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Background Due to ageing of the population the incidence of multimorbidity and polypharmacy is rising. Polypharmacy is a risk factor for medication-related (re)admission and therefore places a significant burden on the healthcare system. The reported incidence of medication-related (re)admissions varies widely due to the lack of a clear definition. Some medications are known to increase the risk for medication-related admission and are therefore published in the triggerlist of the Dutch guideline for Polypharmacy in older patients. Different interventions to support medication optimization have been studied to reduce medication-related (re)admissions. However, the optimal template of medication optimization is still unknown, which contributes to the large heterogeneity of their effect on hospital readmissions. Therefore, we implemented a clinical decision support system (CDSS) to optimize medication lists and investigate whether continuous use of a CDSS reduces the number of hospital readmissions in older patients, who previously have had an unplanned probably medication-related hospitalization. Methods The CHECkUP study is a multicentre randomized study in older (≥60 years) patients with an unplanned hospitalization, polypharmacy (≥5 medications) and using at least two medications from the triggerlist, from Zuyderland Medical Centre and Maastricht University Medical Centre+ in the Netherlands. Patients will be randomized. The intervention consists of continuous (weekly) use of a CDSS, which generates a Medication Optimization Profile, which will be sent to the patient’s general practitioner and pharmacist. The control group will receive standard care. The primary outcome is hospital readmission within 1 year after study inclusion. Secondary outcomes are one-year mortality, number of emergency department visits, nursing home admissions, time to hospital readmissions and we will evaluate the quality of life and socio-economic status. Discussion This study is expected to add evidence on the knowledge of medication optimization and whether use of a continuous CDSS ameliorates the risk of adverse outcomes in older patients, already at an increased risk of medication-related (re)admission. To our knowledge, this is the first large study, providing one-year follow-up data and reporting not only on quality of care indicators, but also on quality-of-life. Trial registration The trial was registered in the Netherlands Trial Register on October 14, 2018, identifier: NL7449 (NTR7691). https://www.trialregister.nl/trial/7449.

A large proportion of the global population received a single dose of the Ad26.COV2.S coronavirus disease-2019 (COVID-19) vaccine as priming vaccination, which was shown to provide protection against moderate to severe COVID-19. However, the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants that harbor immune-evasive mutations in the spike protein led to the recommendation of booster vaccinations after Ad26.COV2.S priming. Recent studies showed that heterologous booster vaccination with an mRNA-based vaccine following Ad26.COV2.S priming leads to high antibody levels. However, how heterologous booster vaccination affects other functional aspects of the immune response remains unknown. Here, we performed immunological profiling on samples obtained from Ad26.COV2.S-vaccinated individuals before and after a homologous (Ad26.COV2.S) or heterologous (mRNA-1273 or BNT162b2) booster vaccination. Both homologous and heterologous booster vaccination increased antibodies with multiple functionalities towards ancestral SARS-CoV-2, the Delta and Omicron BA.1 variants. Especially, mRNA-based booster vaccination induced high levels of neutralizing antibodies and antibodies with various Fc-mediated effector functions such as antibody-dependent cellular cytotoxicity and phagocytosis. In contrast, T cell responses were similar in magnitude following homologous or heterologous booster vaccination, and retained functionality towards Delta and Omicron BA.1. However, only heterologous booster vaccination with an mRNA-based vaccine led to the expansion of SARS-CoV-2-specific T cell clones, without an increase in the breadth of the T cell repertoire as assessed by T cell receptor sequencing. In conclusion, we show that Ad26.COV2.S priming vaccination provides a solid immunological base for heterologous boosting with an mRNA-based COVID-19 vaccine, increasing humoral and cellular responses targeting newly emerging variants of concern.One sentence summaryAd26.COV2.S priming provides a solid immunological base for extension of cellular and humoral immune responses following an mRNA-based booster.

Romy van der Groef,1 Pascal HP de Jong,1 Dirk Jan Hijnen,2 Christien J van der Woude,3 Jan AM van Laar,4 P Hugo M van der Kuy,5 Jan-Dietert Brugma,6 Annelieke Pasma1 1Department of Rheumatology, Erasmus University Medical Center, Rotterdam, the Netherlands; 2Department of Dermatology, Erasmus University Medical Center, Rotterdam, the Netherlands; 3Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands; 4Department of Internal Medicine and Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; 5Department of Clinical Pharmacy, Erasmus University Medical Center, Rotterdam, the Netherlands; 6Department of Outpatient Pharmacy, Erasmus University Medical Center, Rotterdam, the NetherlandsCorrespondence: Romy van der Groef, Erasmus University Medical Center, Department of Rheumatology, Room Na-523, PO Box 2040, 3000 CA, Rotterdam, the Netherlands, Tel +31 648284141, Email r.vandergroef@erasmusmc.nlPurpose: During the SARS-CoV-2 pandemic, national and international societies have recommended continuing biological agents in patients with immune-mediated inflammatory diseases (IMID) in the absence of SARS-CoV-2 symptoms. However, adherence to biological treatment might decrease, because these recommendations contradict patients’ beliefs. Especially an increased concern about side effects could have influenced the adherence to biological treatment during the first lockdown. The primary objective was to investigate the impact of the first SARS-CoV-2 lockdown on adherence to biological treatment in IMID patients.Patients and Methods: In this prospective cohort study, IMID patients who received a biological agent before and during the first SARS-CoV-2 lockdown (March 2020- June 2020) were included. Patients were excluded if they did not complete the medication adherence report scale-5 (MARS-5) questionnaire at ≥ 1 visit before the lockdown and ≥ 1 visit during the lockdown. Adherence to biological treatment was measured with the MARS-5 and Medication Possession Ratio (MPR).Results: We included 157 IMID patients. The percentage of adherent patients, defined as MARS-5 score > 21, was significantly lower during the lockdown compared to the period before the lockdown (88.5% vs 84.1%, p< 0.001). Additionally, the overall percentage of adherent patients during the lockdown based on the MPR ≥ 90% was significantly lower compared to adherence based upon the MARS-5 (65.1% vs 84.1%, p< 0.001).Conclusion: This study showed that the first SARS-CoV-2 lockdown negatively impacts adherence to biological treatment in IMID patients. Therefore, treating physicians should be aware of this problem to minimize the potential harmful effects of non-adherence.Keywords: adherence, biological, SARS-CoV-2, immune-mediated inflammatory diseases

