Professor Jennifer Martin

Background Contact tracing is a key component in controlling the spread of COVID-19, however little research has focused on learning from the experiences of contact tracing staff. Harnessing learning from those in this role can provide valuable insights into the process of contact tracing and how best to support staff in this crucial role. Methods Thematic analysis was used to analyse 47 semi-structured interviews conducted with contact tracing staff via telephone or Zoom at three time points in 2021: March, May and September- October. Results Six themes related to the contact tracing role were identified, including training, workforce culture, systems issues, motivation and support. While initially nervous in the role, participants were motivated to contribute to the pandemic response and believed the role provided them with valuable transferable skills. Participants described the training as having improved over time while desiring more proactive training. Sources of frustration included a perceived lack of opportunity for feedback and involvement in process changes, feelings of low autonomy, and a perception of high staff turnover. Participants expressed a need for improved communication of formal emotional supports. Increased managerial support and provision of opportunities for career advancement may contribute to increased motivation among staff. Conclusions These findings identify the experiences of contact tracing staff working during the COVID- 19 pandemic, and have important implications for the improvement of the contact tracing system. Recommendations based on learning from participants offer suggestions as to how best to support the needs of contact tracing staff during a pandemic response.

Background: Capecitabine is an oral chemotherapy prodrug of 5-fluorouracil (5-FU) with unpredictable toxicity, especially in older adults. The aim of this study was to evaluate the pharmacokinetics (PK) of capecitabine and its metabolites in younger adults (< 70¿years) and older adults (= 70¿years) receiving capecitabine for solid cancer. Methods: Eligible participants receiving capecitabine had 2 venous samples collected on day 14 of cycle 1 and cycle 2 of their treatment. Capecitabine and metabolite concentrations were determined using liquid chromatography with tandem mass spectrometry. A Bayesian estimation approach was used to generate individual estimates of PK parameters for 5-FU. A linear mixed-effect analysis of variance (ANOVA) model was used to compare dose-normalised log-transformed PK parameters between age groups. Correlations were determined by linear regression and logistic regression analyses. Results: Of the total 26 participants, 58% were male with a median age of 67¿years (range, 37¿85) with 54% aged < 70¿years and 46% aged = 70¿years. Participants aged = 70¿years, compared to those aged < 70¿years, had a greater 5-FU exposure based on area under the concentration¿time curve (AUC) of 17% (90% CI 103¿134%; 0.893 vs. 0.762¿mg h/L) and 14% increase in maximal concentration, Cmax (90% CI 82.1¿159%; 0.343 vs. 0.300¿mg/L). The 5-FU Cmax was positively associated with time up and go (TUG) (Pearson¿s correlation 0.77, p = 0.01), but not other geriatric assessment domains or severe toxicity. Conclusion: 5-FU exposure was significantly increased in older adults compared to younger adults receiving equivalent doses of capecitabine, and is a possible cause for increased toxicity in older adults.

We have developed a mechanistic model of SARS-CoV-2 and SARS-CoV infection, exploring the relationship between the viral diffusion in the mucosa and viral affinity for the angiotensin converting enzyme 2 (ACE2) target. Utilising the structural similarity of SARS-CoV and SARS-CoV-2 and a shared viral target receptor (ACE2), but a dramatic difference in upper or lower respiratory tract infectivity, we were able to generate insights into the linkage of mucosal diffusion and target receptor affinity in determining the pathophysiological pathways of these two viruses. Our analysis reveals that for SARS-CoV-2 the higher affinity of ACE2 binding, the faster and more complete the mucosal diffusion in its transport from the upper airway to the region of the ACE2 target on the epithelium. This diffusional process is essential for the presentation of this virus to the furin catalysed highly efficient entry and infection process in the upper respiratory tract epithelial cells. A failure of SARS-CoV to follow this path is associated with lower respiratory tract infection and decreased infectivity. Thus, our analysis supports the view that through tropism SARS-CoV-2 has evolved a highly efficient membrane entry process that can act in concert with a high binding affinity of this virus and its variants for its ACE2 which in turn promotes enhanced movement of the virus from airway to epithelium. In this way ongoing mutations yielding higher affinities of SARS-CoV-2 for the ACE2 target becomes the basis for higher upper respiratory tract infectivity and greater viral spread. It is concluded that SARS-CoV-2 is constrained in the extent of its activities by the fundamental laws of physics and thermodynamics. Laws that describe diffusion and molecular binding. Moreover it can be speculated that the very earliest contact of this virus with the human mucosa defines the pathogenesis of this infection.

Purpose: This paper describes a quality improvement project to improve oversight of quality at national board level using statistical process control (SPC) methods, complimented by a qualitative experience of patients and frontline staff. It demonstrates the application of the ¿Picture-Understanding-Action¿ approach and shares the lessons learnt. Design/methodology/approach: Using co-design and applying the ¿Picture-Understanding-Action¿ approach, the project team supported the directors of the Irish health system to identify and test a qualitative and quantitative picture of the quality of care across the health system. A ¿Quality Profile¿ consisting of quantitative indicators, analysed using SPC methods was used to provide an overview of the ¿critical few¿ indicators across health and social care. Patient and front-line staff experiences added depth and context to the data. These methods were tested and evolved over the course of six meetings, leading to quality of care being prioritised and interrogated at board level. Findings: This project resulted in the integration of quality as a substantive and prioritised agenda item. Using best practice SPC methods with associated training produced better understanding of performance of the system. In addition, bringing patient and staff experiences of quality to the forefront ¿people-ised¿ the data. Originality/value: The application of the ¿Picture-Understanding-Action¿ approach facilitated the development of a co-designed quality agenda item. This is a novel process that shifted the focus from ¿providing¿ information to co-designing fit-for-purpose information at board level.

Background: Contact tracing is a key control measure in the response to the COVID-19 pandemic. While quantitative research has been conducted on the psychological impact of the pandemic on other frontline healthcare workers, none has explored the impact on contact tracing staff. Methods: A longitudinal study was conducted using two repeated measures with contact tracing staff employed in Ireland during the COVID-19 pandemic using two-tailed independent samples t tests and exploratory linear mixed models. Results: The study sample included 137 contact tracers in March 2021 (T1) and 218 in September 2021 (T3). There was an increase from T1 to T3 in burnout related exhaustion (p < 0·001), post-traumatic stress disorder (PTSD) symptom scores (p < 0·001), mental distress (p < 0·01), perceived stress (p < 0·001) and tension and pressure (p < 0·001). In those aged 18¿30, there was an increase in exhaustion related burnout (p < 0·01), PTSD symptoms (p < 0·05), and tension and pressure scores (p < 0·05). Additionally, participants with a background in healthcare showed an increase in PTSD symptom scores by T3 (p < 0·001), reaching mean scores equivalent to those of participants who did not have a background in healthcare. Conclusions: Contact tracing staff working during the COVID-19 pandemic experienced an increase in adverse psychological outcomes. These findings highlight a need for further research on psychological supports required by contact tracing staff with differing demographic profiles.

Background: N-methyl-2-pyrrolidone (NMP) is an epigenetically active chemical fragment and organic solvent with numerous applications including use as a drug-delivery vehicle. Previously considered biologically inert, NMP demonstrates immunomodulatory and anti-myeloma properties that are partly explained by acetyllysine mimetic properties and non-specific bromodomain inhibition. We therefore evaluated orally administered NMP in a phase 1 dose-escalation trial to establish its maximum tolerated dose (MTD) in patients with relapsed/refractory multiple myeloma (RR¿MM). Secondary endpoints were safety, pharmacokinetics (PK), overall response rate and immunological biomarkers of activity. Results: Thirteen patients received NMP at starting doses between 50 and 400¿mg daily. Intra-patient dose escalation occurred in five patients, with one attaining the ceiling protocolised dose of 1¿g daily. Median number of monthly cycles commenced was three (range 1¿20). Grade 3¿4 adverse events (AEs) were reported in seven (54%; 95% CI 25¿81%) patients. Most common AEs (> 30% of patients) of any grade were nausea and musculoskeletal pain. The only dose limiting toxicity (DLT) was diarrhoea in a patient receiving 200¿mg NMP (overall DLT rate 8%; 95% CI 0¿36%). Hence, the MTD was not defined. Median progression-free and overall survival were 57 (range 29¿539) days and 33 (95% CI 9.7¿ > 44) months, respectively. The best response of stable disease (SD) was achieved in nine patients (69%; 95% CI 39¿91%). PK analysis demonstrated proportional dose¿concentrations up to 400¿mg daily, with a more linear relationship above 500¿mg. Maximum plasma concentrations (Cmax) of 16.7¿mg/L at the 800¿mg dose were below those predicted to inhibit BET-bromodomains. Peripheral blood immune-profiling demonstrated maintenance of natural killer (NK) cells, and a gene expression signature suggestive of enhanced T, B and NK cell functions; a subject with prolonged exposure manifested sustained recovery of B and NK cells at 12¿months. Conclusions: NMP demonstrated potential disease stabilising and immunomodulatory activity at sub-BET inhibitory plasma concentrations and was well tolerated in RR¿MM; an MTD was not determined up to a maximum dose of 1¿g daily. Further dose-finding studies are required to optimise NMP dosing strategies for therapeutic intervention.

Objective: To identify points for improvements within the health system where Aboriginal and Torres Strait Islander cancer patients may experience a lack of continuity in their cancer care. The optimal care pathway for Aboriginal and Torres Strait Islander people with cancer (OCP) framework was utilised as a tool in this work. Methods: Semi-structured interviews were conducted with health professionals at the primary health care (PHC) and hospital setting. Data were categorised into six steps using the OCP framework. Results: This study identified multiple time-points in the cancer pathways that could be strengthened to increase the continuity of cancer care for these patients. In addition, the provision of person-centred care and adequate education tailored to patients' and health professionals' needs can help minimise the likelihood of patients experiencing a lack of continuity in their cancer care. Participants were recruited from an urban hospital (n¿=¿9) and from six Aboriginal Community Controlled Health Services (n¿=¿17) across geographical locations in Queensland. The provision of culturally competent care, effective communication, coordination and collaboration between services along the cancer pathway from prevention and early diagnosis through to end-of-life care were highlighted as important to enhance care continuity for Indigenous Australians. Conclusion: The implementation of recommendations outlined in the OCP framework may help with improving cancer care continuity for Indigenous patients with cancer. Summary: Aboriginal and Torres Strait Islander people can sometimes find cancer care pathways complex and difficult to navigate. This study identified points in the cancer pathways that could be strengthened to increase the continuity of cancer care for these patients which could potentially lead to improved outcomes.

Introduction: This phase¿I open-label study examined pharmacokinetics, safety, and tolerability of escalating doses of a novel combination cannabinoid medication (1:1 tetrahydrocannabinol [THC]/cannabidiol [CBD]) in patients with chronic non-cancer pain (CNCP) on high dose opioid analgesia. Methods: Nine people with CNCP and oral morphine equivalent daily dose of 60¿mg or higher were recruited. Blood concentrations of THC, 11-hydroxytetrahydrocannabinol (OH-THC), 11-nor-9-carboxy-tetrahydrocannabinol (COOH-THC), and CBD were assayed weekly. Concentrations were measured after a single dose of 2.5¿mg THC/2.5¿mg CBD on day¿1, and daily escalating doses up to a single dose of 12.5¿mg THC/12.5¿mg CBD on day¿29. Follow-up was on day¿36 after a 7-day washout. Secondary outcome data encompassed pain, mood, and sleep parameters. Results: The parent compounds THC, and CBD, and metabolites OH-THC and COOH-THC were detected at most time points. In general, the concentration of all analytes increased until 2¿h post-administration, decreasing to approximately pre-dose concentrations by 8¿h. There was considerable inter- and intra-individual variability. The study medication was well tolerated. Eight participants reported at least one adverse event (AE), with a total of 62 AEs; most common were euphoric mood, headache, and agitation, none classified as severe. There was no significant change to pain severity self-ratings, nor use of pain medications. Improvements in pain interference scores, mood, and some sleep parameters were observed. Conclusion: The THC/CBD formulation was tolerated well in a group of patients with CNCP. Between-participant variability supports personalized dosing and ¿start low¿go slow¿ titration. To validate and quantify improvements in secondary efficacy outcomes a randomized placebo-controlled study is needed. Trial Registration: Australian New Zealand Clinical Trials Register (CT-2019-CTN-01224-1).

