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Background: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19., Methods: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort., Results: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively)., Conclusions: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19., Competing Interests: Conflicts of interest: The authors declare no potential conflicts of interest., (Copyright ©The authors 2023.)

Background The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA-IMT was 0.71 mm (SD, 0.17 mm). Over a median follow-up of 5.9 years (5th-95th percentile, 1.9-19.0 years), 8278 individuals developed first-ever carotid plaque. We combined study-specific odds ratios (ORs) for incident carotid plaque using random-effects meta-analysis. Baseline CCA-IMT was approximately log-linearly associated with the odds of developing carotid plaque. The age-, sex-, and trial arm-adjusted OR for carotid plaque per SD higher baseline CCA-IMT was 1.40 (95% CI, 1.31-1.50; I 2 =63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low- and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication was 1.34 (95% CI, 1.24-1.45; I 2 =59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29-1.47]; I 2 =57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large-scale individual participant data meta-analysis demonstrated that CCA-IMT is associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors.

The relationship between race and biology is complex. In contemporary medical science, race is a social construct that is measured via self-identification of study participants. But even though race has no biological essence, it is often used as variable in medical guidelines (e.g., treatment recommendations specific for Black people with hypertension). Such recommendations are based on clinical trials in which there was a significant correlation between self-identified race and actual, but often unmeasured, health-related factors such as (pharmaco)genetics, diet, sun exposure, etc. Many teachers are insufficiently aware of this complexity. In their classes, they (unintentionally) portray self-reported race as having a biological essence. This may cause students to see people of shared race as biologically or genetically homogeneous, and believe that race-based recommendations are true for all individuals (rather than reflecting the average of a heterogeneous group). This medicalizes race and reinforces already existing healthcare disparities. Moreover, students may fail to learn that the relation between race and health is easily biased by factors such as socioeconomic status, racism, ancestry, and environment and that this limits the generalizability of race-based recommendations. We observed that the clinical case vignettes that we use in our teaching contain many stereotypes and biases, and do not generally reflect the diversity of actual patients. This guide, written by clinical pharmacology and therapeutics teachers, aims to help our colleagues and teachers in other health professions to reflect on and improve our teaching on race-based medical guidelines and to make our clinical case vignettes more inclusive and diverse., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: We investigated if the addition of an inter-professional student-led medication review team (ISP-team) to standard care can increase the number of detected ADRs and reduce the number of ADRs 3 months after an outpatient visit., Research Design and Methods: In this controlled clinical trial, patients were allocated to standard care (control group) or standard care plus the ISP team (intervention group). The ISP team consisted of medical and pharmacy students and student nurse practitioners. The team performed a structured medication review and adjusted medication to reduce the number of ADRs. Three months after the outpatient visit, a clinical pharmacologist who was blinded for allocation performed a follow-up telephone interview to determine whether patients experienced ADRs., Results: During the outpatient clinic visit, significantly more (p < 0.001) ADRs were detected in the intervention group (n = 48) than in the control group (n = 10). In both groups, 60-63% of all detected ADRs were managed. Three months after the outpatient visit, significantly fewer (predominantly mild and moderately severe) ADRs related to benzodiazepine derivatives and antihypertensive causing dizziness were detected in the patients of the intervention group., Conclusions: An ISP team in addition to standard care increases the detection and management of ADRs in elderly patients resulting in fewer mild and moderately severe ADRs.

Surveillance data and literature have shown a worldwide increase in infections with resistant bacteria, which has led to increased prescriptions of carbapenems, which in turn has led to increased carbapenem resistance. There is also an increasing use of carbapenems in the Netherlands, a county usually very conservative in antibiotic use. Carbapenem sparing strategies are essential in an attempt to prevent further rise of infections caused by carbapenem resistant bacteria. This article discusses carbapenem sparing strategies with old forgotten antibiotics and novel antibiotics from a Dutch perspective.

The European Open Platform for Prescribing Education (EurOP 2 E) seeks to improve and harmonize European clinical pharmacology and therapeutics (CPT) education by facilitating international collaboration and sharing problem-based, online, open educational resources. The COVID-19 pandemic forced teachers to switch to virtual modalities, highlighting the need for high-quality online teaching materials. The goal of this study was to establish the online problem-based teaching resources needed to sustain prescribing education during the pandemic and thereafter. A nominal group technique study was conducted with prescribing teachers from 15 European countries. Results were analyzed through thematic analysis. In four meetings, 20 teachers from 15 countries proposed and ranked 35 teaching materials. According to the participants, the most necessary problem-based-online teaching materials related to three overarching themes. Related to learning outcomes for CPT, participants proposed creating prescription scenarios, including materials focusing on background knowledge and resources on personalized medicine and topical/ethical issues such as the prescription's impact on planetary health. Second, related to teaching, they proposed online case discussions, gamification and decision support systems. Finally, in relation to faculty development, they recommend teacher courses, a repository of reusable exam questions and harmonized formularies. Future work will aim to collaboratively produce such materials., (© 2022. The Author(s).)