BACKGROUND Despite enormous clinical improvements, due to better management strategies and the availability of biologicals, immune-mediated inflammatory diseases (IMIDs) still have a significant impact on patients’ lives. To further reduce disease burden, provider- as well as patient-reported outcomes (PROs) should be taken into account during treatment and follow-up. Web-based collection of these outcomes generates valuable repeated measurements, which could be used (1) in daily clinical practice for patient-centered care, including shared decision-making; (2) for research purposes; and (3) as an essential step toward the implementation of value-based health care (VBHC). Our ultimate goal is that our health care delivery system is completely aligned with the principles of VBHC. For aforementioned reasons, we implemented the IMID registry. OBJECTIVE The IMID registry is a digital system for routine outcome measurement that mainly includes PROs to improve care for patients with IMIDs. METHODS The IMID registry is a longitudinal observational prospective cohort study within the departments of rheumatology, gastroenterology, dermatology, immunology, clinical pharmacy, and outpatient pharmacy of the Erasmus MC, the Netherlands. Patients with the following diseases are eligible for inclusion: inflammatory arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, uveitis, Behçet disease, sarcoidosis, and systemic vasculitis. Generic and disease-specific (patient-reported) outcomes, including adherence to medication, side effects, quality of life, work productivity, disease damage, and activity, are collected from patients and providers at fixed intervals before and during outpatient clinic visits. Data are collected and visualized through a data capture system, which is linked directly to the patients’ electronic health record, which not only facilitates a more holistic care approach, but also helps with shared decision-making. RESULTS The IMID registry is an ongoing cohort with no end date. Inclusion started in April 2018. From start until September 2022, a total of 1417 patients have been included from the participating departments. The mean age at inclusion was 46 (SD 16) years, and 56% of the patient population is female. The average percentage of filled out questionnaires at baseline is 84%, which drops to 72% after 1 year of follow-up. This decline may be due to the fact that the outcomes are not always discussed during the outpatient clinic visit or because the questionnaires were sometimes forgotten to set out. The registry is also used for research purposes and 92% of the patients with IMIDs gave informed consent to use their data for that. CONCLUSIONS The IMID registry is a web-based digital system that collects provider- and PROs. The collected outcomes are used to improve care for the individual patient with an IMID and facilitate shared decision-making, and they are also used for research purposes. The measurement of these outcomes is an essential step toward the implementation of VBHC. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/43230

Summary This protocol describes an innovative study to investigate the relationship between sleep, shift work and the immune response to severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2; coronavirus disease 2019 [COVID‐19]) vaccination. As the COVID‐19 pandemic is a global crisis with devastating health, social and economic impacts, there is a pressing need for effective vaccination programmes. Previous influenza and hepatitis vaccination studies suggest that lack of sleep can negatively alter immune responsiveness, while circadian misalignment most likely may also play an important role in the immune response to vaccination. Our present study will be the first to address this question in actual shift workers and in relation to COVID‐19 vaccination. We hypothesise that the occurrence of recent night shifts and diminished sleep will negatively alter the immune response to vaccination in shift workers compared to dayworkers. We aim to recruit 50 shift workers and 50 dayworkers. Participants will receive an mRNA‐based vaccination, through the Dutch vaccination programme. To assess immune responsiveness, blood will be drawn at baseline (before first vaccination), 10 days after first vaccination, the day prior to the second vaccination; and 28 days, 6 and 12 months after the second vaccination. Actigraphy and daily sleep e‐diaries will be implemented for 7 days around each vaccination to assess sleep. The Pittsburgh Sleep Quality Index will be used to monitor sleep in the long term. Optimising the efficacy of the COVID‐19 vaccines is of outmost importance and results of this study could provide insights to develop sleep and circadian‐based interventions to enhance vaccination immunity, and thereby improve global health.

ObjectivesPhase III cancer clinical trials are expensive and time-consuming phases in drug development. Effective patient enrolment can reduce delays and save costs, offering patients an opportunity to benefit from innovative treatments. However, the current evidence base does not fully explain the persistence of barriers to patient enrolment in phase III cancer clinical trials. The aim was to explore clinicians’ and pharmaceutical representatives’ views on these barriers.DesignA qualitative study was performed. In-depth information was collected from 15 experts in the field of oncology clinical trials, in particular clinical oncologists acting as principal investigators (PIs) and clinical research associates. By means of semistructured interviews, based on a questionnaire derived from our newly developed conceptual framework, they were asked to identify barriers to patient enrolment they had experienced and comment on barriers identified in literature.FindingsExisting knowledge on barriers to patient enrolment was confirmed by all interviewees. Two new key barriers to patient enrolment were identified, that is, insufficient attention to the importance of clinical trial-based research in medical training and a trust gap between PIs and pharmaceutical representatives. A third important barrier was increasingly narrow patient inclusion criteria.ConclusionsThe success rate of patient enrolment in phase III cancer clinical trials highly depends on the clinicians’ willingness to take part in clinical trials. Raising awareness of the importance of clinical trials in medical training and among practising oncologists is recommended. Furthermore, to reduce barriers to patient enrolment, it is essential that both clinicians and pharmaceutical representatives acknowledge each other’s expertise, become acquainted with each other’s procedures and regulations, and work on building trust relationships. Finally, in accordance with our key findings, we propose to add two new barriers to our newly developed conceptual framework; insufficient attention to clinical trial research in medical training and trust gap.

IntroductionAdequately addressing the needs of patients at the end of life and their relatives is pivotal in preventing unnecessary suffering and optimising their quality of life. The purpose of the iLIVE study is to contribute to high-quality personalised care at the end of life in different countries and cultures, by investigating the experiences, concerns, preferences and use of care of terminally ill patients and their families.Methods and analysisThe iLIVE study is an international cohort study in which patients with an estimated life expectancy of 6 months or less are followed up until they die. In total, 2200 patients will be included in 11 countries, that is, 200 per country. In addition, one relative per patient is invited to participate. All participants will be asked to fill in a questionnaire, at baseline and after 4 weeks. If a patient dies within 6 months of follow-up, the relative will be asked to fill in a post-bereavement questionnaire. Healthcare use in the last week of life will be evaluated as well; healthcare staff who attended the patient will be asked to fill in a brief questionnaire to evaluate the care that was provided. Qualitative interviews will be conducted with patients, relatives and healthcare professionals in all countries to gain more in-depth insights.Ethics and disseminationThe cohort study has been approved by ethics committees and the institutional review boards (IRBs) of participating institutes in all countries. Results will be disseminated through the project website, publications in scientific journals and at conferences. Within the project, there will be a working group focusing on enhancing the engagement of the community at large with the reality of death and dying.Trial registration numberNCT04271085.

The severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) Omicron variant (B.1.1.529) is spreading rapidly, even in vaccinated individuals, raising concerns about immune escape. Here, we studied neutralizing antibodies and T-cell responses to SARS-CoV-2 D614G (wildtype, WT), and the B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron) variants of concern (VOC) in a cohort of 60 health care workers (HCW) after immunization with ChAdOx-1 S, Ad26.COV2.S, mRNA-1273 or BNT162b2. High binding antibody levels against WT SARS-CoV-2 spike (S) were detected 28 days after vaccination with both mRNA vaccines (mRNA-1273 or BNT162b2), which significantly decreased after 6 months. In contrast, antibody levels were lower after Ad26.COV2.S vaccination but did not wane. Neutralization assays with authentic virus showed consistent cross-neutralization of the Beta and Delta variants in study participants, but Omicron-specific responses were significantly lower or absent (up to a 34-fold decrease compared to D614G). Notably, BNT162b2 booster vaccination after either two mRNA-1273 immunizations or Ad26.COV.2 priming partially restored neutralization of the Omicron variant, but responses were still up to-17-fold decreased compared to D614G. CD4+ T-cell responses were detected up to 6 months after all vaccination regimens; S-specific T-cell responses were highest after mRNA-1273 vaccination. No significant differences were detected between D614G- and variant-specific T-cell responses, including Omicron, indicating minimal escape at the T-cell level. This study shows that vaccinated individuals retain T-cell immunity to the SARS-CoV-2 Omicron variant, potentially balancing the lack of neutralizing antibodies in preventing or limiting severe COVID-19. Booster vaccinations may be needed to further restore Omicron cross-neutralization by antibodies.

