Background: Clarithromycin is a commonly used macrolide antibiotic. Infection is a major source of mortality and morbidity in critical care units. Pharmacokinetics may vary during critical illness and suboptimal antimicrobial exposure has been shown to be associated with treatment failure. The pharmacokinetics of intravenous clarithromycin in critical illness have not previously been described. Methods: Pharmacokinetic, clinical and demographic data were collected from critically ill adults receiving intravenous clarithromycin. Drug concentrations were measured using high-performance liquid chromatography/mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM version 7.5.1. Allometric weight scaling was added, and periods of renal replacement therapy were excluded a priori. Simulations of 10,000 patients were performed to assess pharmacokinetic-pharmacodynamic (PKPD) target attainment. Results: The analysis included 121 samples taken from 19 participants. A two-compartment model was found to provide the best fit. The addition of covariates did not improve model fit. There was no evidence of auto-inhibition in this population. Population parameter estimates of clearance and volume of distribution were lower than previously reported, with high interindividual variability. Simulations suggested reasonable pharmacokinetic-pharmacodynamic (PKPD) target attainment with current dosing regimens for most organisms that clarithromycin is used to treat with known clinical breakpoints. Conclusions: To our knowledge, this is the first study to describe the pharmacokinetics of intravenous clarithromycin in humans. Although our simulations suggest reasonable target attainment, further investigation into appropriate PKPD targets and clinical breakpoints for clarithromycin may enable dosing optimisation in this population.

OBJECTIVE:The use of alcoholic beverages with 'diet' mixers is becoming more popular. The purpose of this study was to assess BrAC and the pace of stomach emptying in healthy volunteers after consuming either sucrose-containing or artificially sweetened alcoholic beverages. METHOD:This was a two-way crossover trial with an open label. The subjects consumed alcohol on two consecutive occasions conducted in the morning (9:00am-12:00 pm), once with diet coke and once with standard coke. In a randomised order, twelve healthy participants (n = 12, 8 male and 4 female) aged 19-64 years were studied twice. They drank a standardised (0.5 g/kg body weight) volume of vodka (37.5 % ABV) over a time period of 1 minute in each session, prepared with either 'regular' coke with 35 g sugar in 330 mL or 'diet' coke with artificial sweetener which is aspartame. Their BrAC was measured every 15 minutes for 3 hours. Their breath samples for stomach emptying measurement were taken separately in breath bags right after the breath alcohol measurement. The gastric half-emptying time (t1/2) and lag phase time (tlag) characteristics of these breath samples were determined. RESULTS:Diet coke increased both the peak BrAC (38.3 ± 9.45 vs. 34.8 ± 6.82 μg/100 mL) and the area under the breath ethanol curve between 0 and 180 minutes (45249.0 ± 95.7 vs. 40439.25 ± 72.5 μg·min/L). Using nonlinear regression analysis, the diet drink showed a shorter half-emptying time (t1/2) than the regular drink (100.09 ± 35.42 vs. 110.74 ± 66.71 min), while the lag phase (tlag) was slightly longer (49.35 ± 13.52 vs. 46.63 ± 13.90 min)." CONCLUSIONS:This study emphasises the need of considering factors other than the alcohol level of a drink when determining safe quantities of intake and the potential of intoxication. The lack of sucrose in diet mixers may cause faster stomach emptying of alcohol, increasing its absorption rate into the blood, resulting in higher peak BrAC and increased exposure to other alcohol-related dangers.

This chapter summarizes some of the factors relating to the monitoring of antiarrhythmic and cardioactive drugs in the light of the results of the Cardiac Arrhythmia Suppression Trial (CAST). Patients were recruited into CAST if they had asymptomatic or mildly symptomatic ventricular arrhythmia following acute myocardial infarction. The results of CAST should also be seen in the context of the therapeutic alternatives to antiarrhythmic drugs which are now available to clinicians. Mortality following acute myocardial infarction has been reduced by the use of thrombolytic agents, and sudden cardiac death has been reduced by the introduction of implantable defibrillators. The interpretation of drug concentrations may be influenced by such factors as the type of arrhythmia, its spontaneous variability, other drug therapy, other underlying morbidity, and the age of the patient.