Background: With increasing use of medicinal cannabis for symptom management, clinical trials nurses need to consider the various legal, social, ethical, and interdisciplinary care issues of implementing these clinical trials, especially in a palliative care population. Aim: To define the trials nurses¿ role in operationalising a medicinal cannabis pharmacokinetic inpatient trial in an advanced cancer population. Methods: A qualitative, descriptive design incorporating case study methodology was used. Data were collected from minuted meetings, field notes, telephone, and email discussions involving trials nurses at two palliative care sites. Data were integrated and synthesised to identify the key considerations required to operationalise the trial and define the trials nurses¿ role. Findings: Three key considerations were identified: (i) Normalising the trial, (ii) Creating the environment to undertake the trial, and (iii) Managing the complexity. The trials nurses¿ role was explored through subthemes of these considerations including: their understanding of the purpose of the research and training in the protocol; organising inpatient resources, pharmacy requirements and managing the external scrutiny; participant recruitment, staffing requirements, safety, and supporting caregivers. Discussion: This study emphasises the multifactorial role of the trials nurses in managing a complex palliative care trial, and the importance of their early involvement and recognition as the vital link between all parties. Conclusion: Defining the trials nurses¿ role, within the confines of the protocol, the context of efficient nursing processes and ensuring a patient-centred approach enabled the operationalisation of a Phase I/II medicinal cannabis trial which will have global impact.

Purpose: The purpose of this study is to present a quality improvement approach titled ¿Picture-Understanding-Action¿ used in Ireland to enhance the role of healthcare boards in the oversight of healthcare quality and its improvement. Design/methodology/approach: The novel and practical ¿Picture-Understanding-Action¿ approach was implemented using the Model for Improvement to iteratively introduce changes across three quality improvement projects. This approach outlines the concepts and activities used at each step to support planning and implementation of processes that allow a board to effectively achieve its role in overseeing and improving quality. This approach matured over three quality improvement projects. Findings: The ¿Picture¿ included quantitative and qualitative aspects. The quantitative ¿Picture¿ consisted of a quality dashboard/profile of board selected outcome indicators representative of the health system using statistical process control (SPC) charts to focus discussion on real signals of change. The qualitative picture was based on the experience of people who use and work in health services which ¿people-ised¿ the numbers. Probing this ¿Picture¿ with collective grounding, curiosity and expert training/facilitation developed a shared ¿Understanding¿. This led to ¿Action(s)¿ from board members to improve the ¿Picture¿ and ¿Understanding¿ (feedback action), to ask better questions and make better decisions and recommendations to the executive (feed-forward action). The Model for Improvement, Plan-Do-Study-Act cycles and a co-design approach in design and implementation were key to success. Originality/value: To the authors¿ knowledge, this is the first time a board has undertaken a quality improvement (QI) project to enhance its own processes. It addresses a gap in research by outlining actions that boards can take to improve their oversight of quality of care.

5-fluorouracil (5-FU) and its oral formulation, capecitabine, are widely used in treating a range of malignancies, either alone or in combination with other antineoplastic drugs. Body surface area-based dosing is used for these agents, despite this approach leading to substantial variability in drug exposure and often resulting in either toxicity or treatment failure. Tailoring therapeutic regimens for individual patients using therapeutic drug monitoring (TDM) has been shown to significantly reduce toxicity and improve cancer outcomes. However, for optimum TDM, sample timing is crucial, along with the need for a venepuncture blood sample to obtain the plasma currently used for 5-FU measurement. In addition to complex blood sample handling requirements, large sample volume and frequent sampling required for pharmacokinetic analysis is another barrier to successfully implementing TDM in a healthcare setting. Microsampling is an alternative collection method to venepuncture, which, combined with the now readily available liquid chromatography mass spectrometry (LC-MS/MS) technology, overcomes the plasma-associated issues. It also has the significant advantage of enabling at home and remote sampling, thus facilitating 5-FU TDM in clinical practice. A LC-MS/MS method for simultaneous measurement of capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine and 5-FU using Mitra® microsampling devices for sample collection was developed. A Shimadzu 8060 LC-MS/MS equipped with electrospray ionisation source interface, operated in positive and negative ion modes, with reversed-phase chromatographic separation was employed for sample analysis. Samples were extracted from Mitra® devices using acetonitrile containing stable isotope-labelled internal standards, sonicated, evaporated under vacuum and resuspended in 0.1 % formic acid before injection into the LC-MS/MS. Chromatographic separation was on a Luna Omega Polar C18 (100 × 2.1 mm, 1.6 µm) column with gradient elution of 0.1 % formic acid in water and acetonitrile. Total run time was 5 min, with the injection volume of 1 µL. The intra and inter-day imprecision ranged from 3.0 to 8.1 and 6.3¿13.3 % respectively. Accuracy ranged from 95 -114 % for all analytes. Lower limit of quantification with imprecision of < 19 % and accuracy between 89 and 114 % was 0.05 mg/L for 5-FU and 10 µg/L for other analytes. Assays were linear from 0.05 to 50 mg/L for 5-FU and 10¿10,000 µg/L for all other analytes. Analytes were stable on Mitra® devices for up to 9 months at room temperature, 2 years at -30 ¿ and 3 days at 50 ¿. The method was successfully applied for the analysis of samples from patients undergoing cancer treatment with 5-FU and capecitabine. Microsampling using volumetric absorptive microsampling proved to be as reliable as conventional blood collection for 5-FU and capecitabine. This sampling technique may lead to less invasive and better-timed sample collection for TDM, supporting dose optimization strategy.

Background and Aims: For infants exposed in utero to anti-tumour necrosis factor-a [TNF] medications, it is advised that live-attenuated vaccinations be postponed until the drug is cleared, but little is known about time to clearance. To minimize delays before live-attenuated vaccination can be given, we aimed to develop a pharmacokinetic model to predict time-to-clearance in infants exposed during pregnancy. Methods: We prospectively followed in utero infliximab/adalimumab-exposed infants of mothers with inflammatory bowel disease across four countries between 2011 and 2018. Infants with a detectable anti-TNF umbilical-cord level and at least one other blood sample during the first year of life were included. Results: Overall, 107 infants were enrolled, including 166 blood samples from 71 infliximab-exposed infants and 77 samples from 36 adalimumab-exposed infants. Anti-TNF was detectable in 23% [n=25] of infants at 6 months. At 12 months, adalimumab was not detected but 4% [n=3] had detectable infliximab. A Bayesian forecasting method was developed using a one-compartment pharmacokinetic model. Model validation showed that the predicted clearing time was in accordance with the measured observations. A clinician-friendly online calculator was developed for calculating full anti-TNF clearing time: https://xiaozhu.shinyapps.io/antiTNFcalculator2/. Conclusions: Almost one-quarter of infants born to mothers receiving anti-TNF during pregnancy have detectable anti-TNF at 6 months. To limit the time to live-attenuated vaccination in infants of mothers receiving anti-TNF during pregnancy, the results of a cord drug level at birth and a second sample =1 month thereafter can be used to estimate the time for full anti-TNF clearance in these children.

With any new disease a framework for the development of preventative or treatment therapeutics is key; the absence of such in COVID-19 has enabled ineffective and potentially unsafe treatments to be taken up by governments and clinicians desperate to have options for patients. As we still have few therapies and nil vaccines yet available, the void of a clear framework for research and practice is increasingly clear. We describe a framework that has been used to prioritise therapeutic research in previous pandemics which could be used to progress clinical pharmacology and therapeutics research in COVID-19. This is particularly relevant as discussion has already moved on from antiviral therapeutics to delineating the treatment of the host from treatment and elimination of the infective agent. Focussing on the host brings together three concepts: host treatment, the damage response framework and therapeutic repurposing. The integration of these three areas plays to the traditional strength of pharmaceuticals in providing a period of stabilization to permit time for the development of novel antiviral drugs and vaccines. In integrating approaches to repurposing, host treatment and damage response we identified three key properties that a potentially effective repurposed drug must possess by way of a framework. There must be homology, i.e., the same or similar relation with the pathogenesis of the disease, ideally targeted to the conserved pathophysiological outcomes of the viral attack; there must be a defined locus within the spectrum to prevention to severe disease and the framework must draw upon the historical dose and safety experience of the repurposed drug. To illustrate, we have mapped therapeutics that impact upon a key dysregulated pathway in COVID-19 ¿ the renin angiotensin system ¿ using this approach. Collectively this type of analysis reveals the importance of existing data (repurposed information and administrative observational data) and the importance of the details of the known pathophysiological response to viruses in approaches to treating the host.

Monoclonal antibodies (Mabs) have become key drugs in cancer treatment, either as targeted therapies or more recently as immune checkpoint inhibitors (ICIs). The fact that only some patients benefit from these drugs poses the usual question in the field of onco-hematology: that of the benefit of individual dosing and the potential of therapeutic drug monitoring (TDM) to carry out this individualization. However, Mabs present unique pharmacological characteristics for TDM, and the pharmacokinetic¿pharmacodynamic relationship observed should be interpreted differently than that observed for conventional drugs and small molecules. This pharmacology practice review has been summarized from a public debate between the authors at the International TDM and Clinical Toxicology meeting in Banff, 2020, regarding the potential roles of TDM in the Mab/ICI setting.

Objectives: The objective of this study was to inform public health practitioners who are designing, adapting and implementing testing and tracing strategies for Coronavirus disease (COVID-19) control. Study design: The study design is monitoring and evaluation of a national public health protection programme. Methods: All close contacts of laboratory-confirmed cases of COVID-19 identified between the 19th May and 2nd August were included; secondary attack rates and numbers needed to test were estimated. Results: Four thousand five hundred eighty six of 7272 (63%) close contacts of cases were tested with at least one test. The secondary attack rate in close contacts who were tested was 7% (95% Confidence Interval [CI]: 6.3 ¿ 7.8%). At the ¿day 0¿ test, 14.6% (95% CI: 11.6¿17.6%) of symptomatic close contacts tested positive compared with 5.2% (95% CI: 4.4¿5.9%) of asymptomatic close contacts. Conclusions: The application of additional symptom-based criteria for testing in this high-incidence population (close contacts) is of limited utility because of the low negative predictive value of absence of symptoms.

Introduction: The ability of health care professionals to measure change is critical for successful quality improvement (QI) efforts. Currently, there are no systematic reviews focusing on continuing education for health care professionals in data skills for QI. The purpose of this systematic review is to define effectiveness and sustainability of QI programs for health care professionals containing a measurement skills component and to identify barriers and facilitators to effectiveness and sustainability. Methods: The systematic review involved study identification, screening, full text review, and data extraction. Four electronics databases and grey literature sources were searched to identify studies published between 2009 and 2019 (11 years). A customized data extraction form was developed. Mixed methods appraisal tool was used for quality assessment and a thematic analysis was conducted for narrative synthesis. Results: Fifty-three studies from 11 countries were included. Most study designs were quantitative descriptive (17/53) and used a blended learning approach (25/53) combining face-to face and distance learning modes. The programs included basic, intermediate, and advanced data skills concepts. Overall, studies reported positive outcomes for participant reaction, learning, and behavior, but reported variable success in sustainability and spread of QI. Discussion: Studies discussed measurement as a key competency for clinical QI. Effectiveness definitions focused on the short-term impact of the programs, whereas sustainability definitions emphasized maintenance of outcomes and skills in the long-term. Factors that influenced effectiveness and sustainability of the included studies were strategic approach to QI, organizational support, intervention design, communication, accountability, leadership support, and learning networks.

