Search

The hepatitis E virus (HEV) is an emerging infectious disease with zoonotic potential, causing acute hepatitis in humans. Infections in healthy individuals are often acute, self-limiting and asymptomatic, thus leading to the underdiagnosis of HEV infections. Asymptomatic HEV infections pose a problem for blood transfusion safety by increasing the risk for transfusion-transmitted HEV infections. Here, we describe the journey from determining the HEV seroprevalence among blood donors to the implementation of routine HEV RNA testing of all blood products in Switzerland in 2018 and summarise the HEV cases detected since. In total, 290 HEV-positive blood donations were detected by mini-pool nucleic acid testing (NAT) in Switzerland in the period of October 2018-December 2023, equal to an incidence of 20.7 per 100,000 donations. Thanks to the implemented scheme, no transfusion-transmitted infections occurred in this period. Furthermore, blood donation monitoring has proven to be an effective means of detecting HEV outbreaks in the general population. HEV cases in Swiss blood donors are caused by two major genotypes, the Swiss-endemic subtypes 3h3 and 3c. Interestingly, 11 HEV cases (5%) were of genotype 3ra, a variant found in wild and farmed rabbits. Our results indicate that mini-pool NAT is an efficient method to reduce the risk of transfusion-transmitted HEV infections.

Incidents involving ionizing radiation pose a risk of immediate and long-term clinical consequences for both victims and responders in the event of secondary contamination. Rapid identification of the problem and a coordinated response are crucial. This article summarizes the key challenges related to the emergency management of a single patient or multiple victims, addressing the importance of recognizing such a case, radioprotection measures, decontamination, and available treatments., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Introduction: Hepatitis E virus (HEV) genotype 3 is the major cause of acute viral hepatitis in several European countries. It is acquired mainly by ingesting contaminated pork, but has also been reported to be transmitted through blood transfusion. Although most HEV infections, including those via blood products, are usually self-limiting, they may become chronic in immunocompromised persons. It is thus essential to identify HEV-infected blood donations to prevent transmission to vulnerable recipients., Aims: Prior to the decision whether to introduce HEV RNA screening for all Swiss blood donations, a 2-year nationwide prevalence study was conducted., Methods: All blood donations were screened in pools of 12-24 samples at five regional blood donation services, and HEV RNA-positive pools were subsequently resolved to the individual donation index donation (X). The viral load, HEV IgG and IgM serology, and HEV genotype were determined. Follow-up investigations were conducted on future control donations (X + 1) and previous archived donations of the donor (X - 1) where available., Results: Between October 2018 and September 2020, 541,349 blood donations were screened and 125 confirmed positive donations were identified (prevalence 1:4331 donations). At the time of blood donation, the HEV RNA-positive individuals were symptom-free. The median viral load was 554 IU/mL (range: 2.01-2,500,000 IU/mL). Men (88; 70%) were more frequently infected than women (37; 30%), as compared with the sex distribution in the Swiss donor population (57% male/43% female, p < 0.01). Of the 106 genotyped cases (85%), all belonged to genotype 3. Two HEV sub-genotypes predominated; 3h3 (formerly 3s) and 3c. The remaining sub-genotypes are all known to circulate in Europe. Five 3ra genotypes were identified, this being a variant associated with rabbits. In total, 85 (68%) X donations were negative for HEV IgM and IgG. The remaining 40 (32%) were positive for HEV IgG and/or IgM, and consistent with an active infection. We found no markers of previous HEV in 87 of the 89 available and analyzed archive samples (X - 1). Two donors were HEV IgG-positive in the X - 1 donation suggesting insufficient immunity to prevent HEV reinfection. Time of collection of the 90 (72%) analyzed X + 1 donations varied between 2.9 and 101.9 weeks (median of 35 weeks) after X donation. As expected, none of those tested were positive for HEV RNA. Most donors (89; 99%) were positive for anti-HEV lgG/lgM (i.e., seroconversion). HEV lgM-positivity (23; 26%) indicates an often-long persistence of lgM antibodies post-HEV infection., Conclusion: The data collected during the first year of the study provided the basis for the decision to establish mandatory HEV RNA universal screening of all Swiss blood donations in minipools, a vital step in providing safer blood for all recipients, especially those who are immunosuppressed.

Background: The COVID-19 pandemic strained healthcare systems immensely as of 2020. Switzerland's hospital pharmacies' responses during the first wave were surveyed with a view to improving the quality of pharmaceutical management in future health crises., Methods: An online survey was sent to the heads of all of Switzerland's hospital pharmacies. The questionnaire was organised into eleven sections of questions covering many topics regarding the management of COVID-19's first wave. Data collection occurred from May to June 2020., Results: Analyses were performed using the 43 questionnaires (66%), with at least one answer per questionnaire, out of 65 distributed. Seventeen of 41 pharmacies responding (41%) had existing standard operating procedures or pandemic plans and 95% of these (39/41) set up crisis management steering committees. Twenty-nine of 43 pharmacies responding (67%) created new activities to respond to the pandemic's specific needs. Twenty-six of 39 pharmacies responding (67%) created new drug lists for: COVID-19-specific treatments (85%; 22/26), sedatives (81%; 21/26), anaesthetics (77%; 20/26) and antibiotics (73%; 19/26). Drug availability in designated COVID-19 wards was managed by increasing existing stocks (54%; 22/41 pharmacies) and creating extra storage space (51%; 21/41). Two drugs generated the greatest concern about shortages: propofol (49%; 19/39 pharmacies) and midazolam (44%; 17/39). Remdesivir stocks ran out in 26% of pharmacies (10/39). Twelve of 43 pharmacies (28%) drafted specific new documents to respond to medical needs regarding drug administration, 12 (28%) did so for drug preparation and 10 (23%) did so for treatment choices., Conclusions: Switzerland's hospital pharmacies encountered many challenges related to the COVID-19 crisis and had to find solutions quickly, effectively and safely. The survey highlighted the key role that hospital pharmacies played in many aspects of the pandemic by providing logistical and clinical support to medical and nursing care teams. The lessons and experiences outlined could be used to improve the quality of hospital pharmacies' readiness for similar future events., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Purpose: To evaluate collagen scaffolds (CS) in terms of their in vitro resorption behavior, surface structure, swelling behavior, and mechanical properties in physiologically simulated environments, compared with porcine native connective tissue., Materials and Methods: Three test materials-one porcine collagen matrix (p-CM), two acellular dermal matrices (porcine = p-ADM, allogenic = a-ADM)-and porcine native connective tissue (p-CTG) as a control material were examined for resorption in four solutions using a high-precision scale. The solutions were artificial saliva (AS) and simulated body fluid (SBF), both with and without collagenase (0.5 U/ml at 37 °C). In addition, the surface structures of CS were analyzed using a scanning electron microscope (SEM) before and after exposure to AS or SBF. The swelling behavior of CS was evaluated by measuring volume change and liquid absorption capacity in phosphate-buffered saline (PBS). Finally, the mechanical properties of CS and p-CTG were investigated using cyclic compression testing in PBS., Results: Solutions containing collagenase demonstrated high resorption rates with significant differences (p < 0.04) between the tested materials after 4 h, 8 h and 24 h, ranging from 54.1 to 100% after 24 h. SEM images revealed cross-linked collagen structures in all untreated specimens. Unlike a-ADM, the scaffolds of p-CM and p-ADM displayed a flake-like structure. The swelling ratio and fluid absorption capacity per area ranged from 13.4 to 25.5% among the test materials and showed following pattern: p-CM > a-ADM > p-ADM. P-CM exhibited higher elastic properties than p-ADM, whereas a-ADM, like p-CTG, were barely compressible and lost structural integrity under increasing pressure., Conclusions and Clinical Implications: Collagen scaffolds vary significantly in their physical properties, such as resorption and swelling behavior and elastic properties, depending on their microstructure and composition. When clinically applied, these differences should be taken into consideration to achieve the desired outcomes., (© 2023. Deutsche Gesellschaft für Implantologie im Zahn‐, Mund‐ und Kieferbereich e.V., Japanese Society of Oral Implantology.)