Oncology has been undergoing a profound transition in the last ten years or more with the increased usage in oral anti-cancer medication (OAM). Approximately 25% of all anti-cancer medication is now designed for oral use and this is likely to increase prospectively. Oral anti-cancer medications have the potential to alleviate capacity issues in cancer treating units as patients receive their treatment at home. There remains however a requirement for safe and efficient assessment and monitoring but this does not necessarily require them to repeatedly attend a hospital day unit. Therefore the opportunity exists to transition this cohort to a community-based setting to be assessed by a specialist such as an Advanced Nurse Practitioner (ANP) in nurse-led clinics. Having an OAM assessment closer to their home would be more convenient to the patient. Furthermore, this could help alleviate hospital capacity issues which were brought into sharp focus with the onset of the COVID-19 pandemic and the use of nurse-led clinics are promoted in the aims of the current healthcare system reform process in Ireland. Within the context of the Irish healthcare system reform and the COVID-19 pandemic this protocol will outline a collaboration between an Oncology Department in Letterkenny University Hospital in Ireland and the National University of Ireland, Galway aimed to develop and pilot a community-based Advanced Nurse Practitioner-led integrated oncology care model for adults receiving OAM. Phase 1 of this two-phase study commenced in September 2020 and comprised a scoping review, a benchmarking exercise and a qualitative analysis of relevant stakeholders. This protocol paper presents a pilot to be undertaken in phase 2 as OAM care is transitioned to an ANP-led community-based model, which is a radical shift for oncology care in Ireland. The pilot outlined will provide data that will identify potential refinements to the model and address specific uncertainties about a definitive trial. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by The Irish Cancer Society Grant number CNRA19RIC in collaboration with the Health Research Board (HRB) the National Cancer Control Programme (NCCP) and the Office of the Nursing and Midwifery Services Director (ONMSD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Letterkenny University Hospital Research Ethics Committee gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Oncology has been undergoing a profound transition in the last ten years or more with the increased usage in oral anti-cancer medication (OAM). Approximately 25% of all anti-cancer medication is now designed for oral use and this is likely to increase prospectively. Oral anti-cancer medications have the potential to alleviate capacity issues in cancer treating units as patients receive their treatment at home. There remains however a requirement for safe and efficient assessment and monitoring but this does not necessarily require them to repeatedly attend a hospital day unit. Therefore the opportunity exists to transition this cohort to a community-based setting to be assessed by a specialist such as an Advanced Nurse Practitioner (ANP) in nurse-led clinics. Having an OAM assessment closer to their home would be more convenient to the patient. Furthermore, this could help alleviate hospital capacity issues which were brought into sharp focus with the onset of the COVID-19 pandemic and the use of nurse-led clinics are promoted in the aims of the current healthcare system reform process in Ireland. Within the context of the Irish healthcare system reform and the COVID-19 pandemic this protocol will outline a collaboration between an Oncology Department in Letterkenny University Hospital in Ireland and the National University of Ireland, Galway aimed to develop and pilot a community-based Advanced Nurse Practitioner-led integrated oncology care model for adults receiving OAM. Phase 1 of this two-phase study commenced in September 2020 and comprised a scoping review, a benchmarking exercise and a qualitative analysis of relevant stakeholders. This protocol paper presents a pilot to be undertaken in phase 2 as OAM care is transitioned to an ANP-led community-based model, which is a radical shift for oncology care in Ireland. The pilot outlined will provide data that will identify potential refinements to the model and address specific uncertainties about a definitive trial.