Background: Contact tracing is conducted with the primary purpose of interrupting transmission from individuals who are likely to be infectious to others. Secondary analyses of data on the numbers of close contacts of confirmed cases could also: provide an early signal of increases in contact patterns that might precede larger than expected case numbers; evaluate the impact of government interventions on the number of contacts of confirmed cases; or provide data information on contact rates between age cohorts for the purpose of epidemiological modelling. We analysed data from 140,204 close contacts of 39,861 cases in Ireland from 1st May to 1st December 2020. Results: Negative binomial regression models highlighted greater numbers of contacts within specific population demographics, after correcting for temporal associations. Separate segmented regression models of the number of cases over time and the average number of contacts per case indicated that a breakpoint indicating a rapid decrease in the number of contacts per case in October 2020 preceded a breakpoint indicating a reduction in the number of cases by 11 days. Conclusions: We found that the number of contacts per infected case was overdispersed, the mean varied considerable over time and was temporally associated with government interventions. Analysis of the reported number of contacts per individual in contact tracing data may be a useful early indicator of changes in behaviour in response to, or indeed despite, government restrictions. This study provides useful information for triangulating assumptions regarding the contact mixing rates between different age cohorts for epidemiological modelling.

BACKGROUND: The serial interval is the period of time between the onset of symptoms in an infector and an infectee and is an important parameter which can impact on the estimation of the reproduction number. Whilst several parameters influencing infection transmission are expected to be consistent across populations, the serial interval can vary across and within populations over time. Therefore, local estimates are preferable for use in epidemiological models developed at a regional level. We used data collected as part of the national contact tracing process in Ireland to estimate the serial interval of SARS-CoV-2 infection in the Irish population, and to estimate the proportion of transmission events that occurred prior to the onset of symptoms. RESULTS: After data cleaning, the final dataset consisted of 471 infected close contacts from 471 primary cases. The median serial interval was 4¿days, mean serial interval was 4.0 (95% confidence intervals 3.7, 4.3) days, whilst the 25th and 75th percentiles were 2 and 6¿days respectively. We found that intervals were lower when the primary or secondary case were in the older age cohort (greater than 64¿years). Simulating from an incubation period distribution from international literature, we estimated that 67% of transmission events had greater than 50% probability of occurring prior to the onset of symptoms in the infector. CONCLUSIONS: Whilst our analysis was based on a large sample size, data were collected for the primary purpose of interrupting transmission chains. Similar to other studies estimating the serial interval, our analysis is restricted to transmission pairs where the infector is known with some degree of certainty. Such pairs may represent more intense contacts with infected individuals than might occur in the overall population. It is therefore possible that our analysis is biased towards shorter serial intervals than the overall population.

Objectives To profile the aims and characteristics of quality improvement (QI) initiatives conducted in Ireland, to review the quality of their reporting and to assess outcomes and costs. Design Scoping review. Data sources Systematic searches were conducted in PubMed, Web of Science, Embase, Google Scholar, Lenus and rian.ie. Two researchers independently screened abstracts (n=379) and separately reviewed 43 studies identified for inclusion using a 70-item critique tool. The tool was based on the Quality Improvement Minimum Quality Criteria Set (QI-MQCS), an appraisal instrument for QI intervention publications, and health economics reporting criteria. After reaching consensus, the final dataset was analysed using descriptive statistics. To support interpretations, findings were presented at a national stakeholder workshop. Eligibility criteria QI studies implemented and evaluated in Ireland and published between January 2015 and April 2020. Results The 43 studies represented various QI interventions. Most studies were peer-reviewed publications (n=37), conducted in hospitals (n=38). Studies mainly aimed to improve the ¿ effectiveness' (65%), ¿ efficiency' (53%), ¿ timeliness' (47%) and ¿ safety' (44%) of care. Fewer aimed to improve ¿ patient-centredness' (30%), ¿ value for money' (23%) or ¿ staff well-being' (9%). No study aimed to increase ¿ equity'. Seventy per cent of studies described 14 of 16 QI-MQCS dimensions. Least often studies reported the ¿ penetration/reach' of an initiative and only 35% reported health outcomes. While 53% of studies expressed awareness of costs, only eight provided at least one quantifiable figure for costs or savings. No studies assessed the cost-effectiveness of the QI. Conclusion Irish QI studies included in our review demonstrate varied aims and high reporting standards. Strategies are needed to support greater stimulation and dissemination of QI beyond the hospital sector and awareness of equity issues as QI work. Systematic measurement and reporting of costs and outcomes can be facilitated by integrating principles of health economics in QI education and guidelines.

Background: Given the unprecedented nature of the COVID-19 pandemic, the Irish health system required the redeployment of public sector staff and the recruitment of dedicated contact tracing staff in the effort to contain the spread of the virus. Contact tracing is crucial for effective disease control and is normally carried out by public health teams. Contact tracing staff are provided with rapid intensive training but are operating in a dynamic environment where processes and advice are adapting continuously. Real-time data is essential to inform strategy, coordinate interconnected processes, and respond to needs. Given that many contact tracers have been newly recruited or redeployed, they may not have significant experience in healthcare and may experience difficulties in managing the anxieties and emotional distress of the public. Aim: (i) identify emerging needs and issues and feed this information back to the Health Service Executive for updates to the COVID-19 Contact Management Programme (CMP); (ii) understand the psychological impact on contact tracers and inform the development of appropriate supports. Methods: We will use a mixed-methods approach. A brief online survey will be administered at up to three time points during 2021 to measure emotional exhaustion, anxiety, general health, and stress of contact tracing staff, identify tracing systems or processes issues, as well as issues of concern and confusion among the public. Interviews will also be conducted with a subset of participants to achieve a more in-depth understanding of these experiences. Observations may be conducted in contact tracing centres to document processes, practices, and explore any local contextual issues. Impact: Regular briefs arising from this research with data, analysis, and recommendations will aim to support the work of the CMP to identify problems and implement solutions. We will deliver regular feedback on systems issues; challenges; and the psychological well-being of contact tracing staff.

Purpose: Plants belonging to the genus Cannabis have been domesticated and used by humans for millennia. Thought to have originated from central Asia, cannabis has been harnessed for its nutritional, therapeutic, and psychoactive properties, and as a source of fiber (Office of Medicinal Cannabis. Analytical Monograph Cannabis Flos. Den Haag, The Netherlands: Office of Medicinal Cannabis; 2014). Human use of cannabis is not novel; however, its medicalization offers a new pharmacotherapeutic frontier. Methods: The authors recently reported a systematic review of the contaminants of cannabis (National Academies of Sciences Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. Washington, DC; 2017). This article draws on the research limitations identified by that review and examines a collection of the relevant literature to provide an appreciation of the current evidence base. Results: The review explores the current status of cannabis in medical use, the drug development aspects that apply when taking a plant through to pill development, and the roles that therapeutic drug monitoring and pharmacovigilance have to guide practice until the drug development information on medicinal cannabis preparations is complete. Conclusions: A surge of public and clinical interest in the possible therapeutic applications of constituent cannabinoids has potentiated global legislative and policy reform. However, our understanding of its properties, optimized use, and harmful effects remains incomplete (Therapeutic Goods Administration. Guidance for the use of medicinal cannabis in Australia In: Department of Health Department, editor. Woden ACT Australian Government 2017; Dryburgh LM, Bolan NS, Grof CP, Galettis P, Schneider J, Lucas CJ, et al. Cannabis contaminants: sources, distribution, human toxicity and pharmacologic effects. Brit J Clin Pharm. 2018;84(11):2468¿2476). In particular, a comprehensive appreciation of its toxicity profile is lacking.

Background: The presence of elevated systemic inflammation in people with advanced non-small cell lung cancer (NSCLC) is associated with significantly shorter survival following carboplatin-based chemotherapy. Objective: This study investigated whether novel factors, such as systemic inflammation [platelet¿lymphocyte ratio (PLR) and neutrophil¿lymphocyte ratio (NLR)], impact carboplatin pharmacokinetics and drug utilisation. The study also examined the ability of current and alternate dosing regimens to meet therapeutic targets. Methods: Seventy-two people with advanced NSCLC treated with carboplatin-based (460¿1050 mg) doublet chemotherapy were recruited and pharmacokinetic data (n = 61) were analysed using non-linear mixed modelling. Covariate analysis was performed to investigate the impact of standard and novel patient characteristics of carboplatin pharmacokinetics. A Monte Carlo simulation of 100,000 representative NSCLC patients evaluated the ability of the Calvert formula and novel dosing strategies to achieve the targeted therapeutic range. The associations between systemic inflammation and chemotherapy drug utilisation (cycles received, relative dose intensity (RDI) and second-line uptake) and clinical endpoints were also investigated in the pharmacokinetic cohort, and two independent cohorts of people with advanced NSCLC from the Chemotherapy Dosing in Cancer-Related Inflammation (CDCRI) database¿that were administered carboplatin¿paclitaxel (n = 37) or carboplatin¿gemcitabine (n = 358). Results: In all cohorts, 25¿53% of people had elevated systemic inflammation (NLR > 5 or PLR > 300). In the pharmacokinetic cohort, no patients achieved the desired therapeutic target of carboplatin. Carboplatin exposure was related to renal function, as estimated using the Cockcroft¿Gault formula, albumin and inflammation (NLR). In the pharmacokinetic cohort, increasing carboplatin area under the curve (AUC) correlated with greater reductions in red blood cells and haemoglobin. In this cohort, the average measured AUC of partial responders was 2.4¿mg·min/mL. Also in the pharmacokinetic cohort, only 12% of people with an NLR > 5 received four or more cycles of chemotherapy, compared with 62% of patients with an NLR = 5 (p < 0.001). For people in the CDCRI cohort receiving carboplatin¿gemcitabine, those with an NLR > 5 also received less cycles (four or more cycles, 41% vs. 60%; p < 0.01) as well as less second-line chemotherapy (46% vs. 60%; p = 0.02) compared with patients without inflammation. People in the pharmacokinetic cohort with an NLR > 5 had 12¿months less median survival compared with people with an NLR = 5 (6.5 vs. 18¿months; p = 0.08). Similarly, overall survival was significantly shortened in people in the CDCRI cohort receiving carboplatin¿gemcitabine with an NLR > 5 compared with those with an NLR = 5 (7 vs. 12¿months; p < 0.001), and Cox regression analysis showed a 1.5-fold (1.3¿2.1; p < 0.001) increased hazard of death associated with the increased systemic inflammation. Simulations of the newly developed model-based and Calvert dosing assessed the ability to reach this study¿s proposed actual target AUC of 2.2¿2.6¿mg·min/mL. These showed current Calvert dosing was predicted to result in substantial overexposure in patients with high systemic inflammation. The newly developed model showed equivalent levels of carboplatin therapeutic target achievement across the spectrum of inflammation observed in the lung cancer population. Conclusion: An alternate model-based dosing strategy for carboplatin was developed and is predicted to result in consistent drug exposure across the population and improve attainment of therapeutic targets. Further studies of this new model are warranted in people with advanced NSCLC.

Background: The most important two medicinal cannabinoids are ¿9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Vaporised administration is superior due to its higher systemic availability, lower individual variability and faster drug delivery. Although it is common THC is co-administered with CBD, the influence of CBD on the pharmacokinetics, especially the systemic availability of THC after vaporised administration, is unknown. Aims: To investigate the influence of different doses of co-administered CBD on the systemic availability of THC, and to compare the availability of THC and CBD in a sample of frequent and infrequent cannabis users. Methods: The study used a randomised, double-blind, crossover placebo-controlled design. THC and/or CBD in ethanol was vaporised and inhaled. Plasma concentrations of THC and CBD were analysed. The THC data created in this study were pooled together with published THC pharmacokinetic data in order to cover all the phases of THC disposition. Population pharmacokinetic model of THC was developed based on the pooled data. The model of CBD was developed based on the data created in this study. Results: Population pharmacokinetic models of THC and CBD were developed. With concomitant inhalation of high-dose CBD, the systemic availability of THC decreased significantly. Frequent cannabis users appeared to have higher systemic availability of THC and CBD when high-dose CBD was administered. Conclusions: The results observed in this study are useful for guiding future pharmacokinetic studies of medicinal cannabinoids, and for development of dosing guidelines for medical use of cannabis in the ¿real-world¿ setting.