From 2014 to 2016, the number of hepatitis E virus (HEV) infections in southern Switzerland increased dramatically and suggested food as a potential infection reservoir. We evaluated the effects of food control measures introduced to limit HEV infections, assessing anti-HEV IgG and IgM rates in blood donors before and after the implementation of food control measures in 2017. From 2012 to 2013, we screened 1283, and from 2017 to 2019, we screened 1447 donors for IgG and IgM antibodies. No statistically significant differences were detected for IgG (32.8% from 2012 to 2013 vs. 31.1% from 2017 to 2019, p = 0.337) or IgM rates (2.0% from 2012 to 2013 vs. 2.8% from 2017 to 2019, p = 0.21). Rural provenience and age > 66 are predictors for positive IgG serology. A total of 5.9% of 303 donors included in both groups lost IgG positivity. We also determined nucleic acid testing (NAT) rates after the introduction of this test in 2018, comparing 49,345 donation results from southern Switzerland with those of 625,559 Swiss donor controls, and only 9 NAT-positive donors were found from 2018 to 2023. The high HEV seroprevalence in southern Switzerland may depend on different food supply chains in rural and urban areas. Local preventive measures probably have a limited impact on blood HEV risk; thus, continuous NAT testing is recommended., Competing Interests: The authors declare no conflicts of interest.

Introduction: Ultrasound diagnostics is an important examination method in everyday clinical practice, but student education is often inadequate for acquiring sufficient basic skills. Individual universities have therefore started integrating (extra)curricular training concepts into medical education. This study aimed to evaluate sustainable skills development through participation in peer-assisted ultrasound courses., Methods: From 2017, students in the clinical part of medical school could opt for extracurricular peer-assisted ultrasound courses. Depending on the format (10-week course/2-day compact course) these comprised 20 teaching units focusing on abdominal and emergency ultrasonography. Students attending compulsory workshops at the start of their practical year were enrolled in this study, allowing for a comparison between the study group (attended ultrasound course) and the control group (did not attend ultrasound course). Competency from two out of four practical exams (subjects: "aorta", "gallbladder", "kidney" and "lung") was measured, and a theory test on the same subject areas ("pathology recognition") was administered. Additional questions concerned biographical data, subjective competency assessment (7-point Likert scale), and "attitude to ultrasound training in the curriculum"., Results: Analysis included 302 participants in total. Ultrasound courses had been attended on average 2.5 years earlier (10-week course) and 12 months earlier (2-day compact course), respectively. The study group ( n = 141) achieved significantly better results than the control group ( n = 161) in the long-term follow-up. This applies both to practical exams ( p < 0.01) and theory tests ( p < 0.01). After course attendance, participants reported a significantly higher subjective assessment of theoretical ( p < 0.01) and practical ( p < 0.01) ultrasound skills., Conclusions: Peer-assisted ultrasound courses can sustainably increase both theoretical and practical competency of medical students. This highlights the potential and need for standardised implementation of ultrasound courses in the medical education curriculum.

In a COVID-19 sero-surveillance cohort study with predominantly healthy and vaccinated individuals, the objectives were (i) to investigate longitudinally the factors associated with the quantitative dynamics of antispike (anti-S1) IgG antibody levels, (ii) to evaluate whether the levels were associated with protection from SARS-CoV-2 infection, and (iii) to assess whether the association was different in the pre-Omicron compared with the Omicron period. The QuantiVac Euroimmun ELISA test was used to quantify anti-S1 IgG levels. The entire study period (16 months), the 11-month pre-Omicron period and the cross-sectional analysis before the Omicron surge included 3219, 2310, and 895 reactive serum samples from 949, 919, and 895 individuals, respectively. Mixed-effect linear, mixed-effect time-to-event, and logistic regression models were used to achieve the objectives. Age and time since infection or vaccination were the only factors associated with a decline of anti-S1 IgG levels. Higher antibody levels were significantly associated with protection from SARS-CoV-2 infection (0.89, 95% confidence interval [CI] 0.82-0.97), and the association was higher during the time period when Omicron was predominantly circulating compared with the ones when Alpha and Delta variants were predominant (adjusted hazard ratio for interaction 0.66, 95% CI 0.53-0.84). In a prediction model, it was estimated that >8000 BAU/mL anti-S1 IgG was required to reduce the risk of infection with Omicron variants by approximately 20%-30% for 90 days. Though, such high levels were only found in 1.9% of the samples before the Omicron surge, and they were not durable for 3 months. Anti-S1 IgG antibody levels are statistically associated with protection from SARS-CoV-2 infection. However, the prediction impact of the antibody level findings on infection protection is limited., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Therapeutic drug monitoring (TDM) of conventional cytotoxic chemotherapies is strongly supported yet poorly implemented in daily practice in hospitals. Analytical methods for the quantification of cytotoxic drugs are instead widely presented in the scientific literature, while the use of these therapeutics is expected to keep going for longer. There are two main issues hindering the implementation of TDM: turnaround time, which is incompatible with the dosage profiles of these drugs, and exposure surrogate marker, namely total area under the curve (AUC). Therefore, this perspective article aims to define the adjustment needed from current to efficient TDM practice for cytotoxics, namely point-of-care (POC) TDM. For real-time dose adjustment, which is required for chemotherapies, such POC TDM is only achievable with analytical methods that match the sensitivity and selectivity of current methods, such as chromatography, as well as model-informed precision dosing platforms to assist the oncologist with dose fine-tuning based on quantification results and targeted intervals.

Imatinib is a targeted cancer therapy that has significantly improved the care of patients with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, it has been shown that the recommended dosages of imatinib are associated with trough plasma concentration (Cmin) lower than the target value in many patients. The aims of this study were to design a novel model-based dosing approach for imatinib and to compare the performance of this method with that of other dosing methods. Three target interval dosing (TID) methods were developed based on a previously published PK model to optimize the achievement of a target Cmin interval or minimize underexposure. We compared the performance of those methods to that of traditional model-based target concentration dosing (TCD) as well as fixed-dose regimen using simulated patients ( n = 800) as well as real patients' data ( n = 85). Both TID and TCD model-based approaches were effective with about 65% of Cmin achieving the target imatinib Cmin interval of 1000-2000 ng/mL in 800 simulated patients and more than 75% using real data. The TID approach could also minimize underexposure. The standard 400 mg/24 h dosage of imatinib was associated with only 29% and 16.5% of target attainment in simulated and real conditions, respectively. Some other fixed-dose regimens performed better but could not minimize over- or underexposure. Model-based, goal-oriented methods can improve initial dosing of imatinib. Combined with subsequent TDM, these approaches are a rational basis for precision dosing of imatinib and other drugs with exposure-response relationships in oncology.

Purpose: Assess whether full-scale simulation exercises improved hospital pharmacies' disaster preparedness., Methods: Swiss hospital pharmacies performed successive full-scale simulation exercises at least four months apart. An interprofessional team created two scenarios, each representing credible regional-scale disasters involving approximately fifty casualties (a major road accident and a terrorist attack). Four exercise assessors used appraisal forms to evaluate participants' actions and responses during the simulation (rating them using five-point Likert scales)., Results: Four hospital pharmacies performed two full-scale simulation exercises each. Differences between exercises one and two were observed. On average, the four hospitals accomplished 69% ± 6% of the actions expected of them during exercise one. The mean rate of expected actions accomplished increased to 84% ± 7% (p < 0.005) during exercise two. Moreover, the average quality of actions improved from 3.0/5 to 3.6/5 (p = 0.01), and the time required to gather a crisis management team drastically decreased between simulations (from 23 to 5 min). The main challenges were communication (reformulation) and crisis management. Simulation exercise number one resulted in three hospital pharmacies creating disaster action plans and the fourth improving its already existing plan., Conclusion: This study highlighted the value of carrying out full-scale disaster simulations for hospital pharmacies as they improved overall institutional preparedness and increased staff awareness. The number of expected actions accomplished increased significantly. In the future, large-scale studies and concept dissemination are warranted., (© 2022. The Author(s).)