Increasing popularity and known shortfalls in the regulation of electronic cigarettes (ECs) emphasises the urgent need for closer content monitoring and for comprehensible information on their possible health effects. This study investigated components of EC liquids in samples submitted from 2014 to 2021 and discussed the trends driven by legislation changes. Samples originating from prisoners, teenagers and 'test purchases' of commercially available ECs were analysed by gas chromatography-mass spectrometry (GC-MS). For those containing delta-9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD), the content of these components was quantified by liquid chromatography with quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) to show variation of these compounds in EC liquids; 112 EC liquids were included in this study. Nicotine was detected in 87 (78%) of the EC liquids analysed. Twenty-two, including samples from before and after introduction of the UK Psychoactive Substances Act (2016), contained one or more synthetic cannabinoid receptor agonist (SCRA). THC was detected in only 11 samples, whereas a single sample was found to contain CBD only. Six samples contained a mixture of THC and CBD. In all cases where information was available, the THC/CBD content was less than that stated on the product label. The data collected showed great variation in EC liquid content. Therefore, it is important that users are educated regarding risks associated with EC use. Additionally, substances now controlled under both the UK Misuse of Drugs Act and Psychoactive Substances Act were present. These substances each carry a potential risk to health, which is possibly exacerbated if multiple compounds are inhaled concomitantly.

Oncology has been experiencing an increase in oral anti-cancer medications over the last ten years or more. Due to the potential toxicity of OAMs the monitoring of such patients has largely remained within hospitals. The COVID-19 pandemic expedited changes in healthcare and since March 2020, in one Oncology Department in Ireland, there has been a shift to an ANP-led model of care which utilises virtual assessments. To further improve patient experiences' and to increase hospital capacity this study aims to transition this patient cohort to an ANP-led integrated model of care in the community setting. A scoping review was performed to determine clinical practices for the monitoring of patients receiving OAM. This review and additional analysis of international guidelines identified recommendations for clinical practice which were collated and a best practice standard was developed. This standard enabled a benchmarking activity to be performed to measure the current level of adherence to best practice by the ANP. To determine the acceptability of ANP-led care and possible transition to an integrated care model, a qualitative study was performed using telephone interviews with patients (n=9) and focus groups via Zoom™ with health care professionals (n=24). Using thematic analysis four themes were generated from the data. Reflection on the pre-COVID-19 system demonstrated universal agreement that this should not be reverted to. The ANP was perceived as being ideally placed to deliver care for this cohort of patients. It was recognised that robust communication with patients and with the multi-disciplinary team was vital for OAM care delivery. There was agreement that an integrated model of ANP-led care had significant benefits and various infrastructural requirements for this model to be effective were identified. Results demonstrate that the current ANP-led model has already positively impacted patients' experience with safe care evident in the benchmarking activity. Collating the results enabled development of an integrated model for OAM care. It is anticipated that by piloting this model, patient experiences could be further improved upon.

Oncology has been undergoing a profound transition in the last ten years with the increased usage in oral anti-cancer medication. Approximately 25% of all anti-cancer medication is now designed for oral use and this is likely to increase prospectively. These treatments are convenient for patients and are often preferred by them, yet there are similar safety and toxicity concerns as there are to intravenous treatment. Oral anti-cancer medications (OAMs) have the potential to alleviate capacity issues in cancer treating units as patients receive their treatment at home, however there remains a requirement for safe and efficient assessment and care. Consequently, the management of patients on OAMs is of paramount importance. The optimum setting, whether within primary or secondary care, in addition to the appropriate health care professional to carry out patient assessment and monitoring needs to be established. This paper presents a protocol for a scoping review which aims to systematically and comprehensively map the literature on the current management of adults receiving OAMs. The review will follow the published guidance to direct the various steps involved. The protocol will be guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) framework to ensure methodological and reporting quality. Independent full text review will be performed by two reviewers and any disagreements resolved through discussion with a third reviewer. The process will be iterative in nature. This scoping review will provide a narrative synthesis and map the literature on the management of individuals receiving OAMs. This work is an appropriate initial stage in presenting the literature to inform the subsequent steps in a multi-phased research study which aims to establish and analyse the safety and efficacy of an integrated care model for the management of patients receiving OAM in the community by an advanced practitioner.