Background: Early antibiotic discontinuation has been advocated in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia, but its safety is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment., Methods: This non-inferiority, open-label, multicentre, randomised trial was done in six hospitals in the Netherlands. Adult patients (≥18 years) who were treated with intensive chemotherapy or haematopoietic stem-cell transplantation (HSCT) for a haematological malignancy, and had fever of unknown origin during high-risk neutropenia (<0·5 × 10 9 /L expected for ≥7 days) were eligible. After onset of fever, patients received either 500 mg intravenous imipenem-cilastatin four times a day or 1000 mg intravenous meropenem three times a day. Between 48 h and 72 h of treatment, participants were randomly assigned (1:1) by a computer-generated sequence to receive a short-term (72 h [60-84]; short treatment group) or extended (≥9 days until being afebrile for 5 days or neutrophil recovery; extended treatment group) carbapenem regimen. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock or respiratory failure or death from day 4 until neutrophil recovery. The study was designed to assess the non-inferiority of the short treatment compared with the extended treatment regimen, with a non-inferiority margin of 10%. The primary outcome was adjudicated by an independent outcome committee, who were masked to treatment allocation, and was analysed in the intention-to-treat and per-protocol populations. The trial is completed and registered with ClinicalTrials.gov, NCT02149329., Findings: Between Dec 1, 2014, and July 1, 2019, 281 patients were included in the intention-to-treat analysis: 144 (51%) patients were assigned to the short treatment group and 137 (49%) to the extended treatment group. Median age was 59 years (IQR 52-65); 109 (39%) patients were women and 172 (61%) were men; 205 (73%) patients received HSCT. In the intention-to-treat analysis, 28 (19%) of 144 patients in the short treatment group versus 21 (15%) of 137 patients in the extended treatment group had treatment failure (adjusted risk difference [ARD] 4·0% [90% CI -1·7% to 9·7%]; p=0·25). In the per-protocol analysis (n=225), 24 (23%) of 104 patients in the short treatment group and 19 (16%) of 121 patients in the extended treatment group had treatment failure (ARD 7·3% [0·3% to 14·9%]; p=0·11). The most common grade 3-5 infection-related adverse events were mucositis (23 [20%] of 114 adverse events in the short treatment group vs 28 [29%] of 98 adverse events in the extended treatment group), fever of unknown origin (20 [18%] vs 16 [16%] events), and bacteraemia (15 [13%] vs 13 [13%] events). The number of serious adverse events were higher in the short treatment group (23 [16%] of 144 patients) than in the extended treatment group (14 [10%] of 137 patients), due to an increased rate of readmission (17 [12%] patients in the short treatment group vs ten [7%] in the extended treatment group). Death before 30 days after neutrophil recovery occurred in five (3%) participants in the short treatment group: two due to progressive leukaemia, two due to candidaemia, and one due to Enterococcus faecium bacteraemia and drug-induced pneumonitis. One (1%) patient died in the extended treatment group due to candidaemia. None of the deaths were related to carbapenem-sensitive infections., Interpretation: Early discontinuation of carbapenem treatment in patients with febrile neutropenia of unknown origin does not result in increased treatment failure. Our study supports short treatment if patients are afebrile after 3 days of carbapenem treatment. However, because secondary analyses suggested that serious adverse events and all-cause mortality occurred more often in patients who are persistantly febrile the short treatment group, we recommend vigilance for non-susceptible pathogens and early resumption of empirical therapy in patients who are deteriorating., Funding: The Netherlands Organisation for Health Research and Development and Fonds NutsOhra., Competing Interests: Declaration of interests NAdJ, JJS, SZ, AB, PY, AHH, WV, AdK, JLLMC, BL-W, MHHK, MAvA, and JJWMJ received grants from ZonMw and Fonds NutsOhra for the execution of this study. We declare no other competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Neurological monitoring in sedated Intensive Care Unit patients is constrained by the lack of reliable blood-based biomarkers. Neurofilament light is a cross-disease biomarker for neuronal damage with potential clinical applicability for monitoring Intensive Care Unit patients. We studied the trajectory of neurofilament light over a month in Intensive Care Unit patients diagnosed with severe COVID-19 and explored its relation to clinical outcomes and pathophysiological predictors. Data were collected over a month in 31 Intensive Care Unit patients (166 plasma samples) diagnosed with severe COVID-19 at Amsterdam University Medical Centre, and in the first week after emergency department admission in 297 patients with COVID-19 (635 plasma samples) admitted to Massachusetts General hospital. We observed that Neurofilament light increased in a non-linear fashion in the first month of Intensive Care Unit admission and increases faster in the first week of Intensive Care Unit admission when compared with mild-moderate COVID-19 cases. We observed that baseline Neurofilament light did not predict mortality when corrected for age and renal function. Peak neurofilament light levels were associated with a longer duration of delirium after extubation in Intensive Care Unit patients. Disease severity, as measured by the sequential organ failure score, was associated to higher neurofilament light values, and tumour necrosis factor alpha levels at baseline were associated with higher levels of neurofilament light at baseline and a faster increase during admission. These data illustrate the dynamics of Neurofilament light in a critical care setting and show associations to delirium, disease severity and markers for inflammation. Our study contributes to determine the clinical utility and interpretation of neurofilament light levels in Intensive Care Unit patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Excessive and inappropriate use of antibiotics is the most important driver of antimicrobial resistance. The aim of the HAPPY PATIENT project is to evaluate the adaptation of European Union (EU) recommendations on the prudent use of antimicrobials in human health by evaluating the impact of a multifaceted intervention targeting different categories of healthcare professionals (HCPs) on common community-acquired infectious diseases, especially respiratory and urinary tract infections., Methods/design: HAPPY PATIENT was initiated in January 2021 and is planned to end in December 2023. The partners of this project include 15 organizations from 9 countries. Diverse HCPs (doctors, nurses, pharmacists, and pharmacy technicians) will be audited by the Audit Project Odense (APO) method before and after an intervention in four different settings: general practice, out of hours services, nursing homes and community pharmacies in four high antibiotic prescribing countries (France, Poland, Greece, and Spain) and one low prescribing country (Lithuania). About 25 individuals from each professional group will be recruited in each country, who will register at least 25 patients with community-acquired infections during each audit period. Shortly before the second registration participants will undertake a multifaceted intervention and will receive the results from the first registration to allow the identification of possible quality problems. At these meetings participants will receive training courses on enhancement of communication skills, dissemination of clinical guidelines with recommendations for diagnosis and treatment, posters for the waiting rooms, and leaflets for patients. The results of the second registration will be compared with those obtained in the first audit., Discussion: HAPPY PATIENT is an EU-funded project aimed at contributing to the battle against antibiotic resistance through improvement of the quality of management of common community-acquired infections based on interventions by different types of HCPs. It is hypothesized that the use of multifaceted strategies combining active intervention will be effective in reducing inappropriate prescribing and dispensing of antibiotics., Study Registration: EU Health programmes project database https://webgate.ec.europa.eu/chafea&#95;pdb/health/projects/900024/summary ; date of registration: 1 January 2021., (© 2022. The Author(s).)