Introduction: To assess the risk for COVID-19 of police officers, we are studying the seroprevalence in a cohort. The baseline cross-sectional investigation was performed before a vaccination campaign in January/February 2021, and demonstrated a seroprevalence of 12.9%. Here, we demonstrate serosurveillance results after a vaccination campaign., Methods: The cohort consists of 1022 study participants. The 3- and 6-month follow-up visits were performed in April/May and September 2021. Data on infection and vaccination rates were obtained via measuring antibodies to the nucleocapsid protein and spike protein and online questionnaires., Results: The mean age of the population was 41 (SD 8.8) years, 72% were male and 76% had no comorbidity. Seroconversion was identified in 1.05% of the study population at the 3-month visit and in 0.73% at the 6-month visit, resulting in an infection rate of 1.8% over a time period of 6 months. In comparison, the infection rate in the general population over the same time period was higher (3.18%, p = .018). At the 6-month visit, 77.8% of participants reported being vaccinated once and 70.5% twice; 81% had an anti-S antibody titer of >250 U/ml and 87.1% of ≥2 U/ml. No significant association between infection and job role within the department, working region, or years of experience in the job was found. Anti-spike antibody titers of vaccinated study participants showed a calculated decreasing trend 150-200 days after the second vaccine dose., Conclusion: These data confirm the value of the vaccination campaign in an exposed group other than healthcare professionals., (© 2022 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background: Transition between hospital and ambulatory care is a delicate step involving several healthcare professionals and presenting a considerable risk of drug-related problems., Objective: To investigate pharmaceutical interventions made on hospital discharge prescriptions by community pharmacists., Method: This observational, prospective study took place in 14 community pharmacies around a Swiss acute care hospital. We recruited patients with discharge prescriptions (minimum three drugs) from the internal medicine ward of the hospital. The main outcome measures were: number and type of pharmaceutical interventions made by community pharmacists, time spent on discharge prescriptions, number of medication changes during the transition of care., Results: The study included 64 patients discharged from the hospital. Community pharmacists made a total of 439 interventions; a mean of 6.9 ± 3.5 (range 1-16) interventions per patient. All of the discharge prescriptions required pharmaceutical intervention, and 61 (95%) necessitated a telephone call to the patients' hospital physician for clarifications. The most frequent interventions were: confirming voluntary omission of a drug (31.7%), treatment substitution (20.5%), dose adjustment (16.9%), and substitution for reimbursement issues (8.8%). Roughly half (52%) of all discharge prescriptions required 10-20 min for pharmaceutical validation. The mean number of medication changes per patient was 16.4: 9.6 changes between hospital admission and discharge, 2.6 between hospital discharge and community pharmacy, and 4.2 between community pharmacy and a general practitioner's appointment., Conclusion: Hospital discharge prescriptions are complex and present a significant risk of medication errors. Community pharmacists play a key role in preventing and identifying drug-related problems., (© 2021. The Author(s).)

Objectives: Imipenem is a broad-spectrum antibacterial agent used in critically ill neonates after failure of first-line treatments. Few studies have described imipenem disposition in this population. The objectives of our study were: (i) to characterize imipenem population pharmacokinetics (PK) in a cohort of neonates; and (ii) to conduct model-based simulations to evaluate the performance of six different dosing regimens aiming at optimizing PK target attainment., Methods: A total of 173 plasma samples from 82 neonates were collected over 15 years at the Lausanne University Hospital, Switzerland. The majority of study subjects were preterm neonates with a median gestational age (GA) of 27 weeks (range: 24-41), a postnatal age (PNA) of 21 days (2-153) and a body weight (BW) of 1.16 kg (0.5-4.1). PK data were analysed using non-linear mixed-effect modelling (NONMEM)., Results: A one-compartment model best characterized imipenem disposition. Population PK parameters estimates of CL and volume of distribution were 0.21 L/h and 0.73 L, with an interpatient variability (CV%) of 20.1% on CL in a representative neonate (GA 27 weeks, PNA 21 days, BW 1.16 kg, serum creatinine, SCr 46.6 μmol/L). GA and PNA exhibited the greatest impact on PK parameters, followed by SCr. These covariates explained 36% and 15% of interindividual variability in CL, respectively.Simulated regimens using a dose of 20-25 mg/kg every 6-12 h according to postnatal age led to the highest PTA (T>MIC over 100% of time)., Conclusions: Dosing adjustment according to BW, GA and PNA optimizes imipenem exposure in neonates., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

As the chronotype delays progressively throughout puberty, early morning school start times (SSTs) contradict the sleep biology of adolescents. Various studies have demonstrated beneficial effects of later SSTs on sleep and health; however, adolescents' preferences for SSTs have to date never been investigated in detail. The present online survey study aimed to fill this gap and explored influencing factors. A total of 17 high schools in the Canton of Zurich, Switzerland, circulated the survey among their students. Participants were included if they reported their sex, age, and school (n = 5,308). Students indicated whether they preferred later SSTs. Additionally, five predictor blocks were assessed: sociodemographic, school-related, sleep, leisure-time, and health-related characteristics. We applied multivariate logistic regression models with fixed and random effects to predict the preference. The mean (SD) age of the students was 16.09 (1.76) years (65.1% female). The majority (63.2%) endorsed later SSTs with a preferred delay of 55 min (interquartile range 25-75 min). In the multilevel analysis (n = 2,627), sex, mother tongue, sleep characteristics, mobile device use at bedtime, caffeine consumption, and health-related quality of life were significant predictors for the preference. Hence, the majority of adolescents preferred later SSTs, and especially those with sleep or health-related problems. These characteristics have been consistently shown to improve after delaying SSTs. Thus, also from adolescents' view, later SSTs should be considered to improve the adolescents' health., (© 2021 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Importance: Although negative associations of COVID-19 pandemic high school closures with adolescents' health have been demonstrated repeatedly, some research has reported a beneficial association of these closures with adolescents' sleep. The present study was, to our knowledge, the first to combine both perspectives., Objective: To investigate associations between adolescents' sleep and health-related characteristics during COVID-19 pandemic school closures in Switzerland., Design, Setting, and Participants: This survey study used cross-sectional online surveys circulated among the students of 21 public high schools in Zurich, Switzerland. The control sample completed the survey under regular, prepandemic conditions (May to July 2017) and the lockdown sample during school closures (May to June 2020). Survey respondents were included in the study if they provided their sex, age, and school., Exposures: High school closures during the first COVID-19 pandemic wave in Switzerland (March 13 to June 6, 2020)., Main Outcomes and Measures: Sleep-wake patterns, health-related quality of life (HRQoL, assessed by the KIDSCREEN-10 questionnaire), substance use (caffeine, alcohol, and nicotine), and depressive symptoms (lockdown sample only; assessed using the withdrawn/depressed scale from the Youth Self Report). Multilevel regression models were used to assess sample differences and associations of health-related characteristics with sleep duration and depressive symptoms., Results: The total sample consisted of 8972 students, including 5308 (59.2%) in the control sample (3454 [65.1%] female) and 3664 (40.8%) in the lockdown sample (2429 [66.3%] female); the median age in both samples was 16 years (IQR, 15-17 years). During school closures, the sleep period on scheduled days was 75 minutes longer (semipartial R2 statistic [R2β*], 0.238; 95% CI, 0.222-0.254; P < .001) and the students had better HRQoL (R2β*, 0.007; 95% CI, 0.004-0.012; P < .001) and less consumption of caffeine (R2β*, 0.010; 95% CI, 0.006-0.015; P < .001) and alcohol (R2β*, 0.014; 95% CI, 0.008-0.022; P < .001). Longer sleep duration was associated with better HRQoL (R2β*, 0.027; 95% CI, 0.020-0.034; P < .001) and less caffeine consumption (R2β*, 0.013; 95% CI, 0.009-0.019; P < .001). In the lockdown sample, an inverse association was found between depressive symptoms and HRQoL (R2β*, 0.285; 95% CI, 0.260-.0311; P < .001) and a positive association was found with caffeine consumption (R2β*, 0.003; 95% CI, 0.000-0.008; P = .01)., Conclusions and Relevance: In this survey study, 2 opposing associations between school closures and adolescents' health were identified: a negative association with psychological distress and a beneficial association with increased sleep duration. These findings should be considered when evaluating and implementing school closures. Furthermore, the findings provide support for delaying school start times for adolescents.