SummaryThere is equipoise regarding the use of prothrombin complex concentrate vs. fresh frozen plasma in bleeding patients undergoing cardiac surgery. We performed a pilot randomised controlled trial to determine the recruitment rate for a large trial, comparing the impact of prothrombin complex concentrate vs. fresh frozen plasma on haemostasis (1 h and 24 h post‐intervention), and assessing safety. Adult patients who developed bleeding within 24 h of cardiac surgery that required coagulation factor replacement were randomly allocated to receive prothrombin complex concentrate (15 IU.kg−1 based on factor IX) or fresh frozen plasma (15 ml.kg−1). If bleeding continued after the first administration of prothrombin complex concentrate or fresh frozen plasma administration, standard care was administered. From February 2019 to October 2019, 180 patients were screened, of which 134 (74.4% (95%CI 67–81%)) consented, 59 bled excessively and 50 were randomly allocated; 25 in each arm, recruitment rate 35% (95%CI 27–44%). There were 23 trial protocol deviations, 137 adverse events (75 prothrombin complex concentrate vs. 62 fresh frozen plasma) and 18 serious adverse events (5 prothrombin complex concentrate vs. 13 fresh frozen plasma). There was no increase in thromboembolic events with prothrombin complex concentrate. No patient withdrew from the study, four were lost to follow‐up and two died. At 1 h after administration of the intervention there was a significant increase in fibrinogen, Factor V, Factor XII, Factor XIII, α2‐antiplasmin and antithrombin levels in the fresh frozen plasma arm, while Factor II and Factor X were significantly higher in the prothrombin complex concentrate group. At 24 h, there were no significant differences in clotting factor levels. We conclude that recruitment to a larger study is feasible. Haemostatic tests have provided useful insight into the haemostatic changes following prothrombin complex concentrate or fresh frozen plasma administration. A definitive trial is needed to ascertain the benefits and safety for each.

Background: The pharmacokinetics of beta-lactam antibiotics in critical illness remain poorly characterized, particularly in neonates, children and the elderly. We undertook a pharmacokinetic study of commonly used beta-lactam antibiotics in critically ill patients of all ages. The aims were to produce a whole-life beta-lactam pharmacokinetic model and describe the extent to which standard doses achieve pharmacokinetic/pharmacodynamic targets associated with clinical cure. Patients and methods: A total of 212 critically ill participants with an age range from 1 day (gestational age 24 weeks) to 90 years were recruited from a UK hospital, providing 1339 pharmacokinetic samples. Population pharmacokinetic analysis was undertaken using non-linear mixed-effects modelling (NONMEM) for each drug. Pooled data were used to estimate maturation and decline of beta-lactam pharmacokinetics throughout life. Results: Pharmacokinetic models for eight drugs were described, including what is thought to be the first benzyl-penicillin model in critically ill adults. We estimate that 50% of adult beta-lactam clearance is achieved by 43 weeks post-menstrual age (chronological plus gestational age). Fifty percent of decline from peak adult clearance occurs by 71 years. Paediatric participants were significantly less likely than adults to achieve pharmacokinetic/ pharmacodynamic targets with standard antibiotic doses (P< 0.01). Conclusions: We believe this to be the first prospective whole-life antibiotic pharmacokinetic study in the critically ill. The study provides further evidence that standard antibiotic doses fail to achieve pharmacokinetic/ pharmacodynamic targets associated with clinical success in adults, children and neonates. Maturation and decline parameters estimated from this study could be adopted as a standard for future prospective studies.