Purpose: Polypharmacy is a known risk factor for potentially inappropriate prescribing. Recently there is an increasing interest in clinical decision support systems (CDSS) to improve prescribing. The objective of this study was to evaluate the impact of a CDSS, with the START-STOPP criteria as main content in the setting of a geriatric ward. Endpoints were 1) appropriateness of prescribing and 2) acceptance rate of recommendations. Methods: This prospective study comparing the use of a CDSS with usual care involved patients admitted to geriatric wards in two teaching hospitals in the Netherlands. Patients were included from January to May 2017. The medications of 64 patients in the first six weeks was assessed according to the current standard, whereas the medications of 61 patients in the second six weeks were also assessed by using a CDSS. Medication appropriateness was assessed with the Medication Appropriateness Index (MAI). Results: The medications of 125 patients (median age 83 years) were reviewed. In both the usual care group and the intervention group MAI scores decreased significantly from admission to discharge (within group analyses, p<0.001). This effect was significantly larger in the intervention group (p<0.05). MAI scores at discharge in the usual care group and the intervention group were respectively 9.95±6.70 and 7.26±5.07. The CDSS generated 193 recommendations, of which 71 concerned START criteria, 45 STOPP criteria, and 77 potential interactions. Overall, 31.6% of the recommendations were accepted. Conclusion: This study shows that a CDSS to improve prescribing has additional value in the setting of a geriatric ward. Almost one third of the software-generated recommendations were interpreted as clinically relevant and accepted, on average one per patient., (© Individual authors.)

Gurwitz and colleagues showed that a complex intervention, aimed at a reduction of drug-related adverse events and medication errors immediately after hospital discharge, did not result in a significant outcome difference between the intervention and control groups. We feel that the intervention lacked standardization, that a better outcome might have been achieved by intervening prior to hospital discharge, that more details about the nature of observed medication errors and acceptance of the intervenor recommendations should have been reported. Also, the number of unpreventable adverse drug events was higher in the intervention (n = 37) than in the control group (n = 27), suggesting a Hawthorne effect. The small number of adverse drug events detected overall points to a low sensitivity of the detection method used. We recommend that future studies be designed differently, including a stronger focus on physician-pharmacist collaboration, patient participation and improved communication between the hospital and general practice.

Educational escape rooms (EERs) are live-action, team-based games used to teach content-related and generic knowledge and skills. Instead of students just playing the EER, we believed that giving them the opportunity to create their own EERs would augment the learning effects of this teaching method. We report on the feasibility, evaluation, and lessons learned of our assignment on an opioid epidemic-based EER. This original teaching method appealed to most students, but the workload was evaluated to be too high. Our lessons learned include the need for sufficient (extrinsic) motivation, careful explanation of the assignment, and small group sizes., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s) 2021.)

Purpose: Cardiovascular disease (CVD) risk assessment is a suitable way to differentiate between high-risk individuals requiring intervention and risk modification, and those at low risk. However, concerns have been raised when adopting a CVD-risk prediction algorithm for HIV-infected patients in sub-Saharan Africa., Patients and Methods: We compared cardiovascular risk profiles between HIV-infected (with and without antiretroviral therapy (ART)) and HIV-uninfected adults as predicted by the American College of Cardiology/American Heart Association (ASCVD) and the Framingham cardiovascular risk score (FRS) algorithms and assessed the concordance of the algorithms in predicting 10-year CVD risk separately in HIV-infected and uninfected groups in a hospital-based cross-sectional study in Tanzania. A cross-sectional hospital-based study including 40 HIV-infected ART-naive, 64 HIV-infected on ART, and 50 HIV-uninfected adults was conducted. Traditional cardiovascular risk factors were determined by standard investigations. The primary outcome was the absolute 10-year CVD risk score based on the two algorithms., Results: Compared to HIV-uninfected, HIV-infected adults were classified at a higher 10-year CVD risk. ASCVD algorithms predicted a higher proportion of high-risk individuals compared to FRS in both HIV-infected and uninfected groups. The concordance between ASCVD and FRS-lipid algorithms was reasonable for both HIV-infected and uninfected groups though relatively higher in the HIV-uninfected group., Conclusion: HIV-infected individuals have a higher 10-year cardiovascular risk compared to HIV-uninfected persons. The concordance between ASCVD and FRS-lipid algorithms is reasonable in both HIV-uninfected and infected persons in Tanzania. Development of an HIV-specific algorithm is needed to accurately predict CVD risk in this population at high-risk., Competing Interests: The authors declare no conflicts of interest., (© 2021 Msoka et al.)