International audience; Prader-Willi syndrome (PWS) is a rare neuroendocrine genetic syndrome. Characteristics of PWS include hyperphagia, hypotonia, and intellectual disability. Pituitary hormone deficiencies, caused by hypothalamic dysfunction, are common and hypogonadism is the most prevalent. Untreated hypogonadism can cause osteoporosis, which is already an important issue in PWS. Therefore, timely detection and treatment of hypogonadism is crucial. To increase understanding and prevent undertreatment, we (1) performed a cohort study in the Dutch PWS population, (2) thoroughly reviewed the literature on female hypogonadism in PWS and (3) provide clinical recommendations on behalf of an international expert panel. For the cohort study, we retrospectively collected results of a systematic health screening in 64 female adults with PWS, which included a medical questionnaire, medical file search, medical interview, physical examination and biochemical measurements. Our data show that hypogonadism is frequent in females with PWS (94%), but is often undiagnosed and untreated. This could be related to unfamiliarity with the syndrome, fear of behavioral changes, hygienic concerns, or drug interactions. To prevent underdiagnosis and undertreatment, we provide practical recommendations for the screening and treatment of hypogonadism in females with PWS.

The present protocol study was used to summarize the findings of other major COVID-19 vaccination trials and provide an outline of our multicenter, single-blind, randomized controlled trial: the SWITCH trial. In the SWITCH, we compare the immunogenicity and reactogenicity of heterologous versus homologous vaccination strategies of COVID-19 vaccines. We recruit Health Care Workers (HCWs) who received ad.26.Cov2.S as their prime (first vaccination). We randomize HCWs in four groups: no boost (second vaccination), ad.26.Cov2.S, mRNA1273, and BNT162b2). The full protocol of the SWITCH trial can be found in the supplementary material.

Bearing in mind that it is currently not standard practice to publish non-clinical trial research protocols in EJHP , we would like to share our thoughts within the EJHP community on considering publishing these kinds of research protocols. We believe drawing attention to both the academic and societal relevance of submitting non-clinical trial research protocols, especially in the field of pharmacoeconomics, may foster discourse on this delicate subject. To reinforce our arguments we have attached our research protocol for the study ‘Orphan Drug Prices and Market Exclusivity in Western-European Countries’ (see online supplemental file 1).### Supplementary data [ejhpharm-2021-002987supp001.pdf] Primarily, publishing a research protocol is a means to allow the academic community to evaluate whether subsequent analysis and results are in line with the investigators’ initial objectives. Additionally, it informs the academic community on ongoing research and may avoid duplication of work. It can …

Vitamin B12 deficiency is traditionally treated with intramuscular injections of cobalamin, which are stressful events for children. In adults, studies have shown adequate absorption of intranasally administered vitamin B12. To date, data concerning efficacy of intranasal administration of vitamin B12 in children are lacking. We report on ten cases of children with vitamin B12 deficiency who were successfully treated with intranasal administration of a spray containing hydroxocobalamin. The mean baseline vitamin B12 concentration increased from 126.3 pmol/l (SD 55.4) to 1914.7 pmol/l (SD 1509.7). No side effects were reported. Conclusion: In children, intranasal application of vitamin B12 seems a safe and effective alternative to intramuscular injections, leading to higher compliance and less burden to patients.What is Known:• Children with vitamin B12deficiency are traditionally treated with intramuscular cobalamin injections, which are costly and painful.• Studies in adults showed that intranasal application of hydroxocobalamin leads to normalisation of vitamin B12levels.What is New:• The intranasal application of vitamin B12resulted in a substantial increase of the mean baseline vitamin B12levels without any side effect.• These data encourage a systematic evaluation of intranasal treatment of vitamin B12deficiency in order to define safety, optimal dosage and administration frequency.

Introduction Medication reviews are an essential part of daily routine at a hospital ward but are prone to mistakes. With this study we want to assess the strengths and weaknesses of a Clinical Decision Support System (CDSS) and evaluate the additional value on the reduction of medication errors compared with manual medication reviews.Materials and Methods We gathered all remarks related to (potential) errors in the current medication regime (notifications) regarding medication errors for 332 patients from 12 grand rounds of the internal medicine ward and orthopedic ward at the Maastricht University Medical Centre during four months. Simultaneously, we electronically extracted data regarding the patient’s medication list, laboratory data and patient characteristics and entered these data into our CDSS.Results and Discussion One hundred thirty-eight notifications were made during grand rounds. One-hundred and seventy-nine relevant alerts were reported by the CDSS. Only three of the relevant notifications were reported by both. Overall, errors regarding indication without medication and medication without indication were most frequently noticed during grand rounds and contraindications or side effects were most frequently noticed by the CDSS. The CDSS may be a relevant addition to the manual performed medication reviews in the hospital. The strength of the present CDSS lies in the detection of errors regarding contraindications and side effects. Future developments include optimizing the cut off values at which the CDSS should provide an alert is an important next step in improving the CDSS. Additionally, in order to increase notifications about indication without medication and medication without indication, the medical history should be incorporated into the CDSS. Finally, relevance on patient outcome should be determined.

Vitamin B

Background A delirium is common in hospital settings resulting in increased mortality and costs. Prevention of a delirium is clearly preferred over treatment. A delirium risk prediction model can be helpful to identify patients at risk of a delirium, allowing the start of preventive treatment. Current risk prediction models rely on manual calculation of the individual patient risk. Objective The aim of this study was to develop an automated ward independent delirium riskprediction model. To show that such a model can be constructed exclusively from electronically available risk factors and thereby implemented into a clinical decision support system (CDSS) to optimally support the physician to initiate preventive treatment. Setting A Dutch teaching hospital. Methods A retrospective cohort study in which patients, 60 years or older, were selected when admitted to the hospital, with no delirium diagnosis when presenting, or during the first day of admission. We used logistic regression analysis to develop a delirium predictive model out of the electronically available predictive variables. Main outcome measure A delirium risk prediction model. Results A delirium risk prediction model was developed using predictive variables that were significant in the univariable regression analyses. The area under the receiver operating characteristics curve of the "medication model" model was 0.76 after internal validation. Conclusions CDSSs can be used to automatically predict the risk of a delirium in individual hospitalised patients' by exclusively using electronically available predictive variables. To increase the use and improve the quality of predictive models, clinical risk factors should be documented ready for automated use.