Aim: Vancomycin guidelines for therapeutic drug monitoring (TDM) aim to maximise efficacy while minimising toxicity and resistance. Vancomycin is effective against Staphylococcus aureus when it achieves area under the concentration¿time curve (AUC)/minimum inhibitory concentration (MIC) > 400. Studies in children have shown that target trough concentrations poorly correlate to AUC/MIC > 400; however, they are used in practice for clinical convenience. This review in paediatric inpatients aims to audit performance against TDM guidelines and consider what changes are needed to optimise vancomycin monitoring. Methods: Vancomycin prescriptions in patients younger than 18 years old were collected over a 15-month period. Primary outcome measures were vancomycin initial dose (mg/kg/day) and the timing and result of first trough concentration (mg/L). Secondary outcome measures were the numbers achieving recommended targets and whether appropriate dose adjustments were made in response to TDM. Results: A total of 133 courses reached the time when TDM should occur. Average patient age was 6.5 years, and the average initial dose was 52.55 mg/kg/day (range 19.05¿86.54 mg/kg). Only 25% of courses (n = 34) had a trough concentration measured at the recommended time. The mean trough concentration was 11.6 mg/L (range < 2.0¿39.7). Of 40 patients with a low trough concentration, 50% continued without dose adjustment. Conclusion: As shown in the literature, there is a poor correlation between the vancomycin dose given and the trough concentration achieved. Given that recommendations for trough concentration monitoring are designed to simplify the process yet are poorly adhered to, a strategic plan to address these issues is needed.

Aim: To explore health professionals¿ perspectives on communication, continuity and between-service coordination for improving cancer care for Indigenous people in Queensland. Methods: Semi-structured interviews were conducted in a purposive sample of primary health care (PHC) services in Queensland with Indigenous and non-Indigenous health professionals who had experience caring for Indigenous cancer patients in the PHC and hospital setting. The World Health Organisation integrated people-centred health services framework was used to analyse the interview data. Results: Seventeen health staff from six Aboriginal Community Controlled Services and nine health professionals from one tertiary hospital participated in this study. PHC sites were in urban, regional and rural settings and the hospital was in a major city. Analysis of the data suggests that timely communication and information exchange, collaborative approaches, streamlined processes, flexible care delivery, and patient-centred care and support were crucial in improving the continuity and coordination of care between the PHC service and the treating hospital. Conclusion: Communication, collaboration and care coordination are integral in the provision of quality cancer care for Indigenous Australians. It is recommended that health policy and funding be designed to incorporate these aspects across services and settings as a strategy to improve cancer outcomes for Indigenous people in Queensland.

Background: Cancer care involves many different healthcare providers. Delayed or inaccurate communication between specialists and general practitioners (GP) may negatively affect care. Aim: To describe the pattern and variation of communication between primary healthcare (PHC) services and hospitals and specialists in relation to the patient's cancer care. Methods: A retrospective audit of clinical records of Indigenous Australians diagnosed with cancer during 2010¿2016 identified through 10 PHC services in Queensland is described. Poisson regression was used to model the dichotomous outcome availability of hospital discharge summary versus not. Results: A total of 138 patient records was audited; 115 of those patients visited the PHC service for cancer-related care after cancer diagnosis; 40.0% visited the service before a discharge summary was available, and 36.5% of the patients had no discharge summary in their medical notes. While most discharge summaries noted important information about the patient's cancer, 42.4% lacked details regarding the discharge medications regimen. Conclusions: Deficits in communication and information transfer between specialists and GP may adversely affect patient care. Indigenous Australians are a relatively disadvantaged group that experience poor health outcomes and relatively poor access to care. The low proportion of discharge summaries noting discharge medication regimen is of concern among Indigenous Australians with cancer who have high comorbidity burden and low health literacy. Our findings provide an insight into some of the factors associated with quality of cancer care, and may provide guidance for focus areas for further research and improvement efforts.

Aims: Vancomycin dosing and monitoring recommendations are poorly adhered to in many institutions internationally, with concerns of treatment failure and propelling antibiotic resistance. The primary aim of this study was to audit the rate of adherence to American guidelines, with particular interest in loading dose administration. The secondary aims were (i) to determine whether or not guideline adherence results in therapeutic concentrations across body mass index (BMI) groups and (ii) to determine whether or not this was in turn associated with morbidity and hospital mortality. Method: Data were collected in a single tertiary hospital on all patients who had two or more serum vancomycin concentrations measured. Result: In total, 107 patients met the inclusion criteria. Overall, 38.3% of patients were commenced on guideline adherent vancomycin doses, and 28.3% of overweight patients received an adherent first dose compared to 51.1% of non-overweight people (difference 23%, 95% CI 4% to 41%, P = 0.024). Overweight patients were more frequently underdosed compared to non-overweight patients (P = 0.039). The frequency and proportion of underdosing increased with BMI. Overweight patients spent a smaller fraction of their course within the therapeutic range, although the difference was not statistically significant (difference 7.7%; 95% CI 4% to 19.4%; P = 0.195). The overweight group had longer hospital length of stay (LOS), higher mortality and more treatment failures. Conclusion: Adherence to guideline-based prescription is poor, particularly in overweight patients. Patients who are initially underdosed have fewer therapeutic vancomycin days, regardless of BMI. Overweight patients have increased hospital LOS, hospital mortality and treatment failure.

Purpose: The role of general practitioners in cancer care has expanded in recent years. However, little is known about utilization of primary health care (PHC) services by patients with cancer, particularly among socio-economically disadvantaged groups. We describe utilization of PHC services by patients with cancer, and the nature of the care provided. The study focuses on a disadvantaged group in Australia, namely Indigenous Australians. Methods: A retrospective audit of clinical records in ten PHC services in Queensland, Australia. Demographic and clinical data of Indigenous Australians diagnosed with cancer during 2010¿2016 were abstracted from patient¿s medical records at the PHC services. The rates of cancer-related visits were calculated using person years at risk as a denominator. Results: A total of 138 patients¿ records were audited. During 12¿months following the cancer diagnosis, patients visited the PHC service on average 5.95 times per year. Frequency of visits were relatively high in remote areas and among socioeconomic disadvantaged patients (IRR = 1.87, 95%CI 1.61¿2.17; IRR = 1.79, 95%CI 1.45¿2.21, respectively). Over 80% of visits were for seeking attention for symptoms, wound care, and emotional or social support. Patients who did not undergo surgery, had greater comorbidity, received chemotherapy and/or radiotherapy, and male gender had significantly greater rate of visits than their counterparts. Conclusion: The frequency of utilization of PHC services, especially by patients with comorbidities, and the range of reasons for attendance highlights the important role of PHC services in providing cancer care. The reliance on PHC services, particularly by patients in remote and disadvantaged communities, has important implications for appropriate resourcing and support for services in these locations.

Some patients prescribed flucloxacillin (~¿0.01%) develop drug-induced liver injury (DILI). HLA-B*57:01 is an established genetic risk factor for flucloxacillin DILI. To consolidate this finding, identify additional genetic factors, and assess relevance of risk factors for flucloxacillin DILI in relation to DILI due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin DILI cases and 6,835 controls. We imputed single-nucleotide polymorphism and human leukocyte antigen (HLA) genotypes. HLA-B*57:01 was the major risk factor (allelic odds ratio (OR)¿=¿36.62; P¿=¿2.67¿×¿10-97). HLA-B*57:03 also showed an association (OR¿=¿79.21; P¿=¿1.2¿×¿10-6). Within the HLA-B protein sequence, imputation showed valine97, common to HLA-B*57:01 and HLA-B*57:03, had the largest effect (OR¿=¿38.1; P¿=¿9.7¿×¿10-97). We found no HLA-B*57 association with DILI due to other isoxazolyl penicillins (n¿=¿6) or amoxicillin (n¿=¿15) and no significant non-HLA signals for any penicillin-related DILI.

Antihypertensive drugs have usually been approved at doses near the top of their respective dose¿response curves. Efficacy plateaus but adverse drug reactions (ADRs), such as falls, cerebral or renal ischaemia, increase as dose is increased, especially in older patients with comorbidities. ADRs reduce adherence and may be difficult to ascertain reliably. Higher doses have generally not been shown to reduce total mortality, which provides a summary of efficacy and safety. Weight loss and other lifestyle measures are essential and may be sufficient treatment in many young and low risk patients. Most antihypertensive drug lower systolic blood pressure by around 10 mmHg, which reduces stroke and heart failure by about a quarter. Clinical trials have not been designed to demonstrate specific blood pressure treatment thresholds and targets, which are mostly extrapolated from epidemiology. Mean population oral effective dose 50 may be the most appropriate dose at which to commence antihypertensive drugs. The dose can then be titrated up if greater efficacy is demonstrated, or lowered if ADRs develop. Lower dose combination therapy may best balance benefit and harms with fewer ADRs and additive, potentially synergistic, efficacy.

Remifentanil is a short acting opioid currently used in anesthesia and as an analgesic. This paper describes a simple, fast HPLC-MS/MS methodology that allows detection of remifentanil in low volume plasma samples. Acetonitrile protein precipitation is used for sample extraction and clean up. The assay has a lower limit of detection of 0.25 ng/mL and a 3 min run time.

Background & Aims: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. Methods: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. Results: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28¿1.62; P = 1.2 × 10¿9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09¿1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32¿1.98; P = 4.0 × 10¿6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21¿1.56; P = 1.5 × 10¿6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. Conclusions: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.

Purpose: The multiplicity in terms and definitions of medication-related harm has been a long-standing challenge for health researchers, clinicians, and regulatory bodies. The purpose of this narrative review was to report the diversity of terms; compare definitions, classifications, and models describing medication harm; and suggest which may be useful in both clinical practice and the research setting. Methods: A narrative review of key studies defining and/or classifying medication harm terminology was undertaken. Results: This review found that numerous terms are used to describe medication harm, and that there is a lack of consistency in current definitions, classifications, and applications. This lack of consistency applied across clinical jurisdictions and regulatory terminologies. A number of limitations in current definitions and classifications were identified. These included the exclusion of key types of medication harm events, ambiguous wording, and a lack of clarity and consensus on subclassifications. In general, there was some overlap in key models from the literature and these were presented to describe similarities and differences. Conclusion: Without uniformity quantifying, comparing, combining, or extrapolating medication harm data, such as a rate of harm in a specific population, is a challenge for those involved in medication safety and pharmacovigilance. There is a pressing need for further discussion and international consensus on this topic. Adoption of standard descriptors by practitioner groups, regulatory and policy organisations would foster quality improvement and patient safety.

Background: Tacrolimus is one of the most widely used liver transplant medications. With the increasing number of obese patients requiring liver transplants, knowledge of the effect of body size affecting post-transplant outcomes, for example drug exposure is increasingly required. Aims: (i) To investigate whether patient body size (i.e. total bodyweight) affects trough plasma concentrations of tacrolimus when a standard mg/kg dosing regimen is used; and (ii) to investigate whether obese patients have different numbers of plasma concentrations outside the therapeutic range compared to non-obese patients in the first months after liver transplant. Methods: Using a transplant database, data tacrolimus concentrations were available for 69 patients. Tacrolimus was initially dosed at a standard 0.1 mg/kg/day after liver transplant, and adjusted to maintain a target trough concentration. Trough blood samples, phenotypic and outcome variables were analysed. Results: Trough concentrations were similar between obese and non-obese patients (P > 0.05) at each sampling day. At day 7 post-transplant, 85.7% and 79.5% of the observed plasma concentrations were outside the recommended therapeutic range for obese and non-obese patients respectively, at day 30, 52.9% and 57.4%, and at 6 months, 18.7% and 27.5%. Conclusion: In the first week post-transplant, tacrolimus trough concentrations after standard mg/kg dosing post liver transplant appear to be corrected by total bodyweight. Obese patients have a similar number of trough plasma concentrations outside the therapeutic range compared to non-obese patients.