Background: Mortality rates are high among hospitalized patients with COVID-19, especially in those intubated on the ICU. Insight in pathways associated with unfavourable outcome may lead to new treatment strategies., Methods: We performed a prospective cohort study of patients with COVID-19 admitted to general ward or ICU who underwent serial blood sampling. To provide insight in the pathways involved in disease progression, associations were estimated between outcome risk and serial measurements of 64 biomarkers in potential important pathways of COVID-19 infection (inflammation, tissue damage, complement system, coagulation and fibrinolysis) using joint models combining Cox regression and linear mixed-effects models. For patients admitted to the general ward, the primary outcome was admission to the ICU or mortality (unfavourable outcome). For patients admitted to the ICU, the primary outcome was 12-week mortality., Findings: A total of 219 patients were included: 136 (62%) on the ward and 119 patients (54%) on the ICU; 36 patients (26%) were included in both cohorts because they were transferred from general ward to ICU. On the general ward, 54 of 136 patients (40%) had an unfavourable outcome and 31 (23%) patients died. On the ICU, 54 out of 119 patients (45%) died. Unfavourable outcome on the general ward was associated with changes in concentrations of IL-6, IL-8, IL-10, soluble Receptor for Advanced Glycation End Products (sRAGE), vascular cell adhesion molecule 1 (VCAM-1) and Pentraxin-3. Death on the ICU was associated with changes in IL-6, IL-8, IL-10, sRAGE, VCAM-1, Pentraxin-3, urokinase-type plasminogen activator receptor, IL-1-receptor antagonist, CD14, procalcitonin, tumor necrosis factor alfa, tissue factor, complement component 5a, Growth arrest-specific 6, angiopoietin 2, and lactoferrin. Pathway analysis showed that unfavourable outcome on the ward was mainly driven by chemotaxis and interleukin production, whereas death on ICU was associated with a variety of pathways including chemotaxis, cell-cell adhesion, innate host response mechanisms, including the complement system, viral life cycle regulation, angiogenesis, wound healing and response to corticosteroids., Interpretation: Clinical deterioration in patients with severe COVID-19 involves multiple pathways, including chemotaxis and interleukin production, but also endothelial dysfunction, the complement system, and immunothrombosis. Prognostic markers showed considerable overlap between general ward and ICU patients, but we identified distinct differences between groups that should be considered in the development and timing of interventional therapies in COVID-19., Funding: Amsterdam UMC, Amsterdam UMC Corona Fund, and Dr. C.J. Vaillant Fonds., Competing Interests: Declaration of Competing Interest The authors have declared no potential conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aim: Improvement and harmonization of European clinical pharmacology and therapeutics (CPT) education is urgently required. Because digital educational resources can be easily shared, adapted to local situations and re-used widely across a variety of educational systems, they may be ideally suited for this purpose., Methods: With a cross-sectional survey among principal CPT teachers in 279 out of 304 European medical schools, an overview and classification of digital resources was compiled., Results: Teachers from 95 (34%) medical schools in 26 of 28 EU countries responded, 66 (70%) of whom used digital educational resources in their CPT curriculum. A total of 89 of such resources were described in detail, including e-learning (24%), simulators to teach pharmacokinetics and/or pharmacodynamics (10%), virtual patients (8%), and serious games (5%). Together, these resources covered 235 knowledge-based learning objectives, 88 skills, and 13 attitudes. Only one third (27) of the resources were in-part or totally free and only two were licensed open educational resources (free to use, distribute and adapt). A narrative overview of the largest, free and most novel resources is given., Conclusion: Digital educational resources, ranging from e-learning to virtual patients and games, are widely used for CPT education in EU medical schools. Learning objectives are based largely on knowledge rather than skills or attitudes. This may be improved by including more real-life clinical case scenarios. Moreover, the majority of resources are neither free nor open. Therefore, with a view to harmonizing international CPT education, more needs to be learned about why CPT teachers are not currently sharing their educational materials., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: Prescribing medication is a complex process that, when done inappropriately, can lead to adverse drug events, resulting in patient harm and hospital admissions. Worldwide cost is estimated at 42 billion USD each year. Despite several efforts in the past years, medication-related harm has not declined. The aim was to determine whether a prescriber-focussed participatory action intervention, initiated by a multidisciplinary pharmacotherapy team, is able to reduce the number of in-hospital prescriptions containing ≥1 prescribing error (PE), by identifying and reducing challenges in appropriate prescribing., Methods: A prospective single-centre before- and after study was conducted in an academic hospital in the Netherlands. Twelve clinical wards (medical, surgical, mixed and paediatric) were recruited., Results: Overall, 321 patients with a total of 2978 prescriptions at baseline were compared with 201 patients with 2438 prescriptions postintervention. Of these, m456 prescriptions contained ≥1 PE (15.3%) at baseline and 357 prescriptions contained ≥1 PEs (14.6%) postintervention. PEs were determined in multidisciplinary consensus. On some study wards, a trend toward a decreasing number of PEs was observed. The intervention was associated with a nonsignificant difference in PEs (incidence rate ratio 0.96, 95% confidence interval 0.83-1.10), which was unaltered after correction. The most important identified challenges were insufficient knowledge beyond own expertise, unawareness of guidelines and a heavy workload., Conclusion: The tailored interventions developed with and implemented by stakeholders led to a statistically nonsignificant reduction in inappropriate in-hospital prescribing after a 6-month intervention period. Our prescriber-focussed participatory action intervention identified challenges in appropriate in-hospital prescribing on prescriber- and organizational level., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk., Methods: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach., Results: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients., Conclusions: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