General consensus of patient selection criteria for outpatient joint arthroplasty is lacking, which is paramount to prevent prolonged hospital stay, adverse events and/or readmissions. This review highlights patient selection criteria for OJA based on the current literature and expert opinion. A search of the English and International electronic healthcare databases including MEDLINE/PubMed, EMBASE, AMED and the Cochrane library was performed in November 2015 to include studies published during the last 10 years. Furthermore, a survey of physicians from different specialties was performed. Fourteen studies described results regarding outpatient joint arthroplasty. Studies on outpatient hip and/or knee arthroplasty resulted in similar outcome in preselected patients. Patients who are able and willing to participate, with a low ASA classification ( II), bleeding disorders, poorly controlled and/or severe cardiac (e.g. heart failure, arrhythmia) or pulmonary (e.g. embolism, respiratory failure) comorbidities, uncontrolled DM (type I or II), a high BMI (>30 m2/kg), chronic opioid consumption, functional neurological impairments, dependent functional status, chronic/end-stage renal disease and/or reduced preoperative cognitive capacity should be excluded from outpatient joint arthroplasty. The expert opinion-based selection criteria were comparable to literature with a further extension of exclusion for patients with practical issue’s, urologic medical history and/or severe mobility disorders. Based on the current literature, the presented patient selection criteria provide a basis for outpatient joint arthroplasty and can be useful when selecting patients. Together with a change in mindset, a multidisciplinary approach and literature-based protocols, outpatient joint arthroplasty can be applied in daily orthopaedic practice while ensuring patients’ safety. Clinical review, Level III.

Introduction Patient-specific medication reviews might be useful for correcting prescribing omissions. The Dutch Healthcare Inspectorate (IGZ) demands that a medication review is performed by a pharmacist in cooperation with a physician for all residents of nursing homes (twice a year) and residential homes (once a year). Objective This study aims to show the clinical practice of medication reviews for older people in residential and nursing homes by pharmacists. We asked the following research questions. (i) To what extent are medication reviews performed as required by the IGZ? (ii) How much time is needed to perform the required medication reviews? (iii) In the opinion of the pharmacist, is the medication review economically efficient and medically relevant? Methods A web-based survey was sent to 87 hospital pharmacists and 270 community pharmacists. Results In a ‘best case vs worst case’ scenario, 76% vs 42% of the IGZ-required medication reviews are performed. Considering a mean of 730.7 medication reviews required per year and the mean time spent on one medication review (29.3 min), a pharmacist would need to spend 2.5 months a year to meet the IGZ requirements. Almost every pharmacist considers medication reviews to be medically relevant, but only 47% consider them to be economically efficient. Conclusions This survey shows that medication reviews performed in institutional care settings do not meet the IGZ requirements, which is not surprising considering the time needed for one medication review. Automation of medication review processes should be initiated to increase efficiency.

Carlota Mestres Gonzalvo,1 Kim PGM Hurkens,2 Hugo AJM de Wit,3 Brigit PC van Oijen,1 Rob Janknegt,1 Jos MGA Schols,4 Wubbo J Mulder,5 Frans R Verhey,6 Bjorn Winkens,7 Paul-Hugo M van der Kuy1 1Department of Clinical Pharmacology and Toxicology, Orbis Medical Centre, Sittard, 2Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Centre, Amsterdam, 3Department of Clinical Pharmacy and Toxicology, Atrium Medical Centre, Heerlen, 4Department of Family Medicine and Department of Health Services Research, School for Public Health and Primary Care, Maastricht University, 5Department of Internal Medicine, Maastricht University Medical Centre, 6Department of Psychiatry and Neuropsychology, Alzheimer Centre Limburg/School for Mental Health and Neurosciences, 7Department of Methodology and Statistics, School for Public Health and Primary Care, Maastricht University, Maastricht, theNetherlands Background: The aim of this study was to evaluate to what extent laboratory data, actual medication, medical history, and/or drug indication influence the quality of medication reviews for nursing home patients. Methods: Forty-six health care professionals from different fields were requested to perform medication reviews for three different cases. Per case, the amount of information provided varied in three subsequent stages: stage 1, medication list only; stage 2, adding laboratory data and reason for hospital admission; and stage 3, adding medical history/drug indication. Following a slightly modified Delphi method, a multidisciplinary team performed the medication review for each case and stage. The results of these medication reviews were used as reference reviews (gold standard). The remarks from the participants were scored, according to their potential clinical impact, from relevant to harmful on a scale of 3 to -1. A total score per case and stage was calculated and expressed as a percentage of the total score from the expert panel for the same case and stage. Results: The overall mean percentage over all cases, stages, and groups was 37.0% when compared with the reference reviews. For one of the cases, the average score decreased significantly from 40.0% in stage 1, to 30.9% in stage 2, and 27.9% in stage 3; no significant differences between stages was found for the other cases. Conclusion: The low performance, against the gold standard, of medication reviews found in the present study highlights that information is incorrectly used or wrongly interpreted, irrespective of the available information. Performing medication reviews without using the available information in an optimal way can have potential implications for patient safety. Keywords: polypharmacy, medication therapy management, decision support systems management, aged, medication review

Objectives To improve the current standalone pharmacy clinical decision support system (CDSS) by identifying and quantifying the benefits and limitations of the system. Methods Alerts and handling of the executed clinical rules were extracted from the CDSS from the period September 2011 to December 2011. The number of executed clinical rule alerts, number of actions on alerts, and the reason why alerts were classified as not relevant were analyzed. The alerts where considered clinically relevant when the pharmacist needed to contact the physician. Results The 4065 alerts have been separated into: 1137 (28.0%) new alerts, 2797 (68.8%) repeat alerts and 131 (3.2%) double alerts. When the alerts were analyzed, only 3.6% were considered clinically relevant. Reasons why alerts were considered as not to be relevant were: (a) the dosage was correct or already adjusted, (b) the drug was (temporarily) stopped and (c) the monitored laboratory value or drug dosage had already reverted to be within the reference limits. The reasons for no action were linked to three categorical limitations of the used system: ‘algorithm alert criteria’, ‘CDSS optimization’, and ‘data delivery’. Conclusion This study highlighted a number of ways in which the CDSS could be improved. These different aspects have been identified as important for developing an efficient CDSS.

Background Medication reviews are considered to be important to maintain a high quality of pharmacotherapy. However, there is a large variation in the quality of these reviews. Aim To evaluate the covariates that may lead to high-quality medication reviews and to establish their relative importance. Design Healthcare professionals, including community pharmacists, hospital pharmacists, nursing home physicians, general practitioners and geriatricians, were recruited in the province of Limburg, The Netherlands. Method A research group, selected for their expertise in the field of medication reviews, established covariates that could possibly affect the quality of medication reviews. An electronic questionnaire, including these covariates, was developed and was subsequently sent to the participants who rated the covariates using a 10-point scale. Finally, the research group classified the scores. Physicians and pharmacists were evaluated jointly and separately to account for possible differences. Results 29 out of 49 participants completed the study. 13 covariates were evaluated and their medians and ranges were calculated. The five most important covariates were, from most to less important, knowledge of the indication for the drug, use of guidelines, reviewer9s professional field, knowledge of the medical history, and use of laboratory values. Both groups found the indication for the drug the most important covariate. Conclusions We found that the most relevant covariates that may lead to a high-quality medication review are the drug9s indication, use of patients’ medical history, use of guidelines, reviewer9s professional field, and use of laboratory values.