Workplace drug testing in Australia is governed by two standards AS/NZS 4308:2008 for testing in urine and AS 4760:2006 for oral fluid. These standards are prescriptive and describe the drugs tested, procedures for analysis and collection devices. However, the drugs listed are not exhaustive and workers may consume novel psychoactive substances without detection. Here we present a validated method for the detection and quantitation of 19 synthetic cannabinoids in oral fluid. These drugs are AM2233, JWH-200, AB-005, AB-FUBINACA, AB-PINACA, AB-CHMINACA, AM2201, RCS-4, JWH-250, STS-135, JWH-73, XLR-11, JWH-251, JWH-18, JWH-122, JWH-19, UR-144, JWH-20 and AKB-48. The sample volume is 100 µL and is subject to a rapid, simple, protein precipitation step prior to centrifugation and injection into the LC-MS/MS system. Chromatographic separation was achieved in 4 min on a Kinetex Biphenyl column (50 mm × 3 mm × 2.6 µm) using 0.1% formic acid in water and acetonitrile as the mobile phase. The method was validated with a limit of detection (1 ng/mL) limit of quantitation (2.5 ng/mL), selectivity, linearity (2.5-500 ng/mL), accuracy (90.5-112.5% of the target concentration) and precision (3-14.7%). This method provides for the rapid detection of synthetic cannabinoids in oral fluid which is readily applicable to a routine laboratory.

Methotrexate at low doses (5¿25¿mg/week) is first-line therapy for rheumatoid arthritis. However, there is inter- and intrapatient variability in response, with contribution of variability in concentrations of active polyglutamate metabolites, associated with clinical efficacy and toxicity. Prescribing remains heterogeneous across population groups, disease states and regimens. This review examines current knowledge of dose¿response of oral methotrexate in the setting of rheumatoid arthritis, and how this could help inform dosage regimens.

Drug development for cancer chemotherapy has an interesting history. A mix of serendipity, animal, cell line, and standard pharmacological principles of dose, dose-response, dose-concentration, dose intensity and combination therapies have been used to develop optimal dosing schedules. However in practice, significant gaps in the translation of preclinical to clinical dosing schedules persist, and clinical development has instead moved to new drug development. A older chemotherapies are still the backbone of most solid tumour schedules, therapeutic drug monitoring has emerged as a method for optimising the dose for individual patients.

Background: In many health settings, administration of medicinal cannabis poses significant implementation barriers including drug storage and safety for administering staff and surrounding patients. Different modes of administration also provide different yet potentially significant issues. One route that has become of clinical interest owing to the rapid onset of action and patient control of the inhaled amount (via breath timing and depth) is that of vaporisation of cannabinoid products. Although requiring a registered therapeutic device for administration, this is a relatively safe method of intrapulmonary administration that may be particularly useful for patients with difficulty swallowing, and for those in whom higher concentrations of cannabinoids are needed quickly. A particular concern expressed to researchers undertaking clinical trials in the hospital is that other patients, nurses, and clinical or research staff may be exposed to second-hand vapours in the course of administering vaporised products to patients. Objective: The objective of this study was to take samples from two research staff involved in administering vaporised ¿9-tetrahydrocannabinol to participants in a clinical trial, to examine and quantitate cannabinoid presence. Methods: Blood samples from two research staff were taken during the exposure period for three participants (cannabis users) over the course of approximately 2.5¿h and analysed using tandem mass spectrometry. Results: Blood samples taken over a vaporised period revealed exposure below the limit of detection for ¿9-tetrahydrocannabinol and two metabolites, using tandem mass spectrometry analytical methods. Conclusions: These results are reassuring for hospital and clinical trial practices with staff administering vaporised cannabinoid products, and helpful to ethics committees wishing to quantify risk.

Endocannabinoid pharmacology is now relatively well understood with a number of endocannabinoids and endogenous cannabinoid neurotransmitters identified and the pharmacokinetics relatively well ascertained. Further, the cannabinoid receptors are now molecularly and pharmacologically characterised and the cell processes involved in endocannabinoid transcription, synthesis, post-translational modification and protein expression are reported. Endogenous cannabinoids have been shown to have key roles in immune and pain pathways and neuro-behavioural signalling including appetite regulation. Significant recent interest has thus been shown in understanding these pathways to guide the development of agents that inhibit the natural catabolism of endogenous cannabinoids to modify pain and appetite, and to synthesise antagonists for the treatment of disease such as obesity. This research is concurrent with the renewed clinical interest in exogenous cannabinoids and their use in disease. However, the complex pharmacology and physiological effects of exogenous cannabinoids, either as individual components or in combination, as extracts or via administration of the whole plant in humans, are less well known. Yet as with all other therapeutics, including those derived from plants, knowledge of the pharmacokinetics and dynamics of the complete plant, the individual chemical molecules and their synthetic versions, including formulations and excipients is a standard part of drug development. This article covers the key pharmacological knowledge required to guide further exploration of the toxicity and efficacy of different cannabinoids and their formulations in blinded placebo-controlled studies.

Objective: To examine the laxative prescriptions in hospital inpatients with cancer and non-cancer pain on oxycodone compared to oxycodone plus naloxone combination. Design: Retrospective case note review. Setting: A palliative care inpatient unit and a general medical ward in a large tertiary referral hospital. Participants: Eighty-four patients receiving oxycodone or combination oxycodone/naloxone on general medical (45 patients) and palliative care wards (39 patients). Main outcome measures: The primary recorded outcomes were regular opioid dose (milligrams per day) and number of prescribed laxatives (type, doses, and frequency per day). Results: Sixty-three (75%) patients in the study were on at least one laxative. In the general medicine inpatients, those on combined oxycodone/naloxone received on average 3.7 laxative doses per day compared to the oxycodone patients receiving 1.6 doses a day. In the palliative medicine population, both groups received a similar number of laxatives, despite the oxycodone/naloxone patients being on lower opioid doses. Conclusion: This retrospective study of hospital inpatients with cancer and non-cancer pain found that laxative use was not reduced in those on combined oxycodone/naloxone compared to oxycodone alone, suggesting that despite the interpretations of the clinical trials in the phase IV setting, the addition of naloxone had no effect on reducing laxative use.

Indigenous Australians diagnosed with cancer experience higher mortality and lower survival rates compared to non-Indigenous Australians. Reasons are multifaceted and complex. Knowledge about Indigenous cancer survivors' perspectives of positive cancer survivorship is a gap in research evidence. The study explored cancer survivorship perspectives of Indigenous cancer survivors, their support people and healthcare workers with a view to developing recommendations for cancer survivorship. Indigenous Australians who completed cancer treatment in the previous 6 months to 5 years, their support people and primary healthcare workers were recruited from primary healthcare centres and a large tertiary Queensland hospital. Semi-structured interviews and focus groups were conducted with written and informed consent obtained prior. Participants emphasised key action areas and recommendations to enhance cancer survivorship, namely: establishing a community cancer advocate and peer support program, availability and use of a cancer-specific Indigenous primary healthcare worker and hospital-based Indigenous patient navigator, as well as adoption of question prompt lists and cancer survivorship care plans. Existing research suggests significant benefits from implementing the key recommendations identified in this study. Greater support and commitment across health sectors and funding bodies is needed to promote institutional change and health system development.

It is not uncommon to be treating people with addiction who also have significant other health problems, including heart, renal or liver failure, diabetes and vascular disease. These conditions require regular medications to be taken. This can be a problem for people living with addiction and difficult social circumstances affecting compliance, among other issues. Our perspective provides a summary of general pharmacological factors affecting medicine taking in people with addiction problems, to provide a guide for hospital doctors in this setting.

Purpose: The purpose of this study was to explore Indigenous Australian cancer survivors¿ perspectives of follow-up cancer care and management. Methods: This is a qualitative study employing individual interviews with 21 Indigenous cancer survivors (13 females, 8 males) recruited from a rural primary health service and large tertiary hospital in Brisbane, Queensland. Yarning methods were used to conduct semi-structured interviews. Yarning is a culturally appropriate, informal conversational process emphasising the importance of storytelling. Results: Findings describe a range of ways in which follow-up cancer care is experienced with four major categories elucidated, namely: links to tertiary health services, links to primary health services, communication between tertiary and primary health services, and lost in transition. Both positive and negative experiences were described; however, the importance of timely and informative discharge information, continuity of care, good communication between tertiary and primary health services, and strong therapeutic relationships were salient issues raised by participants. Conclusions: These findings highlight the importance of establishing strong therapeutic relationships between patients and tertiary and primary health professionals. Also important for survivorship is provision of discharge summaries or care plans at discharge for survivors and general practitioners as well as access to a range of allied health services. Alternative means for follow-up could be investigated for regional and rural survivors to facilitate convenient and cost-effective follow-up care. Finally, provision of responsive and flexible follow-up care to cater for the diverse range of needs and preferences of cancer survivors is required. A patient navigator available across the cancer continuum could go some way to addressing this.

Introduction: Arterial disease is common in advancing renal failure, culminating in myocardial infarction with cardiac failure, strokes and peripheral and renal artery disease. Attention to cardiac and arterial disease may slow deterioration of renal function. Management of risk factors can reduce these sequelae. Areas covered: Modifiable risk factors for arterial disease and relevant pharmacotherapies. Expert opinion: Cardiovascular disease is the biggest killer in renal failure. Statins are viewed as essential in symptomatic coronary disease and have been shown in non-renal patients to improve survival after myocardial infarction. Cochrane recommends statins in renal failure but not in end stage renal disease or transplant patients. Large well powered clinical trials focussed specifically on renal patients failed to demonstrate cardiovascular outcome or mortality benefits of statins when compared to placebo. Other lipid lowering pharmacotherapies are weaker and adverse effects may account for the absence of net clinical benefit in non-renal patients in published clinical trials. Patients should be started on a statin after myocardial infarction, regardless of lipid levels, but the risk of adverse effects in advanced renal failure with its comorbidities predicates employing only essential doses. Optimal antihypertensive and antithrombotic pharmacotherapy are also priorities.

Glioblastoma is a lethal form of brain tumour usually treated by surgical resection followed by radiotherapy and an alkylating chemotherapeutic agent. Key to the success of this multimodal approach is maintaining apoptotic sensitivity of tumour cells to the alkylating agent. This initial treatment likely establishes conditions contributing to development of drug resistance as alkylating agents form the O6-methylguanine adduct. This activates the mismatch repair (MMR) process inducing apoptosis and mutagenesis. This review describes key juxtaposed drivers in the balance between alkylation induced mutagenesis and apoptosis. Mutations in MMR genes are the probable drivers for alkylation based drug resistance. Critical to this interaction are the dose-response and temporal interactions between adduct formation and MMR mutations. The precision in dose interval, dose-responses and temporal relationships dictate a role for alkylating agents in either promoting experimental tumour formation or inducing tumour cell death with chemotherapy. Importantly, this resultant loss of chemotherapeutic selective pressure provides opportunity to explore novel therapeutics and appropriate combinations to minimise alkylation based drug resistance and tumour relapse.