There is much debate on the use of angiotensin receptor blockers (ARBs) in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-infected patients. Although it has been suggested that ARBs might lead to a higher susceptibility and severity of SARS-CoV-2 infection, experimental data suggest that ARBs may reduce acute lung injury via blocking angiotensin-II-mediated pulmonary permeability, inflammation, and fibrosis. However, despite these hypotheses, specific studies on ARBs in SARS-CoV-2 patients are lacking. METHODS: The PRAETORIAN-COVID trial is a multicenter, double-blind, placebo-controlled 1:1 randomized clinical trial in adult hospitalized SARS-CoV-2-infected patients (n = 651). The primary aim is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death within 14 days of randomization. The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160 mg bid, and the placebo arm will receive matching placebo. Treatment duration will be 14 days, or until the occurrence of the primary end point or until hospital discharge, if either of these occurs within 14 days. The trial is registered at clinicaltrials.gov (NCT04335786, 2020). SUMMARY: The PRAETORIAN-COVID trial is a double-blind, placebo-controlled 1:1 randomized trial to assess the effect of valsartan compared to placebo on the occurrence of ICU admission, mechanical ventilation, and death in hospitalized SARS-CoV-2-infected patients. The results of this study might impact the treatment of SARS-CoV-2 patients globally., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Dental students and dental-care providers should be able to prescribe drugs safely and effectively. As it is unknown whether this is the case, we assessed and compared the prescribing competence of dental students and dental-care providers in the Netherlands. In 2017, all Dutch final-year dental students and a random sample of all qualified general dental practitioners and dental specialists (oral and maxillofacial surgeons and orthodontists) were invited to complete validated prescribing knowledge-assessment and skills-assessment instruments. The knowledge assessment comprised 40 multiple-choice questions covering important drug topics. The skills assessment comprised three common clinical case scenarios. For the knowledge assessment, the response rates were 26 (20%) dental students, 28 (8%) general dental practitioners, and 19 (19%) dental specialists, and for the skills assessment the response rates were 14 (11%) dental students, eight (2%) general dental practitioners, and eight (8%) dental specialists. Dental specialists had higher knowledge scores (78% correct answers) than either dental practitioners (69% correct answers) or dental students (69% correct answers). A substantial proportion of all three groups made inappropriate treatment choices (35%-49%) and prescribing errors (47%-70%). Although there were some differences, dental students and dental-care providers in the Netherlands lack prescribing competence, which is probably because of poor prescribing education during under- and postgraduate dental training. Educational interventions are urgently needed., (© 2019 The Authors. Eur J Oral Sci published by John Wiley & Sons Ltd.)

With the aim to modernize and harmonize prescribing education, the European Association for Clinical Pharmacology and Therapeutics (EACPT) Working Group on education recommended the extensive use and distribution of digital learning resources (DLRs). However, it is unclear whether the complex task of prescribing medicine can be taught digitally. Therefore, the aim of this review was to investigate the effect of diverse DLRs in clinical pharmacology and therapeutics education. Databases PubMed, EMBASE, CINAHL, ERIC, and CENTRAL were systematically searched. Sixty-five articles were included in the analyses. Direct effects on patients were studied, but not detected, in six articles. Skills and behavior were studied in 11 articles, 8 of which reported positive effects. Knowledge acquisition was investigated in 19 articles, all with positive effects. Qualitative analyses yielded 10 recommendations for the future development of DLRs. Digital learning is effective in teaching knowledge, attitudes, and skills associated with safe and effective prescribing., (© 2019 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Almost half of medication-related hospital admissions are preventable. In the primary care setting structured medication reviews (SMRs) are an effective tool to detect and prevent medication errors that may cause harm to patients. Increasingly, SMRs are also being carried out in the clinical setting. SMRs are usually carried out by pharmacists who are well trained in pharmacology and in detecting medication errors. However, the implementation rate of the pharmaceutical interventions that result from SMRs is too low. We have introduced a multidisciplinary pharmacotherapy team of pharmacists and medical doctors into the clinic to carry out Medication review 2.0. The team performs SMRs to detect and prevent medication errors in hospital patients, improves the implementation rate of pharmaceutical interventions by enhancing transmural communication, and gives training and support to clinical prescribers in doing an SMR.