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (C max ) and trough concentration (C trough ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID-19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID-19., (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: To ensure patient safety and the preparedness of medication processes during hospital relocations and evacuations by using Failure Modes, Effects, and Criticality Analysis (FMECA)., Methods: The relocation of six regional hospitals to a single building, resulting in 400 beds being moved, could be compared with an emergency evacuation. An FMECA was performed on the hospital group's internal medicine and intensive care units (IMU and ICU), examining how medication processes would be affected by a hospital relocation or evacuation., Results: We identified 59 hospital relocation and 68 evacuation failure modes. Failure modes were ranked based on their criticality index (CI; range 1-810). The higher the CI, the greater the patient-related risk. Average initial IMU and ICU hospital relocation CI scores were 160 (range 105-294) and 201 (range 125-343), respectively, subsequently reduced to 32 (-80%) and 49 (-76%) after mitigation measures. Average initial IMU and ICU evacuation CI scores were 319 (range 245-504) and 592 (range 441-810), respectively, subsequently reduced to 194 (-39%) and 282 (-52%). Most mitigation measures (17/22), such as for example checklists, could be implemented in both situations. Due to their unpredictable nature, five measures were specific to evacuation situations., Conclusions: This study highlights the value of using an FMECA on medication processes to anticipate potential negative impacts on patient safety during hospital relocations or evacuations. Preparation for a hospital relocation can provide useful knowledge and an opportunity to test mitigation measures that might prove useful in evacuations., Competing Interests: Competing interests: PB received a grant-in-aid from the Swiss Federal Department of Defense, Civil Protection, and Sport, through the Centre of Competence for Military and Disaster Medicine., (© European Association of Hospital Pharmacists 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Documented experiences of relocating hospital pharmacies are rare, but adequate preparation is vital to ensuring smooth pharmacy operation and patient safety. In the autumn of 2019, the Pharmacy of Eastern Vaud Hospitals, composed of four units (Logistics, Manufacturing, Clinical Pharmacy, and Nursing Home Supply), was relocated to a new hospital in just a few days. In this context, a failure modes, effects and criticality analysis (FMECA) was carried out before the relocation in order to anticipate any failure modes likely to affect the pharmacy's missions or patient safety during the move., Methods: The FMECA was performed by a multidisciplinary team (pharmacists and logisticians) which analysed the complete upcoming process of relocating the pharmacy and its implications. Criticality indices (CIs) were defined based on the matrix developed by Williams et al , which sets a maximum score of 810. Every potential failure mode identified was analysed, and mitigation measures were proposed for each one., Results: The analysis identified 86 potential failures. The mean initial CI calculated for the entire pharmacy relocation was 177 (min 4-max 567), but this was estimated to be reduced to 39 (-78%) after mitigation measures were identified. Within the whole pharmacy, the failures with the highest CIs were identified in the Logistics unit. Among these, the time necessary to transfer the pharmacy's drugs from their traditional alphabetical storage location to their new location using robotic, chaotic storage principles was identified as the riskiest potential failure. Indeed, the rapid availability of emergency medicines would have to be guaranteed at all times., Conclusions: The present study highlighted the relevance of using an FMECA-type evaluation to anticipate the impact of a hospital pharmacy relocation. This tool enabled pharmacy professionals to structure their potential relocation problems and reflect on mitigation measures in order to provide concerted, realistically applicable solutions before the move., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Protests and police fieldwork provide a high-exposure environment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. In this cross-sectional analysis, we investigated the seroprevalence among a police cohort, and sociodemographic, work, and health-related factors associated with seropositivity., Methods: Study participants were invited for serological testing of SARS-CoV-2 and to complete online questionnaires. Serum neutralization titers toward the wild-type SARS-CoV-2 spike protein (expressing D614G) and the Alpha and Beta variants were measured in seropositive study participants., Results: A total of 978 police personnel representing 35% of the entire staff participated from February to March 2021. The seroprevalence was 12.9%. It varied by geographic region, ranged from 9% to 13.5% in 3 regions, including the city; and was 22% in Bernese Seeland/Jura with higher odds for seropositivity (odds ratio [OR], 2.38 [95% confidence interval {CI}, 1.28-4.44], P =.006). Job roles with mainly office activity were associated with a lower risk of seropositivity (OR, 0.33 [95% CI, .14-.77], P =.010). Self-reported compliance with mask wearing during working hours was 100%; 45% of seropositive vs 5% of seronegative participants ( P <.001) reported having had contact with a proven coronavirus disease 2019 (COVID-19) case living in the same household prior to serological testing. The level of serum antibody titers correlated with neutralization capacity. Antibodies derived from natural SARS-CoV-2 infection effectively neutralized the SARS-CoV-2 spike protein, but were less effective against the Alpha and Beta variants., Conclusions: The seroprevalence of anti-SARS-CoV-2 antibodies of police officers was comparable to that reported in the general population, suggesting that the personal protective equipment of the police is effective, and that household contacts are the leading transmission venues. The level of serum antibody titers, in particular that of anti-spike antibodies, correlated well with neutralization capacity. Low antibody titers acquired from natural infection were not effective against variants., Clinical Trials Registration: NCT04643444., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The strengthening or substitution of intravenous cytotoxic chemotherapy cycles by oral targeted anticancer therapies, such as protein kinase inhibitors (PKIs), has provided impressive clinical benefits and autonomy as well as a better quality of life for patients with cancer. Despite these advances, adverse event management at home and medication adherence remain challenging. In addition, PKI plasma concentrations vary significantly among patients with cancer receiving the same dosage, which could explain part of the observed variability in the therapeutic response., Objective: The aim of this optimizing oral targeted anticancer therapies (OpTAT) study is to optimize and individualize targeted anticancer treatments to improve patient care and self-monitoring through an interprofessional medication adherence program (IMAP) combined with measurement PKI plasma concentrations., Methods: The OpTAT study has two parts: (1) a 1:1 randomized medication adherence program, in which the intervention consists of regular motivational interviewing sessions between the patient and the pharmacist, along with the delivery of PKIs in electronic monitors, and (2) a systematic collection of blood samples and clinical and biological data for combined pharmacokinetic and pharmacodynamic analysis. On the basis of the electronic monitor data, medication adherence will be compared between groups following the three operational definitions: implementation of treatment during the persistent period, persistence with treatment and longitudinal adherence. The implementation will be described using generalized estimating equation models. The persistence of PKI use will be represented using a Kaplan-Meier survival curve. Longitudinal adherence is defined as the product of persistence and implementation. PKI pharmacokinetics will be studied using a population approach. The relationship between drug exposure and efficacy outcomes will be explored using Cox regression analysis of progression-free survival. The relationship between drug exposure and toxicity will be analyzed using a pharmacokinetic-pharmacodynamic model and by logistic regression analysis. Receiver operating characteristic analyses will be applied to evaluate the best exposure threshold associated with clinical benefits., Results: The first patient was included in May 2015. As of June 2021, 262 patients had participated in at least one part of the study: 250 patients gave at least one blood sample, and 130 participated in the adherence study. Data collection is in process, and the final data analysis is planned to be performed in 2022., Conclusions: The OpTAT study will inform us about the effectiveness of the IMAP program in patients with solid cancers treated with PKIs. It will also shed light on PKI pharmacokinetic and pharmacodynamic properties, with the aim of learning how to adapt the PKI dosage at the individual patient level to increase PKI clinical suitability. The IMAP program will enable interprofessional teams to learn about patients' needs and to consider their concerns about their PKI self-management, considering the patient as an active partner., Trial Registration: ClinicalTrials.gov NCT04484064; https://clinicaltrials.gov/ct2/show/NCT04484064., International Registered Report Identifier (irrid): DERR1-10.2196/30090., (©Carole Bandiera, Evelina Cardoso, Isabella Locatelli, Antonia Digklia, Khalil Zaman, Antonella Diciolla, Valérie Cristina, Athina Stravodimou, Aedo Lopez Veronica, Ana Dolcan, Apostolos Sarivalasis, Aikaterini Liapi, Hasna Bouchaab, Angela Orcurto, Jennifer Dotta-Celio, Solange Peters, Laurent Decosterd, Nicolas Widmer, Dorothea Wagner, Chantal Csajka, Marie Paule Schneider. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 29.06.2021.)