Aim: To investigate the impact of medication beliefs, illness perceptions and quality of life on medication adherence in people with decompensated cirrhosis. Methods: One hundred adults with decompensated cirrhosis completed a structured questionnaire when they attended for routine outpatient hepatology review. Measures of self-reported medication adherence (Morisky Medication Adherence Scale), beliefs surrounding medications (Beliefs about Medicines Questionnaire), perceptions of illness and medicines (Brief Illness Perception Questionnaire), and quality of life (Chronic Liver Disease Questionnaire) were examined. Clinical data were obtained via patient history and review of medical records. Least absolute shrinkage and selection operator and stepwise backwards regression techniques were used to construct the multivariable logistic regression model. Statistical significance was set at alpha = 0.05. Results: Medicat ion adherence was "High" in 42% of participants, "Medium" in 37%, and "Low" in 21%. Compared to patients with "High" adherence, those with "Medium" or "Low" adherence were more likely to report difficulty affording their medications (P < 0.001), lower perception of treatment helpfulness (P = 0.003) and stronger medication concerns relative to medication necessity beliefs (P = 0.003). People with "Low" adherence also experienced greater symptom burden and poorer quality of life, including more frequent abdominal pain (P = 0.023), shortness of breath (P = 0.030), and emotional disturbances (P = 0.050). Multivariable analysis identified having stronger medication concerns relative to necessity beliefs (Necessity-Concerns Differential = 5, OR = 3.66, 95%CI: 1.18-11.40) and more frequent shortness of breath (shortness of breath score = 3, OR = 3.87, 95%CI: 1.22-12.25) as independent predictors of "Low" adherence. Conclusion: The association between "Low" adherence and patients having strong concerns or doubting the necessity or helpfulness of their medications should be explored further given the clinical relevance.

Workplace drug testing in Australia is usually adherent to one of two standards, AS/NZS 4308:2008 for urine or AS 4760:2006 for oral fluid. These standards prescribe the drugs tested, devices used and testing methodology followed by the testing agency. However, they are not comprehensive and for many years workers have been able to consume novel psychoactive substances to avoid detection and without consequences. Here, we present a validated method for the detection of 32 Synthetic Stimulant and Hallucogenic drugs, commonly sold as bath salts, in oral fluid. These drugs are cathinone, ephedrone, methylone, flephedrone, MDA, PMA, methedrone, TMA, MDMA, butylone, mephedrone, MDEA, MEC, pentedrone, MBDB, MTA, Alpha-PVP, MPBP, 2C-B, MDPV, DOB, 2C-T-2, TFMPP, DOET, 2C-T-7, naphyrone, MDAI, FMA, DMA, 25C-NBOMe, 25B-NBOMe and 25T4-NBOMe. Sample preparation was undertaken using a simple protein precipitation in acetonitrile. Chromatographic separation was achieved in 7.5 min on a Kinetex F5 column (50mm × 3mm × 2.6 µm) using 0.1% formic acid in water and acetonitrile as the mobile phases. The method was validated with limit of detection (1 ng/mL), limit of quantitation (2.5 ng/mL), selectivity, linearity (2.5-500 ng/mL), accuracy (85.3-108.4% of the target concentration) and precision (1.9-14%). This method was applied to 12 samples previously submitted for routine testing and two were found to contain 2-CB and DOB (5 and 4 ng/mL) and, MPBP and TFMPP (both at 4 ng/mL). This method provides for the rapid detection of a large number of compounds in oral fluid which is readily applicable to routine testing laboratories.

The prerequisites for the successful implementation of therapeutic drug monitoring (TDM) include high inter-subject variation, low inter-occasion variation, narrow therapeutic index and a strong link between plasma drug concentrations and clinical effects. The degree to which targeted anticancer drugs meet these criteria is not the only consideration in implementing precision dosing. Methodological, logistical, funding and cultural barriers also provide challenges to the successful implementation of approaches to individualised therapy. This review considers the barriers to the routine use of TDM, using examples from both conventional (cytotoxic) anticancer, but also considering more recent data and examples more relevant to chronic, oral administration of targeted therapies. Based on these examples and the associated principles for the implementation of precision dosing, proposals may be made for a more rational, real-world approach to the best use of precision medicines.

Generally, licensed drug-dosing recommendations for chemotherapy are based on results from clinical trials in which subjects are usually of relatively normal body size, middle-aged, and are relatively racially homogeneous, with minimal comorbidity and specific tumor characteristics. Very few nontrial patients meet these characteristics, resulting in clinical practice having to extrapolate dosing recommendations to the specific patient. There is insufficient research on the impact of obesity-associated physiological changes prevalent in patients with common cancers on standard pharmacokinetic and pharmacodynamic parameters. Yet quantifying the influence of obesity on the pharmacology of chemotherapy is vital, as dosing inappropriate for body composition (ie, flat dosing or mg/kg based on total body weight) may increase the risk of adverse events and reduce clinical effectiveness. Unfortunately, there are few cancer guidelines to aid clinicians in selecting the optimal dose in the obese¿even recent guidelines are based predominantly on clinical opinion/current practice in treating obese patients, rather than evidence. Data in many other vulnerable groups, for example, those with significant comorbidity and older patients, are also scarce. Because of the known limitations of body surface area¿guided dosing, therapeutic drug monitoring or pharmacokinetic-guided dosing, which predicts an individual's exposure, has increasingly been shown to be a powerful tool in cancer therapy. Used appropriately, it can adjust for differences in pharmacokinetic parameters not considered when body size¿based dosing or ¿one dose fits all¿ is used. This review will focus predominantly on the rationale for pharmacokinetic-guided dosing of the newer oral molecularly targeted antineoplastics in people whose drug exposure is not predicted by their physiology or body composition.

Background: Australian clinical trials are planned to evaluate medicinal cannabis in a range of clinical contexts. Aims: To explore the preferences, attitudes and beliefs of patients eligible and willing to consider participation in a clinical trial of medicinal cannabis for poor appetite and appetite-related symptoms from advanced cancer. Methods: A cross-sectional anonymous survey was administered from July to December 2015 online and in eight adult outpatient palliative care and/or cancer services. Respondents were eligible if they were =18 years, had advanced cancer and poor appetite/taste problems/weight loss and might consider participating in a medicinal cannabis trial. Survey items focused on medicinal rather than recreational cannabis use and did not specify botanical or pharmaceutical products. Items asked about previous medicinal cannabis use and preferences for delivery route and invited comments and concerns. Results: There were 204 survey respondents, of whom 26 (13%) reported prior medicinal cannabis use. Tablets/capsules were the preferred delivery mode (n = 144, 71%), followed by mouth spray (n = 84, 42%) and vaporiser (n = 83, 41%). Explanations for preferences (n = 134) most commonly cited convenience (n = 66; 49%). A total of 82% (n = 168) of respondents indicated that they had no trial-related concerns, but a small number volunteered concerns about adverse effects (n = 14) or wanted more information/advice (n = 8). Six respondents volunteered a belief that cannabis might cure cancer, while two wanted assurance of efficacy before participating in a trial. Conclusion: Justification of modes other than tablets/capsules and variable understanding about cannabis and trials will need addressing in trial-related information to optimise recruitment and ensure that consent is properly informed.

Background: Misdiagnosis, either over-or underdiagnosis, exposes older patients to increased risk of inappropriate or omitted investigations and treatments, psychological distress, and financial burden. Objective: To evaluate the frequency and nature of diagnostic errors in 16 conditions prevalent in older patients by undertaking a systematic literature review. Data sources and study selection: Cohort studies, cross-sectional studies, or systematic reviews of such studies published in Medline between September 1993 and May 2014 were searched using key search terms of ¿diagnostic error¿, ¿misdiagnosis¿, ¿accuracy¿, ¿validity¿, or ¿diagnosis¿ and terms relating to each disease. Data synthesis: A total of 938 articles were retrieved. Diagnostic error rates of >10% for both over-and underdiagnosis were seen in chronic obstructive pulmonary disease, dementia, Parkinson¿s disease, heart failure, stroke/transient ischemic attack, and acute myocardial infarction. Diabetes was overdiagnosed in <5% of cases. Conclusion: Over-and underdiagnosis are common in older patients. Explanations for overdiagnosis include subjective diagnostic criteria and the use of criteria not validated in older patients. Underdiagnosis was associated with long preclinical phases of disease or lack of sensitive diagnostic criteria. Factors that predispose to misdiagnosis in older patients must be emphasized in education and clinical guidelines.

Purpose: The purpose of the present study is to explore the role of the general practitioners, family physicians and primary care physicians (GP) in the provision of follow-up cancer care. Methods: PubMed, MEDLINE and CINAHL were systematically searched for primary research focussing on the role of the GP from the perspective of GPs and patients. Data were extracted using a standardised form and synthesised using a qualitative descriptive approach. Results: The initial search generated 6487 articles: 25 quantitative and 33 qualitative articles were included. Articles focused on patients¿ and GPs¿ perspectives of the GP role in follow-up cancer care. Some studies reported on the current role of the GP, barriers and enablers to GP involvement from the perspective of the GP and suggestions for future GP roles. Variations in guidelines and practice of follow-up cancer care in the primary health care sector exist. However, GPs and patients across the included studies supported a greater GP role in follow-up cancer care. This included greater support for care coordination, screening, diagnosis and management of physical and psychological effects of cancer and its treatment, symptom and pain relief, health promotion, palliative care and continuing normal general health care provision. Conclusion: While there are variations in guidelines and practice of follow-up cancer care in the primary health care sector, GPs and patients across the reviewed studies supported a greater role by the GP. Implications for Cancer Survivors: Greater GP role in cancer care could improve the quality of patient care for cancer survivors. Better communication between the tertiary sector and GP across the cancer phases would enable clear delineation of roles.

There are a number of complex and seemingly ignored issues around prescribing safely and effectively for older people, particularly for very old women. These issues include polypharmacy, possible compliance issues and communication barriers between patient, specialists and general practitioners (GPs). There are specific pharmacokinetic (PK) and pharmacodynamic (PD) parameters that change in older age generally, and in women more specifically, which if ignored are likely to cause symptoms and to impair quality of life when drug dosage is unchanged. These changed PK and PD parameters are not all-or-nothing processes, but a continuum across age, sex and comorbidity. Very old people also have less ¿reserve¿ when drugs are used in ¿standard' doses, are more likely to have multiple concurrent therapies, and the risk of adverse effects of drugs in this group is very high. Doctors need to consider these issues when providing therapy for this group, or when trying to unravel the complex prescribing cascade here. This review outlines general principles to consider when prescribing for older people, focusing on age- and sex-related changes in both PK and PD processes.

To investigate health professionals' perspectives about factors that impede or facilitate cancer care for Indigenous people. Semi-structured interviews with 22 health professionals involved in Indigenous cancer care. Data were interpreted using an inductive thematic analysis approach. Participants presented their perspectives on a number of barriers and enablers to Indigenous cancer care. Barriers were related to challenges with communication, the health system and coordination of care, issues around individual and community priorities and views of cancer treatment and health professional judgement. Enablers to cancer care were related to the importance of trust and rapport as well as health care system and support factors. The findings highlighted the need for recording of Indigenous status in medical records and a coordinated approach to the provision of evidence-based and culturally appropriate cancer care. This could go some way to improving Indigenous patient's engagement with tertiary cancer care services.

Background: Tumour necrosis factor-alpha inhibitors (anti-TNFa) and anakinra are monoclonal antibodies against pro-inflammatory cytokines overexpressed in many systemic inflammatory diseases. In Australia, they are registered for the treatment of several rheumatological, gastroenterological and dermatological indications. Despite increasing observational evidence for their use in off-label indications, there is a paucity of outcome research from the Australian hospital sector. Aims: To describe the off-label use of anti-TNFa and anakinra at a tertiary referral hospital in Queensland, Australia and consideration of a drug register to inform future clinical decision-making. Methods: We performed an in-depth retrospective chart audit of off-label treatment with anti-TNFa or anakinra at the Royal Brisbane and Women's Hospital from mid-2010 to mid-2014, linking demographic, phenotypic, pathology and outcome data with these drugs. Results: Off-label use was identified in 10 patients. The most frequent indications were sarcoidosis and dermatological conditions. Three patients required sequential therapy with a second anti-TNFa (total responses = 13). Complete response occurred in 46%, partial response in 38% and primary non-response in 8%. Response was unable to be determined in 8%. We recorded 14 adverse events (infections most common). Conclusion: This study suggests that anti-TNFa may be beneficial for some off-label indications (e.g. sarcoidosis). However, the observational design of this study (and pre-existing research) limits the ability to infer causality and generalise results. We propose the creation of a mandatory drug register to monitor off-label use. Whilst comparative efficacy cannot be established without a matched placebo arm, a register would enable some reporting on effectiveness in rare diseases and identify infrequent but serious adverse events.