OBJECTIVE To investigate whether the safety culture of a hospital unit is associated with the ability to improve. DESIGN Qualitative investigation of safety culture on hospital units following a before-and-after trial on hand hygiene. SETTING VU University Medical Center, a tertiary-care hospital in the Netherlands. METHODS With support from hospital management, we implemented a hospital-wide program to improve compliance. Over 2 years, compliance was measured through direct observation, twice before, and 4 times after interventions. We analyzed changes in compliance from baseline, and selected units to evaluate safety culture using a positive deviance approach: the hospital unit with the highest hand hygiene compliance and 2 units that showed significant improvement (21% and 16%, respectively) were selected as high performing. Another 2 units showed no improvement and were selected as low performing. A blinded, independent observer conducted interviews with unit management, physicians, and nurses, based on the Hospital Survey on Patient Safety Culture. Safety culture was categorized as pathological (lowest level), reactive, bureaucratic, proactive, or generative (highest level). RESULTS Overall, 3 units showed a proactive or generative safety culture and 2 units had bureaucratic or pathological safety cultures. When comparing compliance and interview results, high-performing units showed high levels of safety culture, while low-performing units showed low levels of safety culture. CONCLUSIONS Safety culture is associated with the ability to improve hand hygiene. Interventions may not be effective when applied in units with low levels of safety culture. Although additional research is needed to corroborate our findings, the safety culture on a unit can benefit from enhancement strategies such as team-building exercises. Strengthening the safety culture before implementing interventions could aid improvement and prevent nonproductive interventions. Infect Control Hosp Epidemiol 2017;38:1277-1283.

Pharmacovigilance centres monitor the safety of drugs, based on adverse drug reactions (ADRs) reported by doctors, pharmacists and pharmaceutical companies. However, the under-reporting of ADRs remains a major problem. Our aim was to investigate preparedness of future doctors for their role in pharmacovigilance, by assessing their pharmacovigilance awareness, skills and knowledge. The study was a nationwide e-survey among medical students (third to sixth year) of all eight medical schools in the Netherlands. The survey consisted of questions regarding pharmacovigilance awareness, skills and knowledge. Overall, 874 students provided informed consent and participated (response 12%). Almost all students (96%) intended to report serious ADRs in their future practice. Almost half (44%) of the students did not know where to report an ADR, and 78% did not know which items were necessary for a good-quality ADR report. While more than 78% of the students agreed that pharmacovigilance is an important topic in their medical education, only 26% found that their current curriculum covered pharmacovigilance adequately. Although ADR reporting is considered relevant and important among future doctors, many do not know where and what to report. This is highly undesirable and should have consequences for pharmacotherapy teaching., (© 2016 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Given the increasing healthcare costs of an ageing population, there is growing interest in rational prescribing, which takes costs of medication into account. We aimed to gain insight into the attitude to and knowledge of medication costs of medical students and doctors in daily practice. This was a cross-sectional electronic survey among medical students (bachelor/master) and doctors (consultants/registrars). Attitude to costs was evaluated using a cost-consciousness scale. In open questions, the participants estimated the cost of commonly prescribed (generic/non-generic) drugs (including separate pharmacy dispensing costs). They were asked where they could find information about drug costs. Overall, a reasonable cost-consciousness was found. Students were less conscious of the cost than were doctors (15.56 SD 3.25 versus 17.81 SD 2.25; scale 0-24; p = 0.001). In contrast to this consciousness, actual estimated drug costs were within a 25% margin for only 5.4% of generic and 13.7% of proprietary drugs (Wilcoxon signed-rank, p < 0.001). The price of generic drugs was frequently overestimated (77.5%) and that of proprietary drugs was underestimated (51.4%). The dispensing costs were estimated correctly for 30% of the drugs. Most doctors (84%) and a minority of students (40%) were able to identify at least one source of information about drug costs. While doctors and students considered it important to be aware of the cost of drugs, this attitude is not reflected in their ability to estimate the cost of frequently prescribed drugs. Cost awareness is important in therapeutic reasoning and cost-effective prescribing. Both should be better addressed in (undergraduate) pharmacotherapy education., (© 2016 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

The aim of this study was to identify the information about commonly prescribed drugs that junior doctors should know in order to prescribe rationally in daily practice, defined as essential drug knowledge (EDK). A two-round Internet Delphi study was carried out involving general practitioners from one practice cluster, and registrars and consultants from two Dutch academic and eight teaching hospitals. A preliminary list of 377 potential EDK items for three commonly prescribed drugs was assessed on a dichotomous scale; an item was considered EDK if at least 80% consensus was reached. The consensus list of EDK items was discussed by the research team to identify similarities between the three drugs, with a view to forming a list of general EDK items applicable to other commonly prescribed drugs. Sixty experts considered 93 of the 377 items (25%) as EDK. These items were then used to form a list of 10 general EDK items. The list of EDK items identified by primary and secondary care doctors could be used in medical curricula and training programmes and for assessing the prescribing competence of future junior doctors. Further research is needed to evaluate the generalizability of this list for other commonly prescribed drugs., (© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Rationale, Aims and Objectives: Structuring the diagnostic section of the medical record (MR) improves diagnosis and communication between doctors. However, little is known about the therapeutic section of the MR. The aim of this study was to gain insight into the extent to which MRs are structured for therapeutic information, to determine which therapeutic data registrars and clinical consultants consider should be recorded in the MR and to what extent registrars record this information themselves., Methods: A multicentre observational study was carried out in the internal medicine outpatient clinics of five teaching hospitals in the Netherlands. Preformatted structure, importance and actual recording of therapeutic information was compared with a reference list of 35 therapeutic items based on the WHO Guide to Good Prescribing (e.g. drug name, indication for drug)., Results: The preformatted structure of four paper MRs and one electronic MR was assessed. Eight of the 35 therapeutic items were listed in the paper MRs and 18 items in the electronic MR. Registrars and consultants agreed on the importance of recording most of the therapeutic items in the MR, 25 and 27 out of the 35 items, respectively; however, registrars recorded only 11 of the 35 items in the paper MR and 20 of the 35 items in the electronic MR., Conclusions: The structure and content of paper and electronic MRs are not adequate. While both registrars and consultants agree on the importance of recording therapeutic items in the MR, registrars fail to record most of this information in practice. The results of this study can be used as starting point for the discussion regarding the necessity of structured recording of therapeutic information in the MR and its possible benefits with regard to medication safety and training of the new generation of prescribers., (© 2015 John Wiley & Sons, Ltd.)

