenolate sodium and standard exposure cyclosporine. Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the seven-year risk of incident cancer and other graft outcomes among a subgroup of recipients who had participated in the A2309 study using adjusted Cox proportional hazard models. Of 95 recipients, 66 were randomized to everolimus (1.5 mg or 3 mg) with reduced cyclosporine and 29 received mycophenolate sodium and standard exposure cyclosporine. Compared to mycophenolate sodium and standard exposure cyclosporine, everolimus treatment was associated with unadjusted hazard ratios of 0.28 (95% confidence interval 0.11-0.74), 0.39 (0.16-0.98) and 0.41 (0.23-0.71), respectively for nonmelanoma skin cancer, non-skin cancers and any cancers. Interestingly, the adjusted hazard ratios were 0.34 (0.13-0.91), 0.35 (0.09-1.25) and 0.32 (0.15-0.71), respectively. There was no association between treatment groups and rejection, graft loss or death. Compared to standard-exposure cyclosporine, everolimus with reduced exposure to cyclosporine may be associated with a reduced risk of cancer, particularly for non-melanoma skin cancer. Thus, if confirmed in larger patient cohorts, de novo use of everolimus with reduced exposure to calcineurin inhibitors may enable a reduction in cancer burden after transplantation.Copyright © 2017 International Society of Nephrology

Objectives: To determine factors associated with damage accrual in a prospective cohort of patients with SLE. Method(s): Patients with SLE who attended the Lupus Clinic at Monash Health, Australia, between 2007 and 2013 were studied. Clinical variables included disease activity (Systemic Lupus Erythematosus Disease Activity Index-2K, SLEDAI-2K), time-adjusted mean SLEDAI, cumulative glucocorticoid dose and organ damage (Systemic Lupus International Collaborating Clinics Damage Index (SDI)). Multivariate logistic regression analyses were performed to identify factors associated with damage accrual. Result(s): A total of 162 patients were observed over a median (IQR) 3.6 (2.0-4.7) years. Seventy-five per cent (n=121) of patients received glucocorticoids. Damage accrual was significantly more frequent in glucocorticoid-exposed patients (42% vs 15%, p<0.01). Higher glucocorticoid exposure was independently associated with overall damage accrual after controlling for factors including ethnicity and disease activity and was significant at time-adjusted mean doses above 4.42 mg prednisolone/day; the OR of damage accrual in patients in the highest quartile of cumulative glucocorticoid exposure was over 10. Glucocorticoid exposure was independently associated with damage accrual in glucocorticoid-related and nonglucocorticoid related domains of the SDI. Conclusion(s): Glucocorticoid use is independently associated with the accrual of damage in SLE, including in non-glucocorticoid related domains.

Context: The paracetamol-aminotransferase multiplication product (APAP x ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses. Objective(s): The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose. Method(s): We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase >=1000 IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L. Result(s): Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product <10,000 mg/L x IU/L developed hepatotoxicity (sensitivity 100% [95%CI 48%, 100%], specificity 97% [90%, 100%]). Specificity fell to 54% (95%CI: 34, 59%) at a product cut-off point <1500 mg/L x IU/L. When calculated within eight hours of ingestion, mild elevations of the multiplication product fell quickly on repeat testing in patients without ALI or hepatotoxicity. Conclusion(s): In modified-release paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000 mg/L x IU/L, it was very strongly assoc