Objective: This study was focused on reviewing the emergency and disaster preparedness of European hospital pharmacists., Methods: An online survey based on International Pharmaceutical Federation (FIP) guidelines for natural disasters was sent to European hospital pharmacies, with the support of the European Association of Hospital Pharmacists. Additional questions were added about the characteristics of respondents, as well as preparedness and experience of manmade disasters. Descriptive statistics were used to analyze the results., Results: Hospital pharmacists in France (20%) and Spain (19%) returned most of the 306 questionnaires completed in 27 countries. Half of the respondents had analyzed their regional disaster risk, but 65% had never practiced emergency drills. Fifteen percent of respondents had experienced at least 1 major emergency or disaster event in the last 5 years. Fifty-six percent of those respondents who experienced a disaster subsequently created and promoted internal standard operating procedures (SOPs) for future emergencies, versus 23% for those who had not experienced disasters. Among pharmacists having experienced disasters, 40% organized a post-disaster debriefing to improve their future response., Conclusions: Results highlighted that most European hospital pharmacists were not fully compliant with FIP guidelines. However, respondents who had experienced disasters were more likely to create and promote SOPs for future disasters. Further worldwide analysis and benchmarking are necessary, and FIP guidelines should be more strongly promoted.

Objective: Unpredictable pharmacokinetics of antibiotics in patients with life-threatening bacterial infections is associated with drug under- or overdosing. Therapeutic drug monitoring (TDM) may guide dosing adjustment aimed at maximizing antibacterial efficacy and minimizing toxicity. Rapid and accurate analytical methods are key for real-time TDM. Our objective was to develop a robust high-performance liquid chromatography-tandem mass spectrometry method (HPLC-MS/MS) for multiplex quantification of plasma concentrations of 12 antibiotics: imipenem/cilastatin, meropenem, ertapenem, cefepime, ceftazidime, ceftriaxone, piperacillin/tazobactam, amoxicillin, flucloxacillin, rifampicin, daptomycin., Methods: A single extraction procedure consisting in methanol plasma protein precipitation and H 2 O dilution was used for all analytes. After chromatographic separation on an Acquity UPLC HSS-T3 2.1 × 50 mm, 1.8 µm (Waters®) column, quantification was performed by electro-spray ionisation-triple quadrupole mass spectrometry with selected reaction monitoring detection. Antibiotics were divided in two pools of calibration according to the frequency of analyses requests in the hospital routine antibiotic TDM program. Stable isotopically-labelled analogues were used as internal standards. A single analytical run lasted less than 9 min., Results: The method was validated based on FDA recommendations, including assessment of extraction yield (96-113.8%), matrix effects, and analytical recovery (86.3-99.6%). The method was sensitive (lower limits of quantification 0.02-0.5 µg/mL), accurate (intra/inter-assay bias -11.3 to +12.7%) and precise (intra/inter-assay CVs 2.1-11.5%) over the clinically relevant plasma concentration ranges (upper limits of quantification 20-160 µg/mL). The application of the TDM assay was illustrated with clinical cases that highlight the impact on patients' management of an analytical assay providing information with short turn-around time on antibiotic plasma concentration., Conclusion: This simple, robust high-throughput multiplex HPLC-MS/MS assay for simultaneous quantification of plasma concentrations of 12 daily used antibiotics is optimally suited for clinically efficient real-time TDM., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Nowadays, most blood products are leukocyte-reduced. After this procedure, the residual risk for transfusion transmitted cytomegalovirus (TT-CMV) is mostly attributed to cell-free viruses in the plasma of blood donors following primary infection or viral reactivation. Here, objectives are: 1) to study the behaviour of cell-free CMV through the blood component processing; 2) to determine the anti-CMV seroprevalence, the level of viremia, the window-period in blood donor population; and 3) to identify cases of TT-CMV in bone marrow transplant (BMT) recipients., Materials and Methods: Cell-free CMV was injected into blood bags originating from regular donors. Blood components were processed according to either the CompoSelect ® or the CompoFlow ® (Fresenius Kabi AG) techniques. Samples were analysed at each step for presence of virus DNA using quantitative polymerase chain reaction (PCR). The anti-CMV seroprevalence in our donor population was taken from our donor data system. The viremia was assessed in pooled plasmas samples from routine donations by quantitative PCR. Medical charts of 165 BMT anti-CMV seronegative recipients/anti-CMV seronegative donors who received CMV-unscreened blood products were reviewed., Results: Cell-free CMV passes without any decrease in viral load through all stages of blood processing. The anti-CMV seroprevalence was 46.13%. Four DNA positive samples out of 42,240 individual blood donations were identified (0.009%); all had low levels of viremia (range 11-255 IU/mL). No window-period donation was identified. No TT-CMV was found., Discussion: Cell-free CMV remains a concern with current blood component processing as it passes through all the processes. However, since low levels of CMV DNA were identified in the donations tested, and no BMT recipients had TT-CMV, the residual threat of TT-CMV after leukocyte reduction appears to be very low.

Purpose: Erlotinib is an oral first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for non-small cell lung cancers (NSCLC) with EGFR-activating mutations. Older patients experience more toxicities compared with younger patients at the standard recommended dose of 150 mg once daily. The aims of this study were to describe the pharmacokinetic profile of erlotinib in unselected patients with NSCLC, to quantify and explain its variability, to challenge the standard recommended dose in older patients, and to propose clinical recommendations for the therapeutic management of patients taking erlotinib., Methods: A population pharmacokinetic model was developed using erlotinib plasma concentrations collected from patients with NSCLC participating in a routine therapeutic drug monitoring program (with the nonlinear mixed effect modeling program NONMEM). Relevant demographic characteristics, clinical factors, and co-medications were tested as potential covariates. An independent dataset was used for model validation. Simulations based on the final model allowed comparison of expected erlotinib concentrations under standard and alternative dosing regimens for smokers and for several age groups., Findings: A total of 481 erlotinib plasma concentrations from 91 patients with NSCLC were used for model building and 239 plasma drug concentrations from 107 patients for model validation. A one-compartment model with first-order absorption and elimination provided the best fit. Average erlotinib CL/F with interindividual variability (%CV) was 3.8 L/h (41.5%), and V/F was 166 L (53.8%). The absorption rate constant was 1.48 h -1 . The external validation showed a negligible bias of -4% (95% CI, -7 to -1) in the individual predictions, with a precision of 23%. Current smoking and use of proton pump inhibitors were associated with higher CL/F, whereas age was associated with lower CL/F. Simulations suggest that a lower dose in older patients would decrease the risk of overexposure., Implications: This large cohort study confirms the substantial interindividual variability in erlotinib plasma exposure and the impact of smoking and proton pump inhibitor intake. This large variability in erlotinib pharmacokinetics indicates that the standard recommended dose of 150 mg once daily is likely not appropriate to reach the expected concentrations in each patient. Concentration monitoring should be performed to individually adjust the erlotinib dosing regimen. The observed decrease in erlotinib CL/F with age suggests that a lower starting daily dose of 100 mg with concentration-guided dose adjustment would prevent overexposure and potential toxicity in older frail patients with co-morbidities., (Copyright © 2020. Published by Elsevier Inc.)