Unlabelled: Medical students should be better prepared for their future role as prescribers. A new educational concept to achieve this is learning by doing. This encompasses legitimate, context-based training and gives students responsibility as early as possible in their medical education. Student-run clinics (SRCs) are an example of this concept., Aim: Describe the development of a new SRC for insured patients, primarily focused on medical (pharmacotherapy) education, the learner-centered student-run clinic (LC-SRC), and its feasibility., Methods: Teams each comprising of three students (first, third, and fifth year) performed consultations including proposing management plans, all under the supervision of an internist. Patients were voluntary selected from the internal medicine outpatient clinic for follow-up in the LC-SRC. Feasibility was evaluated using a set of questionnaires for patients, supervisors, and students., Results: In total, 31 consultations were conducted; 31 students and 4 clinical specialists participated. A pharmacotherapeutic treatment plan was drawn up in 33 % of the consultations. Patients were content with the care provided and rated the consultation with a 7.9 (SD 1.21) (1(min)-10(max)). Supervisors regarded LC-SRC safe for patients with guaranteed quality of care. They found the LC-SRC a valuable tool in medical education although it was time-consuming. Students appreciated their (new) responsibility for patient care and considered the LC-SRC a very valuable extracurricular activity., Discussion: The LC-SRC is feasible, and all participants considered it to be a valuable educational activity. It offers students the opportunity to learn in a real interprofessional and longitudinal setting for their future role as prescriber in clinical practice. The benefits and learner effects need to be investigated in a larger study with a longer follow-up.

Context: Student-run clinics (SRCs) have existed for many years and may provide the most realistic setting for context-based learning and legitimate early clinical experiences with responsibility for patient care. We reviewed the literature on student outcomes of participation in SRCs., Methods: A systematic literature review was performed using the PubMed, EMBASE, PsycINFO and ERIC databases. Included articles were reviewed for conclusions and outcomes; study quality was assessed using the Medical Education Research Study Quality Instrument (MERSQI)., Results: A total of 42 articles met the inclusion criteria and were included in the quantitative synthesis. The effects of participation on students' attitudes were mainly positive: students valued the SRC experience. Data on the effects of SRC participation on students' skills and knowledge were based mainly on expert opinions and student surveys. Students reported improved skills and indicated that they had acquired knowledge they were unlikely to have gained elsewhere in the curriculum. The quality of specific aspects of care delivered by students was comparable with that of regular care., Conclusions: The suggestion that students should be trained as medical professionals with responsibility for patient care early in the curriculum is attractive. In an SRC this responsibility is central. Students valued the early training opportunity in SRCs and liked participating. However, little is known about the effect of SRC participation on students' skills and knowledge. The quality of care provided by students seemed adequate. Further research is needed to assess the effect of SRC participation on students' skills, knowledge and behaviour., (© 2015 John Wiley & Sons Ltd.)

Purpose: The aim of this study is to evaluate the effect of different levels of realism of context learning on the prescribing competencies of medical students during the clinical clerkship in internal medicine., Methods: Between 2001 and 2007, 164 medical students took part in the prospective explorative study during their clinical clerkship in internal medicine at the VU University Medical Center, Amsterdam, The Netherlands. In a fixed order, each student had to formulate a treatment plan for a real patient in three situations of increasing realism: a minimal level (studying a patient record), medium level (preparing for a therapeutic consultation), and optimal level (preparing for and performing a therapeutic consultation with the patient)., Results: In comparison to studying a patient record (minimal context level), preparing a therapeutic consultation (medium context) improved four of the six steps of the WHO six-step plan. Preparing and performing a therapeutic consultation with a real patient (optimal context) further improved three essential prescribing competencies, namely checking for contraindications and interactions, prescription writing, and instructions to the patient., Conclusion and Recommendations: The results of this first explorative study suggest that enrichment of the learning context (responsibility for patient care) might be an important factor to improve the training of rational prescribing skills of medical students during their clinical clerkship in internal medicine. Clinical (pharmacology) teachers should be aware that seemingly small adaptations in the learning context of prescribing training during clinical clerkships (i.e., with or without involvement with and responsibility for patient care) may have relatively large impact on the development of prescribing competencies of our future doctors.