Item does not contain fulltext PURPOSE: The results of a feasibility study of blister-pack smart technology for monitoring medication adherence are reported. METHODS: Research in the area of objective therapy compliance measurement has led to the development of microprocessor-driven systems that record the time a unit dose is removed from blister packaging. One device under development is the Smart Blister-a label imprinted with event-detection circuitry that can be affixed to standard commercial blister cards. In the first trial of the device in actual clinical practice, 115 community-dwelling Dutch patients receiving valsartan maintenance therapy (160 mg once daily) were given 14-day blister packages equipped with the Smart Blister. On the return of empty blister cards to the 20 participating community pharmacies, the stored information was scanned and downloaded for data analysis and patient counseling purposes. RESULTS: A total of 245 Smart Blister-equipped packages were used by valsartan recipients during the eight-month study. The device was largely effective in recording patient and blister-card identification data and other desired information. However, in 17% of cases, the Smart Blister system registered multiple tablet-removal events at the same time, presumably indicating unintentional breakage of nearby conductive circuits and the need for design refinements. The Smart Blister-equipped medication cards were generally well received by patients and pharmacies. CONCLUSION: An evaluation of the functionality and robustness of the Smart Blister in a real-world clinical practice situation yielded some promising results, but the findings also indicated a need for design refinements and additional performance testing of the device.

Contains fulltext : 107733.pdf (Publisher’s version ) (Open Access) BACKGROUND: Although it is generally acknowledged that electronic monitoring of adherence to treatment improves blood pressure (BP) control by increasing patients' awareness to their treatment, little information is available on the long-term effect of this intervention. METHODS: In this observational study among a total of 470 patients with mild-to-moderate hypertension, adherence was measured in 228 patients by means of both the Medication Event Monitoring System (MEMS) and pill count (intervention group), and in 242 patients by means of pill count alone (control group). During a follow-up period of 1 year consisting of seven visits to the physician's office, BP measurements were performed and medication adjusted based on the achieved BP. In addition, at each visit adherence to treatment was assessed. RESULTS: On the basis of pill counts, median adherence to treatment did not differ between the intervention group and the control group (96.1% vs. 94.2%; P = 0.97). In both groups, systolic and diastolic BP decreased similarly: 23/13 vs. 22/12 mm Hg in the intervention and control group respectively. Drug changes and the number of drugs used were associated with BP at the start of study, but not with electronic monitoring. CONCLUSIONS: In this study, electronic monitoring of adherence to treatment by means of MEMS did not lead to better long-term BP control nor did it result in less drug changes and drug use.

Objectives: First, to estimate the added value of a clinical decision support system (CDSS) in the performance of medication reviews in hospitalised elderly. Second, to identify the limitations of the current CDSS by analysing generated drug-related problems (DRPs). Methods: Medication reviews were performed in patients admitted to the geriatric ward of the Zuyderland medical centre. Additionally, electronically available patient information was introduced into a CDSS. The DRP notifications generated by the CDSS were compared with those found in the medication review. The DRP notifications were analysed to learn how to improve the CDSS. Results: A total of 223 DRP strategies were identified during the medication reviews. The CDSS generated 70 clinically relevant DRP notifications. Of these DRP notifications, 63 % (44) were also found during the medication reviews. The CDSS generated 10 % (26) new DRP notifications and conveyed 28 % (70) of all 249 clinically relevant DRPs that were found. Classification of the CDSS generated DRP notifications related to 'medication error type' revealed that 'contraindications/interactions/side effects' and 'indication without medication' were the main categories not identified during the manual medication review. The error types 'medication without indication', 'double medication', and 'wrong medication' were mostly not identified by the CDSS. Conclusions: The CDSS used in this study is not yet sufficiently advanced to replace the manual medication review, though it does add value to the manual medication review. The strengths and weaknesses of the current CDSS can be determined according to the medication error types.

Background: Intranasal (IN) midazolam is a potential alternative to rectal diazepam for the acute treatment of epileptic seizures. Objective: The purpose of this pilot study was to investigate the pharmacokinetics and tolerability of IN midazolam (50 mg/mL) compared with intravenous (IV) midazolam (2.5 mg) in healthy adult volunteers. Methods: In this single-dose, randomized-sequence, open-label, 2-period crossover pilot study subjects were randomly assigned to receive IN or IV midazolam, with a washout period of at least 5 days between treatments. The 50-mg/mL IN midazolam formulation consisted of 5 mg midazolam base per 0.1 mL (1 spray) and was administered once in 1 nostril. The IV midazolam solution (2.5 mg) was infused over 10 seconds. Blood samples were taken before and at regular intervals up to 240 minutes after dosing. Pharmacokinetic data (ie, C-max, T-max, t(1/2), and AUC) were analyzed using a 2-compartment model. Results: Of 9 volunteers screened and enrolled, 7 completed the study (mean age 34.1 [9.0] years; mean weight, 68.6 [10.4] kg, range 53-89 kg; 6 men, 3 women; all white). The mean C-max of 78 (40) ng/mL was reached 44 minutes after IN administration, whereas the mean C-max was 51 (5) ng/mL after IV administration. The mean estimated C-t=5 min was 31.4 (28.1) ng/mL after IN administration. The elimination t(1/2) was 1.9 (0.41) hours for IN midazolam and 2.3 (0.19) hours for IV midazolam. The bioavailability of IN midazolam was 82%. There were few adverse events, with a local burning feeling in the nose being the most reported event (6 of 7 subjects). Conclusions: In this select group of healthy volunteers, concentrations of midazolam >30 ng/mL were reached within 5 minutes of IN administration at a dose of 5 mg/0.1 mL. A burning feeling in the nostril was the main adverse effect. Additional research is needed to evaluate the safety profile, convenience, satisfaction, and efficacy of nasal midazolam in the treatment of adults with seizures. This trial is registered at www.isrctn.org, No. ISRCTN79059168. (Clin Ther. 2011;33:2022-2028)

Poor adherence to treatment is one of the major determinants of an uncontrolled blood pressure. Participation in a clinical trial may increase patient's adherence to treatment. This prompted us to investigate adherence and persistence profiles in patients with hypertension who had participated in a clinical trial, by collecting pharmacy refill data before, during, and after participation in the trial. Pharmacy refill data of 182 patients with hypertension who participated in the Home Versus Office Blood Pressure Measurements: Reduction of Unnecessary Treatment Study between 2001 and 2005 were obtained from 1999 until 2010. Refill adherence to treatment was compared for the periods before, during, and after this trial. Persistence to medication was investigated for the period after termination of the trial. Refill data were available for 22 600 prescriptions. Participation into the trial significantly increased refill adherence, from 90.6% to 95.6% ( P P P =0.45). Except for adherence to trial medication, adherence to nontrial-related drugs also increased as a consequence of trial participation, from 77.6% to 89.6% ( P 90%) were less likely to discontinue treatment compared with nonadherent participants (odds ratio: 0.66 [95% CI: 0.45 to 0.98]). Participation in a clinical trial significantly increases adherence to both trial-related and nontrial-related treatment, suggesting that participants in a trial are more involved with their conditions and treatments.