3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) tablets are widely used recreationally, and not only vary in appearance, but also in MDMA content. Recently, the prevalence of high-content tablets is of concern to public health authorities. To compare UK data with other countries, we evaluated MDMA content of 412 tablets collected from the UK, 2001-2018, and investigated within-batch content variability for a sub-set of these samples. In addition, we investigated dissolution profiles of tablets using pharmaceutical industry-standard dissolution experiments on 247 tablets. All analyses were carried out using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our data supported other studies, in that recent samples (2016-2018) tend to have higher MDMA content compared to earlier years. In 2018, the median MDMA content exceeded 100 mg free-base for the first time. Dramatic within-batch content variability (up to 136 mg difference) was also demonstrated. Statistical evaluation of dissolution profiles at 15-minutes allowed tablets to be categorized as fast-, intermediate-, or slow-releasing, but no tablet characteristics correlated with dissolution classification. Hence, there would be no way of users knowing a priori whether a tablet is more likely to be fast or slow-releasing. Further, within-batch variation in dissolution rate was observed. Rapid assessment of MDMA content alone provides important data for harm reduction, but does not account for variability in (a) the remainder of tablets in a batch, or (b) MDMA dissolution profiles. Clinical manifestations of MDMA toxicity, especially for high-content, slow-releasing tablets, may be delayed or prolonged, and there is a significant risk of users re-dosing if absorption is delayed.

Introduction: Reducing positive margins and need for re-excision yet maintaining cosmesis is key in breast cancer surgery. This study assessed if low margin positivity resulted in adverse cosmesis, pain and functional outcomes in patients undergoing wide local excision (WLE).

BackgroundUp to 65% of newly diagnosed breast cancer patients had not been screened correctly before diagnosis resulting in increased stage of cancer at presentation. This study assessed whether their primary relatives are, in turn, assessed appropriately.MethodsAn ethically approved prospective study involving 274 primary relatives of women diagnosed with breast cancer, between 2009-2012, at a symptomatic breast unit in Ireland. Telephone interview established: demographics, menstrual history, family history verification, breast screening history. Personal risk level was calculated and whether current screening met screening guidelines. Participants were enrolled into appropriate screening programs if currently not in one and results analyzed.ResultsTwo hundred and fifteen of the 280 (76.8%) newly diagnosed patients responded giving details of their 274 primary relatives; this made up the study cohort. Mean age 50 +/- 10 (35-75). Thirty two percent were low risk, 64% moderate and 4% high. 190/274 (69%) were being screened appropriately. Seventy five relatives were then assessed with: mammography in 55, Mg and US in 16. Four underwent a biopsy and to date none had cancer. Surveillance was: annual screening in 48%; national screening program and General Practitioner (GP) in 33%; GP only in over 65s in 13%; 6% await further assessment at specialist genetics clinics where their surveillance will be decided.ConclusionsThis study has identified an opportunity to improve the delivery of appropriate screening to higher risk primary relatives of patients with breast cancer. This necessitates an integrated national approach involving providers of primary care, patients and screening breast programs.

Antimicrobials are the medicines most commonly pres c ibed to children, so the correct dose is of key importance to improve outcome and reduce tox icity [1]. This is particularly true for patients in intensive care, where effective antimic robial therapy is absolutely crucial, and influences therapeutic outcomes in both children an d dults [2]. One key factor in improving treatment outcomes is the optimization of antibioti c dosing [3,4,5,6]. On average, each child in Europe receives one course of antibiotics per year, but there is considerable variation in the rate of antimicrobial prescribing in different coun tries and also the doses used. Even for very common antibiotics, there remains a marked lack of inf rmation about the optimal dosing in the context of critical illness. Although antibioti cs are extensively used for patients in intensive care (ICU), very few pharmacokinetic (PK) studies h ave been conducted in this patient population [7], despite numerous studies on toxicit y. Penicillins are the important grop of antimicrobial s widely used in children and adults for over 50 years. Penicillins are β-lactam antimicrobials and therefore especially int olerant to the stress conditions since the degradation of penicillins occ ur in different ways in different conditions. The stability of penicillins have been evaluated in stress conditions previously [8]. The instability of penicillins is reported through the β-lactam ring opening (Fig 1) in acidic and basic conditions, enzymatic (hydrolysis and aminoly sis) degradation, degradation by the presence of metal ions and by temperature changes.