Pharmacometric methods have hugely benefited from progress in analytical and computer sciences during the past decades, and play nowadays a central role in the clinical development of new medicinal drugs. It is time that these methods translate into patient care through therapeutic drug monitoring (TDM), due to become a mainstay of precision medicine no less than genomic approaches to control variability in drug response and improve the efficacy and safety of treatments. In this review, we make the case for structuring TDM development along five generic questions: 1) Is the concerned drug a candidate to TDM? 2) What is the normal range for the drug's concentration? 3) What is the therapeutic target for the drug's concentration? 4) How to adjust the dosage of the drug to drive concentrations close to target? 5) Does evidence support the usefulness of TDM for this drug? We exemplify this approach through an overview of our development of the TDM of imatinib, the very first targeted anticancer agent. We express our position that a similar story shall apply to other drugs in this class, as well as to a wide range of treatments critical for the control of various life-threatening conditions. Despite hurdles that still jeopardize progress in TDM, there is no doubt that upcoming technological advances will shape and foster many innovative therapeutic monitoring methods., (Copyright © 2020 Buclin, Thoma, Widmer, André, Guidi, Csajka and Decosterd.)

Background: Therapeutic response to oral targeted anticancer protein kinase inhibitors (PKIs) varies widely between patients, with insufficient efficacy of some of them and unacceptable adverse reactions of others. There are several possible causes for this heterogeneity, such as pharmacokinetic (PK) variability affecting blood concentrations, fluctuating medication adherence, and constitutional or acquired drug resistance of cancer cells. The appropriate management of oncology patients with PKI treatments thus requires concerted efforts to optimize the utilization of these drug agents, which have probably not yet revealed their full potential., Methods: An extensive literature review was performed on MEDLINE on the PK, pharmacodynamics, and therapeutic drug monitoring (TDM) of PKIs (up to April 2019)., Results: This review provides the criteria for determining PKIs suitable candidates for TDM (eg, availability of analytical methods, observational PK studies, PK-pharmacodynamics relationship analysis, and randomized controlled studies). It reviews the major characteristics and limitations of PKIs, the expected benefits of TDM for cancer patients receiving them, and the prerequisites for the appropriate utilization of TDM. Finally, it discusses various important practical aspects and pitfalls of TDM for supporting better implementation in the field of cancer treatment., Conclusions: Adaptation of PKIs dosage regimens at the individual patient level, through a rational TDM approach, could prevent oncology patients from being exposed to ineffective or unnecessarily toxic drug concentrations in the era of personalized medicine.

The use of DNA aptamers in biosensors for the quantification of pharmaceuticals in the clinics would help to overcome the limitations of antibody-based detection for small molecules. The interest for such systems is proven by the ever-increasing number of aptamer-based solutions for analytics proposed in the literature as proof-of-concept demonstrators. Despite such diversity, these platforms often lack a comparative assessment of their performances against the current standard of practice in the clinics when using real samples. We employed an aptamer against tobramycin discovered in our laboratory to quantify through surface plasmon resonance the concentration of the antibiotic in clinical samples obtained from patients treated with tobramycin and undergoing therapeutic drug monitoring. We then compared the performances of our detection strategy against the current standard of practice. Our results show how, using adequate calibration and matrix complexity reduction, DNA aptamer-based direct assays can assess clinically relevant concentrations of small molecules in patient serum and with good correlation to current standards used in the clinics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and aimHepatitis E virus (HEV) is a virus of emerging importance to transfusion medicine. Studies from several European countries, including Switzerland, have reported high seroprevalence of hepatitis E as a consequence of endemic infections. Published HEV seroprevalence estimates within developed countries vary considerably; primarily due to improved diagnostic assays. The purpose of this study was to investigate the seroprevalence of anti-HEV IgG in Swiss blood donations. Methods: We used the highly sensitive Wantai HEV IgG EIA and assessed regional distribution patterns. We analysed age- and sex-matched archive plasma dating back 20 years from canton Bern to investigate recent changes in HEV seroprevalence levels. Results: On average, 20.4% (95% confidence intervals: 19.1-21.8) of the 3,609 blood samples collected in 2014-16 were anti-HEV IgG positive; however, distinct differences between geographical regions were observed (range: 12.8-33.6%). Seroprevalence increased with age with 30.7% of males and 34.3% of women being positive donors over > 60 years old. Differences between sexes may be attributed to dissimilarities in the average age of this group. Within the specified region of the Bern canton, overall prevalence has declined over two decades from 30.3% in 1997/98 to 27.0% in 2006 and 22.3% in 2015/6. Conclusions: HEV seroprevalence in Switzerland is high, but has declined over the last decades. The result shows that primarily endemic HEV infections occur and that current blood products may pose a risk to vulnerable transfusion recipients. Nucleic acid screening of all blood products for HEV will begin in November 2018.

Self-reported social mixing patterns are commonly used in mathematical models of infectious diseases. It is particularly important to quantify patterns for school-age children given their disproportionate role in transmission, but it remains unclear how the structure of such social interactions changes over time. By integrating data collection into a public engagement programme, we examined self-reported contact networks in year 7 groups in four UK secondary schools. We collected data from 460 unique participants across four rounds of data collection conducted between January and June 2015, with 7,315 identifiable contacts reported in total. Although individual-level contacts varied over the study period, we were able to obtain out-of-sample accuracies of more than 90% and F-scores of 0.49-0.84 when predicting the presence or absence of social contacts between specific individuals across rounds of data collection. Network properties such as clustering and number of communities were broadly consistent within schools between survey rounds, but varied significantly between schools. Networks were assortative according to gender, and to a lesser extent school class, with the estimated clustering coefficient larger among males in all surveyed co-educational schools. Our results demonstrate that it is feasible to collect longitudinal self-reported social contact data from school children and that key properties of these data are consistent between rounds of data collection., Competing Interests: The authors have declared that no competing interests exist.

A sensitive and selective method of high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS) has been developed for the simultaneous quantification of six anticancer protein kinase inhibitors (PKIs), dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib, and two active metabolites (regorafenib-M2 and regorafenib-M5) in human plasma. Plasma protein precipitation with methanol enables the sample extraction of 100 μL aliquot of plasma. Analytes are detected by electrospray triple-stage quadrupole mass spectrometry and quantified using the calibration curves with stable isotope-labeled internal standards. The method was validated based on FDA recommendations, including assessment of extraction yield (74-104%), matrix effects, analytical recovery (94-104%) with low variability (<15%). The method is sensitive (lower limits of quantification within 1 to 200 ng/mL), accurate (intra- and inter-assay bias: -0.3% to +12.7%, and -3.2% to +6.3%, respectively) and precise (intra- and inter-assay CVs within 0.7-7.3% and 2.5-8.0%, respectively) over the clinically relevant concentration range (upper limits of quantification 500 to 100,000 ng/mL). This method is applied in our laboratory for both clinical research programs and routine therapeutic drug monitoring service of PKIs., (Copyright © 2018. Published by Elsevier B.V.)