Purpose. Factors influencing the bar-code verification by nurses during medication administration in a Dutch hospital were studied. Summary. The use of bar-code verification during medication administration in five medical departments was recorded daily for three weeks. These data were collected via electronic medication administration records. The frequency of bar-code verification was calculated as a percentage of all administrations, corrected for the availability of bar-coded packages. Nurses were asked why bar-code verification was not always used. A total of 23,492 medication administrations were recorded, 15,162 (64.5%) of which required bar-code verification. Bar-code verification was significantly influenced by the medical department, deviation between prescribed and administered times, administration route of the drug, number of nurses available in each department, and age of the nurse. The five most cited reasons for not verifying bar codes were difficulties in scanning bar codes on the medication labels, lack of awareness of bar codes on medication labels, delays in responses from the computerized system, shortage of time, and administration of medication before prescription. Conclusion. Nurses verified the bar codes of only about half of medications administered to patients. Various factors influenced the frequency of bar-code verification by nurses except the number of medications administered. More education regarding medication safety is warranted to increase compliance to a bar-code-enabled point-of-care system.

It is still uncertain whether one can safely base treatment decisions on self-measurement of blood pressure. In the present study, we investigated whether antihypertensive treatment based on self-measurement of blood pressure leads to the use of less medication without the loss of blood pressure control. We randomly assigned 430 hypertensive patients to receive treatment either on the basis of self-measured pressures (n=216) or office pressures (OPs; n=214). During 1-year follow-up, blood pressure was measured by office measurement (10 visits), ambulatory monitoring (start and end), and self-measurement (8 times, self-pressure group only). In addition, drug use, associated costs, and degree of target organ damage (echocardiography and microalbuminuria) were assessed. The self-pressure group used less medication than the OP group (1.47 versus 2.48 drug steps; P P P =0.25/0.20), in changes in left ventricular mass index (−6.5 g/m 2 versus −5.6 g/m 2 ; P =0.72), or in median urinary microalbumin concentration (−1.7 versus −1.5 mg per 24 hours; P =0.87). Nevertheless, 24-hour ambulatory blood pressure values at the end of the trial were higher in the self-pressure than in the OP group: 125.9 versus 123.8 mm Hg ( P P

Local infiltration analgesia (LIA) is widely applied in patients undergoing total knee arthroplasty (TKA). In daily practice, adrenaline is added to the LIA mixture to achieve vasoconstriction. However, adrenaline has some possible negative side effects (e.g. tissue necrosis). This trial investigated whether ropivacaine alone is at least as effective for postoperative pain relief after LIA. Fifty patients scheduled for primary TKA were included in this prospective randomized, double-blind, controlled pilot study receiving high-volume (150 mL) single-shot intra-capsular LIA with ropivacaine (2 %) with (Ropi+) or without (Ropi−) adrenaline (0.01 %). All patients received the same pre-, peri- and postoperative care with multimodal oral pain protocol. Postoperative pain was assessed before and after the first mobilization and during the first 48 h postoperative using the visual analogue scale (VAS). Secondary outcomes were rescue medication use, early mobilization, length of hospital stay, adverse events (AE’s) and readmission rates. Patient reported outcomes measures (PROMS); Oxford Knee Score and WOMAC, were obtained preoperative and 3 months postoperative. VAS scores were not significantly different before (n.s.) and after the first mobilization (n.s.), neither over the first 48 h postoperative (n.s.). Patients who needed rescue medication (n.s.), who mobilized

Objective: To describe a patient who developed torsade de pointes while being treated with fluconazole. Case Summary: A 33-year-old woman with a 5 year history of systemic lupus erythematosus was admitted to the intensive care unit because of respiratory insufficiency due to Candida albicans pneumonia. Therapy with intravenous fluconazole 200 mg/day, with dose later adjusted according to her renal function, was started. Prolongation of the QTc interval and torsade de pointes occurred. Initially, domperidone, which had been initiated the day before fluconazole, was suspected as the possible cause and was discontinued; ultimately, both drugs were discontinued. However, torsade de pointes recurred several weeks later when the patient was treated with fluconazole for a second time and disappeared again on withdrawal of the drug. According to the Naranjo probability scale, this adverse reaction was highly probable. Discussion: The risk of torsade de pointes does not correlate in a linear fashion with prolongation of the QTc interval, but an interval beyond 500 msec is considered a significant risk factor. Given that both fluconazole and domperidone are metabolized by the cytochrome P450 system, they may intensify each other's proarrhythmic effects, particularly in patients with concurrent renal dysfunction. These risks are of particular concern in patients whose baseline QTc interval is prolonged for any reason. Conclusions: From the case history, as well as use of the Naranjo scale, we concluded that fluconazole was the highly probable cause of the development of torsade de pointes in our patient.

Shortly after the invention of nitroglycerin (NTG), it was noticed that this substance is capable of inducing a violent headache. Only recently, it became known that this was due to the release of nitric oxide (NO) by NTG. As the molecular mechanism of migraine pain remains to be determined, NTG, being pro-drug for NO, has been used to study the aetiology and pathophysiology of migraine. Such studies with NTG- and also histamine-induced headaches, have led to propose that NO may be the causative molecule in migraine pain. The evidence supporting the role of NO in migraine is discussed, e.g. substances capable of inducing experimental vascular headache do so with NO as the common mediator, while drugs with antimigraine activity inhibit NO and the cascade of intracellular reactions triggered by NO. The importance of NO as a potential initiator of the migraine attack opens new directions for the pharmacological treatment of migraine and other vascular headaches.

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The frail elderly populations of nursing homes frequently use drugs and suffer from considerable comorbidities. Medication reviews are intended to support evidence based prescribing and optimise therapy. However, literature is still ambiguous regarding the optimal method and the effects of medication reviews. Innovative computerised systems may support the medication reviews in the future. We are developing a clinical decision support system (CDSS) that, independently of the prescribing software, continuously monitors all prescribed drugs while taking into account co-medication, laboratory-data and co-morbidities. The CDSS will be developed in five phases: (1) development of the computerised system, (2) development of the clinical rules, (3) validation of the CDSS, (4) randomised controlled trial, and (5) feasibility for implementation in different nursing homes. The clinical decision support system aims at supporting the traditional medication review.

Objective: To assess the methods and frequency by which medication reviews are performed by general practitioners and nursing home physicians by means of a survey. Methods: 134 nursing home physicians and general practitioners working in the southern part of the Netherlands, the province of Limburg were asked to fill in a digital questionnaire. Non response was followed by second emailing and a questionnaire on paper by regular post. The questionnaire was developed by an expert panel, consisting of two hospital pharmacists, an internist, a nursing home physician and a neuropsychiatrist. Results: There was substantial inconsistency in the frequency of performing medication reviews, ranging from monthly (in 40%) by the nursing home physicians to four times a year (in 50%) by the general practitioners. Time spent on one review also varied significantly between groups, namely 10 minutes for a nursing home physician and 20 minutes for general practitioners. Meetings between the physician and pharmacist took place regularly (91%), but these were not organised for medication reviewing of individual patients. When medication was changed by another doctor, 47% of nursing home physicians and 44% of the general practitioners were informed often, whereas 40% and 50% respectively were only informed sometimes, and 13% of nursing home physicians and 6% of general practitioners never received any notice. 59% of the nursing home physicians and 89% of general practitioners considered workload to be a limiting factor in performing reviews. Conclusions: This survey shows great inconsistency in the way medication reviews are done. To achieve a high standard, we may have to reconsider the way medication reviews are done.