Objectives: Early and rapid identification of Clostridium difficile infections (CDI) is important to prevent transmission. In this study we assessed the diagnostic accuracy of a trained detection dog for detecting CDI cases on hospital wards in an outbreak setting., Methods: During a CDI outbreak in a large Dutch university hospital, we screened affected hospital wards repeatedly with a trained detection dog. The dog's response was compared to the clinical diagnosis, supported by laboratory results., Results: During a total of 9 hospital visits, the dog performed 651 screenings involving 371 participants. The dog correctly identified 12 out of 14 CDI cases [sensitivity 86% (95% confidence interval (CI): 56-97%)] and 346 out of 357 CDI negative participants [specificity of 97% (95% CI: 94-98%)]. Interestingly, of the 11 CDI negative participants that were 'falsely' indicated by the dog as positive, 2 (18%) did actually developed CDI during the 3 months of follow-up after the detection period; compared to only 12 of the 346 participants (3.5%) that the dog identified as C. difficile negative (p = 0.06)., Conclusion: A trained detection dog can accurately detect CDI in hospitalized patients during an outbreak. A (repeated) positive dog response is a strong indication of a CDI episode coming, be it the next day or possibly up to a month., (Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

The Netherlands has approximately 20,000 registered HIV-infected patients. The current HIV prevention policy consisting of condom use and active HIV testing does not effectively mitigate the HIV epidemic in all risk groups. In July of 2012, tenofovir/emtricitabine (TDF/FTC) was approved by the American Food and Drug Administration (FDA) for pre-exposure prophylaxis (PrEP) for long-term use in persons who exhibit frequent risky and unsafe sexual behaviour. With once-daily use and good therapy compliance, TDF/FTC has proved to be effective as PrEP, and few side effects are reported. Drawbacks in the use of TDF/FTC as PrEP are the potential risk of viral resistance and reduced condom use, the relatively high cost and the intensive counselling required. In special cases, long-term PrEP could enhance the current Dutch preventive policy. Further research is needed into the practical feasibility and protective efficacy of the ad hoc use of TDF/FTC as PrEP before a high-risk contact occurs.

Background: Significant nephrotoxicity develops in 1%-2% of HIV-infected adults receiving tenofovir (TDF). This nephrotoxicity is said to resolve rapidly, but this assessment is based on short follow-up, very few patients and use of serum creatinine, an insensitive measure of renal function., Methods: We determined the reversibility of TDF-related nephrotoxicity in 24 HIV-infected male outpatients who ceased TDF for renal impairment by retrospective assessment of estimated glomerular filtration rate (eGFR) using the Modified Diet in Renal Disease equation., Results: Median (interquartile range) eGFR pre-TDF was 74 (61-88) mL.min.1.73 m, fell to 51 (39-61) mL.min.1.73 m at TDF cessation and increased to 58 (48-70) mL.min.1.73 m a median 13 months after TDF cessation (most recent vs pre-TDF eGFR; P = 0.0008). Results were similar with the Cockcroft-Gault equation and after exclusion of patients who had shorter follow-up after TDF cessation. Only 10 (42%) patients reached their pre-TDF eGFR. Greater eGFR improvement was significantly associated with more rapid decline in eGFR on TDF therapy and in those who received TDF with a protease inhibitor, with a trend for shorter duration of TDF therapy., Discussion: In this population, TDF-related renal toxicity was not always fully reversible.

Hyporesponsiveness (anti-HBs 10-100 IU/l) or non-responsiveness (anti-HBs < 10 IU/l) to hepatitis B vaccines is a problem in approximately 20-70% of HIV-positive patients. Mechanisms for impaired humoral and cellular immunity related to the HIV infection are reviewed. Contributing risk factors like age, gender, CD4+ T-cell count, HIV RNA load and coinfection with hepatitis C are highlighted. New developments in improving the HBV vaccine immunogenicity are discussed and clinical recommendations are given for HBV-re-vaccination of HIV patients who failed on standard HBV vaccination.

HLA-B27 is known for its strong association with inflammatory spondyloarthropathies (SpA), a group of rheumatic diseases. Apart from playing its role in the onset of these inflammatory diseases, HLA-827 is so ubiquitous in the world that the carrying of this gene must have also have an advantage. There are some indications that a beneficial effect can be found as a less severe course of viral infections among B27-carriers. The literature on this subject was reviewed and revealed a favorable course of infection with influenza virus, herpes simplex type 2 virus, Epstein-Barr virus and, even more interesting, a protective effect of HLA-B27 in the progression of HIV infections. The course of HIV infection differs among individuals and is thought to be partly related to host-factor variability, reflecting broad genetic heterogeneity. The polymorphic human leukocyte antigens (HLA) are herein analyzed intensively with respect to this relationship. Cytotoxic T lymphocyte (CTL) responses, activated by HLA antigen presentation, are implicated in the control of HIV replication. An immunological explanation for the protective role for HLA B27 in HIV disease is that B27+ patients have a specific and strong CTL response against the p24 epitope, a conservative HIV protein that does not easily mutate. Some HLA genes seen in long-term non-progressors (LTNP) (>10 years disease free) are associated with a favorable prognosis. One of the alleles found predominantly in LTNPs is HLA-B27. More genetic factors seem to influence disease progression in HIV infections. Therefore, it would be interesting to further explore the influence of the genetic make up of these HIV-infected individuals. Knowledge of the immunogenetic profile might give clues for the individual course of the HIV infection, may influence the development of drug-resistant viruses and will possibly lead to a tailored therapeutic strategy in HIV-infected persons.