The emergence of oral targeted anticancer agents transformed several cancers into chronic conditions with a need for long-term oral treatment. Although cancer is a life-threatening condition, oncology medication adherence-the extent to which a patient follows the drug regimen that is intended by the prescriber-can be suboptimal in the long term, as in any other chronic disease. Poor adherence can impact negatively on clinical outcomes, notably because most of these drugs are given as a standard non-individualized dosage despite marked inter-individual variabilities that can lead to toxic or inefficacious drug concentrations. This has been especially studied with the prototypal drug imatinib. In the context of therapeutic drug monitoring (TDM), increasingly advocated for oral anticancer treatment optimization, unreported suboptimal adherence affecting drug intake history may lead to significant bias in the concentration interpretation and inappropriate dosage adjustments. In the same way, suboptimal adherence may also bias the results of pharmacokinetic modeling studies, which will affect in turn Bayesian TDM interpretation that relies on such population models. Detailed knowledge of the influence of adherence on plasma concentrations in pharmacokinetic studies or in routine TDM programs is however presently missing in the oncology field. Studies on this topic are therefore eagerly awaited to better pilot the treatment of cancer with the new targeted agents and to find their optimal dosage regimen. Hence, the development and assessment of effective medication adherence programs are warranted for these treatments.

Background: In recent years, the number of prescriptions for sedative drugs has increased significantly, as has their long-term use. Moreover, sedative use is frequently initiated during hospital stays., Objectives: This study aimed to describe new prescriptions of sedative drugs during hospital stays and evaluate their maintenance as discharge medication., Methods: This observational prospective study took place in an internal medicine ward of a Swiss hospital over a period of 3 months in 2014. Demographic (age, sex, diagnosis, comorbidities) and medication data [long-term use of sedative drugs, new regular or pro re nata ('as needed') prescriptions of sedative drugs, drug-related problems] were collected. Sedative medications included: benzodiazepines, Z-drugs, antihistamines, antidepressants, neuroleptics, herbal drugs, and clomethiazole. McNemar's test was used for comparison., Results: Of 290 patients included, 212 (73%) were over 65 years old and 169 (58%) were women; 34% (n = 98) were using sedative drugs long term before their hospital stay, and 44% (n = 128) had a prescription for sedative drugs at discharge-a 10% increase (p < 0.05). Sedative drugs were newly prescribed to 37% (n = 108) of patients during their stay. Among these, 37% (n = 40) received a repeat prescription at discharge. Over half of the sedative drugs were prescribed within 24 h of admission. Drug-related problems were detected in 76% of new prescriptions, of which 90% were drug-drug interactions., Conclusion: This study showed that hospital stays increased the proportion of patients who were prescribed a sedative drug at discharge by 10% (absolute increase). These prescriptions may generate long-term use and expose patients to drug-related problems. Promoting alternative approaches for managing insomnia are recommended.

Background: Continuity of care between hospitals and community pharmacies needs to be improved to ensure medication safety. This study aimed to evaluate whether a set of pharmaceutical interventions to prepare hospital discharge facilitates the transition of care., Methods: This study took place in the internal medicine ward and in surrounding community pharmacies. The intervention group's patients underwent a set of pharmaceutical interventions during their hospital stay: medication reconciliation at admission, medication review, and discharge planning. The two groups were compared with regards to: number of community pharmacist interventions, time spent on discharge prescriptions, and number of treatment changes., Results: Comparison between the groups showed a much lower (77% lower) number of community pharmacist interventions per discharge prescription in the intervention (n=54 patients) compared to the control group (n=64 patients): 6.9 versus 1.6 interventions, respectively (p<0.0001); less time working on discharge prescriptions; less interventions requiring a telephone call to a hospital physician. The number of medication changes at different steps was also significantly lower in the intervention group: 40% fewer (p<0.0001) changes between hospital admission and discharge, 66% fewer (p<0.0001) between hospital discharge and community pharmacy care, and 25% fewer (p=0.002) between community pharmacy care and care by a general practitioner., Conclusion: An intervention group underwent significantly fewer medication changes in subsequent steps in the transition of care after a set of interventions performed during their hospital stay. Community pharmacists had to perform fewer interventions on discharge prescriptions. Altogether, this improves continuity of care., (Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: During clinical trials, researchers rarely question nominal doses specified on labels of investigational products, overlooking the potential for inaccuracies that may result when calculating pharmacokinetic and pharmacodynamic parameters. This study evaluated the disparity between nominal doses and the doses actually administered in two Phase I trials of a biosimilar drug., Methods: In Trial A, 12 healthy volunteers received various doses of an interferon β-1a biosimilar via either subcutaneous or intravenous injection, prepared by partially emptying 0.53 ml syringes supplied by the manufacturer. In Trial B, 12 volunteers received three different formulations of the drug via intravenous injection (biosimilar with and without albumin and a comparator), followed by multiple subcutaneous injections. In both trials, the dose administered was calculated as D = C × V - losses, where C is the drug concentration assessed using ELISA, V is the volume administered calculated using syringe weighing and losses are deduced from in-vitro experiments. Interferon binding to added albumin and infusion lines was evaluated using a (125)I-interferon tracer with gel-filtration chromatography., Results: In Trial A, measured concentrations were close to the nominal strength indicated by the manufacturer (median bias: -6 %), whereas in Trial B they differed significantly for all three formulations (median biases: +67 %, +73 % and +31 % for the biosimilar with albumin, the biosimilar without albumin and the comparator, respectively). In Trial A, the doses actually administered showed large variability and biases, especially at the lowest doses. Indeed, actually injected volumes differed by as much as 74 % from theoretical volumes - a phenomenon mainly attributed to unnoticed fluid re-aspiration through the syringe needle. This was corrected in Trial B. Interferon was not significantly adsorbed on the infusion lines used for intravenous administration. Its binding to albumin was slow, reaching 50 % after a 16 h incubation., Conclusions: These examples illustrate the importance of assessing the actual doses administered in clinical trials, to ensure accuracy in the determination of clearance, distribution volume, bioavailability and dose-response relationships., Trial Registration: Clinicaltrials.gov NCT02515695 (Trial A) and NCT02517788 (Trial B). Registered on 24 July and 5 August 2015, respectively.

There is significant interindividual variation in acute mountain sickness (AMS) susceptibility in humans. To identify genes related to AMS susceptibility, we used a genome-wide association study (GWAS) to simultaneously test associations between genetic variants dispersed throughout the genome and the presence and severity of AMS. DNA samples were collected from subjects who ascended rapidly to Gosainkunda, Nepal (4380 m), as part of the 2005, 2010, and 2012 Janai Purnima festivals. The Lake Louise Score was used to measure AMS severity. The primary analysis was based on 99 male subjects (43 with AMS; 56 without AMS). Genotyping for the GWAS was performed using Infinium Human Core Exome Bead Chips (542,556 single-nucleotide polymorphisms were assayed), and validation genotyping was performed with pyrosequencing in two additional cohorts (n = 101 for each). In total, 270,389 single nucleotide polymorphisms (SNPs) passed quality control, and 4 SNPs (one intronic, three nonsynonymous) in the FAM149A gene were associated with AMS severity after correcting for multiple hypothesis testing (p = 1.8E-7); however, in the validation cohorts, FAM149A was not associated with the presence or severity of AMS. No other genes were associated with AMS susceptibility at the genome-wide level. Due to the large influence of environmental factors (i.e., ascent rate and altitude attained) and the difficulties associated with the AMS phenotype (i.e., low repeatability, nonspecific symptoms, potentially independent ailments), we suggest that future studies addressing the variation in the acute human hypoxia response should focus on objective responses to acute hypoxia instead of AMS.