OBJECTIVE: To clarify the mechanism of interaction between nortriptyline and terbinafine. CASE SUMMARY: Nortriptyline intoxication secondary to terbinafine treatment was observed in a woman with a major depressive disorder. This is the second report of this interaction. A rechallenge was performed during which serum concentrations were measured of nortriptyline and the 2 hydroxy metabolites. To document the case, genotyping of CYP2D6 was also performed. DISCUSSION: Metabolism by CYP2D6 is of major importance for the hydroxylation of nortriptyline, making it susceptible to competitive inhibition by terbinafine. CONCLUSIONS: The pharmacokinetic interaction between nortriptyline and terbinafine is probably due to inhibition of CYP2D6 of the nortriptyline metabolism by terbinafine. The interaction is not restricted to a subpopulation, but may occur even in persons without deviations in CYP2D6.

Background: Although acetaminophen is used to reduce pain after breast reduction or augmentation surgery, pain during the removal of the surgical drains is typically not specifically treated. Intranasally administered fentanyl may be suitable for pain control during removal of drains. The reported therapeutic window of fentanyl is between 0.2 and 1.2 ng/mL. Objective: The aim of this study was to evaluate the analgesic effect, tolerability, and pharmacokinetics of a single preprocedural dose of intranasal fentanyl administered before removal of surgical drains in patients who had undergone breast reduction or augmentation surgery. Methods: This was a randomized, double-blind, prospective study in healthy women (American Society of Anesthesiologists physical status I or II) between the ages of 18 and 65 years who were scheduled to undergo removal of surgical drains 1 to 4 days after breast reduction or augmentation surgery. A single dose of fentanyl nasal spray 0.05 mg/0.1 mL or placebo (preserved normal saline) 0.1 mL was administered 10 minutes before removal of drains. Because drain removal is generally carried out without specific analgesia, no rescue medication was provided. Pain intensity was measured on a visual analog scale (VAS) from 0=no pain at all to 100=worst pain possible. Pain intensity was evaluated immediately before administration of study medication (t = 0), at the time of drain removal (t = 10), and at 15, 20, 25, 40, and 70 minutes after administration of study medication. Safety measures included oxygen saturation, respiratory rate, heart rate, and blood pressure. Local and systemic adverse events were elicited by direct questioning throughout the study. Blood samples for pharmacokinetic analysis were collected at baseline and at 5, 10, 15, 30, 60, and 120 minutes after administration of study medication. The population pharmacokinetic parameters of fentanyl were calculated according to a 1-compartment open model with an iterative 2-stage Bayesian fitting procedure. Results: Thirty-six women were randomized to treatment, and 33 completed the study. Their mean (SD) age was 39.2 (13.0) years, and their mean weight was 68.9 (10.7) kg. Mean VAS scores at baseline were 14.8 (17.8) for the fentanyl group and 6.0 (9.7) for the placebo group ( P = NS); at the time of drain removal, the corresponding VAS scores were 31.0 (20.6) and 33.8 (25.7) ( P = NS). Analysis of a random-effects model with mean VAS scores as a function of time as the dependent variable indicated a significant difference in mean VAS scores between the fentanyl and placebo groups ( P = 0.006). The overall incidence of adverse events was 39.4% (13/33). Among the 17 patients in the fentanyl group, 8 reported ≥1 adverse event; among the 16 patients in the placebo group, 9 reported ≥1 adverse event. A mean estimated C max of 0.184 (0.069) ng/mL was reached at 13.76 (3.56) minutes after administration of intranasal fentanyl. The mean measured C max was 0.22 (0.088) ng/mL. Conclusions: In these women who had undergone breast reduction or augmentation surgery, a single preprocedural dose of intranasal fentanyl was significantly more effective than placebo in reducing pain intensity over the hour after removal of surgical drains. However, there was no significant difference in pain intensity between fentanyl at the time of drain removal and placebo. Intranasal fentanyl was generally well tolerated. At the dose used (0.05 mg), plasma fentanyl concentrations were below the reported therapeutic window.

Contains fulltext : 88311.pdf (Publisher’s version ) (Closed access) BACKGROUND: Poor adherence to antihypertensive medication is one of the major problems in the treatment of hypertension. Electronic monitoring is currently considered to be the gold standard for assessing adherence, but it may trigger patients to open the pill bottle without taking medication or to take out more than prescribed. In adjunct to electronic monitoring, pill count could be a valuable tool for exploring adherence patterns, and their effects on blood pressure reduction. METHODS: Among a total of 228 patients with mild-to-moderate hypertension, adherence to treatment was measured by means of both the Medication Event Monitoring System (MEMS) and pill count. Patients were followed-up for seven visits over a period of 1 year. At each visit to the physician's office, patient's adherence was assessed by both methods. RESULTS: Adherence is defined as the percentage of days with correct dosing; median adherence according to MEMS was lower than median adherence according to pill count (91.6 vs. 96.1; P < 0.001). Both methods agreed in defining patients as adherent in 107 (47%) and nonadherent in 33 (14%) patients. Thirty-one (14%) patients were adherent only by MEMS and 59 (25%) patients only by pill count. At the end of the study, patients in the four categories reached comparable blood pressure values and reductions. CONCLUSIONS: Pill count could be a useful adjunct to electronic monitoring in assessing adherence patterns. Although deviant intake behavior occurred frequently, the effect on achieved blood pressure and blood pressure reduction was not remarkable. 01 februari 2010

Contains fulltext : 88743.pdf (Publisher’s version ) (Closed access) BACKGROUND: Poor adherence to treatment is one of the major problems in the treatment of hypertension. Self blood pressure measurement may help patients to improve their adherence to treatment. METHOD: In this prospective, randomized, controlled study coordinated by a university hospital, a total of 228 mild-to-moderate hypertensive patients were randomized to either a group that performed self-measurements at home in addition to office blood pressure measurements [the self-pressure group (n = 114)] or a group that only underwent office blood pressure measurement [the office pressure group (n = 114)]. Patients were followed for 1 year in which treatment was adjusted, if necessary, at each visit to the physician's office according to the achieved blood pressure. Adherence to treatment was assessed by means of medication event monitoring system TrackCaps. RESULTS: Median adherence was slightly greater in patients from the self-pressure group than in those from the office pressure group (92.3 vs. 90.9%; P = 0.043). Although identical among both groups, in the week directly after each visit to the physician's office, adherence [71.4% (interquartile range 71-79%)] was significantly lower (P < 0.001) than that at the last 7 days prior to each visit [100% (interquartile range 90-100%)]. On the remaining days between the visits, patients from the self-pressure group displayed a modestly better adherence than patients from the office pressure group (97.6 vs. 97.0%; P = 0.024). CONCLUSION: Although self-blood pressure measurement as an adjunct to office blood pressure measurement led to somewhat better adherence to treatment in this study, the difference was only small and not clinically significant. The time relative to a visit to the doctor seems to be a more important predictor of adherence. 01 maart 2010