Model based personalised dosing (MBPD) is a sophisticated form of individualised therapy, where a population pharmacokinetic (PK) or pharmacodynamic model is utilised to estimate the dose required to reach a target exposure or effect. The choice of which model to implement in MBPD is a subjective decision. By choosing one model, information from the remaining models is ignored, as well as the rest of the literature base. This manuscript describes a methodology to develop a ¿hybrid¿ model for voriconazole that incorporated information from prior models in a biologically plausible manner. Voriconazole is a triazole antifungal with difficult to predict PK, although it does have a defined exposure¿response relationship. Nine population PK models of voriconazole were identified from the literature. The models differed significantly in structural components. The hybrid model contained a two-compartment disposition model with mixed linear and nonlinear time-dependent clearance. The parameters for the hybrid model were determined using simulation techniques. Validation of the hybrid model was assessed via visual predictive checks, which indicated the majority of the variability in the literature models was captured by the hybrid model. The predictive performance was assessed using four different sampling strategies of limited concentrations from ten richly PK sampled subjects to predict future concentrations. Overall, the hybrid model predicted future concentrations with good precision. Further prospective and retrospective validation of the hybrid model is required before it could be used in clinical practice.

Objectives: We compared patterns of care, comorbidity, disability-adjusted life-years (DALYs) and survival in Indigenous and non-Indigenous women with breast cancer in Queensland, Australia (1998¿2004). Methods: A cohort study of Indigenous (n¿=¿110) and non-Indigenous women (n¿=¿105), frequency matched on age and remoteness. We used Pearson¿s Chi-squared analysis to compare proportions, hazard models to assess survival differences and calculated disability-adjusted life years (DALYs). Results: Indigenous women were more likely to be socially disadvantaged (43 vs. 20¿%, p¿<¿0.01) have comorbidity (42 vs. 18¿% p¿<¿0.01), and have regional spread or distant metastasis (metastasis, 51 vs. 36¿%, p¿=¿0.02) than non-Indigenous women; there was no difference in treatment patterns. More Indigenous women died in the follow-up period (p¿=¿0.01). DALY¿s were 469 and 665 per 100,000 for Indigenous and non-Indigenous women, respectively, with a larger proportion of the burden attributed to premature death among the former (63 vs. 59¿%). Conclusions: Indigenous women with breast cancer received comparable treatment to their non-Indigenous counterparts. The higher proportion of DALYs related to early death in Indigenous women suggests higher fatality with breast cancer in this group. Later stage at diagnosis and higher comorbidity presence among Indigenous women reinforce the need for early detection and improved management of co-existing disease.

Model Based Personalised Dosing (MBPD) requires a population pharmacokinetic (PK) or pharmacodynamic model to determine the optimal dose of medication for an individual. Often several models are published, and the decision of which model is implemented in MBPD may have a large impact on its clinical utility. As quoted by Box, ¿all models are wrong, the practical question is how wrong can they be and still be useful¿. Voriconzole, a triazole antifungal and the example used in this manuscript, currently has nine population PK models published. To assess the impact of model-misspecification on MBPD, five structurally mis-specified models for voriconazole were developed. Intensive plasma concentrations were simulated for 100 virtual subjects. The dose adjustments required to reach a target exposure were determined by using the empirical Bayes estimates of the PK parameters under each of the mis-specified models. The predicted plasma concentrations and the probability of clinical outcomes, upon following the dose recommendations, were determined. Models that did not contain non-linear clearance performed poorly, with a median dose recommendation 155¿310¿mg higher than appropriate doses, when only one plasma concentration was available. Removal of body weight and CYP2C9 genotype as covariates had no clinically significant impact on outcomes. In summary, the removal of important structural components, such as non-linear clearance in the case of voriconazole, had a large impact on the clinical utility of MBPD. The removal of patient covariates, even highly influential covariates such as CYP2C9 genotype for voriconazole, had no clinical impact.

Background: Therapeutic anticoagulation with enoxaparin in pregnancy is complex due to varying pharmacokinetics and the increasing prevalence of obesity. There is limited evidence to support current dosing and monitoring strategies of enoxaparin in this population. Aim: To describe the current practice in therapeutic anticoagulation in the pregnant population at a tertiary institution. Methods: A retrospective study of pregnant women on therapeutic enoxaparin between January 2007 and December 2011. Results: Forty-four pregnant women requiring therapeutic anticoagulation were identified and divided into two groups, monitored with anti-factor Xa (AXA) concentrations and unmonitored. Fifty-five percent of monitored women were initiated on the recommended 1 mg/kg twice a day (bd) enoxaparin dose-strategy. Eighty-two percent of women were monitored; however, there was variability regarding the timing, frequency and subsequent dose adjustments from monitoring. Overall, as pregnancies progressed, there was both increasing dose adjustments and increasing frequency of monitoring. Fourteen women had a BMI over 30 kg/m2, and 13 of these women were monitored. Nine monitored obese women required doses less than 1 mg/kg/bd to maintain a therapeutic AXA level. Management appeared to be individualised. There were small numbers of toxicity events. Conclusion: Variation exists in dosing and monitoring practices for therapeutic enoxaparin in the pregnant population. Dosing obese patients using 1 mg/kg twice daily can lead to toxic AXA concentrations, and dose reductions are required to maintain a therapeutic range. A larger prospective study reviewing dose, AXA concentrations and outcome data is necessary to make dosing recommendations in this group.

Glioblastoma is a brain neoplasm with limited 5-year survival rates. Developments of new treatment regimens that improve patient survival in patients with glioblastoma are needed. It is likely that a number of existing drugs used in other conditions have potential anticancer effects that offer significant survival benefit to glioblastoma patients. Identification of such drugs could provide a novel treatment paradigm.

Although 60 years have passed since it became widely available on the therapeutic market, paracetamol dosage in patients with liver disease remains a controversial subject. Fulminant hepatic failure has been a well documented consequence of paracetamol overdose since its introduction, while short and long term use have both been associated with elevation of liver transaminases, a surrogate marker for acute liver injury. From these reports it has been assumed that paracetamol use should be restricted or the dosage reduced in patients with chronic liver disease. We review the factors that have been purported to increase risk of hepatocellular injury from paracetamol and the pharmacokinetic alterations in different pathologies of chronic liver disease which may affect this risk. We postulate that inadvertent under-dosing may result in concentrations too low to enable efficacy. Specific research to improve the evidence base for prescribing paracetamol in patients with different aetiologies of chronic liver disease is needed.

Tyrosine kinase inhibitors have been marketed as a fixed dose, ¿one size fits all¿ treatment strategy. Physicians have also been interested in this method of dosing, knowing the complex planning of other current cancer therapies administered on a mg/m2 or mg/kg basis and subsequent occurrence of dosing error or concern for underdosing. The ¿simple and safe¿ strategy of a single dose of tyrosine kinase inhibitor for cancer has thus been widely adopted. However, the benefits purported to exist in the clinical trials do not appear to be borne out in clinical practice, particularly in solid tumours. In order to investigate whether pharmacokinetic variability is a contributor to the variable outcomes, pharmacokinetic targets to enable individualisation of tyrosine kinase inhibitor administration are now emerging. Evidence suggests there is not a clear relationship of a single dose to maximum plasma concentration (Cmax), steady-state trough concentration (Ctrough) or area under the curve (AUC). Furthermore, a significant number of questions remain related to the specific timing and frequency of sample collection required to achieve optimal outcomes. This article reviews the wide variability in the literature on this topic, specifically the different pharmacokinetic targets of the same drug for different cancers, for different states of cancer, and changing pharmacokinetic parameters over a treatment interval in cancer. It appears the optimal sampling times to enable appropriate dose recommendations across patients and diseases may vary, and are not always trough concentrations at steady state. Importantly, the need to be pragmatic in a clinical setting is paramount. Lastly, international collaborations to increase sample size are highly recommended to ensure enough patients are sampled to be sure of a clinical benefit from this concentration-directed methodology.

OBJECTIVE: To examine urban-rural differences and individual risk factors for a late stage of breast cancer at diagnosis in Australian women.

Anorexia can affect up to 90¿% of people with advanced cancer. It is a complex symptom associated with changes in taste, lack of hunger at mealtimes and lack of food enjoyment. Associated weight loss is part of the physical decline that occurs as cancer worsens. Weight loss can also occur from cachexia, the increased metabolism of energy due to raised inflammatory cytokines, liver metastases and other factors seen in several advanced cancers. Independent of anorexia, although frequently associated (where it is referred to as the cachexia-anorexia syndrome), it accounts for a significant amount of morbidity and deaths in people with cancer. In particular, quality of life for the patient and the family is significantly affected with this syndrome as it causes anxiety and distress. Therefore, it is important that research into therapies is undertaken, particularly focusing on an understanding of the pharmacokinetic properties of compounds in this cachexic population. Cannabinoids are one such group of therapies that have received a large amount of media focus recently. However, there appears to be a lack on rigorous pharmacokinetic data of these complex and varied compounds in the cachexic population. Similarly, there is a lack of pharmacokinetic data in any population group for the non- tetrahydrocannabinol (THC) and cannabidiol (CBD) cannabinoids (often due to the lack of analytical standards for quantification). This review will thus examine the pharmacokinetics of major cannabinoids i.e. THC and CBD in a cancer population. Overall, based on the current literature, evidence for the use of cannabinoids for the treatment of cancer-related cachexia-anorexia syndrome remains equivocal. A high-quality, rigorous, phase I/II study to elicit pharmacokinetic dose¿concentration and concentration¿response data, with a clinically acceptable mode of delivery to reduce intrapatient variability and enable more consistent bioavailability is needed in this population.

Paediatric patients, particularly preterm neonates, present many pharmacological challenges. Due to the difficulty in conducting clinical trials in these populations dosing information is often extrapolated from adult populations. As the processes of absorption, distribution, metabolism and excretion of drugs change throughout growth and development extrapolation presents risk of over or underestimating the doses required. Information about the development these processes, particularly drug metabolism pathways, is still limited with weight based dose adjustment presenting the best method of estimating pharmacokinetic changes due to growth and development. New innovations in pharmacokinetic research, such as population pharmacokinetic modelling, present unique opportunities to conduct clinical trials in these populations improving the safety and effectiveness of the drugs used. More research is required into this area to ensure the best outcomes for our most vulnerable patients.

Objective: Aboriginal and Torres Strait Islander women have a higher mortality rate due to gynecologic cancer compared with non-Indigenous women. For cervical cancer, Australian Indigenous women are less likely to survive 5 years following diagnoses than non-Indigenous women. This study investigates the factors associated with gynecologic cancer treatment and survival among Queensland indigenous and non-Indigenous women. Methods: Australian Indigenous women diagnosed with uterine, cervical, ovarian, or other gynecologic cancers during 1998-2004 in the public hospital system were included. They were frequency matched on age (±5 years), residential remoteness, and cancer type to a random sample of non-Indigenous women. One- and 5-year cancer-specific survival was examined according to Indigenous status using Cox proportional hazards regression. Results: Indigenous women (n = 137) compared with non-Indigenous women (n = 120) were less likely to be diagnosed with localized disease (49% vs 65%, P = 0.02) and had more comorbidities (52% vs 21%, P < 0.001). Indigenous women were less likely to receive any cancer treatment compared with non-Indigenous women (91% vs 98%, P = 0.01), although when excluding those with metastatic cancer, there was no significant difference in uptake of treatment (95% vs 91%, respectively, P = 0.31). Among those who did undergo treatment, there was no difference in time to treatment (median difference 0.5 days, P = 0.98). Gynecologic cancer-specific survival differences between Indigenous and non-Indigenous women were most prominent in the first year following diagnosis (hazard ratio [HR], 1.89; 95% confidence interval [CI], 1.06-3.38) and were no longer significant 5 years after diagnosis (HR, 1.47 [95% CI, 0.97-2.25]). For cervical cancer, crude 1-year survival was poorer for Indigenous women compared with non-Indigenous women (HR, 2.46 [95% CI, 1.03-5.90]), but was no different when adjusted for stage and treatment of cancer (HR, 1.00 [95% CI, 0.45-2.24]). Conclusions: Improving the early diagnosis of cervical cancer in Indigenous women may increase cancer-specific survival in the year following diagnosis.