Erlotinib is currently marketed at fixed standard dosage against pancreatic cancer and non-small-cell lung carcinoma. However, erlotinib pharmacokinetics (PK) is characterized by significant variability that may affect efficacy and tolerability. The aim of this review is to assess evidence that would justify therapeutic drug monitoring (TDM) and provide key information for the interpretation of erlotinib plasma concentrations. Literature was systematically reviewed to evaluate the standard criteria defining the potential clinical usefulness of TDM. Assessment was focused on the existence of unpredictable and wide PK variability and of consistent PK-pharmacodynamic relationships. PK parameters actually show marked variability (apparent clearance estimated to 4.85 ± 4.71 L/h, elimination half-life to 21.86 ± 28.35 hours, and apparent volume of distribution to 208 ± 133 L). Many covariates influence these parameters (CYP3A4 inducers or inhibitors, food, age, liver impairment), but most sources of variability still have to be identified. Some studies have demonstrated a relationship between exposure to erlotinib and clinical outcomes or skin toxicity. Erlotinib activity and target concentrations furthermore depend on tumor characteristics (eg, mutations on epidermal growth factor receptor and on K-ras). These results are in favor of TDM in addition to treatment adjustment for tumor biomarkers, but prospective clinical trials validating its clinical benefits are lacking. This review provides all the relevant information available to assist clinical interpretation of erlotinib plasma measurements. PK percentile curves and consideration to covariates yield information on whether a concentration measured is expected, whereas half maximal inhibitory concentration values determined in vitro provide preliminary insights on target concentration values to reach. Eventually, dosage adaptation might be considered in patients with intolerable toxicity because of excessive plasma levels or conversely nonresponse imputable to insufficient exposure.

New oral targeted anticancer therapies are revolutionizing cancer treatment by transforming previously deadly malignancies into chronically manageable conditions. Nevertheless, drug resistance, persistence of cancer stem cells, and adverse drug effects still limit their ability to stabilize or cure malignant diseases in the long term. Response to targeted anticancer therapy is influenced by tumor genetics and by variability in drug concentrations. However, despite a significant inter-patient pharmacokinetic variability, targeted anticancer drugs are essentially licensed at fixed doses. Their therapeutic use could however be optimized by individualization of their dosage, based on blood concentration measurements via the therapeutic drug monitoring (TDM). TDM can increase the probability of therapeutic responses to targeted anticancer therapies, and would help minimize the risk of major adverse reactions.

Purpose: This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM)., Methods: Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395)., Results: Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml)., Conclusions: This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.

Aim: This study aims to investigate the clinical and demographic factors influencing gentamicin pharmacokinetics in a large cohort of unselected premature and term newborns and to evaluate optimal regimens in this population., Methods: All gentamicin concentration data, along with clinical and demographic characteristics, were retrieved from medical charts in a Neonatal Intensive Care Unit over 5 years within the frame of a routine therapeutic drug monitoring programme. Data were described using non-linear mixed-effects regression analysis ( nonmem®)., Results: A total of 3039 gentamicin concentrations collected in 994 preterm and 455 term newborns were included in the analysis. A two compartment model best characterized gentamicin disposition. The average parameter estimates, for a median body weight of 2170 g, were clearance (CL) 0.089 l h(-1) (CV 28%), central volume of distribution (Vc ) 0.908 l (CV 18%), intercompartmental clearance (Q) 0.157 l h(-1) and peripheral volume of distribution (Vp ) 0.560 l. Body weight, gestational age and post-natal age positively influenced CL. Dopamine co-administration had a significant negative effect on CL, whereas the influence of indomethacin and furosemide was not significant. Both body weight and gestational age significantly influenced Vc . Model-based simulations confirmed that, compared with term neonates, preterm infants need higher doses, superior to 4 mg kg(-1) , at extended intervals to achieve adequate concentrations., Conclusions: This observational study conducted in a large cohort of newborns confirms the importance of body weight and gestational age for dosage adjustment. The model will serve to set up dosing recommendations and elaborate a Bayesian tool for dosage individualization based on concentration monitoring., (© 2014 The British Pharmacological Society.)

Objectives: Darunavir is a protease inhibitor that is administered with low-dose ritonavir to enhance its bioavailability. It is prescribed at standard dosage regimens of 600/100 mg twice daily in treatment-experienced patients and 800/100 mg once daily in naive patients. A population pharmacokinetic approach was used to characterize the pharmacokinetics of both drugs and their interaction in a cohort of unselected patients and to compare darunavir exposure expected under alternative dosage regimens., Methods: The study population included 105 HIV-infected individuals who provided darunavir and ritonavir plasma concentrations. Firstly, a population pharmacokinetic analysis for darunavir and ritonavir was conducted, with inclusion of patients' demographic, clinical and genetic characteristics as potential covariates (NONMEM(®)). Then, the interaction between darunavir and ritonavir was studied while incorporating levels of both drugs into different inhibitory models. Finally, model-based simulations were performed to compare trough concentrations (Cmin) between the recommended dosage regimen and alternative combinations of darunavir and ritonavir., Results: A one-compartment model with first-order absorption adequately characterized darunavir and ritonavir pharmacokinetics. The between-subject variability in both compounds was important [coefficient of variation (CV%) 34% and 47% for darunavir and ritonavir clearance, respectively]. Lopinavir and ritonavir exposure (AUC) affected darunavir clearance, while body weight and darunavir AUC influenced ritonavir elimination. None of the tested genetic variants showed any influence on darunavir or ritonavir pharmacokinetics. The simulations predicted darunavir Cmin much higher than the IC50 thresholds for wild-type and protease inhibitor-resistant HIV-1 strains (55 and 550 ng/mL, respectively) under standard dosing in >98% of experienced and naive patients. Alternative regimens of darunavir/ritonavir 1200/100 or 1200/200 mg once daily also had predicted adequate Cmin (>550 ng/mL) in 84% and 93% of patients, respectively. Reduction of darunavir/ritonavir dosage to 600/50 mg twice daily led to a 23% reduction in average Cmin, still with only 3.8% of patients having concentrations below the IC50 for resistant strains., Conclusions: The important variability in darunavir and ritonavir pharmacokinetics is poorly explained by clinical covariates and genetic influences. In experienced patients, treatment simplification strategies guided by drug level measurements and adherence monitoring could be proposed., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Most of oral targeted therapies are tyrosine kinase inhibitors (TKIs). Oral administration generates a complex step in the pharmacokinetics (PK) of these drugs. Inter-individual PK variability is often large and variability observed in response is influenced not only by the genetic heterogeneity of drug targets, but also by the pharmacogenetic background of the patient (e.g. cytochome P450 and ABC transporter polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure, reflected in the area under the plasma concentration-time curve (AUC) correlates with treatment response (efficacy/toxicity) in various cancers. Nevertheless levels of evidence for therapeutic drug monitoring (TDM) are however heterogeneous among these agents and TDM is still uncommon for the majority of them. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and/or concerns over adherence treatment. Interpatient PK variability observed with monoclonal antibodies (mAbs) is comparable or slightly lower to that observed with TKIs. There are still few data with these agents in favour of TDM approaches, even if data showed encouraging results with rituximab, cetuximab and bevacizumab. At this time, TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Most anticancer drugs are characterised by a steep dose-response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target ranges, common use of combination chemotherapies for many tumour types, analytical challenges with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials and 'Day1 = Day21' administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in paediatric oncology represents an important challenge. Established TDM approaches includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration-effect relationships and to utilise tools such as population PK/PD models and comparative randomised trials of classic dosing versus pharmacokinetically guided adaptive dosing. There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

This observational study analyzed imatinib pharmacokinetics and response in 2478 chronic myeloid leukemia (CML) patients. Data were obtained through centralized therapeutic drug monitoring (TDM) at median treatment duration of ≥ 2 years. First, individual initial trough concentrations under 400mg/day imatinib starting dose were estimated. Second, their correlation (Cmin(400mg)) with reported treatment response was verified. Low imatinib levels were predicted in young male patients and those receiving P-gp/CYP3A4 inducers. These patients had also lower response rates (7% lower 18-months MMR in male, 17% lower 1-year CCyR in young patients, Kaplan-Meier estimates). Time-point independent multivariate regression confirmed a correlation of individual Cmin(400mg) with response and adverse events. Possibly due to confounding factors (e.g. dose modifications, patient selection bias), the relationship seemed however flatter than previously reported from prospective controlled studies. Nonetheless, these observational results strongly suggest that a subgroup of patients could benefit from early dosage optimization assisted by TDM, because of lower imatinib concentrations and lower response rates., (Copyright © 2014 Elsevier Ltd. All rights reserved.)