Background: Interest in the development of drugdelivery devices that might improve treatment compliance is growing. A dosage formulation that is easy to use, such as intranasal application with transmucosal absorption, may offer advantages compared with other routes of drug delivery. The literature concerning intranasal application is diffuse, with a large number of published studies on this topic. Some cerebroactive pharmaceuticals delivered intranasally might follow the pathway from the nose to the systemic circulation to the brain. To determine the suitability of these drugs for intranasal drug delivery, a systematic review was performed. Objective: The aim of this review was to compare the pharmacokinetic properties of intranasal, intravenous, and oral formulations in 3 classes of cerebroactive drugs that might be suitable for intranasal delivery—opioids, benzodiazepines, and antimigraine agents. Methods: A search of MEDLINE, PubMed, Cumulative Index of Nursing and Allied Health Literature, EMBASE, and Cochrane Database of Systematic Reviews (dates: 1964–April 2009) was conducted for pharmacokinetic studies of drugs that might be suitable for intranasal delivery. A comparison of pharmacokinetic data was made between these 3 routes of administration. Results: A total of 45 studies were included in this review. Most of the opioids formulated as an intranasal spray reached a T max within 25 minutes. The bioavailability of intranasal opioids was high; in general, >50% compared with opioids administered intravenously. Intranasal benzodiazepines had an overall T max that varied from 10 to 25 minutes, and bioavailability was between 38% and 98%. T max for most intranasal antimigraine drugs varied from 25 to 90 minutes. Intranasal bioavailability varied from 5% to 40%. Conclusions: This review found that intranasal administration of all 3 classes of drugs was suitable for indications of rapid delivery, and that the pharmacokinetic properties differed between the intranasal, oral, and intravenous formulations (intravenous > intranasal > oral).

Adequate iron stores are a prerequisite for successful erythropoietin (EPO) therapy in hemodialysis (HD) patients. Nevertheless, iron status estimation in HD patients remains problematic, as most parameters are influenced by inflammation. The reticulocyte hemoglobin content (CHr) has recently been proposed as a useful tool in iron status assessment. However, the effect of inflammation on CHr remains unstudied. This study aimed to assess the relationship between CHr with other parameters of iron status as well as with C-reactive protein (CRP). This relationship was studied in all the patients (n=61) at our dialysis unit. CHr was significantly and positively related to transferrin saturation (TS) (rho=0.26; p0.05) and inversely to the percentage of hypochromic red blood cells (%Hypo) (rho=-0.63; p0.0001), but not to serum ferritin. CHr was strongly and inversely related to log CRP (rho=-0.50; p0.0001). Despite the use of maintenance intravenous (i.v.) iron doses and relatively high serum ferritin levels, a large percentage of patients were in a state of functional iron deficiency (%Hypoor = 6 in 41% of patients and CHror = 29 pg in 13% of patients). This percentage was far lower in patients with CRP levels below the detection limit (2 mg/L) (26% and 0%, respectively). In conclusion, CHr is related to both TS and %Hypo, but not to serum ferritin, and is strongly influenced by the presence of inflammation (as determined by CRP). In patients with elevated CRP levels, it is very difficult to reach target iron status levels without exceeding the upper limits for serum ferritin.

Shortly after the invention of nitroglycerin (NTG), it was noticed that this substance is capable of inducing a violent headache. Only recently, it became known that this was due to the release of nitric oxide (NO) by NTG. As the molecular mechanism of migraine pain remains to be determined, NTG, being pro-drug for NO, has been used to study the aetiology and pathophysiology of migraine. Such studies with NTG- and also histamine-induced headaches, have led to propose that NO may be the causative molecule in migraine pain. The evidence supporting the role of NO in migraine is discussed, e.g. substances capable of inducing experimental vascular headache do so with NO as the common mediator, while drugs with antimigraine activity inhibit NO and the cascade of intracellular reactions triggered by NO. The importance of NO as a potential initiator of the migraine attack opens new directions for the pharmacological treatment of migraine and other vascular headaches.

The severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is spreading rapidly, even in vaccinated individuals, raising concerns about immune escape. Here, we studied neutralizing antibodies and T cell responses targeting SARS-CoV-2 D614G [wild type (WT)] and the Beta, Delta, and Omicron variants of concern in a cohort of 60 health care workers after immunization with ChAdOx-1 S, Ad26.COV2.S, mRNA-1273, or BNT162b2. High binding antibody levels against WT SARS-CoV-2 spike (S) were detected 28 days after vaccination with both mRNA vaccines (mRNA-1273 or BNT162b2), which substantially decreased after 6 months. In contrast, antibody levels were lower after Ad26.COV2.S vaccination but did not wane. Neutralization assays showed consistent cross-neutralization of the Beta and Delta variants, but neutralization of Omicron was significantly lower or absent. BNT162b2 booster vaccination after either two mRNA-1273 immunizations or Ad26.COV2 priming partially restored neutralization of the Omicron variant, but responses were still up to 17-fold decreased compared with WT. SARS-CoV-2–specific T cells were detected up to 6 months after all vaccination regimens, with more consistent detection of specific CD4 + than CD8 + T cells. No significant differences were detected between WT- and variant-specific CD4 + or CD8 + T cell responses, including Omicron, indicating minimal escape at the T cell level. This study shows that vaccinated individuals retain T cell immunity to the SARS-CoV-2 Omicron variant, potentially balancing the lack of neutralizing antibodies in preventing or limiting severe COVID-19. Booster vaccinations are needed to further restore Omicron cross-neutralization by antibodies.

BACKGROUND: In the nursing home population, it is estimated that 1 in every 3 patients is polymedicated and given their considerable frailty, these patients are especially prone to adverse drug reactions. Clinical pharmacist-led medication reviews are considered successful interventions to improve medication safety in the inpatient setting. Due to the limited available evidence concerning the benefits of medication reviews performed in the nursing home setting, we propose a study aiming to demonstrate a positive effect that a clinical decision support system, as a health care intervention, may have on the target population. The primary objective of this study is to reduce the number of patients with at least one event when using the clinical decision support system compared to the regular care. These events consist of hospital referrals, delirium, falls, and/or deaths.METHOD/DESIGN: This study is a multicentre, prospective, randomised study with a cluster group design. The randomisation will be per main nursing home physician and stratified per ward (somatic and psychogeriatric). In the intervention group the clinical decision support system will be used to screen medication list, laboratory values and medical history in order to obtain potential clinical relevant remarks. The remarks will be sent to the main physician and feedback will be provided whether the advice was followed or not. In the control group regular care will be applied.DISCUSSION: We strongly believe that by using a clinical decision support system, medication reviews are performed in a standardised way which leads to comparable results between patients. In addition, using a clinical decision support system eliminates the time factor to perform medication reviews as the major problems related to medication, laboratory values, indications and/or established patient characteristics will be directly available. In this way, and in order to make the medication review process complete, consultation within healthcare professionals and/or the patient itself will be time effective and the medication surveillance could be performed around the clock.TRIAL REGISTRATION: The Netherlands National Trial Register NTR5165 . Registered 2nd April 2015.