This study examined the effects of Tai Chi, a low-impact mind-body movement therapy, on severity of depression, anxiety, and stress symptoms in centrally obese people with elevated depression symptoms. In total, 213 participants were randomized to a 24-week Tai Chi intervention program or a wait-list control group. Assessments were conducted at baseline and 12 and 24 weeks. Outcomes were severity of depression, anxiety, and stress symptoms, leg strength, central obesity, and other measures of metabolic symptom. There were statistically significant between-group differences in favor of the Tai Chi group in depression (mean difference = -5.6 units, P < 0.001), anxiety (-2.3 units, P < 0.01), and stress (-3.6 units, P < 0.001) symptom scores and leg strength (1.1 units, P < 0.001) at 12 weeks. These changes were further improved or maintained in the Tai Chi group relative to the control group during the second 12 weeks of follow-up. Tai Chi appears to be beneficial for reducing severity of depression, anxiety, and stress and leg strength in centrally obese people with depression symptoms. More studies with longer follow-up are needed to confirm the findings. This trial is registered with ACTRN12613000010796.

Background Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. Methods Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75 000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. Findings 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. Interpretation International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems. Funding Canadian Partnership Against Cancer (Toronto, Canada), Cancer Focus Northern Ireland (Belfast, UK), Cancer Institute New South Wales (Sydney, Australia), Cancer Research UK (London, UK), Centers for Disease Control and Prevention (Atlanta, GA, USA), Swiss Re (London, UK), Swiss Cancer Research foundation (Bern, Switzerland), Swiss Cancer League (Bern, Switzerland), and University of Kentucky (Lexington, KY, USA).

Personalized medicine has been helpful for drug development in diseases with single and relatively stable gene mutations. The benefit for complex solid tumours with heterogeneous and changing genetic profiles is less clear. Whether it is efficient to continue diverting resources from combined biological and pharmacological approaches to trial new and existing genetic ¿targeted therapies¿ for brain tumours is unknown but of developing concern in resource constrained environments.

Introduction: Accurate knowledge of O6-methylguanine methyltransferase (MGMT) gene promoter subtype in patients with glioblastoma (GBM) is important for treatment. However, this test is not always available. Pre-operative diffusion MRI (dMRI) can be used to probe tumour biology using the apparent diffusion coefficient (ADC); however, its ability to act as a surrogate to predict MGMT status has shown mixed results. We investigated whether this was due to variations in the method used to analyse ADC. Methods: We undertook a retrospective study of 32 patients with GBM who had MGMT status measured. Matching pre-operative MRI data were used to calculate the ADC within contrast enhancing regions of tumour. The relationship between ADC and MGMT was examined using two published ADC methods. Results: A strong trend between a measure of 'minimum ADC' and methylation status was seen. An elevated minimum ADC was more likely in the methylated compared to the unmethylated MGMT group (U = 56, P = 0.0561). In contrast, utilising a two-mixture model histogram approach, a significant reduction in mean measure of the 'low ADC' component within the histogram was associated with an MGMT promoter methylation subtype (P < 0.0246). Conclusion: This study shows that within the same patient cohort, the method selected to analyse ADC measures has a significant bearing on the use of that metric as a surrogate marker of MGMT status. Thus for dMRI data to be clinically useful, consistent methods of data analysis need to be established prior to establishing any relationship with genetic or epigenetic profiling.

Inappropriate polypharmacy, especially in older people, imposes a substantial burden of adverse drug events, ill health, disability, hospitalization, and even death. The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed drugs. Deprescribing is the process of tapering or stopping drugs, aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies. A deprescribing protocol is proposed comprising 5 steps: (1) ascertain all drugs the patient is currently taking and the reasons for each one; (2) consider overall risk of drug-induced harm in individual patients in determining the required intensity of deprescribing intervention; (3) assess each drug in regard to its current or future benefit potential compared with current or future harm or burden potential; (4) prioritize drugs for discontinuation that have the lowest benefit-harm ratio and lowest likelihood of adverse withdrawal reactions or disease rebound syndromes; and (5) implement a discontinuation regimen and monitor patients closely for improvement in outcomes or onset of adverse effects. Whereas patient and prescriber barriers to deprescribing exist, resources and strategies are available that facilitate deliberate yet judicious deprescribing and deserve wider application.

Glioblastoma multiforme (GBM) has nearly uniformly fatal with a median survival of less than 2¿years. While there have not been any novel anti-GBM therapeutics approved for many years, there has been the gradual accumulation of clinical data suggesting that the widely used anti-convulsant agent, valproic acid (VPA) may significantly prolong survival in GBM patients. This pre-clinical study aimed to determine the potential clinical utility of VPA in the treatment of GBM. Primary GBM cells were treated with VPA as a monotherapy and in combination with temozolomide and irradiation. At clinically achievable concentrations, VPA was shown to be effective as a monotherapy agent in the five primary lines tested. VPA was then used as a sensitizing agent to in vitro radiation and showed significant augmentation of in vitro irradiation therapy. In addition, when VPA, radiation and temozolomide were combined an additive, rather than synergistic effect was noted. Gene expression profiling demonstrated close clustering of triple treated cells with VPA mono-treated cells while untreated cells clustered closer with TMZ-irradiation dual treated cells. These microarray data suggest a dominant role of VPA at the gene expression level when combining these different treatment options. Moreover, in an in vivo tumor transplantation model, we were able to demonstrate an increase in animal survival when cells were pre-treated with irradiation-VPA and when triple treated. These findings provide a significant rationale for the investigation of VPA in the treatment of GBM patients.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD), characterized by accumulation of hepatic triglycerides (steatosis), is associated with abdominal obesity, insulin resistance, and inflammation. Although weight loss via calorie restriction reduces features of NAFLD, there is no pharmacologic therapy. Resveratrol is a polyphenol that prevents high-energy diet-induced steatosis and insulin resistance in animals by up-regulating pathways that regulate energy metabolism. We performed a placebo-controlled trial to assess the effects of resveratrol in patients with NAFLD. Methods: Overweight or obese men diagnosed with NAFLD were recruited from hepatology outpatient clinics in Brisbane, Australia from 2011 through 2012. They were randomly assigned to groups given 3000 mg resveratrol (n= 10) or placebo (n= 10) daily for 8 weeks. Outcomes included insulin resistance (assessed by the euglycemic-hyperinsulinemic clamp), hepatic steatosis, and abdominal fat distribution (assessed by magnetic resonance spectroscopy and imaging). Plasma markers of inflammation, as well as metabolic, hepatic, and antioxidant function, were measured; transcription of target genes was measured in peripheral blood mononuclear cells. Resveratrol pharmacokinetics and safety were assessed. Results: Eight-week administration of resveratrol did not reduce insulin resistance, steatosis, or abdominal fat distribution when compared with baseline. No change was observed in plasma lipids or antioxidant activity. Levels of alanine and aspartate aminotransferases increased significantly among patients in the resveratrol group until week 6 when compared with the placebo group. Resveratrol did not significantly alter transcription of NQO1, PTP1B, IL6, or HO1 in peripheral blood mononuclear cells. Resveratrol was well-tolerated. Conclusions: Eight weeks administration of resveratrol did not significantly improve any features of NAFLD, compared with placebo, but it increased hepatic stress, based on observed increases in levels of liver enzymes. Further studies are needed to determine whether agents that are purported to mimic calorie restriction, such as resveratrol, are safe and effective for complications of obesity. Clinical trials registration no: ACTRN12612001135808.

INTRODUCTION: The lower breast cancer survival rate observed among rural women may be related to differences in screening access and utilization. We evaluated existing evidence for rural and urban differences in mammography service use in adult women.

Phenytoin is regularly employed in the critically ill for prophylaxis against or treatment of seizure disorders. No prior studies have examined current dosing practices in an Australasian intensive care unit (ICU) setting. The aims of this study were to: a) describe the adequacy of contemporary dosing in respect to free and total serum phenytoin concentrations; b) identify factors associated with therapeutic drug concentrations; and c) examine the accuracy of predictive equations that estimate free concentrations in this setting. All patients receiving a loading dose of phenytoin in a tertiary-level ICU were eligible for enrolment; 53 patients were enrolled in the study. Serum samples to determine free and total phenytoin concentrations (measured by high performance liquid chromatography) were then drawn prior to the following dose. Free concentrations below the recommended target (<1 mg/l) were considered as suboptimal. The most common indication for phenytoin loading was traumatic brain injury (49%) and the mean administered dose was 14.5 (3.66) mg/kg. Twenty-six patients (49%) had suboptimal trough free concentrations, although this subgroup was significantly heavier and therefore received a lower per kilogram dose (12.8 [3.1] vs 16.3 [3.4] mg/kg, P=0.001). In multivariate analysis, larger weight adjusted doses (P=0.018), higher albumin concentration (P=0.034) and receiving phenytoin for an indication other than seizure (P=0.035), were associated with a greater likelihood of adequate concentrations. In conclusion, phenytoin dosing remains complex in critically ill patients, although lower per kilogram loading doses are strongly associated with free concentrations below the desired target.

When patients enter hospital they may have to stop smoking abruptly if the hospital has a 'no smoking' policy. Abrupt smoking cessation can affect the metabolism of drugs. Cigarette smoking induces the activity of human cytochromes P450 (CYP) 1A2 and 2B6. These enzymes metabolise several clinically important drugs, including clozapine, olanzapine and methadone. Decreased CYP1A2 activity after smoking cessation increases the risk of adverse drug reactions, with reports of increased toxicity from clozapine and olanzapine. Predicting the required dose reduction of drugs metabolised by CYP1A2 after smoking cessation is challenging. Therapeutic drug monitoring should be used when possible. Nicotine replacement therapy does not influence CYP1A2 activity.

Purpose: To ask whether dose-rate influences low-dose hyper- radiosensitivity and induced radioresistance (HRS/IRR) response in rat colon progressive (PRO) and regressive (REG) cells. Methods: Clonogenic survival was applied to tumorigenic PRO and non-tumorigenic REG cells irradiated with 60Co ¿-rays at 0.0025-500 mGy.min-1. Both clonogenic survival and non-homologous end-joining (NHEJ) pathway involved in DNA double-strand breaks (DSB) repair assays were applied to PRO cells irradiated at 25 mGy.min-1 with 75 kV X-rays only. Results: Irrespective of dose-rates, marked HRS/IRR responses were observed in PRO but not in REG cells. For PRO cells, the doses at which HRS and IRR responses are maximal were dependent on dose-rate; conversely exposure times during which HRS and IRR responses are maximal (tHRSmax and tIRRmax) were independent of dose-rate. The tHRSmax and tIRRmax values were 23 ± 5 s and 66 ± 7 s (mean ± standard error of the mean [SEM], n = 7), in agreement with literature data. Repair data show that tHRSmax may correspond to exposure time during which NHEJ is deficient while tIRRmax may correspond to exposure time during which NHEJ is complete. Conclusion: HRS response may be maximal if exposure times are shorter than tHRSmax irrespective of dose, dose-rate and cellular model. Potential application of HRS response in radiotherapy is discussed. © 2013 Informa UK, Ltd.